J&J has announced early trial results that suggest its single-shot coronavirus vaccine provides a sustained response against the virus ahead of a phase 3 trial readout due later this month.
The UK has caused controversy in recent weeks by tinkering with the dosing regimens for coronavirus vaccines from AstraZeneca and Pfizer/BioNTech, which are being rolled as part of the country’s mass vaccination programme.
Both of these vaccines require two doses, as does the most recently approved shot from Moderna, which is due to arrive in the UK in the spring.
In order to make the best use of scarce vaccine resources the UK has opted to extend the time between doses to up to 12 weeks, a strategy that has been criticised by some scientists who are fearful that it could cause vaccine-tolerant strains of the virus to emerge.
Johnson & Johnson’s Janssen pharma unit is further behind in the development of its vaccine, which has the crucial advantage of being administered in a single shot.
The UK government has an order of 30 million doses of the vaccine from J&J and an option for an additional 22 million doses in an agreement signed last summer.
Latest data give hope that the vaccine could be added to the campaign after phase 1/2a data showed that the shot provided an immune response that lasted for at least 71 days, the duration of time measured in the study involving patients aged 18-55 years.
The phase 1/2a interim analysis showed that the Company’s COVID-19 vaccine candidate induced an immune response and was generally well-tolerated across all study participants.
Data demonstrated that, after a single vaccination, neutralising antibodies against COVID-19 were detected in over 90% of study participants at day 29 and 100% of participants aged 18-55 years at day 57.
These neutralising antibodies remained stable through day 71, currently the latest timepoint available in this ongoing study.
Data on durability of immune responses in trial participants aged over 65 years will be available in late January and longer-term follow-up to one year is planned.
Top line data from a phase 3 study is due later this month, although this timing may change due to disease events.
J&J expects to file with the FDA first, followed by other regulators. The European Medicines Agency is conducting a rolling review of the vaccine to speed up the process.
While pharma has raced to develop COVID-19 vaccines, US-based company NeuroRx is taking a different approach to treating the virus. CEO Dr. Jonathan Javitt tells pharmaphorum about the science behind the company’s Zyesami, which targets the alveolar type II cells in the lung that are critical for transmission of oxygen.
Zyesami was developed in conjunction with partner Relief Therapeutics, and NeuroRx is currently awaiting results from a Phase 2b/3 trial (COVID-AIV) evaluating the therapeutic for the treatment of respiratory failure in COVID-19 patients.
Based on years of research by Professor Sami Said at New York’s Stony Brook University, the drug is a synthetic formulation of Vasoactive Intestinal Peptide (VIP), a naturally occurring peptide that is highly concentrated in the lungs. VIP is known to have potent anti-inflammatory effects and can inhibit coronavirus replication and block the formation of inflammatory cytokines.
“Every air-breathing warm-blooded animal makes this peptide to protect the lungs from the toxic effects of breathing air,” NeuroRx CEO, Jonathan Javitt, MD, MPH, told pharmaphorum. “It protects the lungs against all injuries and turns out it has some extraordinarily valuable properties for patients with COVID-19.”
“The cytokine storm story became popular, but it was mostly popularised by companies who already had drugs against cytokines. They created the story and then threw their monoclonal antibodies against COVID-19 but there is real scepticism now about whether COVID-19 is really a cytokine storm problem”
‘A fish out of water’
When SARS-CoV-2 invades the body, it attacks the alveolar type II (ATII) cell in the lining of the lung which shuts down the production of surfactant and stimulates a cytokine response.
“This is how you go from somebody who is infected by the virus but not particularly sick to somebody who’s on a ventilator dying of COVID-19,” explained Dr. Javitt.
“For example – when a fish swims through water, seawater goes across its gills and oxygen is then absorbed from the seawater. The fish derives enough oxygen from that to carry out all the functions it needs to live. However, the minute you put that fish on the land, the fish dies. But why? There is more oxygen in the air than there is in the sea, so why would the fish die?”
The problem, he says, is due to the fact the atmosphere is toxic to the fish’s epithelial cells.
“In humans it is the same. The mixture of gases that we breathe all the time are toxic if it touches the lung’s cell, so the lung is covered by this layer of fluid that creates a barrier between the atmosphere, the air, and the cell membrane.”
The minute the ATII cells die due to the SARS-CoV-2 virus, the lung is no longer capable of oxygenation and the patient dies as well.
“It is like a fish out of water.”
Zyesami works by binding to receptors on ATII cells in the lung and protecting the surrounding pulmonary epithelium by blocking cytokines, preventing apoptosis, and upregulating the production of surfactant.
By targeting the vulnerable ATII, NeuroRx and Relief Therapeutics believe they can help the most critically ill COVID-19 patients. “Until we focus on the specific lesion associated with this virus, we’re not going to have any real cures,” concluded Dr. Javitt.
While other COVID-19 therapeutics, such as Gilead’s Veklury (remdesivir) have focused on controlling the cytokine storm triggered by COVID-19, Dr. Javitt believes this is only one piece of the puzzle.
“The cytokine storm story became popular, but it was mostly popularised by companies who already had drugs against cytokines. They created the story and then threw their monoclonal antibodies against COVID-19 but there is real scepticism now about whether COVID-19 is really a cytokine storm problem.
“Personally, I don’t think it is. I think cytokine storms are a secondary problem and until we really face the lesion that occurs when the SARS-CoV-2 virus infects the lungs and causes COVID-19, we’re not going to have a solution.”
The next steps
Top line data from Zyesami’s Phase 2b/3 trial is expected by the end of January/beginning of February and if successful, the drug could quickly receive emergency use authorisation from the FDA.
The multicenter, randomised trial was initially conducted at a single centre and expanded to 196 patients at 12 study sites. Patients were administered with escalating doses of Zyesami by intravenous infusion and compared to a placebo control group.
Early data from trials were encouraging, with results from a study at Houston Methodist hospital in Texas showing approximately 81% of the patients who received the drug survived beyond 60 days, compared to just 17% of control patients. Those who had the treatment also demonstrated a nine-fold increased probability of survival and recovery from respiratory failure.
“These patients included in our study are those who were too sick to be admitted to any other clinical trial,” said Dr. Javitt. “There were extremely ill patients who had had lung transplants, severe lung disease, heart disease, renal failure and kidney transplants so the results we have seen bring a lot of hope for how we can treat COVID-19 in future.”
Although the arrival of COVID-19 vaccines is providing hope for people, there is still a need for effective treatments. “We hope that the vaccine will reduce the number of COVID-19 cases. However, we believe it likely that population wide vaccination will be slow in coming and the vaccine is not 100% effective,” said Dr. Javitt.
NeuroRx is also gearing up for a phase of rapid expansion after closing a deal in December to combine with investment firm Big Rock Partners. The merger created a company with an estimated post-transaction equity value of more than $500 million.
The deal is expected to complete in the first quarter of 2021 and will increase NeuroRx’s access to capital for Zyesami and spur development of its other drug pipeline targeting treatment of bipolar depression.
The company is also looking at advancing trials for Zyesami in other countries around the world, with a Phase 2b/3 trial set to begin in Europe.
“One thing about our drug compared to all of these monoclonal antibodies is we can make it at enormous scale relatively inexpensively and it’s within the cost range that works for the rest of the world,” said Dr. Javitt.
About the interviewee
Dr. Jonathan Javitt is founder, chairman and CEO of NeuroRx. He is a physician with a background in information technology, health economics, and public health. His scientific publications have been cited by more than 17,000 people and he is ranked among the top 1% of quoted scientists worldwide.
South Korea’s Celltrion has announced encouraging top-line results for its potential antibody therapy for COVID-19, with the first part of a phase 2/3 trial showing it could cut recovery times and chances of progression from moderate to more severe disease.
Several other companies are also working on antibody therapies and Eli Lilly’s bamlanivimab gained an FDA Emergency Use Authorization in November last year, shortly after Regeneron’s cocktail of casirivimab and imdevimab.
There are doubts over efficacy of Lilly’s antibody, which failed to produce benefits in hospitalised patients in a phase 3 trial last month.
AstraZeneca is developing an antibody therapy and so is its UK rival GlaxoSmithKline, which this week announced a deal with VIR Biotechnology to trial VIR-7832 in mild to moderate COVID-19 patients.
Until COVID-19 hit Celltrion was best known for producing biosimilars, which are near-copies of biologic drugs that have been shown to be as safe and effective in rigorous trials and tests.
But the company is using its expertise to develop an antibody therapy, CT-P59, to help the effort against the pandemic.
Celltrion filed the therapy with the Korean regulator at the end of December and plans to submit data to regulators in Europe and the US in the coming months.
A spokesperson said in an email that company is “working closely with the regulatory agencies to accelerate the regulatory procedures”.
Part I of the trial enrolled 327 patients with mild-to-moderate symptoms of COVID-19 across three treatment groups (40mg/kg, 80mg/kg and placebo), in which approximately 60% of patients with moderate symptoms suffered from COVID-19 related pneumonia.
This data analysis has demonstrated that at day 28, CT-P59 treated patients presented with a significantly reduced risk of COVID-19 related hospitalisation and oxygenation without mortality.
When compared to placebo, CT-P59 treated patients reported reduced progression rates to severe COVID-19 by 54% for mild-to-moderate patients and 68% for moderate patients aged 50 years and over.
CT-P59 treatment groups also reported with significantly shortened time to clinical recovery ranging from 3.4 to 6.4 days quicker compared to placebo.
Patients treated with CT-P59 recovered 3.4 days earlier than those in a placebo group, while patients with pneumonia reported that their recovery time was 5.1 days shorter compared with placebo.
A group of patients with moderate disease aged 50 years and over treated with CR-P59 reported that their recovery time was 6.4 days shorter than placebo, the company said.
CT-P59 treated patients rapidly and significantly reduced viral load through Day 7 compared to placebo. Top-line results from the trial shows CT-P59 to have a positive safety profile, comparable to that of the placebo group, with no serious adverse advents reported.
Infusion related reactions were mild and transient, with the CT-P59 treatment group having reported 0.5%, compared to 1.8% reported with placebo.
Feature image courtesy of Rocky Mountain Laboratories/NIH
When Eli Lilly reported results for donanemab in Alzheimer’s disease earlier this week it was hailed as a rare win for the amyloid hypothesis, although there’s no shortage of candidates that have failed despite positive mid-stage trial results.
Some analysts have intimated that given the small size of the study at just over 270 patients, rival amyloid drug developers Biogen and Eisai could claim the biggest benefit from the data in positive sentiment ahead of an FDA decision later this year.
Goldman Sachs analyst Terence Flynn said the result was a “positive surprise” after Lilly revealed top-line data from the TRAILBLAZER-ALZ study showing that donanemab slowed cognitive decline by a third in people with early Alzheimer’s and completely resolved the amyloid beta plaques that are a hallmark of the disease.
Flynn also said the data was an “incremental positive” for Biogen, whose Eisai-partnered aducanumab is already filed for approval and awaiting an FDA decision by 7 March, as it lends further weight to the amyloid beta hypothesis of Alzheimer’s.
Biogen is nearest to market with aducanumab but a positive verdict from the US regulator is far from assured. In November, an FDA advisory committee voted ten to one against approval, saying the clinical data backing the drug was inconclusive, but that came on the back of a positive assessment by the FDA’s own reviewer.
Wolfe analyst Tim Anderson said in a research note issued ahead of the donanemab readout that the FDA could be influenced by the donanemab data and – if positive – that would raise the chances of a greenlight for aducanumab.
There’s an alternative view however that donanemab’s data might actually harm aducanumab’s prospects. Analysts at Jefferies told Barron’s this week that the FDA may have been minded to approve Biogen and Eisai’s drug because there were no other late-stage candidates in play, but Lilly’s drug could change that perception.
Donanemab is unlike most other amyloid-targeting drugs – including aducanumab – because it targets a pyroglutamated form of amyloid beta called N3pG that is found only in amyloid plaques and according to some research can stimulate misfolding of proteins.
Lilly’s hypothesis – as yet unproven – is that clearing those plaques has a direct association with cognitive benefits.
Lilly says TRAILBLAZER-ALZ met its primary endpoint, slowing decline on the Integrated Alzheimer’s Disease Rating Scale in the donanemab group by 32% compared to placebo, with trends towards improvement on secondary endpoints that didn’t hit statistical significance.
On safety, around 27% of the treatment arm showed ARIA-E – an inflammatory reactions also seen with other amyloid-targeting antibodies – but there’s little other data available yet.
Lilly started a 500-patient phase 2 trial called TRAILBLAZER-ALZ-2 last June that it suggests could serve as a confirmatory pivotal study and potentially support regulatory filings – dramatically shortening the development timeline for the drug. That’s due to read out in next year or later.
Previous COVID-19 infection provides some immunity for at least five months, but people may still carry and transmit the virus, according to a study by Public Health England.
A first report from PHE’s SIREN study found antibodies from previous COVID-19 infection provide 83% protection against reinfection for at least five months.
It found that reinfections in people with antibodies were rare, with only 44 potential reinfections among 6,614 participants who showed evidence of previous infection.
But a small number of people with antibodies may still be able to carry and transmit COVID-19 according to the study.
As a result, PHE stressed the importance of following “stay at home” rules currently in place in the UK to prevent the virus from spreading.
Public Health England has been regularly testing tens of thousands of health care workers across the UK since June for new COVID-19 infections as well as the presence of antibodies, which suggest people have been infected before.
SIREN study leaders are clear this first report provides no evidence towards the antibody or other immune responses from COVID-19 vaccines, nor should any conclusions be drawn on their effectiveness. The SIREN study will consider vaccine responses later this year.
Professor Susan Hopkins, senior medical advisor at Public Health England and the SIREN study lead said: “This study has given us the clearest picture to date of the nature of antibody protection against COVID-19 but it is critical people do not misunderstand these early findings.
“We now know that most of those who have had the virus, and developed antibodies, are protected from reinfection, but this is not total and we do not yet know how long protection lasts. Crucially, we believe people may still be able to pass the virus on.”
The news comes as the UK continues to endure high levels of infections despite a national lockdown.
There have been more than 74,000 deaths following coronavirus infections and nearly 43,000 new cases were recorded in the last day.
Last year the government announced that PHE is to be scrapped and merged with the NHS test and trace programme and the UK’s Joint Biosecurity Centre.
UK biotech Synairgen is pushing ahead with a phase 3 trial of SNG001 in hospitalised COVID-19 patients, after encouraging topline results from a phase 2 study that started last March.
The inhaled formulation of interferon beta-1a – delivered using a nebuliser – will be tested in 610 hospitalised COVID-19 patients who require supplemental oxygen in around 20 countries in the study, called SG018.
Interferon beta-1a is already used in an injectable form for multiple sclerosis, and before the pandemic took hold Synairgen was already putting its inhaled version through its paces in trials involving subjects with asthma and chronic obstructive pulmonary disease (COPD).
The cytokine is part of the body’s response to a viral infection, and there is some evidence to suggest that people who get dangerously sick after being infected with the SARS-CoV-2 virus have lower than usual levels of interferon beta in the lungs.
The Southampton-based company says it has appointed contract research organisation (CRO) Parexel to help conduct the phase 3 trial, with several UK sites now set up and others in the US and the EU expected to follow soon.
The first patient received the treatment at Hull Royal Infirmary this week, and Synairgen is hoping to get results available in the summer, which means emergency approvals could be feasible by the autumn.
Preliminary results from Synairgen’s 100-patient phase 2 trial SG016 were published in The Lancet last November, and found that patients treated with SNG001 had greater odds of improvement and recovered more rapidly from SARS-CoV-2 infection than patients who received placebo.
The main endpoint in the trial was Ordinal Scale for Clinical Improvement (OSCI) – a standard nine-point measure developed by the World Health Organization (WHO).
Patients taking SNG001 were more likely to show an improvement on the OSCI scale on day 15 or 16 after dosing started, and were more likely than those receiving placebo to recover to an OSCI score of 1 – with no limitation of their daily activities – during treatment.
There were also three deaths in the placebo group and none among patients taking SNG001, although the trial wasn’t statistically powerful enough to gauge whether that was a real effect or due to chance.
The UK’s National Institute for Health Research (NIHR) has given the phase 3 trial Urgent Public Health status, so it qualifies for support by the NIHR’s clinical research network. Meanwhile, the FDA has awarded fast-track status to SNG001 for COVID-19.
While the vaccine roll-out is raising spirits in the midst of the pandemic, Synairgen chief executive Richard Marsden said treatments are still needed for “cases where vaccines are not effective, for those who do not get vaccinated, and in case the virus mutates to the point where vaccines become less effective.”
“We believe this trial presents an opportunity for a significant UK scientific breakthrough and, if given the right support, our drug could rapidly assist with the global crisis,” he added.
Synairgen told the BBC that a course of treatment with SNG001 would cost around £2,000, which according to Marsden will represent “good value for money”.
Healthcare technology firm Seqster has introduced a new version of its service that aims to help pharma companies work with patients’ data while on virtual clinical trials.
Seqster announced the new version of its platform had been launched on the Microsoft Azure cloud at the annual JP Morgan Healthcare Conference.
The new Seqster 7.1 service will allow secure access to real-world data from electronic health records (EHRs), DNA analysis and fitness wearables.
However, the company’s head of strategic business development Parsi Parsinejad said that the system is differentiated from competitors by its focus on putting patients in control of their data.
By making pharma companies sign data use agreements directly with the patient, Seqster says it has been able to create a platform that allows patients to create a one-point login they can control many forms of US health data.
This can range from health records to ancestry data, allowing patients to track their data in a similar way that the Mint budget tracker allows people to control their expenditure.
The platform is FDA 21 CFR Part 11 compliant enabling secure delivery of EHR documents directly to regulated clinical trial management systems and allowing eConsent-based visualisation of participants’ data.
Parsinejad told pharmaphorum in an interview: “You have been seeing a proliferation of cloud services. They are introducing a cloud-based service and industry specific applications.
“What Seqster does for pharma clinical trials is it brings together in real time a health record for participants. Patients can bring together their data wherever it resides.”
He added the tool could be used to help run virtual trials, which have become increasingly common due to the shift towards electronic technology in healthcare because of the pandemic.
The data gathered can be used as the basis for filings with the FDA, although for now the system works only with data gathered by US-based services.
The company adds that it has split data into two silos to prevent hackers from using it in the unlikely event of a breach.
Parsinejad said: “It’s highly secure, 256 bit encryption the same as Azure. Patient identified data is in a separate container from health data. If there is a breach they would not be able to make sense of the data.”
The acute phase of the COVID-19 pandemic tested the UK’s capacity and capability to rapidly deliver crucial clinical research at a time of immense pressure and stress on personnel and resources.
It triggered a system-wide response which took the UK’s collaborative culture to new levels. This multi-agency approach enabled unprecedented speed and efficiency in trial approvals, set-up and recruitment. By eliminating delays and duplication, and optimising all available resources throughout our NHS, the UK was able to answer questions of global importance about COVID-19, including treatment and management.
Having successfully demonstrated our ability to coordinate, expedite and accelerate research delivery there is now an opportunity to reflect on what the UK did well and what this means for the future.
This pharmaphorum webinar, held in association with the National Institute for Health Research (NIHR), will take place on Thursday 25th February13:00 GMT / 14:00 CET and discuss the UK’s approach to delivering research during the COVID-19 pandemic. It will examine lessons learnt from implementing complex design trials on a national scale and question what the UK could have done differently.
The webinar will also cover:
How research was prioritised
Processes for streamlining approvals
Learnings on site selection and set-up
Strategies for successful and rapid recruitment
View the webinar* by clicking on the link in the window above or by clicking here.
Dr Kirsty Wydenbach is an expert medical assessor and the deputy unit manager in the Clinical Trials Unit at MHRA, having joined in 2009. She has been involved in the UK regulation of clinical trials across all therapy areas and all phases of development, including ATMPs and numerous first-in-human studies. She has also been involved in European discussions aiming to establish an EU harmonised approach to clinical trials, particularly for Developmental Safety Update Reports (DSURs) and Reference Safety Information (RSI). She was also an EMA expert for the update of the First-in-Human guideline. Other recent work has included collaboration with external industry groups and regulators regarding adaptive and novel trial designs: she is leading on this aspect for the MHRA in order to implement that aspect of the Life Sciences Industrial Strategy and was a contributor to the EU CTFG Recommendation Paper on the Initiation and Conduct of Complex Clinical Trials. More recently Kirsty has overseen the clinical trial work for COVID-19 and provided regulatory expertise on vaccines both within MHRA but also as part of the government Vaccine Taskforce.
Sir Terence Stephenson is an eminent clinical academic and took up the position of chair at the Health Research Agency on 1 September 2019. He is Nuffield Professor of Child Health at the University College London Great Ormond Street Institute of Child Health and Honorary Consultant Paediatrician at UCL Hospitals NHS Foundation Trust & Great Ormond Street Hospital for Children NHS Foundation Trust. Sir Terence is also a former Dean of the University of Nottingham’s Medical School, President of the Royal College of Paediatrics and Child Health, Chair of the Academy of Medical Royal Colleges, and most recently of the General Medical Council.
Professor Nick Lemoine is medical director of the National Institute for Health Research Clinical Research Network for England. Nick has recently been appointed chair of the COVID-19 urgent public health studies group for the UK. The group’s remit is to consider all clinical studies relating to COVID-19 and to fast-track those with the greatest promise. Nick also chairs the NIHR Invention for Innovation Challenge Panel. Nick is director of the Barts Cancer Institute, Queen Mary University of London, and director of research & development for Cancer at Barts Health NHS Trust, the largest NHS Trust in the country. Among other commitments, he is the chair of Trustees of the Medical Research Foundation (the MRC’s independent charity), and executive dean of the Academy of Medical Sciences, Zhengzhou University, People’s Republic of China. He was elected as a Fellow of the Academy of Medical Sciences in 2006, and as a Foreign Academician of the Chinese Academy of Engineers in 2017.
Dominic Tyer, interim managing editor, pharmaphorum [moderator] Dominic Tyer is a trained journalist and editor with 19 years of pharmaceutical and healthcare publishing experience. He serves as interim managing editor at pharmaphorum media, which facilitates productive engagement for pharma, bringing healthcare together to drive medical innovation. He is also creative and editorial director at the company’s specialist healthcare content consultancy, pharmaphorum connect.
IO Biotech, an oncology specialist formed and backed by Denmark’s Novo Holdings, has raised €127 million ($155 million) to further develop its cancer vaccine technology that has boosted efficacy of PD-1 immunotherapy in early trials.
The Series B fundraiser follows the FDA’s decision to grant Breakthrough Therapy designation last month for a combination of its lead immune-oncology therapies IO102 and IO103, with anti-PD-1 monoclonal antibodies for patients with metastatic melanoma.
IO Biotech intends to use the proceeds from the financing to advance clinical trials for its early and late-stage immune-oncology programs, including a large randomised trial for the IO102 and IO103 with anti-PD-1 combination in metastatic melanoma.
IO102 and IO103 are cancer first-in-class vaccines based on IO Biotech’s proprietary T-win technology platform.
The company said this enables the identification of compounds with a dual mechanism of action targeting and killing immunosuppressive cells and tumour cells while indirectly activating other T-effectors.
They are designed to engage and activate IDO and PD-L1 specific human T-cells, which leads to strong anti-tumour responses without adding additional safety concern.
The FDA’s decision to grant breakthrough therapy designation was based on data from the MM1636 phase 1/2 clinical trial of 30 patients with metastatic melanoma receiving IO102, IO103 and anti-PD-1 monoclonal antibodies.
According to the data recently presented in a late-breaking abstract at the European Society for Medical Oncology Virtual Congress 2020, the combination of IO102 and IO103 vaccines and nivolumab was shown to be safe with encouraging early efficacy data.
An overall response rate (ORR) of 79% was reached and 45% of patients achieved a complete response (CR), or complete disappearance of their tumours. Vaccine specific T-cells were located in the peripheral blood mononuclear cells (PBMCs) and at the tumour site.
The financing round was led by HBM Healthcare Investments with the participation of existing investors Novo Seeds, Lundbeckfonden Emerge and Sunstone Life Science Ventures.
Other new investors joining the round included Vivo Capital, Kurma Partners, Avoro Capital, RA Capital, Samsara Biocapital, Idinvest Partners (Subsidiary of Eurazeo), PFM Health Sciences, Soleus Capital, Eir Ventures and Serrado Capital.
IO biotech was created and launched by Novo Seeds in 2015, which is the investment arm of Novo Holdings, a private company wholly owned by the Novo Nordisk Foundation.
ImmunityBio has licensed technology underpinning a COVID-19 vaccine that could be administered orally rather than by injection from UK biotech iosBio.
Approvals for injectable vaccines for COVID-19 are starting to build, but non-injectables like oral and intranasal vaccines could be required if the pandemic is to be fought across all areas of the globe, according to Wayne Channon, the UK firm’s chairman.
“Non-injectables remove the need for health professional-led immunisation programmes, making widespread vaccine roll-outs quicker and easier and more affordable,” Channon told pharmaphorum.
“They also offer the potential for self-administration at home rather than in a health setting, making compliance with booster dosage potentially higher.”
ImmunityBio’s hAd5 candidate – using iosBio’s technology – has already shown encouraging preclinical results in non-human primates using an initial injection followed by two oral booster doses.
An injectable/oral ‘prime and boost’ regimen is in a phase 1b study due to conclude in November, according to the clinicaltrials.gov database, and ImmunityBio has said it is also recruiting patients for a phase 2/3 trial.
In time, it may be possible to deliver the entire immunisation course by the oral route, according to iosBio, while ImmunityBio has suggested the oral candidate could be used to provide a boost to other injectable vaccinations.
One of the primary advantages of this approach is that the oral vaccine capsules are stable at room temperature, which means they do not require cold chain storage. They are also cheaper to produce and store and can be distributed across the globe easily – all without the need for specialised equipment or personnel – according to iosBio.
“This is particularly important in developing countries, where access to cold-chain is limited,” said Channon.
There are other theoretical advantages as well. For instance, oral vaccines could allow repeat dosing without a treatment-limiting anti-vector response – where the body generates an immune response against the harmless, non-replicating viruses used to deliver the COVID-19 antigens.
“This can render the repeat administration of that vaccine as a booster, or a vaccine against a different infectious disease using the same viral vector, ineffective,” according to Channon.
The lack of anti-vector immunity in the gastrointestinal (GI) tract means repeat dosing with vaccines based on iosBio’s tech is possible, he suggested, because of the natural level of tolerance in the gut that avoids generating an immune response to food, for instance.
“This allows the same vector to be repeatedly orally administered and re-used for multiple vaccine programmes.”
ImmunityBio – led by billionaire surgeon and Nantworks and NantKwest founder Patrick Soon-Shiong – isn’t the only company looking at non-injectable COVID-19 vaccines.
Vaxart said in November it had completed enrolment in a phase 1 trial of its oral COVID-19 vaccine VXA-CoV2-1, having reported viral load reduction and antibody responses in a COVID-19 hamster challenge model. Symvivo also has an oral candidate in a phase 1 study which started last November.
Altimmune meanwhile is taking a different tack with its single-dose intranasal candidate AdCOVID, which had been due to generate initial clinical study results in the next few weeks but was placed on a clinical hold by the FDA last month after a request for more manufacturing data.
Soon-Shiong said that oral vaccines could have another key advantage as they stimulate mucosal, systemic and T-cell immune responses.
“As we see multiple mutations in the SARS-CoV-2 spike protein, there is an urgent need for a vaccine that not only offers immediate protection but also activates T-cells to clear the virus,” he said.
ImmunityBio’s vaccine design drives both antibody and T-cells to the spike (S) protein and nucleocapsid (N) protein.
That means it could “potentially serve as a universal boost to current vaccines that focus only on the monovalent S protein, as well as address future mutations of the S protein,” according to Soon-Shiong.
ImmunityBio and NantKwest announced last month they will merge into a single company focusing on immunotherapies and cell therapies for cancer and infectious diseases.
US biotech Atalanta Therapeutics has come out of stealth mode backed with $110m from Biogen and Roche, who have also signed separate partnerships to develop new therapies for neurological diseases using RNA interference (RNAi) technology.
While there are RNAi products on the marketplace, with Alnylam becoming the first company to get a product approved in 2018, it is difficult to get this class of drug distributed through the brain and spinal cord.
But with new technology based on branched silencing RNA licensed from the University of Massachusetts Medical School, Atalanta says it could change this.
Co-founded by Craig Mello, who won the Nobel Prize for Physiology or Medicine in 2006 for his work on RNAi, the company says the technology could be used to treat central nervous system diseases such as Huntington’s, Alzheimer’s and Parkinson’s.
Atalanta has actually been working since 2018 with co-founders Anastasia Khvorova, a UMass biochemist and Neil Aronin, a professor from University of Massachusetts Medical School, providing early leadership.
The company hired Alicia Secor as CEO in summer of 2019, who has previously been CEO of Juniper Pharmaceuticals and serves on the boards of neurology and rare diseases firms GW Pharmaceuticals and Orchard Therapeutics.
Atalanta starts life with two different strategic collaborations with its big pharma backers.
The partnership with Biogen will develop RNAi therapeutics for multiple targets, including HTT for the treatment of Huntington’s disease, as well as additional unnamed CNS targets.
Atalanta will be eligible to receive development and milestone payments as well as undisclosed royalties on any resulting products.
The strategic collaboration with Genentech entails the development of RNAi therapeutics for multiple CNS targets for neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease.
This could also result in development and milestone payments and royalties.
Unprecedented and astounding
In an interview with pharmaphorum Secor said that the technology comes from a discovery in Khvorova’s lab, which showed the technology allowed potent silencing of Huntington’s for six months in mice.
In 2019 results were published in Nature Biotechnology of the research findings, which were described by Secor as “unprecedented and astounding”.
The founders formed the company with backing from investor F-Prime Capital and has just launched its Series A round with Roche’s Genentech unit and Biogen the first to invest.
Secor said: “In my 30 years I have never seen this level of interest.”
The technology could be used in several indications, according to chief scientific officer and RNAi expert Aimee Jackson.
“There is distribution to multiple regions and deep brain structures and enhanced potency and duration of action,” she said.
With the backing the company already has, Secor said the plan is to focus on preclinical development without needing to worry about funding for the time being.
Quizzed about the possibility of an IPO or buyout from a big pharma company, Secor said the focus is very much on developing the technology.
She told pharmaphorum: “Our long-term vision is to be discovery research and commercialisation platform and product company for a very long time.
“We have a long cash runway to do some building,” she added.
Secor also noted the strong role that women have played in founding and running the company, noting that the name Atalanta refers to the famous female character from Greek mythology.
It also reflects the contribution from Khorova as the founder of the company.
There’s also a connection with Greek mythology from the name of the protein that is targeted by the RNAi drug in Huntington’s – Argonaute 2.
In many versions of Jason’s quest for the Golden Fleece, Atalanta served as the only woman on the crew of the Argo.
Secor noted the recent appointments of Emma Walmsley and Reshma Kewalramani as CEOs at GlaxoSmithKline and Vertex, respectively.
She told pharmaphorum: “I wanted to keep the name to remind us we were named after a woman.
“I think there is a big movement around diversity and inclusion its an opportunity to break through those glass ceilings women should be feeling empowered to take leadership roles.
“It creates a whole lot of opportunities for women. This is a good time for women and I am excited to see more women step into leadership roles.”
US biotech bluebird bio has announced plans to split into two this year, with a separate oncology business spinning off as the company prepares to bring its products to market.
Under the plans the company’s rare disease drugs will remain under the aegis of bluebird with current genetic disease president Andrew Obenshain taking the reins as CEO.
Meanwhile the as-yet unnamed oncology company will spin off under the leadership of bluebird’s current chief executive Nick Leschly.
Leschly will also take the role of executive chair at bluebird, according to a company statement.
While bluebird has conducted pioneering work in gene therapy for blood disorders and in cancer cell therapy, products have been delayed by issues with filing data for the FDA.
Late last year, bluebird’s shares tanked after the FDA laid out additional manufacturing standards for its lead gene therapy product, Lentiglobin, in sickle cell anaemia that could hold up filing until late 2022.
Bluebird’s lead CAR-T cancer cell therapy idecabtagene vicleucel (ide-cel) was last year hit with an FDA refuse-to-file letter, which required additional data on chemistry, manufacturing and controls before reviewing the company’s dossier.
That made things difficult for development partner Bristol-Myers Squibb, which inherited the drug previously known as bb2121 through its acquisition of Celgene late in 2019.
The FDA is now due to make a decision on ide-cel as a treatment for multiple myeloma in late March.
Laying out the rationale for the spin-off, bluebird said that operating individually the two companies will be more effective at allocating capital.
The companies will be better equipped to deliver on goals and operations will be streamlined and simplified.
They will also be better at raising money with tailored investment theses and increased strategic flexibility.
The gene therapy firm will be focused on its most important therapies in beta-thalassemia, cerebral adrenoleukodystrophy and sickle cell disease in the US And Europe.
Zynteglo is already in beta-thalassemia in Europe, where the company will seek to expand access despite its hefty $1.8 million price tag.
On the oncology side, bluebird has also strengthened its board with the appointment of Dr Ramy Ibrahim, a high-profile leader in clinical development in immunotherapy and cell therapy.
Ibrahim is currently serving as a consultant for the Parker Institute for Cancer Immunotherapy (PICI) and built the clinical capabilities within the institute.
Ibrahim also worked as vice president and global therapeutic head for immuno-oncology at AstraZeneca and MedImmune, helping to develop the immunotherapy Yervoy (ipilimumab) at Bristol-Myers Squibb.
China’s Chi-Med and Inmagene Biopharmaceuticals have agreed a strategic partnership to develop preclinical drug candidates for potential treatment of several immunological diseases.
Funded by Inmagene, the companies will work together to move drug candidates towards regulatory filings with the FDA.
Chi-Med, full name Hutchison China MediTech, has granted Inmagene exclusive options to four drug candidates only for treatment of immunological diseases.
If Inmagene decides to exercise the option, it will have the right to further develop, manufacture and market that specific drug candidate globally.
Chi-Med will retain first rights to co-market in mainland China and for each drug candidate will be entitled to development milestone payments of up to $95 million, plus commercial milestones of up to $135 million, plus double-digit sales royalties.
Inmagene has wholly-owned subsidiaries in Shanghai, San Diego and Hangzhou, and is focused on building its drugs pipeline.
It’s lead candidate, IMG-020, is about to enter global clinical trials in several different indications that the company has not specified.
Chi-Med has been working on targeted therapies for immune diseases and cancer and has a portfolio of nine cancer drugs in clinical studies around the world.
Chi Med had been working with AstraZeneca on a late-stage oncology drug, savolitinib, for renal cell carcinoma.
However, the UK pharma opted to dump the MET inhibitor drug from its pipeline after the Chi-Med said that it looked unlikely to beat Pfizer’s Sutent in papillary renal cell carcinoma.
Chi-Med has also worked with Eli Lilly on another investigational cancer drug, fruquintinib.
Christian Hogg, chief executive officer of Chi-Med, said, “This partnership will enable Inmagene to investigate the immunological disease applications of these four drug candidates, discovered by our in-house discovery organisation.
“We believe that these four candidates have scope in multiple immunological diseases and we are pleased to see these opportunities investigated further by Inmagene.”
Sanofi is to acquire UK biotech Kymab in a deal worth up to $1.45 billion as the big French pharma seeks to add to its pipeline of drugs that treat inflammatory diseases and cancer.
Cambridge-based Kymab is one of several rising stars on the UK biotech scene, with technology that uses transgenic mice to develop antibodies optimised for the human immune system.
It has previously signed a bi-specific immune-oncology antibody deal with China’s EpimAb and had begun early research with The Scripps Research Institute in California about a potential new approach to an HIV vaccine.
Kymab has attracted the interest of Sanofi with its fully human monoclonal antibody, KY1005, which has a novel mechanism of action and has the potential to treat a wide variety of immune-mediated diseases and inflammatory disorders.
In August last year Kymab said KY10005 had met both primary endpoints in a phase 2 trial in moderate to severe atopic dermatitis, otherwise known as eczema.
KY1005 demonstrated a consistent treatment effect versus placebo across various key endpoints, including in the Eczema Area and Severity Index (EASI) and additional objective clinical measures.
KY1005 works by bonding to the OX40-Ligand (OX40-L), which forms an important part of the process that activates the immune system.
Interaction between OX40-L and its binding partner OX40 have been shown to play a central role in several inflammatory and autoimmune diseases.
Sanofi and Regeneron’s Dupixent (dupilumab) has already built a blockbuster presence as an injected drug for eczema and asthma.
Regeneron also uses similar technology based on transgenic mice to develop its drugs, and Kymab is therefore a good fit that could allow Sanofi to develop a new generation of immunology drugs in-house.
Kymab’s pipeline also includes the oncology asset KY1044, an ICOS agonist monoclonal antibody, currently in early phase 1/2 development as monotherapy and in combination with an anti-PD-L1.
It’s the latest acquisition from Sanofi as the company looks to build on the success of Dupixent, focusing on cancer and inflammatory diseases drugs while turning its back on the market for diabetes drugs after its big-selling insulin Lantus lost ground to cheaper competitors.
The Kymab deal comes after Sanofi agreed to buy US biotech Principia Biopharma for $3.4 billion in August last year, adding several BTK inhibitor drugs to its pipeline to treat autoimmune disorders.
There’s a new player in the neurology and mental health drugs market after Italy’s Angelini Pharma merged with Switzerland’s Arvelle Therapeutics in a deal worth up to $960 million based around the anti-seizure drug cenobamate.
Angelini is an international pharma company that is part of the privately-owned Italian Angelini Group, while Arvelle is focused on bringing innovative treatments to patients suffering from CNS disorders.
The deal gives Angelini an exclusive European license to market cenobamate, a drug being developed for drug-resistant focal-onset seizures in adults.
It is already in the late stages of development and expected to be approved in Europe later this year.
The license covers the European Union and other countries in the European Economic Area, such as Switzerland and the UK. As a result the all-cash deal will see Angelini pay $610 million following regulatory approval of cenobamate, followed by a further payment of $340 million.
Arvelle was founded in 2019 and has been focused on developing cenobamate, which has already been designated as a Promising Innovative Medicine by the UK regulator, the Medicines and Healthcare products Regulatory Agency (MHRA).
It is a small molecule with a dual action, which stimulates the γ-aminobutyric acid (GABAA) ion channel while also inhibiting voltage-gated sodium currents.
Study findings so far have shown cenobamate can produce a significantly greater reduction in median seizure frequency and more patients achieving a 50% or greater reduction in seizure frequency compared to the placebo group.
It is already approved by the FDA as an anti-seizure drug for partial-onset (focal onset) seizures in adults, where it is available under the brand name Xcopri and marketed by SK Biopharmaceuticals, which discovered and developed it.
SK Biopharmaceuticals, a pharmaceutical company listed on the Korea Stock Exchange, announced that it has agreed to sell its 12% stake in Arvelle Therapeutics to Angelini Pharma.
SK Biopharmaceuticals will remain eligible to receive all payments inherited by a license agreement signed between Arvelle Therapeutics and SK Biopharmaceuticals in February 2019.
Revenue share payments due to certain of the Arvelle shareholders will be assumed by Angelini Pharma.
As COVID-19 vaccines are hastily deployed in the UK for priority groups, a debate rages over the government’s controversial strategy to delay time between vaccine doses.
When the UK announced the approval of the Pfizer-BioNTech and Oxford/AstraZeneca COVID-19 vaccines, it marked an exciting moment for the nation.
After months of turbulent lockdown measures, the dawn of approved vaccinations signalled hope COVID-19 could finally be under control.
Sadly, the chaos is continuing as the UK grapples with the emergence of a new variant of SARS-CoV-2, estimated to be up to 70% more transmissible than the previous form of the virus.
As cases surge, the UK’s decision to delay second doses of the vaccine beyond the 3-4 weeks tested and approved during Phase III clinical trials is causing widespread concern. Many believe the strategy is too risky – prioritising political expediency over science and using the British public as laboratory subjects during an already severe crisis.
The advice, which first came from the UK’s Joint Committee on Vaccination and Immunisation (JCVI), stated a maximum interval of 12 weeks should take place between the first and second doses of both Pfizer and AstraZeneca’s vaccines.
JCVI said this is likely to have a greater public health impact in the short term and reduce the number of preventable deaths from COVID-19.
“The rate of vaccine delivery in the UK is currently limited by vaccine supply rather than by workforce capacity,” said the committee. “An extended interval between vaccine doses together with initial prioritisation of the first vaccine dose would increase the flow of vaccine supply in the short term. This will allow for more first doses to be delivered to more people earlier.”
The advice has been endorsed by the UK’s four chief medical officers but has been met with backlash from the medical community. Many healthcare workers have aired grievances on Twitter protesting the changes.
Just received this email cancelling my 2nd dose of the Pfizer vaccine. On the basis of UK government guidance yesterday. This means that the vaccine is not being delivered as licensed. I DID NOT consent to receive an off-label drug with NO evidence of benefit with a single dose. pic.twitter.com/ZDtIjm1z8W
The British Medical Association (BMA) also blasted the decision as “unreasonable and totally unfair”.
“The Government must see that it’s only right that existing bookings for the oldest and most vulnerable members of our society are honoured, and it must also as soon as possible publish a scientifically-validated justification for its new approach,” said the BMA.
“As doctors, we believe this can and should be done even as practices and the wider NHS step up the COVID-19 vaccination programme to deliver initial doses of vaccination to other vulnerable people, including frontline healthcare professionals – many of whom still have not even received their first vaccination.”
‘Erosion of public trust’’
The NHS Confederation, which represents leaders across the organisation, told pharmaphorum the government needed to be very clear in its communications with the public about exactly what they are being asked to do and why.
“We have committed time and time again to make decisions based on data and science. Until vaccine manufacturers have data and science supporting a change, we continue to strongly recommend that health care providers follow the FDA-authorised dosing schedule for each COVID-19 vaccine”
“Protecting frontline staff from infection is vital to help them care for patients with COVID, as well as delivering the vaccination programme,” said NHS Confederation director Layla McCay. “However, there has been concern about changes to the vaccination schedule, which were announced at short notice and led to confusion and anxiety for patients and could lead to an erosion of public trust in healthcare providers. As always, NHS teams will pull out all the stops to respond to changing guidance, but the government must do more to explain the rationale for this change.”
Internationally, the decision has been met with scepticism. The FDA issued a statement regarding dosing schedules on 4 January 2021. “We know that some of these discussions about changing the dosing schedule or dose are based on a belief that changing the dose or dosing schedule can help get more vaccines to the public faster. However, making such changes that are not supported by adequate scientific evidence may ultimately be counterproductive to public health.
“We have committed time and time again to make decisions based on data and science. Until vaccine manufacturers have data and science supporting a change, we continue to strongly recommend that health care providers follow the FDA-authorized dosing schedule for each COVID-19 vaccine.”
In a joint statement Pfizer and BioNTech warned there was no data to demonstrate that protection after the first dose is sustained after 21 days. “The safety and efficacy of the vaccine has not been evaluated on different dosing schedules as the majority of trial participants received the second dose within the window specified in the study design,” said the companies.
The Oxford-AstraZeneca vaccine trial did include difference spacing between doses and showed longer gaps (two to three months) yielded a greater immune response. The combined trial results published in the Lancet showed that vaccine efficacy 14 days after a second dose was higher in the group that had more than six weeks between the two doses (65.4%) than in the group that had less than six weeks between doses (53.4%).
Andrew Pollard, head of the Oxford Vaccine Group and chief trial investigator vaccine told the BMJ that extending the gap between doses made sense.
“Generally, a longer gap between vaccine doses leads to a better immune response, with the second dose causing a better boost. (With HPV vaccine for girls, for example, the gap is a year and gives better responses than a one-month gap.) From the Oxford vaccine trials, there is 70% protection after the first dose up to the second dose, and the immune response was about three times greater after the second dose when the second dose was delayed, comparing second dose after four weeks versus second dose after two-three months.”
Akiko Iwasaki, professor of immunobiology at Yale Medical school also tweeted support for the changes, stating the new SARS-CoV-2 variant as the deciding factor.
I am still a proponent of 2 dose vaccine but given the urgency, we can delay the 2nd dose until more vaccines become available. I know many others have been saying this all along, but it was the B.1.1.7 variant transmission rate that did it for me. (8/n)https://t.co/qrwvtOLyGv
“I am still a proponent of two-dose vaccine but given the urgency, we can delay the seconnd dose until more vaccines become available. I know many others have been saying this all along, but it was the B.1.1.7 variant transmission rate that did it for me,” said Iwasaki.
David Grainger, chief scientific advisor at life sciences investment firm Medicix, also expressed confidence in the strategy, referring to modelling by the University of Toronto that predicts increasing the number of people protected, by limiting individuals to a single dose, reduces severe COVID events (ICU stays and death) by between 30-40% over a 6-month period. This could amount to over 20,000 lives saved.
“The vaccine only must be 50% effective in two people to reduce the overall risk of infection that is achieved with 95% protection in one person,” said Grainger. “If I protect 10,000 people out of a population of 20,000 with 1% risk of infection at 95% efficacy, I get five cases from the protected subgroup and 95 cases in the unprotected subgroup for a total of 100 infections; if I protect all 20,000 people with 50% efficacy, again I get 100 infections. The existing data strongly suggests that a single dose will deliver at least 50% protection for at least a few months.”
He added that during the pandemic, decisions often needed to be made in the absence of proper data. “It teaches us that we cannot just ‘follow the science’ because that pathway is way too conservative (at least if that means only do things for which there is clear, direct evidence).
“This is why we should have scientific advisors, but not rely on scientists to make decisions. It is why scientists rarely make good investors or businessmen – too many decisions need to be made in the absence of much information.”
Shortly after launching large-scale trials of its COVID-19 vaccine candidate, CureVac has the partner it will need to roll the shot out at scale if it works as hoped.
Bayer has joined forces with the German biotech to support the development and supply of CVnCoV, an mRNA candidate using a similar technology to the Pfizer/BioNTech and Moderna jabs, with the drugmaker saying it will help CureVac produce “several hundred million doses”.
CureVac has been working steadily on CVnCoV over the last few months as the spotlight was trained on candidates originated by BioNTech, Moderna and AstraZeneca, which were a little further ahead in development, but began its own phase 2b/3 study in mid-December.
It’s hoping for interim results from that in the first quarter of this year, which if positive could be followed by rolling regulatory submissions and – potentially at least – emergency approvals sometime towards the late spring/early summer.
The trial is assessing the safety and efficacy of CVnCoV in adults of various ages and once fully enrolled will include more than 35,000 participants in Europe and Latin America.
It aims to demonstrate the efficacy of CVnCoV in preventing first cases of confirmed COVID-19 of any severity, as well as preventing moderate to severe disease, in participants who have never been infected with the SARS-CoV-2 virus.
The European Commission – which has just approved the Moderna vaccine and previously gave a green light to the Pfizer/BioNTech shot – already has an order in for 405 million doses of the CureVac vaccine. It gave CureVac €75 million in funding to develop CVnCoV last July, adding to around €100 million provided by the German government in 2020.
The biotech would likely struggle to supply without the help of its new big pharma partner, although it has been expanding its production capacity in the last few weeks with the help of contract manufacturers like Wacker and Fareva.
Bayer said it will contribute in areas like clinical operations, regulatory affairs, pharmacovigilance, medical information, and supply chain performance to help get the vaccine to the public as quickly as possible.
“We are highly committed to making our capabilities and networks available to help end this pandemic,” said Stefan Oelrich, president of the German group’s pharma division.
Bayer is providing assistance to CureVac primarily in the EU and some other markets, where the German biotech will be the marketing authorisation holder, but has an option to seek approval of CVnCoV on its own account in countries outside Europe.
CureVac has previously said however that it does not intend to introduce its vaccine in the US – at least while the pandemic is ongoing – because the government there has already ordered enough supplies of rival jabs to immunise the entire population.
At last count, there are more than 60 coronavirus vaccines at in clinical development around the world, with another 170 in preclinical testing, according to the World Health Organization (WHO).
AbbVie is in a race against time as US patent expiry of its Humira inflammatory diseases blockbuster looms in 2023 – but it just scored two crucial phase 3 trial victories that could help rebuild sales when cheaper biosimilars flood the market in two years’ time.
The company’s follow-up drug Skyrizi is a key plank in AbbVie’s strategy to negotiate the $20 billion patent cliff from Humira, which has already seen sales decline outside of the US where it has already lost protection from cheaper competitors.
In its latest announcement, AbbVie said Skyrizi had beaten placebo at improving psoriatic arthritis outcomes patients in two phase 3 trials in psoriatic arthritis, as well as hitting important secondary endpoints such as skin clearance, physical function and disease activity.
The results in psoriatic arthritis, one of the many indications covered by Humira, could pave the way for a launch in a second indication for Skyrizi.
An IL-23 inhibitor, Skyrizi is already approved in moderate to severe plaque psoriasis and together with the oral rheumatoid arthritis drug Rinvoq (upadicitinb), AbbVie hopes to cover many of the indications where Humira has become standard therapy.
Specifically in the KEEPsAKE-1 and KEEPsAKE-2, 57% and 51% of patients receiving Skyrizi achieved the primary endpoint of ACR20 response at week 24, respectively, versus 34% and 27% receiving placebo.
KEEPsAKE-1 and KEEPsAKE-2 tested Skyrizi in adults with active psoriatic arthritis and included patients who had responded inadequately or were intolerant to biologic therapy and/or non-biologic disease-modifying anti-rheumatic drugs.
AbbVie said that safety results were consistent with those seen in previous studies.
Aside from psoriatic arthritis, AbbVie is also testing Skyrizi in other indications where Humira has become established – Crohn’s disease and ulcerative colitis.
However AbbVie’s Q3 results reveal the scale of the task ahead – Humira’s sales in the US continue to mount at nearly $4.8 billion, while Skyrizi and Rinvoq generated revenues of $379 million and $1912 million, respectively.
Analysts are continuing to back Inventiva’s lanifibranor as a potential “best-in-class” drug for the fatty liver disease NASH, as the company prepares for the launch of a phase 3 trial in spring.
A team of analysts from Jefferies led by Lucy Codrington noted the design of the trial, which will have a dual goal measuring both liver inflammation and scarring could give an edge over potential competitors.
There are no approved drugs for NASH – full name non-alcoholic steatohepatitis – after the FDA rejected Intercept’s obeticholic acid last year.
The regulator said it wanted more long-term safety and efficacy data from the REGENERATE study before making a final decision on the drug, which had been expected to be the first entrant into a likely multi-billion dollar market niche.
According to the latest analysis from Jefferies the design for the phase 3 NATIVE3 study from Inventiva has been okayed by regulators and the case for lanifribanor has already been boosted by “stellar” results in phase 2.
The decision to include two endpoints of inflammation and scarring is important because improvements in both these measures are likely to lead to an improved prognosis.
Lanifibranor is also taken orally, making it convenient for patients and Inventiva is hoping to offer a choice of two doses offering doctors the ability lower the strength of the medication to control side-effects such as oedema.
The trial will take a while however, with results not due until the second half of 2023, with sales forecast to peak at around $2.6 billion annually if approved.
The Jefferies team also noted that the French biotech is also partnered with AbbVie to develop an oral successor to its inflammatory diseases blockbuster Humira (adalimumab).
Proof-of-concept phase 1b data is due from the drug codenamed ABBV-157 is due this quarter, which will help AbbVie decide on whether to continue development.
A host of other pharma companies including Gilead, Novo Nordisk, Merck & Co are also developing potential NASH drugs.
Only this morning, Novo Nordisk selected the first candidate from a project with Dicerna to find new gene-silencing drugs to treat liver-related diseases including NASH.
The UK government has promised a “massive uplift” in the number of coronavirus vaccinations carried out this week, while conceding a target of 13.9 million jabs offered by the end of February will be “challenging”.
As the number of daily recorded cases in the country exceeded 60,000 for the first time, vaccine minister Nadhim Zahawi told BBC Radio 4’s today programme: “My absolute focus is to get to 13.9 million…offered a vaccine by the middle of February.
“That is my target and I’m confident the NHS has a plan and we will meet that target.”
The number of vaccinations will continue to rise, he promised, adding that a quarter of over-80s had already been vaccinated.
Zahawi stopped short of saying when the government would reach the 300,000 vaccinations a day required to meet the goal.
More than a million people are thought to be infected with virus at the moment and hospitals across in the worst-affected areas are running at full capacity because of the disease.
All of the country is now in a strict lockdown, with mixing indoors banned and people instructed to stay except to get exercise and other essential tasks such as buying food.
According to reports elsewhere there are a number of backlogs that are causing delays to the roll-out of the vaccine from AstraZeneca, which will be offered to the majority of patients.
The UK has ordered 100 million doses of the vaccine and AZ has reportedly manufactured around 3.5 million doses in addition to the half million or so shots that are already available.
But Sky News reported that the extra doses are still waiting to be batch tested by the country’s regulator, the Medicines and Healthcare Products Regulatory Agency.
Sky reported that the MHRA is working in parallel with AstraZeneca’s own batch testing system to speed up a process that usually takes up to three weeks.
There are also issues with Pfizer/BioNTech vaccine, which is not manufactured in the UK like the AZ shot but in Belgium.
It has already been placed into glass vials by the time it arrives in the country, but a worldwide shortage of these means that five million doses have been delivered.
This is less than half the number that should have been because of the problems with manufacturing including the fill-and-finish process, according to the BBC.
Feature image courtesy of NIH/Rocky Mountain Laboratories
Two years after starting to work together, Novo Nordisk and Dicerna have selected the first candidate from a joint project to find new, gene-silencing drugs for liver-related cardiometabolic diseases.
Danish drugmaker Novo Nordisk signed a deal with the US biotech in 2019 valued at up to $675.5 million – including $175 million upfront and an equity investment of $50 million – to find multiple RNA interference (RNAi) candidates for diseases like non-alcoholic steatohepatitis (NASH) and type 2 diabetes.
The nomination of a first candidate in the collaboration that will advance into development triggers a $2.5 million milestone payment to Dicerna, which says it also earned the targeted $25 million in alliance revenues last year after delivering multiple other RNAi drugs into Novo’s pipeline.
RNAi uses small RNA molecules to bind to messenger RNA, which is responsible for synthesising proteins, and either destroy it or recruit other cellular factors that regulate its activity.
In 2018, Alnylam’s Onpattro (patisiran) became the first ever RNAi drug to be approved by the FDA, getting a green light to treat nerve damage caused by the rare disease hereditary transthyretin-mediated amyloidosis (hATTR).
Since then Alnylam has picked up approval for two more RNAis, Givlaari (givosiran) for acute hepatic porphyria (AHP) and Oxlumo (lumasiran) for primary hyperoxaluria type 1 (PH1), and Novartis has the go-ahead in Europe for its cholesterol-lowering drug Leqvio (inclisiran), although it was turned down by the FDA because of questions about conditions at a site run by a contract manufacturer.
Several others are in late-stage development, including fitusiran for haemophilia, which Sanofi is developing under license from Alnylam.
Dicerna is carrying out discovery and preclinical development to clinical candidate selection for each liver cell target under its deal with Novo Nordisk, with the Danish pharma responsible for all further development.
Each company will retain rights to co-develop and co-market the drugs developed using Dicerna’s proprietary GalXC RNAi platform, which along with NASH and diabetes could also include candidates for obesity and chronic liver diseases.
Dicerna stands to received $25 million a year in 2021 and 2022 if the project continues to run to plan. Meanwhile, for Novo Nordisk the alliance could provide a stream of R&D pipeline candidates in its core areas of diabetes and metabolism and growing interest in liver diseases like NASH.
NASH – a form of fatty liver disease – is predicted to create billions of dollars in revenues for pharma, and Novo Nordisk has been building a presence in this area, headed by GLP-1 agonist semaglutide which is being put through its paces in NASH in combination with drugs from Gilead.
In 2019 the Danish company also licensed a preclinical-stage, small-molecule candidate for NASH from Japan’s UBE.
Episode two of the Alderley Park Discovery Podcast covers access to skills in the life sciences sector, with a focus on support for aspiring scientists and UK staffing trends.
In this instalment Dominic Tyer’s guests on the podcast are Sai Life Sciences’ head of global R&D Dean Edney, Joynes & Hunt’s managing director Steve Joynes and Dr Kath Mackay, managing director at Bruntwood SciTech’s Alderley Park.
Dr Mackay talks about why university connections are vital for a life science and tech cluster like Alderley Park and how the campus works to inspire the next generation of scientists.
From Dean Edney there’s a look at the expansion story of India-headquartered Sai Life Sciences and what the research development services company needed when it came to setting up its first European base of operations.
The podcast also features a rundown of recruitment trends in UK life sciences from Steve Joynes from specialist staffing solutions provider Joynes & Hunt. He discusses how recruitment has changed over the past decade and reveals some of the impacts from the COVID-19 pandemic on staffing.
The Alderley Park Discovery Podcast, produced in partnership with pharmaphorum, presents perspectives on UK and global bioscience innovation trends, with input from leading experts at Alderley Park in the North West of England.
In episode one of the podcast Dr Mackay talked about the challenges of rapidly building capacity to test thousands of patients a day for coronavirus at the Alderley Park Lighthouse Lab.
Alderley Park, a development by Bruntwood SciTech, is the UK’s largest single-site life science campus and offers bioscience facilities for R&D-focussed life science companies at every stage of their lifecycle, from start-up to global corporate.
Episode two of the Alderley Park Discovery Podcast is available in the player below, where you can listen to it, download it to your computer or find – and subscribe to the series, and other pharmaphorum podcasts – in iTunes, Spotify, acast and Stitcher.
Biotech Clene Nanomedicine has gone public with a mission to use nanotherapeutics that will use gold to treat devastating neurological diseases including Parkinson’s disease.
Over the Christmas period Clene closed a reverse merger with Tottenham Acquisition I Limited, allowing shares to be publicly traded on the Nasdaq stock exchange.
The US-based company says it aims to revolutionise treatment of diseases including multiple sclerosis and amyotrophic lateral sclerosis with a new class of drugs that use gold to catalyse the cellular reactions fundamental to life.
Proceeds from the transaction totalled $31.9 million, combining funds held in Tottenham’s trust account and financing from Clene shareholders.
The current pipeline includes a phase 3 study in ALS and four phase 2 studies in ALS, MS and Parkinson’s.
Lead candidate is CNM-Au8, is an orally administered, bioenergetic gold nanocatalyst designed to enhance critical intracellular bioenergetic reactions necessary for repairing and reversing neuronal damage.
The company says its approach is based on the understanding that energy is the essential building block to life and that bioenergetic failure underlies the makeup of many neurodegenerative diseases.
Clene says its technology is based on active nanocrystals to activate reactions within the body that have shown to enhance cellular repair and regeneration.
Preliminary blinded data from the phase 2 RESCUE-ALS trial announced at the Symposium on ALS/MND show that more than 40% of enrolled patients with completed 12-week data experienced an improvement in motor neuron function as assessed by a standardised score.
Compared to baseline values the average score showed an increase that exceeded the expectations on which the study was based, the company said.
This suggested that CNM-Au8 may have neuro-reparative potential in ALS and expects completed unblinded results from the RESCUE-ALS study in the second half of 2021.
CNM-Au8 was selected as one of the first drug regimens to be evaluated in the phase 3 HEALEY ALS Platform Trial, a placebo-controlled study testing several novel ALS therapies at the same time to cut costs.
It includes substantial financial support from philanthropic donors and foundations and provides access to 54 expert ALS clinical trial sites across the US.
Dosing was initiated in the Clene-specific portion of the platform trial in July 2020 and full enrolment is expected by the end of Q2 2021, with top-line data available in the first half of 2022.
Roche looks set to mount a challenge to Bayer’s ophthalmology drug Eylea in 2021 after its faricimab antibody showed comparable results in diabetic macular oedema (DME) but with half the injections, in twin phase 3 studies.
While Eylea (aflibercept) is taken in doses eight weeks apart, results from the YOSEMITE and RHINE studies showed faricimab produces a similar effect but with a 16-week dosing regimen.
Roche’s approach is similar to that taken by Novartis with its ophthalmology drug Beovu (brolucizumab), which can be taken three months apart by some patients in wet age-related macular degeneration, another indication where Eylea is well established.
Roche’s two non-inferiority trials met their main goals, showing that that faricimab given every eight weeks and at personalised dosing intervals of up to 16 weeks gave similar visual acuity gains compared with Eylea given every eight weeks.
Faricimab was generally well-tolerated, with no new safety signals identified, Roche said.
The studies each have three treatment arms, with participants randomised to receive either faricimab or aflibercept at fixed eight-week intervals, or faricimab at personalised intervals of up to 16 weeks, following a loading phase.
In a secondary endpoint, across both studies, more than half of participants in the faricimab personalised dosing arms achieved an extended time between treatments of 16 weeks at year one.
This is the first time any investigational medicine has achieved this level of durability in a phase 3 study of people with DME, Roche noted.
Faricimab also has different mechanism of action compared with Eylea and is the first bispecific antibody designed especially for the eye.
It targets two pathways – via angiopoietin-2 (Ang-2) and VEGF-A – that drive a number of retinal conditions, including DME.
Roche is also testing the long-term safety and tolerability of faricimab in DME in the phase 3 Rhone-X study.
Detailed results of YOSEMITE and RHINE will be presented at the Angiogenesis, Exudation and Degeneration 2021 medical conference in Miami next month, and filed with regulators around the world.
A serotonin sensor designed using Artificial Intelligence (AI) could help scientists study sleep and mental health and potentially find new neurology drugs.
The US National Institutes of Health said that the research it had co-funded used AI to transform a bacterial protein into a new research tool.
It is hoped that the protein, which “catches” serotonin molecules and allows them to be tracked, could detect subtle, real-time changes in serotonin levels during sleep, fear and social interactions.
The technique could also be used to test the effectiveness of new psychoactive drugs, according to the US-government funded NIH.
This study in mice was funded by the NIH’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) initiative, which aims to revolutionise understanding of the brain under healthy and disease conditions.
It was led by researchers in the lab of Dr Lin Tian, principal investigator at the University of California Davis School of Medicine.
In the study, researchers transformed a nutrient-grabbing Venus-flytrap shaped bacterial protein into a highly sensitive fluorescent sensor that lights up when it captures serotonin.
Tian’s lab builds on the work of scientists in the lab of Dr Loren Looger, Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia, who used traditional genetic engineering techniques to convert the bacterial protein into a sensor of the neurotransmitter acetylcholine.
Tian worked with Looger’s team and used artificial intelligence to completely redesign the protein known as OpuBC to catch serotonin instead.
The researchers used machine learning algorithms to help a computer ‘think up’ 250,000 new designs. After three rounds of testing, the scientists settled on one.
Experiments in mouse brain slices showed the sensor responded to serotonin signals sent between neurons at synaptic communications points.
Further experiments on cells in petri dishes suggested that the sensor could effectively monitor changes in these signals caused by drugs, including cocaine, MDMA and several commonly used antidepressants.
Mouse studies showed the sensor monitored an expected rise in serotonin levels when mice were awake and a fall as mice fell asleep.
They also spotted a greater drop when the mice eventually entered the deeper, REM sleep states.
The UK’s COVID-19 vaccination programme could get a speed boost, with the country’s drugs regulator expected to make a decision on a shot from Oxford University/AstraZeneca in the next few days.
If the vaccine becomes available the UK will be able to step up its vaccination programme as large swathes of the country face draconian “Tier 4” restrictions due to the emergence of as more infectious variant.
Latest figures show that there were nearly 40,000 cases recorded yesterday, the highest since mass testing began, although it’s thought infection rates were higher during the first wave of the virus in spring when tests were not readily available.
The Medicines and Healthcare products Regulatory Agency (MHRA) began a fast-track rolling review of the vaccine in November and reports point towards a decision between Christmas and New Year.
The UK has ordered 100 million doses of the vaccine, which is based on an adenovirus vector and is easy to handle than rivals from Pfizer/BioNTech and Moderna.
AZ’s vaccine, dubbed AZD1222, is stored at normal refrigerator temperatures while the Pfizer/BioNTech and Moderna shots need to be kept at around -70C and -20C respectively to maintain the integrity of their RNA structure.
According to health secretary Matt Hancock, the full dossier of trial evidence is now with the regulator, which is poised to make a decision in the coming days.
AZ’s vaccine is safe and effective, according to the data publicly available so far, although it seems that giving a half-dose shot first following a second full dose is more effective.
Just how this will be viewed by regulators is unclear, as are the plans to distribute the vaccine.
With two full doses, efficacy is around 62%, according to findings released towards the end of last month based on data from nearly 9,000 patients in the UK and Brazil.
Efficacy rose to around 90% in just over 2,700 patients given the low dose-high dose formulation, which was stumbled on by mistake because of a manufacturing error.
Quite what the MHRA will make of this is not clear, nor is it known whether the regulator has more up-to-date figures than those announced at the end of November.
Professor Sir John Bell, the government’s life sciences tsar and Regius Chair of Medicine at the University of Oxford, told BBC Radio 4’s Today programme yesterday: “We are getting to be about prime time now.
“I would expect some news pretty shortly, I doubt we will make Christmas now but just after Christmas I would expect.
“And I have no concerns whatsoever, the data looks better than ever.”
AstraZeneca and Amgen looked on course to cruise to approval of their severe asthma drug tezepelumab with a pair of positive clinical trials, but the failure of a third threatens to derail the programme.
The new study – called SOURCE – was supposed to back up the encouraging readouts from the phase 3 NAVIGATOR trial and phase 2b PATHWAY, which found that the antibody benefited asthma patients whose symptoms were so bad they needed oral corticosteroid (OCS) therapy.
SOURCE has changed the script however by missing its primary objective, proving unable to significantly reduce the daily dose of OCS needed by patients in the 150-subject trial, although AZ and Amgen still think the drug is approvable based on the “totality of evidence”.
AZ and Amgen have only released the top-line data, so it could be a while before an explanation for the failure emerges, although AZ’s head of biopharmaceuticals R&D Mene Pangalos suggested it may have resulted from flaws in the trial design.
Just a month ago, AZ and Amgen trumpeted the result of the NAVIGATOR trial of tezepelumab, a first-in-class inhibitor of the cytokine thymic stromal lymphopoietin (TSLP) that analysts have said could have blockbuster potential if approved, perhaps reaching as much as $2.5 billion in annual sales.
NAVIGATOR found that the antibody reduced the asthma exacerbations compared to placebo when added to standard care, and crucially also seemed to have a positive impact on patients with low levels of white blood cells called eosinophils.
Biologics like GlaxoSmithKline’s Nucala (mepolizumab) and AZ’s Fasenra (benralizumab) – both IL-5 inhibitors – and Sanofi/Regeneron’s IL-4 and IL-13 blocker Dupixent (dupilumab) are already approved to treat severe eosinophilic asthma but treatment options are limited for patients with non-eosinophilic forms.
Tezepelumab claimed a breakthrough designation in non-eosinophilic asthma from the FDA in 2018, on the promise that it could provide an option for these patients, who account for around a third of all severe asthma cases.
The drug acts further upstream in the inflammatory cascade than its rivals and so could be effective for a broader range of patients, according to its developers.
AZ and Amgen say they still plan to press ahead with plans for regulatory filings for tezepelumab next year, and will prevent detailed results from NAVIGATOR and SOURCE at a future medical conference.
The two partners started working together on tezepelumab in 2012, and was one of five drugs covered by that alliance. It has previously failed a mid-stage study in atopic dermatitis, but is still in development for that indication as well as chronic obstructive pulmonary disease (COPD).
GlaxoSmithKline has closed the year with a flurry of deals, leaving its development pipeline bulging like Santa’s sack as chief scientific officer Hal Barron pursues a strategy to develop “transformational medicines”.
Barron took over as GSK’s CSO in 2018 under instructions from CEO Emma Walmsley to revamp the company’s flagging R&D effort.
Since then Barron has been busy signing deals for therapies that are validated genetically, hoping that this will make them more likely to succeed in the clinic.
The latest deals include a license agreement with San Diego-based Ligand Therapeutics, which has a subsidiary producing technology for neurological disorders.
This deal involves an upfront payment of $7 million but there is up to $154.5 million on the table if certain development, regulatory and sales goals are achieved.
GSK also announced a deal with Sosei Heptares, based in Tokyo and Cambridge, UK, to discover and develop a small molecule target for inflammatory bowel disease and other gastrointestinal immune disorders.
The Sosei Heptares deal involves an upfront payment and near-term development payment of up to £34 million ($44 million) and potential downstream payments of up to £336 million ($437 million).
These followed two deals late last week – on Thursday GSK made an $85 million licensing agreement with Surface Oncology for an early-stage antibody asset, which adds a natural killer cell approach to the company’s oncology portfolio.
Surface could receive up to $730 million in future milestone payments as well as tiered royalties on global net sales.
The antibody targets PVRIG, an inhibitory protein expressed on natural killer cells (NK cells) and T-cells.
GSK thinks the drug codenamed SRF813 could be used as a monotherapy or in combination with other drugs in GSK’s cancer pipeline targeting CD96 and PD-1.
The license agreement, together with the biotech’s cash reserves, is enough to fund operations through 2023.
And on Friday it announced a multi-year collaboration with UK-based Adestia Therapeutics to discover novel drug targets worth up to £172 million ($230 million).
The Adestia deal is based around the biotech’s “synthetic viability” technology, a concept where diseased cells are “rescued”, which will be combined with GSK’s expertise in human genetics and functional genomics.
BioNTech CEO Ugur Sahin has said that it is “highly likely” the company’s COVID-19 vaccine will work against the more infectious strain circulating in the south east of England, although further studies will be needed.
Sahin was addressing a news conference after the vaccine was approved by the European Union, three weeks after the shot was independently backed by the UK’s regulator.
The variant has caused concern globally, prompting dozens of countries to close travel borders with the UK to prevent it from spreading.
There is no evidence to suggest the new strain causes more serious illness, but it does show variations in the “spike” protein that the virus uses to infect cells – the same protein that the Pfizer/BioNTech shot uses to confer immunity.
Sahin said: “We don’t know at the moment if our vaccine is also able to provide protection against this new variant.
“But scientifically, it is highly likely that the immune response by this vaccine also can deal with the new virus variants.”
Proteins on the UK variant are 99% the same as on the prevailing strains and BioNTech has “scientific confidence” that the vaccine will be effective.
“But we will know it only if the experiment is done and we will need about two weeks from now to get the data,” Sahin said. “The likelihood that our vaccine works … is relatively high.”
It would take around six weeks to adjust the vaccine for the new variant in a worst-case scenario, although regulators would likely have to approve the changes before the vaccines could be used.
The UK Medicines and Healthcare products Regulatory Agency (MHRA) is reportedly close to a decision on a rival vaccine from Oxford University and AstraZeneca and may make a ruling in the coming days.
The MHRA begun a rolling review of the vaccine early in November, around the same time as it began to review Pfizer’s shot.
It is thought the review has been delayed by the range of results produced by the vaccine, after a manufacturing error led to the accidental discovery that an initial half dose of the two-shot vaccine seemed to produce stronger protection.
Feature image copyright BioNTech SE 2020, all rights reserved
Two weeks ago, Vicore reported mid-stage data showing that its lead drug C21 could boost the benefit of steroid therapy in treating COVID-19. Now, it has new data from the trial to back up that promise, and says the drug could act as a “complement” to coronavirus vaccines.
The Swedish biotech’s chief executive Carl-Johan Dalsgaarl said on a conference call that the extended analysis from the ATTRACT trial reinforced earlier data showing that C21 reduced the need for supplemental oxygen and restored lung function in hospitalised COVID-19 patients.
The company is now planning to start a large phase 2/3 trial in the second quarter of next year to try to reproduce the findings in moderate to severe disease requiring hospitalisation – a group where other drugs including Eli Lilly’s antibody bamlanivimab and Gilead’s Veklury (remdesivir) haven’t shown a benefit.
C21 (also known as VP01) is an oral angiotensin II type two receptor (AT2R) agonist that is also being developed for idiopathic pulmonary fibrosis (IPF) and lung complications of systemic sclerosis (SSc), as well as being repurposed for COVID-19.
Two weeks ago, Vicore reported that giving C21 to coronavirus patients reduced the need for oxygen therapy by 40% after seven days’ dosing, which approached but didn’t quite reach statistical significance.
Now, with additional follow-up, it says that at day eight after start of treatment the risk reduction is 57%, which reached significance threshold with a statistical p value of 0.014, below the generally acknowledged threshold of 0.05.
ATTRACT recruited 106 patients, 61 on the study drug and 55 on placebo, who had been hospitalised and on testing showed evidence of severe inflammation – a situation that predicts a poor prognosis – and in almost all cases were on steroid therapy, which has been proven to cut deaths in COVID-19.
At the end of the trial, the effect was even more pronounced with only one patient in the C21 group still needing oxygen…compared to 11 in the placebo group,” Dalsgaarl said.
There was also a statistically significant reduction in C-reactive protein, a marker of inflammation – although only in the group needing oxygen and not the entire C2 group – as well as trends towards a reduce need for mechanical ventilation and a lower death rate.
Vicore now plans to follow up patients for 24 weeks to see if the drug can have an impact on longer term lung injury.
C21 is thought to normalise gas exchange in the lung cells, restoring their function, according to Dalsgaarl.
“The critical incident in COVID-19 that makes this disease different to a common cold is the progression to the distal airways with respiratory distress and subsequent need for oxygen supplementation”, said Dalsgaard.
“Our data clearly show that C21 can restore lung function on top of steroids and normalise gas exchange.”
Moreover, with a new strain in the UK raising fears that the virus may start to elude current therapies, there could be advantages for a drug that bypasses the virus to work on the lung itself.
Vicore is also intrigued by the possibility of using C21 as an oral treatment that can be used as an outpatient therapy for milder disease, potentially reducing the need for hospitalisation, that could be used in conjunction with immunisation programmes.
It would like to look at that in a second phase 2/3 trial but acknowledges it may need a larger partner to take that forward.
There was a time, before 2020, when most of the clinical trial start-up and nearly all clinical trial training was done in person. Remember those days? Unfortunately, that work also made up a huge budget line item – with the average price tag for big meetings (like a series of global investigator meetings) coming in […]
Moderna and BioNTech, two rising stars in biotech, were in the limelight this year with their pioneering mRNA vaccines against COVID-19. Just who are these companies and who is behind them, asks Richard Staines.
A year ago, the names Moderna and BioNTech were known mainly to those who followed biotech and pharma dealings.
But the tragic events of 2020 have meant these companies have become household names as their trailblazing mRNA vaccines became the first to be approved by regulators against the COVID-19 scourge.
Compared with many of the established names in pharma these companies are young upstarts but they have managed to achieve what other big names in the industry have failed to do and harness the power of mRNA to make medicine.
Their technology is based on synthetic messenger RNA – short for ribose nucleic acid – which is a short transcript of a longer DNA code.
As it’s just a messenger molecule, it does not affect the body’s own genetic code when it is injected as a vaccine – but what it does do is instruct cells to code for copies of a certain protein.
In this case that is the “spike” protein seen on the surface of the coronavirus that it uses to invade host cells.
The body produces antibodies against the protein, which neutralise the virus in the event of an infection.
It’s a revolutionary approach that allowed the vaccine to be made within a few days of the SARS-CoV-2 genetic code becoming available – what’s taken months are the rigorous clinical trials that proved the vaccines were safe and effective.
There has been considerable anxiety over whether using such an untried technology would be the best approach against COVID-19.
What the companies have now proved is that the technology can be used to make safe and effective vaccines in record time.
The companies are based on opposite sides of the Atlantic – Moderna was founded in Massachusetts in 2010 under the name ModeRNA Therapeutics by a team of investors two years after BioNTech began operating from a small lab in Mainz, Germany.
But both drew on the mRNA technology developed by Katalin Kariko from the University of Pennsylvania and her collaborator Drew Weissman, an immunologist from Boston University.
Together the pair had managed to find a way to get the human body to accept strands of mRNA without an immune reaction, by tinkering with the chemical make-up of the molecule.
It was a landmark discovery that meant a technology once derided as being a pipe dream could have applications in the real world as a medicinal therapy.
Moderna’s founders were led by Derrick Rossi, a post doctorate fellow from Stanford University who championed the technology to a team from Flagship Ventures, a Massachusetts firm founded and run by Noubar Afeyan.
CEO Stephane Bancel was hired the following year from France’s bioMerieux and Moderna went on to raise more than $2.6 billion in a series of private funding rounds, while fiercely guarding any details about the technology it was developing.
This changed in 2018 when Moderna went public with what was at that time the largest IPO in biotech history.
The launch raised $500m from investors using what is arguably the slickest stock market ticker out there – MRNA.
Its portfolio of products was broad – including a drug being developed with AstraZeneca for cardiovascular diseases, a cancer immunotherapy and a potential Zika vaccine.
“I was intrigued by the personalities of the founders. They are very good doctors, scientists and entrepreneurs. Whatever they were beginning they did it with the end in mind.”
While Moderna blazed its investment trail and tried to find ways to make sure its mRNA vaccines did not produce dangerous immune reactions, a small biotech called BioNTech had licensed in the technology from Kariko and Weissman.
Run by husband-and-wife team Ugur Sahin and his wife Ozlem Tureci, BioNTech wanted to use the technology to create individualised cancer therapies.
Matthias Kromayer, a general partner at the German investment fund MIG that helped found BioNTech in 2008, said he first met the pair 15 years ago and was immediately intrigued.
He told pharmaphorum: “They are very good doctors, scientists and entrepreneurs. Whatever they were beginning they did it with the end in mind.”
The company began to strike several deals with big pharma companies to develop cancer drugs and in 2013 hired Kariko, who had spent years working on mRNA at Penn, to oversee the mRNA work as senior vice president.
Fast-forward to the beginning of 2020 and the companies realised that they would have to quickly change their research priorities to vaccine development as the coronavirus pandemic began to emerge in China.
Kromayer said the risks and opportunities to take on the coronavirus vaccine challenge were huge for BioNTech, which only went public on the Nasdaq at the end of 2019.
He said: “It was a risk – if (the vaccine) had failed it would have shed negative light on mRNA tech. But it was a once in a lifetime opportunity.”
But according to Kromayer the BioNTech team were confident that mRNA was the solution to the coronavirus problem, as mRNA sequences can be generated in such a short amount of time.
“You can manufacture mRNA vaccine overnight and still it is stable,” said Kromayer.
The rest is history – Pfizer stepped in and licensed the technology, choosing the most promising of four potential mRNA vaccines from BioNTech.
Both Moderna and Pfizer’s shots aced the quickly convened clinical trials and became the first vaccines to make it to market less than a year after the pandemic began.
Thanks to the innovation there are hopes that peoples’ lives may return to normal as 2021 progresses but according to Kromayer this is just the tip of the iceberg for mRNA therapeutics.
The founders of both Moderna and BioNTech realised early on that this is far more than just a vaccine and could be used to tackle diseases that have proved impossible to tackle with the previous generations of medical technology.
Rossi, who left Moderna in 2014 had initially thought it could be used to reprogramme cells to act like stem cells but realised its potential after a bruising encounter with Robert Langer, the legendary MIT scientist and entrepreneur.
According to Kromayer potential uses include pre-emptive vaccines for diseases such as Parkinson’s as well as to create personalised cancer therapies.
Kromayer concluded: “The message is that mRNA based medicines are not just here to serve as vaccines it is much, much, more. This will revolutionise medicine over the next 10-15 years in areas we do not even imagine.”
The FDA is looking to quickly approve Moderna’s COVID-19 vaccine after it was unanimously backed by a panel of experts.
Yesterday’s advisory panel meeting voted 20-0 in favour of approving Moderna’s vaccine and although the vote is non-binding, you could probably bet your house on the FDA backing the shot as it rarely goes against the advice of its experts after such strong backing.
The vaccine was also given a glowing review by FDA staffers in a briefing document posted ahead of the meeting and looks set to become the second COVID-19 vaccine to hit the US market after Pfizer/BioNTech’s rival was approved last week.
Pfizer’s vaccine was approved within a day of a positive vote from the Vaccines and Related Biological Products Advisory Committee.
Roll-out of the Pfizer vaccine has already begun and FDA commissioner Stephen Hahn said the agency will work “rapidly” towards issuing an Emergency Use Authorization for Moderna’s shot.
The US has agreed to buy 200 million doses and there are six million doses ready move to ship as soon as the vaccine is officially approved.
Yesterday’s panel vote heard that the vaccine worked in 94% of cases, based on clinical data gathered so far, and is safe.
It is also slightly easier to move around – although it is an mRNA-based shot like Pfizer the storage temperature is around -20C, considerably less demanding than temperatures of around -75C required to maintain the integrity of its already-approved rival.
Moderna’s vaccine is also given in two shots, with the injections four weeks apart compared with the three-week interval required for Pfizer’s.
The UK has also pre-ordered seven million doses of the Moderna vaccine, which is also being reviewed by the country’s regulator the Medicines and Healthcare products Regulatory Agency (MHRA).
Canada also plans to get two million doses by March, part of a total 56 million doses ordered from Moderna.
The European Union has also announced a contract to buy 80 million doses and an option to buy 80 million more once the vaccine is formally approved.
Trials of a fifth COVID-19 vaccine have begun in the UK, as IT issues threaten to delay the roll-out of the shot from Pfizer/BioNTech.
France’s Valneva begun the phase 1/2 clinical study of the inactivated vaccine candidate VLA2001 in sites across the UK, supported by the National Institute for Health Research (NIHR).
It is the first publicly announced inactivated COVID-19 vaccine candidate to begin clinical development in Europe.
The vaccine is based of inactivated viruses grown in culture and includes an adjuvant used to boost the immune response.
Primary endpoint read-out will be two weeks of completion of the immunisation given in two doses, 21 days apart.
Valneva plans to include more than 4,000 participants in additional trials, which it believes could support an initial regulatory approval in the fourth quarter of 2021.
But the two-dose schedule being used by many of the vaccines is proving to be a stumbling block as the shot is rolled out across the UK.
It’s vital to track who received the vaccine and when, so they can be called in for the second booster shot at the right time.
But according to Sky News GP practices have been forced to collect data on the rollout of the vaccine shot by hand.
This follows problems with the software being used to keep track of who has been given the jab.
Citing a senior health official, Sky said that the IT system used was “failing constantly” and that GPs were “having to record on paper and then transfer”.
Vaccine minister Nadhim Zahawi tweeted what the Department for Health Social Care described as “provisional figures” on how many people had received the vaccine on Wednesday morning.
The official said GPs were not able to find out who had already been vaccinated by a hospital, causing delays as checks were made and raising the risk people might get missed, or even vaccinated twice.
In the US, advisers to the FDA are to meet later today in a vote that will inform whether Moderna’s rival vaccine should get an Emergency Use Authorization.
The vote from the Vaccines ands Related Biological Products Advisory Committee is non-binding but the FDA usually follows the advice of its experts.
FDA staffers have already given the vaccine a glowing review ahead of the meeting.
According to the World Health Organization, there are 52 candidate vaccines in clinical development, and 13 have made it through to phase 3 trials.
Novartis is to buy neuroscience drugs firm Cadent Therapeutics in a deal worth up to $770 million.
The big Swiss pharma already has a presence in neurology with its multiple sclerosis drug Gilenya (fingolimod) and the more recently approved Aimovig (erenumab).
With the acquisition of Cambridge, Massachusetts-based Cadent, Novartis gains rights to a portfolio of neurology drugs.
This includes CAD-9303, a NMDAr positive allosteric modulator that could be used to treat schizophrenia, and MIJ-821, a NMDAr negative allosteric modulator for depression that was licensed to Novartis in 2015.
MIJ-821 is already in phase 2 development for treatment-resistant depression in a trial overseen by Novartis and the acquisition includes a buyout of milestones payments and royalties for the drug.
Gopi Shanker, the interim co-head of neuroscience at the Novartis Institutes for BioMedical Research (NIBR), added: “There is good evidence, both from human genetics as well as clinical studies, that NMDA receptors, which regulate learning, memory and plasticity in the brain function sub-optimally in schizophrenia.
“By modulating the activity of these receptors, we think CAD-9303 could potentially treat negative and cognitive symptoms and help address one of the key gaps in schizophrenia care.”
Additionally, Novartis will gain full rights to CAD-1883, a clinical stage SK channel positive allosteric modulator in development for movement disorders.
Cadent, which launched in 2017 through the merger of Luc Therapeutics and Ataxion Therapeutics, will receive $210 million up front, and up to $560 million in milestone payments.
No other financial details were disclosed.
Cadent said that its pipeline of drugs could also be used to treat indications such as movement disorders.
The transaction has been approved by the board of directors and stockholders of Cadent Therapeutics. Cadent and Novartis expect the transaction will close during the first quarter of 2021.
Closing of the transaction is subject to customary closing conditions, including antitrust review under us antitrust laws.
Investors in Cadent include Atlas Venture, Cowen Healthcare Investments, Qiming Venture Partners, Access Industries, Clal Biotechnology Industries, Novartis Corporate and Slater Technology Fund.
UK-based EUSA Pharma has begun a late-stage trial of its antibody siltuximab in COVID-19, hoping that the IL-6 inhibitor will succeed where class rivals from Roche and Sanofi/Regeneron have failed.
Hertfordshire-based EUSA said recruitment has begun in phase 3 trial involving patients with COVID-19 previously treated with corticosteroids and other respiratory viruses associated with serious respiratory complications.
This pivotal study is designed to confirm results from the smaller SISCO study that investigated siltuximab plus standard of care in COVID-19 patients with serious respiratory complications.
Primary outcome of the SILVAR study will be all-cause 28-day mortality.
Siltuximab is an IL-6 inhibiting drug that was originally developed and marketed by the Johnson & Johnson’s Janssen unit for the rare disorder idiopathic multicentric Castleman’s disease.
EUSA Pharma bought global rights to the drug from Janssen in $115 million.
Roche and Sanofi/Regeneron have already tried to alleviate symptoms with their respective IL-6 drugs, Actemra (tocilizumab) and Kevzara (sarilumab), but trials did not produce supportive results.
EUSA said that unlike previous studies of agents targeting the IL-6 signalling pathway, the SILVAR study has been rationally designed to select those hospitalised patients still suffering from serious viral acute respiratory distress syndrome (ARDS).
Patients selected will be in a hyperinflammatory state that will most likely benefit from the addition of an immunomodulator, such as siltuximab.
Respiratory failure from ARDS is the leading cause of mortality in patients with COVID-19.
Siltuximab binds to and neutralises IL-6, a chemical signal in the body that is recognised as a key driver of ARDS in COVID-19 and other respiratory infections.
The SISCO trial earlier this year in COVID-19 compared 30 patients treated with siltuximab with 30 matched controls, and showed that treatment with the drug led to a 54% reduction in risk of 30-day all-cause mortality.
EUSA Pharma’s CEO Lee Morley said: “This clinical trial represents an important step in finding a solution for hospitalised patients with serious respiratory complications due to an over reactive immune response to (coronavirus) infection that is not fully responsive to corticosteroid therapy, as well as those with any other respiratory virus infection associated with serious ARDS.”
Feature image courtesy of Rocky Mountain Laboratories/NIH
In the last few years, biopharma companies focusing on psychedelic medicines have been springing up like mushrooms – magic or otherwise – and venture capital money is starting to follow.
Today sees the launch of the first investment fund in the UK devoted to psychedelic healthcare, with plans to invest in “revolutionary mind-altering medicines to treat illnesses including depression, addiction, anxiety and inflammation.”
The fund has been set up by London-based VC Neo Kuma Ventures, a new group formed by Sean McLintock, Clara Burtenshaw and Nick David in 2019. The co-founders say it has already attracted “millions of pounds” in investment, and will continue to draw funds through the first half of next year.
Last year Neo Kuma’s founders backed ATAI Life Sciences AG, a part owner of Compass Pathways, which is a UK-based company trying to develop medicines based on a synthetic version of psilocybin, the main psychoactive constituent in magic mushrooms.
In September, Compass became the first psychedelic medicine company to float on the Nasdaq, raising $127 million, and is now trading at a market cap of $1.98 billion.
Shortly after, US biotech Mind Medicine – already trading publicly on Canada’s Neo exchange – applied for a Nasdaq up-listing as it advances a suite of psychedelic medicines based on MDMA, LSD and ibogaine derivative 18-MC. It is going after disorders like anxiety, opioid addiction and adult attention-deficit hyperactivity disorder.
Around the same time, Toronto-based Field Trip Psychedelics went public on Canada’s CSE after it completed a reverse takeover of oil and gas company Newton Energy Corp, which followed an CAD 12 million private placement deal.
As well as offering ketamine-assisted treatment clinics, the company is also working on FT104, a novel synthetic hallucinogen for mental health disorders. Meanwhile, other players in the sector include Cybin – which has just acquired rival Adelia Therapeutics for just under $16 million – as well as Numinus Wellness and Verrian Ontario.
Data Bridge Market Research published report earlier this year suggesting that the psychedelic drugs market is projected to grow at around 16% per year over the next eight years to reach $6.85 billion in 2027, spearheaded by new therapies like Johnson & Johnson’s Spravato (esketamine) for treatment-resistant depression.
NeoKuma draws parallels with the medicinal cannabis market, citing research which suggests that in the US it has surged from around $2 billion in 2014 to an estimated $35 billion this year.
“As the medical benefits of psychedelics become more well-known and regulators steadily increase their embrace of these types of drugs, the industry is set for a boom,” says McLintock.
“While much of the conversation on psychedelics is taking place in the US, Europe is the true hub of the burgeoning psychedelic healthcare sector. We look forward to investing in the most exciting, high quality and scientifically-sound European players in the industry to facilitate their ground-breaking research.”
Episode four of Kantar Health’s Health Heroes podcast tackles pharma’s rare disease challenges, the role of patient registries and hears a moving story about the rare genetic disorder Tay-Sachs disease.
Joining me for this instalment of Health Heroes are Geneviève Bonnélye-Fesnien, global head of real-world evidence, research and consulting at Kantar Health, and Dan Lewi, co-founder of The Cure & Action for Tay-Sachs (or CATS) Foundation.
Dan’s eldest daughter Amelie was diagnosed with Tay-Sachs in 2011 at 15 months of age and he shares the emotional story of caring for her and how that led to setting up The CATS Foundation.
This episode of the podcast also looks at how the GM2 Disease Registry, managed by The CATS Foundation with support from Kantar Health, and it will help both patients and the pharma companies working on treatments for them.
The podcast finishes up with an overview from Geneviève on the current outlook for rare diseases.
The Health Heroes podcast series aims to inform and educate life sciences companies on ways for getting closer to patients to help drive improved health outcomes.
The 9th Neurodegenerative Drug Development Summit is the industry’s definitive and unrivalled forum focused on revealing hot and promising pockets of innovation in drug discovery for neurodegenerative diseases and combating translational challenges by shining a light on pioneering companies leading the way to meet this dire medical need.
Building on the success of last year’s meeting, this year’s program showcases new biotechs trailblazing this space and will put the spotlight on the latest scientific in diverse targets, novel modalities and innovative trial design. Hear from our expert speakers from the likes of Sanofi, Alzheon, European Medicines Agency, Lundbeckand Alector.
Across 3 action-packed, case-study driven days and 2 parallel tracks of content, we present the opportunity to join us online in 2021 to overcome technical and operational challenges preventing you and your team from translating promising preclinical research into evidenced clinical benefit.
Whether you are working in a team dedicated to Parkinson’s, Alzheimer’s, ALS, Frontotemporal Dementia or a rare neurodegenerative disorder, join this intimate, industry-led forum to not only to learn from those spearheading this space, but to network and build meaningful partnerships with over 180 neurodegenerative drug development experts. After all, collaboration in this industry is pivotal.
AbbVie is to begin clinical development of an antibody designed to neutralise the SARS-CoV-2 coronavirus after licensing the therapy in from Harbour BioMed and Utrecht University.
In a joint statement, the biotech and the university said that the antibody, dubbed ABBV-47D11, will be developed for prevention and treatment of COVID-19 and related coronaviruses.
AbbVie has begun a phase 1 clinical trial of the antibody, with clinical development beginning in the US and expanding into Europe.
The antibody has been developed by Harbour using transgenic mice, which enabled the quick discovery and development of several candidates.
From these ABBV-47D11 was selected because of its cross-reactive neutralising nature.
The antibody targets a conserved region of the SARS-CoV-2 spike protein and has been developed through a collaboration between Harbour (HBM) and Utrecht University (UU).
The license agreement will help advance the development of ABBV-47D11, which in pre-clinical research demonstrated potential against SARS-CoV-2, as well as the related SARS-CoV-1 virus that caused an outbreak in Asia in 2003.
AbbVie will conduct clinical development of ABBV-47D11, and if successful, will manufacture and market the product worldwide.
AbbVie will pay HBM and UU an undisclosed one-time license fee and will also make payments upon achievement of certain development, regulatory and sales-based milestones.
The pharma will also pay tiered royalties on commercial net sales of the antibody.
Erasmus University Medical Center, based in Rotterdam, Netherlands, was involved in the fundamental science but is not involved in the license agreement.
The phase 1 trial will be a randomised, double-blind, placebo-controlled, study to evaluate the safety, pharmacokinetics, and pharmacodynamics of single ascending doses of ABBV-47D11 in adults hospitalized with COVID-19.
The antibody will be tested in three different doses on 24 patients across global study sites to evaluate study-drug related adverse events as primary endpoints, and several other secondary outcomes.
Regeneron and Eli Lilly have been leading the charge to develop antibody-based therapies against the coronavirus.
Regeneron’s cocktail, REGN-COV2 and Eli Lilly’s bamlanivimab have emergency approvals from the FDA and AstraZeneca has begun clinical development of its rival antibody cocktail last month.
Harbour BioMed is a clinical-stage biotech specialising in antibody therapeutics with operations in Cambridge, Massachusetts; Rotterdam, The Netherlands; and Suzhou and Shanghai, China.
Feature image courtesy of Rocky Mountain Laboratories/NIH
Eli Lilly has acquired Prevail, a biotech focusing on gene therapies for neurodegenerative diseases including Parkinson’s, in a deal potentially worth more than $1 billion.
The big US pharma is to pay up to $1.04 billion to buy Prevail, paying $22.5 per share up front plus a $4 contingent value right (CVR) to sweeten the deal.
The CVR pays out if one of Prevail’s gene therapies is approved in one of several developed countries before December 31, 2024.
Prevail is working on gene therapies based on adeno-associated virus 9 (AAV9) technology, which must be approved in any of the group of countries comprising the US, Japan, UK, Germany, France, Italy, or Spain.
Lilly pointed out that there can be no assurance of payouts from the CVR – something that shareholders in other companies have found out the hard way.
Sanofi last year settled with holders of a CVR dating back to the French pharma’s acquisition of Genzyme that was contingent on MS drug Lemtrada achieving several goals – cash that never materialised.
And former Celgene shareholders are currently sweating over a CVR relating to three cancer drugs that looks increasingly unlikely to pay out because of delays with FDA reviews.
The acquisition is set to close in the first quarter of 2021 and will see several gene therapies added to the company’s pipeline.
Top of the list is PR001, a potentially disease-modifying single-dose gene therapy for Parkinson’s disease with GBA1 mutations (PD-GBA) and the rare condition neuronopathic Gaucher disease (nGD) that is injected into a gap at the base of the brain stem.
The phase 1/2 PROPEL clinical trial in PD-GBA is ongoing and the phase 1/2 PROVIDE trial in nGD has been granted Fast Track Designation in these indications.
Also in the pipeline is PR006 for patients with frontotemporal dementia with GRN mutations (FTD-GRN), also delivered by an injection in the same place.
This is being tested in the phase 1/2 PROCLAIM trial, where the first patient was dosed earlier this month.
Prevail is also developing PR004 for neurodegenerative diseases associated by the abnormal accumulation of alpha-synuclein protein in neurons, nerve fibres or glial cells.
It is also working on therapies for Alzheimer’s and amyotrophic lateral sclerosis (ALS).
Lilly’s CEO David Ricks is pursuing a policy of “bolt-on” acquisitions to add to the company’s pipeline, and scooped up dermatology specialist Dermira in a similar-sized deal at the beginning of the year.
Denmark’s MinervaX has raised €47.4 million (around $56 million) in a Series B funding round to take its novel group B streptococcus (GBS) vaccine into mid-stage clinical trials.
When and if the pandemic finally recedes there will still be an ongoing issue with a dearth of new antibiotics and a growing number of bacterial strains resistant to existing antibacterial medicines.
MinervaX is one company that wants to change this situation, which aims to prevent the spread of GBS infections using a vaccine instead of using an antibacterial agent.
On the back of phase 1b data the Copenhagen-based biotech said it had brought in new investors Sanofi Ventures, Adjuvant Capital and Industrifonden along with existing investors Novo Holdings, REPAIR Impact, Sunstone Life Science Ventures and LF Investment.
Proceeds will advance the clinical development of MinervaX’s novel GBS vaccine through phase 2 clinical trials, as well as manufacturing and regulatory preparation for phase 3.
GBS is responsible for nearly half of all life-threatening infections in newborns. MinervaX’s protein-only GBS vaccine targets pregnant women for the prevention of adverse pregnancy outcomes and life-threatening neonatal infections associated with GBS.
Globally, 15-25% of women are colonised with GBS, and they run the risk of transmitting the bacteria to their child in utero, during birth and / or during their first months of life.
GBS colonisation may lead to late-term abortions, premature delivery or stillbirth; and in newborn children may result in sepsis, pneumonia or meningitis, all of which carry a significant risk of severe morbidity, long-term disability or death.
The only preventive strategy available involves using intravenously delivered antibiotics and this does not comprehensively prevent infection in utero or reliably protect against late-onset infection in newborns.
Phase 1 data from 300 healthy females have so far shown a favourable safety profile, while generating high levels of long-lasting antibodies.
These are capable of mobilising the immune system against GBS bacteria and preventing invasion of epithelial and endothelial cell barriers.
Work began on a potential streptococcus vaccine in the 1980s and in 1996 a phase 1 trial provided a proof of concept that using polysaccharides and antigens from GBS could provide a strong enough immune response.
But there have been no GBS vaccines licensed since then, the Lancet pointed out in an editorial earlier this year.
What happens when you combine the power of industry-leading evidence generation with cutting edge tele-research capabilities? Meet VirTrial, a Signant Health company. https://bit.ly/virtrial Discover an unparalleled platform to digitally enable your research sites across any trial method you want: traditional, remote or hybrid. Tap into a large network of VirTrial certified sites across 46 countries, […]
As the first microbiome-based therapeutic steps closer to market approval, the scientific community continue to demonstrate the functional role of the human microbiome as a novel source of therapeutic, biomarker and diagnostic development. Despite this progress, the vast potential to develop effective treatments that target the human microbiome is still limited by the complex challenges in developing them.
Part of the foremost conference series for microbiome researchers in industry, the 5th Microbiome Movement – Drug Development Europe 2021 will return to unite leading scientists from the biopharmaceutical and academic community to pursue the causal role of the microbiome in disease, and help create a new generation of microbiome-targeted therapeutics with predictable modes of action and consistent clinical outcomes.
Over three jam-packed days of case-studies, discussion and debates, this year’s event will shine a light on how industry and academic leaders are understanding microbiome functionality across key therapeutic modalities, leveraging big data platforms to deduce causality, and overcoming regulatory, clinical and manufacturing hurdles to further accelerate their pipeline across new disease targets.
So whether you’re part of a microbiome-focused biotech, a pharmaceutical organization assessing this exciting field, or an academic researcher with breakthrough findings, join the Microbiome Movement as we explore the global advances in translational microbiome research, and meet like-minded peers who are continuing to understand the causal and therapeutic potential of the ‘second genome’.
Novartis/Incyte’s Jakafi (ruxolitinib) looks unlikely to be added to the list of therapies that can be used against COVID-19, after it failed to cut complications or death in a phase 3 trial.
Data from the phase 3 RUXCOVID study showed that there was no significant reduction in the proportion of COVID-19 patients on ruxolitinib plus standard therapy experiencing severe complications, compared to standard care alone.
Severe complications included death, respiratory failure requiring mechanical ventilation or admission to intensive care.
RUXCOVID is a 29-day placebo-controlled trial testing ruxolitinib in 432 patients aged 12 years or over in patients hospitalised for COVID-19 and not intubated or receiving intensive care before randomisation.
Results were measured against a composite primary endpoint of patients who died, developed respiratory failure requiring mechanical ventilation, or required admission to ICU by day 29.
But the proportion of people meeting this endpoint was almost identical in the two groups – 12% for those treated with ruxolitinib and 11.8% for those treated with placebo plus standard care.
Patients were randomised 2:1 to receive ruxolitinib twice daily or oral-matching placebo for 14 days, with standard therapy decided according to the investigator’s clinical judgement.
Ruxolitinib is already FDA approved under the brand name Jakafi to treat the bone marrow diseases myelofibrosis, polycythemia vera and graft-versus-host disease.
Trials of the drug in other indications are not affected by the outcome, Novartis said.
The drug is an oral inhibitor of JAK 1 and JAK 2 tyrosine kinases and the rationale behind the trial was to investigate whether the down regulation of the immune system conferred by the medicine would reduce the inflammation caused by COVID-19.
Originally developed by Incyte, Novartis licensed in the drug for development and marketing outside the US.
The RUXCOVID trial is sponsored by Novartis outside of the US and by Incyte inside the US.
Many drugs are being trialled against COVID-19, with the cheap steroid dexamethasone producing some of the most promising trial results.
Although Gilead’s Veklury (remdesivir), an antiviral originally intended to treat Ebola, is approved in the US to treat COVID-19 the World Health Organization has recommended against using it because of differing interpretations of trial results.
ERT, a clinical services firm with expertise in digital technology is to merge with clinical imaging firm Bioclinica.
The companies said that the combination will strengthen their offering to pharmaceutical and biotech companies.
The transaction will integrate Bioclinica’s expertise in imaging with ERT’s expertise in electronic clinical outcome assessment, cardiac safety, respiratory and wearables.
The combined company will deliver data analytics, insights, business intelligence, virtual patient visits and hybrid technological solutions.
No financial details were disclosed but the transaction is subject to customary closing conditions, including approval by regulatory agencies. ERT and Bioclinica expect the transaction to close next year.
The acquisition follows the appointment of Joe Eazor as president and CEO of ERT in October, replacing Jim Corrigan who is moving on after seven years in charge.
Eazor said: “As our customers continue to transform their R&D operations, we must continuously deliver a breadth of innovative technology and services.
“Our merger with Bioclinica will allow us to continue to reinvent end-point data collection by delivering higher-fidelity data and more integrated solutions to achieve our customers’ goals for higher effectiveness, greater efficiency, safer trials, and more patient-centric virtual solutions.”
Speaking to pharmaphorum, he said these transformations include a greater focus on how to run strong virtual and remote trials while at the same time delivering a better patient experience.
“People are realising now just how effective remote trials can be – and that they have great benefits for patients in helping them participate in studies.
“I don’t believe we’ll ever completely go back to the way things were; trials will become increasingly virtual over the next few years.”
But Eazor added that the merger was not driven by COVID trends but by the new opportunities open to a combined company.
“Our interest in Bioclinica is in the ability to develop a broader and deeper set of capabilities, with both of us able to work on integrated, consistent solutions in a number of different areas. It’s a strong strategic rationale that goes beyond what’s happening with the pandemic.
“The most exciting aspect is that it will give us sizable scale capabilities to invest in ways we wouldn’t have been able to accomplish as two separate companies.”
Joe Eazor will be the CEO of the newly merged company and the management team will be composed of a combination of both ERT and Bioclinica executives.
In June ERT acquired ADPM Wearable Technologies amid a growing interest in using wearable sensors and handheld devices to collect clinical data during the pandemic.
The logic behind that acquisition is to improve data collection in neurological diseases such as Parkinson’s disease, Multiple Sclerosis and Ataxia.
Data collection using conventional methods relies on episodic visits making trials extremely expensive.
Using wearables technology such as that developed by ADPM could provide precise motion data and allow companies to use novel clinical endpoints.
2020 has been comparatively quiet for mergers in the clinical services sector as contract research organisations busied themselves supporting research into COVID-19 therapies and vaccines.
Genesis Drug Discovery and Development, a member of the Genesis Biotechnology Group bought California’s Comparative Biosciences in August.
Sanofi and GlaxoSmithKline have said their COVID-19 vaccine has hit a snag in clinical development, prompting analysts to note this could delay delivery of potentially more than a billion shots globally by up to nine months.
Interim results from a phase 1/2 clinical trial show the immune response from Sanofi/GSK’s vaccine produced a lower immune response in older adults.
While antibody levels were comparable to those seen in recovering COVID-19 patients in adults aged 18-49, the response was lower in older adults.
This was likely due to an insufficient concentration of the antigen, according to a team of analysts from Jefferies investment bank, who said the companies have decided to investigate an improved formulation.
This demonstrated rapid viral clearance in a challenge study in non-human primates.
A phase 2b study is expected in February next year with support from the US government agency, the Biomedical Advanced Research and Development Agency (BARDA).
This could lead to a phase 3 study next summer and an authorised product at the end of next year delaying deliveries of potentially more than a billion shots, enough to protect half a billion people.
The US government has an agreement to buy 100 million doses, with an option for another 500 million doses and has funded development to the tune of $2.1 billion.
The European Commission has an agreement for 300 million doses, the UK has ordered 60 million doses and the Canadian government has ordered 72 million doses.
AZ to combine vaccine with Russian rival
In a separate development it has emerged that AstraZeneca is to test its whether its COVID-19 vaccine can be combined with a component used in Russia’s Sputnik V shot, according to a statement the government-backed Russian Direct Investment Fund (RDIF).
Clinical trials so far have shown that Sputnik V, which uses two different types of viral vector to produce an immune response, provides protection in around 90% of cases.
The RDIF, which has helped bankroll the vaccine, said AZ had accepted a proposal to begin trials of its AZD-1222 in combination with Sputnik V’s human adenoviral vector type Ad26 by the end of the year.
AZ has already announced findings suggesting that using an initial lower dose of the vaccine produces a protection level of around 90%, while using two maximum strength doses produced protection levels of just over 60%.
The idea behind Sputnik V, developed by a team of scientists from Moscow’s Gamaleya Center, is to use two shots using different viral vectors to reduce the risk of the body developing resistance and not producing a boosted immune response to the second booster shot.
AZ’s vaccine, developed in partnership with Oxford University, looked like one of the most promising vaccine candidates until it was hit with a safety scare that caused trials to be put on hold for a few weeks in September.
While regulators later decided that trials could continue, the announcement that researchers had accidentally stumbled on the low-dose high-dose combination did not go down well and caused the company’s share price to tumble.
Advisers to the FDA have voted in favour of approving Pfizer and BioNTech’s COVID-19 vaccine, with a near-unanimous backing from an expert committee.
While the decision of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) is non-binding, the FDA seldom goes against the ruling of its advisers when making regulatory decisions.
However has were some concerns raised, reflected in the 17 to 4 vote in favour of approval.
Some experts in the public meeting were concerned about the short length of the human trial so far as well as the potential side-effects for people with allergies or pregnant women.
Already approved in the UK, this is the first time that mRNA technology has been used to create a vaccine.
There were also concerns about whether the vaccine should be used in 16-17 year-olds because of a lack of safety data in this group, balanced against the fact people from this age group are unlikely to fall seriously ill.
The committee also considered two cases of allergic reactions seen in the UK this week and has asked Pfizer to monitor for severe allergic reactions.
This may lead to further advice on the label of the vaccine if the FDA decides to go ahead with the Emergency Use Authorization that Pfizer is asking for.
The phase 3 data demonstrated a vaccine efficacy rate of 95% in participants without prior SARS-CoV-2 infection (first primary objective) and also in participants with and without prior SARS-CoV-2 infection (second primary objective), in each case measured from seven days after the second dose.
Pfizer pointed out that the Data Monitoring Committee for the study has not reported any serious safety concerns related to the vaccine.
Efficacy was consistent across age, gender, race and ethnicity demographics. All trial participants will continue to be monitored for an additional two years after their second dose to assess long-term protection and safety.
The US government’s coronavirus vaccine chief has said that Pfizer/BioNTech’s vaccine could carry a warning that it should be avoided by people who are prone to serious allergic reactions.
Moncef Slaoui, co-head of the US government’s Operation Warp Speed COVID-19 vaccine programme, made the comments after the UK drugs regulator advised those with severe allergies to avoid the vaccine.
According to press reports, Slaoui expects an influential FDA advisory committee to say today that people with severe allergies “should not take the vaccine until we know exactly what happened.”
According to the UK’s Medicines and Healthcare products Regulatory Agency (MHRA), people with a “significant history of allergic reactions” should avoid the shot.
This followed two NHS staff members, who both carried adrenaline auto-injectors and had a history of allergic reaction, developing an anaphylactoid reaction after receiving the vaccine on Tuesday.
These individuals developed symptoms of anaphylactoid reaction – a milder reaction than a severe anaphylactic shock – shortly after receiving the vaccine. Both recovered after appropriate treatment.
Professor Stephen Powis, national medical director for the NHS, said in a statement: “As is common with new vaccines the MHRA have advised on a precautionary basis that people with a significant history of allergic reactions do not receive this vaccination after two people with a history of significant allergic reactions responded adversely yesterday. Both are recovering well.”
It’s an issue that’s also likely to come up at today’s meeting of US vaccine experts, who are advising the FDA on whether to go ahead with an Emergency Use Authorization for the shot.
FDA reviewers have already concluded that the vaccine is safe and effective in a briefing document ahead of the Vaccines and Related Biological Products Advisory Committee’s meeting.
The committee will meet in public to discuss the shot and although the FDA is not bound to follow its advice, the regulator usually follows its experts’ advice when making decisions on drugs.
The regulator has run its own analysis of the vaccine and concluded there was a “slight numerical imbalance”, with more adverse events representing allergic reactions in those taking the vaccine compared with the placebo group.
There were 137 people reporting hypersensitivity-related adverse events in the vaccine group and 111 in the placebo group, according to the analysis in the briefing document.
This represented a tiny fraction of the 38,000 people tested in the phase 3 trial at the time of data read-out although the trials so far have excluded people with histories of allergic reactions.
Feature image copyright BioNTech SE 2020, all rights reserved
Eli Lilly’s decision to throw large amounts of research dollars at its next-generation diabetes drug tirzepatide could be vindicated, according to its first phase 3 trial readout.
Results from the phase 3 SURPASS trial showed tirzepatide led to a reduction in both blood sugar and body weight in adults with type 2 disease, compared with placebo.
Shares in the big US pharma were up nearly 6% following the announcement, although the pharma stocks in general were buoyed by optimism over BioNTech/Pfizer’s COVID-19 vaccine.
Lilly said that the highest dose of tirzepatide monotherapy led to a blood sugar reduction, measured by A1C, 2.07% and reduced body weight by 9.5kg (11%) after 40 weeks of treatment.
More than half (51.7%) of participants in the treatment arm achieved an A1C less than 5.7% – the level seen in people without diabetes.
Lilly said the overall safety profile of tirzepatide was similar to the well-established GLP-1 receptor agonist class, with gastrointestinal side effects being the most commonly reported adverse events.
Treatment discontinuation rates due to adverse events were less than 7% in each tirzepatide treatment arm.
Results are significant because Lilly is looking for a successor to its blockbuster diabetes Trulicity (dulaglutide), which holds a significant share of the hotly-contested GLP-1 class market niche.
Novo Nordisk’s semaglutide, available both as a weekly injection and as a daily pill, is its main competitor and Lilly needs to find a follow-up before the Trulicity’s patent expires in 2027.
Tirzepatide is also taken weekly, cutting the number of injections needed to control blood sugar.
It has a dual action as an agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors.
GIP is a hormone that may complement the effects of stimulating GLP-1, decreasing food intake and increasing energy expenditure.
Until this year the FDA required cardiovascular outcomes trials to ensure diabetes drugs do not damage patients’ hearts – but pharma companies have begun to use these to try and demonstrate their drugs actually cut risks of events such as heart attacks in diabetes patients.
Lilly is going to run a hugely expensive cardiovascular outcome trial for tirzepatide involving 12,500 patients, the largest so far in a bid to find data to give it an edge over the competition from other players in diabetes such as Novo and AstraZeneca.
As well as being in phase 3 development for blood glucose management in adults with type 2 diabetes and chronic weight management, tirzepatide is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH).
A new network of patient recruitment centres is set to shape the future of commercial clinical trials in the UK by offering new approaches to conduct late-phase, large-scale research projects. In a recent pharmaphorum webinar leaders from the NIHR’s five National Patient Recruitment Centres (NPRCs) outlined how they could bring cutting-edge therapies to greater numbers of UK patients.
The NPRCs are one of the Sector Deal 2 commitments from the government’s Life Sciences Industrial Strategy and are the first centres to be funded by the NIHR that are 100% dedicated to delivering commercial research.
The regional centres have been distributed across the country to provide opportunities for patients in areas of England who may not previously have been able to take part in the latest clinical studies.
They have also been designed to improve the speed and consistency through which commercial research is delivered in the NHS.
The goal is to attract life sciences R&D projects by making it easier and quicker to deliver commercial research, in turn improving the UK’s competitiveness in the global market.
pharmaphorum’s webinar, held in association with the NIHR, featured contributions from the directors of the NPRCs, the medical leaders who are leading the programme.
Dr William van’t Hoff, chief executive officer of the NIHR’s Clinical Research Network, began proceedings by highlighting some of the successes that have already been achieved.
“Our aim is to establish a relationship and build trust with our local community, to develop understanding, reduce the fear of research and increase engagement in that way” Yan Yiannakou
These include the delivery of COVID-19 vaccine trials and one of the UK’s first fully virtual interventional commercial clinical trials.
These studies have been made possible by the franchise-like operating model underpinning the network, which allows them to work in a harmonised manner, he said.
Franchise like operating model and collaborative working
The NIHR has provided £1.3 million in funding to each centre over three years to support their activities. Their collaborative model means the NPRCs will operate in an identical manner, offering a number of advantages to study sponsors.
As pointed out by Dr van’t Hoff, there will be a consistency of approach that could boost the UK’s competitiveness in a global market for late-stage clinical trial research.
The centres will benefit from shared standard operating procedures and will collaborate with each other as they host trials, the webinar heard.
Van’t Hoff said: “Each centre will provide a dedicated space and facilities for commercial clinical research, guaranteed access to NHS services to support research delivery, access to NHS clinicians to work as investigators, and a team of dedicated and highly-skilled research delivery staff to conduct the trials.”
Helen Quinn, director of the Joint Office for Clinical Research (University of Exeter and Royal Devon and Exeter NHS Foundation Trust), added that the centre in Exeter has been able to work with others across the country, costing and contracting for commercial research studies in a swift way.
“We can set trials up quickly for our patients, which is the most important consideration for us,” she said.
Speed, ease and volume
Using a franchise like operating model with standard operating procedures can speed up patient recruitment because of improved efficiency.
This was demonstrated by the swift set-up of a phase 3 COVID-19 vaccine study, which took just two weeks to set up and launch with over 1,900 patients recruited across the three NPRCs involved when it closed.
Dr Gavin Galasko is a consultant interventional cardiologist and director of research, development and innovation at Blackpool Teaching Hospitals NHS Foundation Trust, home to the Blackpool Patient Recruitment Centre.
He said: “We were the first in the world to recruit to this phase 3 study. We want to be there for pharma to show that the UK is a place to offer these latest state of the art late phase commercial studies that we can get to the patients quickly, efficiently, and in high numbers.”
Dinesh Saralaya, director of the NIHR Patient Recruitment Centre in Bradford, added that another factor that can allow trials to be quickly set up is the unified approach to costing across all the centres.
Each centre is also supported by research nurses, pharmacists and other research support staff who are dedicated resources available to the commercial trials run at the sites.
NPRCs are entirely focused on commercial research, further reducing the time to set up trials, the webinar heard.
The ‘recruitment engine’
Each centre is also driven by a ‘recruitment engine’ that uses several proactive strategies to reach out into the local community to empower patients to take part in, and to volunteer for, research.
As well as being linked to large hospitals, each centre will also collaborate with other healthcare organisations across primary, community and social care.
They can interact with primary care networks and integrated care partnerships (ICPs) for example to recruit from the local population.
This can help them find trial participants who are not hospitalised but who live with common chronic conditions and are not presenting in secondary care.
At the same time they benefit from links to large hospitals and their experience and expertise.
The centres can easily link with a wide network of GP surgeries and other local healthcare organisations, using linked NHS data sets to help identify patients to take part in research.
Yan Yiannakou, clinical director of the Newcastle NPRC, said that rather than going to a single GP surgery with 5,000 patients on its books, the centre works with federations of surgeries with 250,000 patients.
He said: “By working with a single point of contact in that federation and by working with the core federations around Newcastle, we can cover a population of 650,000 with a single search.”
Other innovative strategies employed at the NPRCs include virtual consultations, something that many other organisations have tried to implement but not succeeded.
Recruitment is further aided by digital consent, data capture and online eligibility checks, with the model already leading to a ground-breaking virtual trial, possibly the first in Europe.
Yiannakou said that the model has already been used to conduct a virtual trial in irritable bowel syndrome with diarrhoea (Relieve IBS-D).
The trial is currently recruiting 10 patients a week, which is twice as many as was being recruited by 28 sites before the study went virtual.
It’s just one of several innovative approaches to patient recruitment that are being explored at the NPRCs.
Yiannakou said: “Our aim is to establish a relationship with our local community, to build trust with the local community, to develop understanding, reduce the fear of research and just increase engagement in that way.”
Other approaches to recruitment will be explored, aiming to put patients and their needs at the centre of the process.
Melanie Davies, professor of diabetes medicine at the University of Leicester and director of the NPRC in Leicester, said: “This is all about bringing research closer to patients across the patch, across the NHS, but to provide it in a way that is attractive and accessible to patients.”
The cutting-edge of global life sciences research
A theme running all the way through the webinar was the sense of collaboration that each centre will bring to research projects.
The NPRC clinical directors all highlighted the centres’ ability to work together and with the wider healthcare ecosystem, such as primary, community and social care to enable access to a wider cohort of patients.
Yiannakou said: “The key is a willingness to develop and a willingness to change, and we have both the drivers and the substrates for that. The drivers are the fact that we are a novel concept centre, that we specialise in a particular area.
“We want to be the best in that area, we are focused in that area, and we have a remit and an intent to refine process and improve recruitment.”
According to Saralaya, the centres are sending a “strong message” to industry about the UK’s intent to be at the cutting edge of global life sciences research.
He said that the work already under way at the five centres shows they can deliver trials at speed, with quality and with very unified costing.
He concluded: “What better advocate can it be for a sponsor wanting to come to the UK?”
About the interviewees
Helen Quinn is the director of the Joint Office for Clinical Research, a collaboration between the University of Exeter and the Royal Devon and Exeter NHS Foundation Trust.
Dinesh Saralaya is a consultant respiratory physician and honorary senior lecturer at Bradford Teaching Hospitals NHS Foundation Trust. He has served as Director of the National NIHR Patient Recruitment Centre, Bradford since June 2020.
Yan Yiannakou is a consultant gastroenterologist and Clinical Director of the NIHR Patient Recruitment Centre (Newcastle).
Melanie J Davies is Professor of Diabetes Medicine at the University of Leicester and an honorary consultant diabetologist at the University Hospitals of Leicester NHS Trust.
Dr Gavin Galasko is a consultant interventional cardiologist and the director of research, development and innovation at Blackpool Teaching Hospitals NHS Foundation Trust.
Shares in Rocket Pharmaceuticals have been living up to their name, shooting up following encouraging early-stage clinical trial results from a gene therapy for a serious inherited rare heart disease.
Results came from a phase 1 trial of RP-A501 for treatment of Danon Disease and sent shares up 75% on the Nasdaq to more than $56, a five-year high.
The surging stock price indicates the market’s confidence in gene therapy products after the successful launch of products such as Roche/Spark Therapeutics’ Luxturna, a gene therapy for a rare inherited eye disease.
Danon Disease is a rare X-linked disorder caused by genetic mutations in the LAMP2 gene and the therapy works by instructing the body to express a healthy copy of the LAMP2B protein in order to correct the condition.
The disease that affects boys and men more severely causes accumulation of autophagosomes – tiny structures that cause cells’ internal structures to break down – in the heart muscle and other tissues.
Together with a build-up of glycogen this can lead to severe and frequently fatal degradation of the heart muscle.
RP-A501 could be the first gene therapy for the disease and the early data showed a positive increase in cardiac protein expression.
As of November, three patients have been treated with a low dose of the therapy and two have been treated with a high dose.
An early trial readout showed two patients with LAMP2B expression that was 50% more than normal, measured nine and 12 months after treatment.
A 15%-20% increase could lead to clinically meaningful improvements in cardiac function and the trial reported a 50% decrease in a key biomarker of heart failure.
There was also a reduction in myocardial cell disarray and a visible reduction in autophagic vacuoles, a hallmark of the disease.
The company also noted stabilisation of three other measures – a heart failure biomarker known as BNP, plus levels of transaminases and creatine kinase that also indicate skeletal and heart muscle damage.
However one patient who received the highest dose and had a degree of immunity to the adeno-associated virus used in the therapy had an immune reaction classified as a serious adverse event.
Rocket said the event was likely due to complement activation, resulting in reversible thrombocytopenia and acute kidney injury requiring a short round of haemodialysis.
The patient returned to baseline within three weeks and regained normal kidney function.
Dr Barry Greenberg, director of the Advanced Heart Failure Treatment Program at UC San Diego Health, Professor of Medicine at UC San Diego School of Medicine, and the principal investigator said: “Children with Danon Disease live with a heavy disease burden. Young boys are often severely afflicted.
“They show evidence of early onset skeletal muscle weakness and heart disease that can progress rapidly to end-stage with death occurring on the average before age 20. A heart transplant can be performed but is not curative and is associated with its own significant problems.
“The results-to-date for this first investigational gene therapy for monogenic heart failure show the potential for direct clinical benefit without emergence of unanticipated side effects of therapy.”
The company has also begun a stock offering of $175 million in shares to fund further development following the results.
Reviewers from the FDA have given their blessing to the Pfizer/BioNTech COVID-19 vaccine ahead of a key meeting tomorrow – but the regulator noted that there are still uncertainties about whether the shot can stop the disease from spreading.
The gist of a briefing document published from FDA reviewers ahead of an expert advisory board meeting is that the vaccine is good to go.
But there are still unanswered questions that can only be addressed once the shot is administered to the wider public.
Thursday’s vote of the Vaccines and Related Biological Products Advisory Committee is non-binding – but the FDA seldom takes a different viewpoint from its experts when it makes a final regulatory decision.
Pfizer and BioNTech are asking for an Emergency Use Authorization of their vaccine based on phase 3 data, which can be converted into a full licence at a later date once further trial information is published.
Phase 3 trials are designed to test whether vaccines are safe and effective and in this regard FDA reviewers said in the document that the Pfizer/BioNTech vaccine is a success, effective in around 95% of cases and with “favourable safety profile”.
The most common adverse reactions seen in a trial cohort of 38,000 patients were at injection sites (84.1%) followed by fatigue (62.9%) and headache (55.1%), and serious adverse reactions occurred in 0% to 4.6% of participants.
There were four cases of Bell’s palsy – a sudden muscle weakness – in the vaccine group and none in a placebo arm.
However the FDA noted there are currently insufficient data to make conclusions about the safety of the vaccine in subpopulations such as children less than 16 years of age, pregnant and lactating women, and those with compromised immune systems.
The biggest issue for the FDA staffers is one that will only be resolved with time – whether or not the shot can prevent people from infecting each other.
Reviewers said that “additional evaluations including data from clinical trials and from vaccine use post-authorisation will be needed to assess the effect of the vaccine in preventing virus shedding and transmission, in particular in individuals with asymptomatic infection”.
Reviewers noted there was no evidence of “vaccine-enhanced disease” but whether the vaccine could lead to a more resistant strain of the virus emerging is also unclear.
The regulator will be keeping a watching brief on this as more study data emerges over the course of the pandemic.
This risk “needs to be evaluated further in ongoing clinical trials and in observational studies that could be conducted following authorisation and/or licensure,” reviewers said.
Hospitals in the UK have already begun immunising high-risk patients after the country’s regulator became the first in the world to approve the Pfizer/BioNTech vaccine last week.
The FDA has placed a clinical hold on a phase 1/2 trial of Bellicum’s cancer cell therapy BPX-601, following a patient death.
Houston, Texas-based Bellicum said that the regulator had placed recruitment and dosing on hold in the dose-escalation trial in patients with previously treated metastatic pancreatic cancer or prostate cancer.
Bellicum is hoping to develop a next-generation CAR-T that has the firepower to tackle solid tumours, something that approved therapies from companies such as Novartis and Gilead are unable to do.
The action was due to the death of a pancreatic cancer patient in the trial reported to the agency by the company and the clinical investigator. Bellicum classified the patient death as unrelated to BPX-601 and rimiducid.
Shares in the biotech were sharply down after the announcement, which came only a few weeks after the company cut development staff following a readout from the trial suggested BPX-601 was not capable of shrinking tumours.
The company had continued with the trial to further investigate how the drug was working and Bellicum said it would work with the FDA to resume the trial.
Recruitment on to a separate phase 1/2 clinical trial of BPX-603, described as a dual-switch cell therapy in patients with HER2+ solid tumours will still go ahead in the coming weeks.
BPX-601 is the company’s first potential drug candidate, a CAR-T cell therapy that is designed to enable production of cytokines and enable the drug to override cancer mechanisms that inhibit the immune system.
The company has dubbed the technology CoCAR-T, which activates two receptors – MyD88 stimulates functioning within immune cells, while stimulating CD40 promotes anti-tumour action from T-cells.
CD40 can also re-educate macrophages to destroy tumour stroma – dense thickets of cells that act as a physical barrier between the cancer and the rest of the body that cell therapies struggle to penetrate.
China’s Sinovac has raised $515 million to increase its distribution and production capacity as clinical development of its potential coronavirus vaccine nears conclusion.
According to press reports Sino Biopharmaceutical, a Hong Kong-listed generics firm, acquired a 15% stake in a subsidiary of Sinovac.
Sinovac has a coronavirus vaccine in late-stage development, which is undergoing large-scale trials in Brazil, Pakistan, Indonesia and Chile.
Also in late-stage development in China are two other candidates developed by state-run Sinopharm.
The company plans to manufacture 300 million doses of the vaccine annually, but capacity will double after a second facility scheduled for construction by the end of the year begins operation.
All the vaccines developed in China are inactivated, meaning they are made of proteins found on the surface of the coronavirus that produce a response that provides immunity in the event of an infection.
This means they do not require the ultra-cool temperatures needed to store the RNA-based vaccines from Pfizer/BioNTech and Moderna.
Sinovac has already made large shipments, according to the Financial Times, in preparation for announcement of phase 3 results.
It is also distributing its vaccine within China as part of a large-scale emergency use programme.
According to the state-run Indonesian news agency Antara, 1.2 million doses were delivered to Indonesia on Sunday.
A further 1.8 million doses are expected to arrive in early January according to president Joko Widodo, who added that the country’s drugs regulator is already reviewing data from clinical trials.
Yin Weidong, Sinovac’s chief executive, reportedly said the investment will enable the company to “improve vaccine sales capabilities (and) expand in Asia markets”.
According to latest information from the World Health Organization, there are 51 vaccine candidates in clinical development.
There are more than a dozen in late stages of clinical development and the UK last week became the first country to approve the coronavirus vaccine from Pfizer/BioNTech.
Feature image courtesy of Rocky Mountain Laboratories/NIH
A gene-editing drug developed by CRISPR Therapeutics and Vertex Pharma has achieved “remarkable” improvements in patients with beta thalassaemia and sickle cell disease in an early-stage trial reported at the American Society of Haematology (ASH) annual meeting.
The data with the CRISPR/Cas9 drug CTX001 is still very early-stage, coming from just seven thalassaemia patients and three with SCD, but provide further evidence that it may be possible to use the gene-editing technology as a one-shot treatment for serious diseases.
All seven thalassaemia patients were seriously ill, requiring regular blood transfusions to control symptoms at enrolment into the study, but all were transfusion-independent three to 18 months after receiving CTX001 as a single infusion.
Similarly, three SCD patients suffered none of the characteristic painful attacks – known as vaso-occlusive crises (VOCs) – in the three to 15-month follow-up period after the treatment.
The trials are the first to test a CRISPR/Cas9 gene editing therapy in humans for a genetic disease, according to the partners.
The only available cure for both diseases is a bone marrow transplant from a closely related donor, an option that is not available for the vast majority of patients because of the difficulty in finding a suitable match, the high cost of the procedure, and the risk of potentially life-threatening complications.
CTX001 is an ‘ex vivo’ application of gene-editing, in which the technology is used to modify a patient’s own cells outside the body.
It uses CRISPR/Cas9 to make a patient’s haematopoietic stem cells produce high levels of foetal haemoglobin (HbF) in red blood cells, by introducing a gene known as BCL11A which down-regulates the production of the adult form of the oxygen-carrying molecule.
Reverting to HbF in thalassaemia and SCD patients produces normal, healthy red blood cells, rather than the misshapen cells produced by faulty haemoglobin in the two disorders. Patients remain in the hospital for approximately one month following the infusion.
“What we have been able to do through this study is a tremendous achievement,” said investigator Haydar Frangoul of the Sarah Cannon Research Institute, who presented the results at ASH.
“By gene editing the patient’s own stem cells we may have the potential to make this therapy an option for many patients facing these blood diseases,” he added.
The success of the study is a shot across the bows of companies trying to develop other genetic therapies for thalassaemia and SCD.
That includes Bluebird Bio, which already has approval in Europe for Zynteglo, its gene therapy for thalassaemia, and is due to file its related therapy LentiGlobin for SCD next year.
Bluebird suffered a setback last month in the US, however, after the FDA asked for more manufacturing data on Zynteglo which could delay the programme by up to a year, allowing CRISPR and Vertex to narrow its lead.
CRISPR and Vertex’s two phase 1/2 studies in thalassaemia and SCD – called CLIMB-111 and CLIMB-211, respectively – have now recruited 19 patients. They are due to enrol 45 apiece, and are scheduled to readout next year.
If positive, the results could lead to regulatory filings, and analysts at EvaluateVantage have suggested that CTX001 could become a $1.3 billion product if it gets approved for both indications.
In October, CRISPR Therapeutics co-founder Emmanuelle Charpentier and Intellia co-founder Jennifer Doudna shared the 2020 Nobel Prize in Chemistry for their work on CRISP/Cas9.
Valneva has said it plans to accelerate research into its Lyme disease vaccine candidate VLA15, bringing forward a trial including children into the first quarter of 2021.
Subject to approval from regulators the vaccine specialist said it plans the trial known as VLA15-221 as a randomised, observer-blind phase 2 study including around 600 healthy people aged 5-65 years of age.
They will receive VLA15 at the dose of 180 micrograms, which was selected based on data from two ongoing phase 2 studies.
First data from the study is expected by the second quarter of 2022 and all three studies will support a phase 3 pivotal efficacy trial including all main target populations for the Lyme vaccine, starting in 2022.
Starting the next phase 2 study will trigger a milestone payment from Pfizer to Valneva of $10 million under a collaboration announced in April this year.
Under the agreement Valneva could receive up to $308 million in cash payments, after Pfizer paid $130 million up front for marketing rights to the vaccine if it succeeds in the clinic.
Pfizer will pay up to $45 million in development related milestone payments and up to $143 million if the vaccine hits early sales targets.
Valneva is paying 30% of development costs and in return Pfizer will pay tiered royalties starting at 19% and will lead late-stage development.
VLA15 is the only active Lyme disease vaccine in clinical development today, and covers six strains that are prevalent in North America and Europe.
This investigational multivalent protein subunit vaccine targets the outer surface protein A (OspA) of the bacterium Borrelia that causes the disease, an established mechanism of action for a Lyme disease vaccine.
OspA is one of the most dominant surface proteins expressed by the bacteria when present in the ticks that spread the disease.
VLA15 has demonstrated a promising immune response and safety data in pre-clinical and clinical studies so far.
Pfizer slashed its production targets for its COVID-19 vaccine because of a lack of raw materials for its supply chain, according to press reports.
The big pharma has said in recent weeks that it expects to produce 50 million doses of the vaccine it developed with the German BioNTech, down from an earlier target of 100 million doses.
That’s enough to inoculate 25 million people as the dosing schedule involves two shots three weeks apart.
A Pfizer spokesperson told Reuters that the “scale-up of the raw material supply chain took longer than expected”.
Results from Pfizer’s clinical trial also took longer than expected to materialise and caused further delays, the spokesperson added.
Modifications to Pfizer’s production lines are complete and finished doses are being made at a rapid pace.
The Wall Street Journal reported the news first, quoting an unnamed source directly involved in the development that some early batches of raw materials had failed to meet standards, causing production delays.
The first shipments of the vaccine are reportedly in the UK following approval by the country’s medicines regulator.
Pfizer has asked the FDA for an emergency authorisation of the vaccine in the US and the US government expects to the first tranche to include about 6.4 million doses.
In a separate announcement, rival vaccine firm Moderna said it expected to have between 100 and 125 million doses available globally in the first quarter of 2021.
Of those 85-100 million will be available in the US and 15-25 million will be available outside the US.
The company said it is still on course to manufacture between 500 million and up to a billion doses of the vaccine globally in 2021.
Moderna’s vaccine is also under review by regulators including the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).
The UK has secured 7 million doses of Moderna’s vaccine after upping its order by 2 million earlier this week.
This could mean the UK could have access to up to 357 million doses of vaccines from seven different developers if they are all approved by regulators.
There are now more than 50 vaccines in clinical development and more than a dozen in late-stage trials, according to a regularly updated document from the World Health Organization.
As the pandemic drags on there are increasing concerns about “Long COVID” – where symptoms persist long after the initial infection has been fought off.
PureTech has joined the effort to find ways to treat the scarring and inflammation that are thought to cause the ongoing symptoms such as shortness of breath and fatigue.
After promising results in an early stage study, the company has begun a phase 2 trial of its LYT-100 (deupirfenidone) in Long COVID respiratory complications and related sequela.
LYT-100 is wholly owned by PureTech, which is already being developed for conditions involving inflammation and fibrosis and disorders of lymphatic flow.
The rationale for treating inflammation and scarring comes from a growing body of evidence from patients recovering from SARS-CoV-2 infection and previous experience with the closely related Severe Acute Respiratory Syndrome (SARS) virus.
PureTech referred to an Italian study showing that more than 40% of COVID-19 survivors reported shortness of breath an average of 60 days following symptom onset.
LYT-100 is based on the already-approved small molecule drug pirfenidone but with the addition of deuterium its half-life has been extended to improve tolerability, allow for less frequent dosing, and potentially increase its efficacy.
It is treated as a new chemical entity and as such fresh trials are needed to establish whether it is safe and effective.
The primary endpoint of the trial will be the six-minute walk test distance.
Secondary endpoints will include pharmacokinetics, inflammatory biomarkers, imaging and patient-reported outcomes and shortness of breath.
The study is to begin in the US and Europe and results are expected in the second half of next year.
PureTech also plans a phase 2a proof-of-concept study testing LYT-100 in patients with breast cancer-related upper limb secondary lymphedema this quarter.
The company is also planning studies to test LYT-100 in idiopathic pulmonary fibrosis (IPF).
Johnson & Johnson’s pharma unit Janssen has bought rights to an investigational gene therapy for a severe form age-related macular degeneration from specialist biotech Hemera Biosciences.
Financial details of the deal have not been disclosed and will add Hemera’s gene therapy HMR59 to Janssen’s pipeline of ophthalmology drugs.
The privately-held biotech has developed the gene therapy as a single shot to treat dry age-related macular degeneration, or dry AMD.
In the form of dry AMD known as geographic atrophy, dysregulation of the complement system can lead to the formation of a “membrane attack complex” that causes cells in the retina to die, leading to progressive loss of vision.
HMR59 is designed as a potential one-time treatment administered in an office setting that increases the ability of retina cells to produce a soluble form of CD59, called sCD59, that blocks the formation of the membrane attack complex and limits further damage to the retina.
It uses a modified adeno-associated virus to deliver the genetic material to the back of the eye.
Geographic atrophy affects five million people globally, and is a leading cause of blindness in people over 50 years of age.
The prevalence of geographic atrophy increases as the global population ages, with roughly one in 29 people over age 75 affected, and nearly one in four people over age 90. There are currently no available therapies other than vitamins and low vision aids.
The phase 1 study of HMR59 for patients with geographic atrophy is complete. A second phase 1 study exploring HMR59 in patients with wet-AMD is currently conducting follow-up visits to evaluate long-term safety.
Janssen established its eye disease portfolio in 2018 and is developing expertise and assets across a range of rare and common eye diseases, including achromatopsia and X-linked retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, and diabetic macular oedema.
Spark Therapeutics, which is now part of Roche, has shown that gene therapies can be converted into marketable ophthalmology drugs, after approval of Luxturna in 2017 for retinal degeneration caused by mutations in the gene RPE65.
Germany’s Merck KGaA has joined with UK-based Artios Pharma in a potential multi-billion dollar deal to investigate novel DNA damage response targets in cancer.
The principle of DNA damage response is already being exploited by AstraZeneca and other companies with their poly (ADP-ribose) polymerase (PARP) inhibitor drugs.
These target the inherent genetic instability in certain cancer cells, which have switched to a backup mechanism to repair damage to their DNA code.
Turning off this mechanism causes tumour cells to die without affecting healthy tissue – a concept scientists term “synthetic lethality”.
German Merck said it plans to work with Artios, a DNA damage response (DDR) collaboration involving Cancer Research UK and research partners worldwide, to find anticancer drugs that exploit a similar mechanism.
Artios will receive $30 million in up-front and near-term payments, plus double-digit option fees and up to $860 million in total milestones per target.
It will also receive up to double digit royalty payments on net sales of each product marketed by Merck KGaA.
Darmstadt-based Merck KGaA will contribute its expertise in DDR and will have exclusive worldwide rights to develop and market selected therapeutics discovered under the collaboration.
The partnership will focus on nucleases, which cancer cells depend on for their survival to repair DNA damage.
In certain cancer with mutations in DNA DDR pathways, inhibiting important nucleases can lead to cancer cell death.
The collaboration does not include Artios’ lead drugs, Pol theta and ATR inhibitors, for which Artios will retain rights.
Artios was founded by SV Health Investors in 2016 and has a partnership with Cancer Research UK, plus collaborations with DNA repair researchers worldwide such as the Institute of Cancer Research in London, the Netherlands Cancer Institute and the National Centre for Biomolecular Research at Masaryk University in the Czech Republic.
Backed by blue-chip investors including AbbVie Ventures, Novartis Venture Fund, Pfizer Ventures Artios is based at the Babraham Research Campus in Cambridge, UK, with offices in New York City.
Swiss biotech Noema has raised 54 million Swiss francs ($59m) to develop four neurological disorder drugs licensed in from Roche.
The company is developing four phase 2 drugs brought in from Roche after the big Swiss pharma decided somebody else should take the risk of developing them.
Roche, which decided the products were surplus to requirements in an already-packed pipeline, also received a shareholding in Noema, in exchange for rights to the four clinical-stage product-candidates.
Lead product is NOE-101, an mGluR5 inhibitor that is ready for phase 2b trials in two indications – for persistent seizures in Tuberous Sclerosis Complex and severe pain in Trigeminal Neuralgia.
The company is also preparing NOE-15, a PDE10A inhibitor for phase 2b testing to treat Tourette Syndrome.
It also has two other clinical stage assets – mGluR2/3 inhibitor NOE-109 and NOE-115, a triple reuptake inhibitor that are being evaluated in undisclosed indications.
The latest financing round was co-led by Sofinnova Partners, a European life sciences venture capital firm based in Paris, London and Milan, and Polaris Partners, a healthcare and technology investment firm based in the US.
The global consortium of new international investors includes Gilde Healthcare, Invus and BioMed Partners.
Noema was founded last year with a seed investment from Sofinnova partners and is led by CEO Luigi Costa, former CEO of haematology and oncology firm Nordic Nanovector.
He was also a senior figure at Onyx Pharmaceuticals, which was acquired by Amgen in 2014 and led the company’s international organisation and the launch of multiple myeloma drug Kyprolis outside the US.
The company also has the expertise of George Garibaldi as chief medical officer, a former Roche vice-president.
Costa said: “The successful licensing of these exciting clinical-stage product-candidates from Roche, together with our up-sized CHF54 million Series A financing, will enable Noema to reach value-creating development milestones with all four products.”
Few companies embody the term ‘pharma giant’ as much as Pfizer. Here we take a look at the colourful history of one of the biggest drugmakers in the world.
Pfizer was founded in 1849 by two recent German immigrants to the USA, Charles Pfizer and Charles Erhart. Both in their mid-twenties, the two men set up what was initially a fine chemicals business in a Brooklyn factory, using a loan from Pfizer’s father as capital. The company’s first product, a palatable anti-parasitic drug, made to taste like toffee, united Pfizer’s skills as a chemist with Erhart’s training as a confectioner. It was a success, and set the pattern for the company’s future development.
Pfizer’s Tokyo building
The convulsion of the American Civil War, which broke out soon after in 1862, had as much of an impact on the nascent pharmaceutical industry as on American society in general. The “first industrial war” involved drug producers as much as weapons manufacturers. Like their competitor Squibb, the sudden need for enormous quantities of painkillers and antiseptics for the Union armies provided a great scope to expand production. By 1868, Pfizer’s revenues had doubled since the start of the war, and their product lines had expanded greatly.
After the war, Pfizer continued to focus on industrial chemicals as much as medicines, producing the citric acid needed for the emerging soft drinks industry, fuelling brands like Coca Cola and Dr Pepper’s expansion in the 1880s. This became their mainstay for many years, laying the basis for their continued growth. Also, when supply of tartaric acid was disrupted due to the civil war and increased tariffs, Pfizer developed its production to become the leading supplier of chemicals in the US.
“The ‘first industrial war’ involved drug producers as much as weapons manufacturers”
Erhart died in 1891, and Pfizer in 1906, leaving a company of around 200 employees in the hands of Emil Pfizer, who served as president until the 1940s, the last member of the Pfizer family to be involved in managing the company. Under his stewardship, Pfizer’s expertise in scientific production methods developed greatly. In 1919 their scientists pioneered mould fermentation production of citric acid from molasses, freeing their citric acid business from European citrus fruit supplies, which had been disrupted by the First World War. They developed a deep tank fermentation process, the principles of which would later be applied to the production of penicillin. As a consequence of Pfizer’s innovation, the price of citric acid tumbled over the succeeding decades, with the value of the chemical falling by 5/6ths in 20 years. In 1936 the company discovered a fermentation free method of producing vitamin C, which they rapidly expanded into vitamins B2 and B12 amongst others, rapidly becoming a leading vitamin producer – chemicals that were very novel at the time.
This expertise in fermentation and large-scale pharmaceutical production put Pfizer in good stead when in 1941 the US government appealed to the pharma industry for support in producing penicillin for the war effort. In an unprecedented collaboration, Pfizer worked with government scientists, the researchers such as Frederick Banting who had been working on the drug before the war, and a plethora of other players in the industry to markedly improve the efficiency of drug production, as they proudly state “most of the penicillin that [went] ashore with Allied force on D-Day [was] made by Pfizer”.
Antibiotics marked the transition to the modern Pfizer. Their follow-up to penicillin, Terramycin, first marketed in 1950, was both their first proprietary drug, and the first for which the company used sales reps, their soon to be formidable force of salesmen starting with just eight members.
Pfizer initiated its first major internationalisation at this stage, moving into nine new countries in 1951. It was at this time they set their site at Sandwich in the UK, initially just to finish processing compounds imported from America, but due to tariffs on imported products the company rapidly expanded the plant to accommodate producing medicines from scratch. Pfizer’s international expansion put great trust in their local staff compared to other organisations, recruiting nationals and giving them a great deal of autonomy.
“Lipitor…became the biggest-selling prescription medicine ever, earning Pfizer $12 billion a year in 2007, one quarter of its total sales”
The areas that Pfizer directed its research into expanded in these years as well. In 1952, it established its Agricultural Division, beginning its foray into animal health, and in 1953 acquired Roerig, a nutritional supplement specialist, which became incorporated as a division in its own right. By the 1960s, Pfizer were at their “most diversified point in [its] history” – in its own words, its interests “stretched from pills to perfume, and petrochemicals to pet products”.
Throughout the 60s and 70s the company continued to bring out new drugs, such as the broad spectrum antibiotic Vibramycin, and broadening its research base, reorganising its R&D operations in 1971 into a Central Research Division, and increasing spend on this area of the company from 5% to 15% of revenue. This attention to innovation began to pay off in the 1980s, with a series of blockbusters, the first of which, the COX inhibitor Feldene, arrived in 1980 rapidly becoming one of the biggest-selling anti-inflammatories in the world. Others rapidly followed, including Glucotrol, aimed at diabetics, and Procardia, an anti-hypertensive. The 1990s and 2000s would soon take this blockbuster-based success to new levels.
The statin Lipitor, approved in 1997 for Warner-Lambert before their merger with Pfizer, became the biggest-selling prescription medicine ever, earning Pfizer $12 billion a year in 2007, one quarter of its total sales. It almost hadn’t made it through clinical development, facing problems with ineffective chiral isomers and limited efficacy in animal testing, but showed such impact in human trials that it blew the competition away.
But Pfizer’s almost Hollywood-level blockbuster of the 1990s was the little blue pill of Viagrar. Formulated initially at the Sandwich site in the UK as an anti-hypertensive, it was found have “unexpected” side effects that made the company rapidly change the indication to erectile dysfunction. But despite the cultural ubiquity, Viagra has recently faced the inevitable threat from competition and generics, dropping from 92% of the ED market in 2000 to around 50% in 2007, with vigorous competition from drugs such as Cialis and Levitra.
“Pfizer is the 6th largest lobbier in Washington, and spent $25 million on lobbying during the passing of Obama’s healthcare reform legislation alone”
Ups and downs
Like most pharma companies of its size, Pfizer has faced its fair share of controversy as one of the most well-known drugmakers in the world.
In 2009, Pfizer faced more than $2 billion in legal settlement payments over marketing practices for drugs, and around the same time announced it would close a large number of manufacturing and R&D sites worldwide, including its Sandwich facility, which at the time employed 2,400 people (though it ended up maintaining a reduced presence at the site).
In the late 2000s/early 2010s, Pfizer, like many other big pharma companies, was experiencing pipeline difficulties too, with drugs accounting for 40% of its sales coming off patent, and a series of high-profile failures of drugs in development, such as the anti-cholesterol drug torcetrapib that caused a marked increase in deaths compared with the control group in clinical trials. The news of this disastrous result came days after CEO Jeff Kindler had hailed the drug as potentially “one of the most important compounds of our generation”. Likewise, tanezumab, an anti-osteoarthritic, failed in trials.
However, these challenges in the core mission of drug discovery led Pfizer to focus on other means of keeping up its dominant position. One thing that highlighted this changed focus was the appointment of Kindler as CEO in 2006. Kindler was trained as a lawyer, and was a relatively new employee when he was given the top job in preference to others of much longer standing with scientific experience, highlighting the increasing importance of legal and marketing issues over traditional R&D. He was succeeded by Ian Read and later Albert Bourla.
Perhaps unsurprisingly for the biggest company in one of the biggest industries in the world, Pfizer has also been proficient in exerting its considerable political influence to preserve its interests, coming in as the 6th largest lobbier in Washington, and spending $US 25 million on lobbying during the passing of Obama’s healthcare reform legislation alone. It has been key in pushing counterfeit drugs up the political agenda, in part due to its ownership of that most counterfeited of drugs, Viagra. It has also been highly critical of parallel trade, and has been one of those militating for a pharmaceutical repackaging ban in the EU.
Despite this political clout, the company also tried to belay its image as a pharma monster, like many others in the industry, by spending generously on charity, donating AIDS drugs both to poor communities in the US, and to developing countries.
The era of mega-mergers
Since the turn of the millennium, Pfizer has embarked on a series of mega-mergers, gobbling up Warner-Lambert in 2000, Pharmacia and Upjohn in 2002, Wyeth in 2009, and Medivation in 2016.
In 2015 the company also paid $17 billion to acquire Hospira, a firm specialising in injectable drugs and biosimilars, at a time when copycat biologics were starting to make real waves in the market. The deal seemed to be a precursor to Pfizer’s plans to separate its patent-protected medicines business from its off-patent portfolio.
These plans were soon abandoned and Hospira has remained a key part of the core Pfizer organisation – but that didn’t put the idea of separate business units to rest completely.
In 2017/2018 Pfizer attempted to sell its consumer health unit, but buyers including Proctor & Gamble and GSK pulled out of negotiations.
This caused Pfizer to change its tactics, and instead the company ended up signing a deal with GSK to combine the two companies’ consumer health businesses and form a joint venture with combined annual sales of $12.7 billion.
Pfizer and GSK plan to divest the business completely in the long term and reap the rewards, while merging the two businesses is also expected to create cost savings for both partners.
Similarly, in 2019 Pfizer announced a deal to merge its Upjohn generics business with Mylan, creating a combined company called Viatris. The $12 billion deal was cleared in November 2020, creating a generics behemoth with annual sales of around $19 to $20 billion and operations in 165 markets around the word.
This era, though, was also marked by two major failed acquisitions, which both courted controversy due to Pfizer’s intention to exploit tax loopholes.
In 2014 the company made an offer of around $100 billion to acquire UK firm AstraZeneca (which at the time was going through a rough patch).
AZ seemed to have little interest in the idea, and the deal was instantly controversial in both Europe and the US. The merger would have created the biggest pharmaceutical company in the world – and would have given Pfizer a way to avoid paying costly US taxes on foreign earnings (a stance that president Barack Obama criticised heavily).
Indeed, critics feared this redomiciling was the main aim of the merger, and that Pfizer wouldn’t sustain investment in UK R&D in the long term.
Unusually, the UK parliament ended up getting involved, perhaps underlining the importance of AZ to the country’s life sciences sector, with both AZ and Pfizer asked to argue for the future of the company in parliamentary hearings. Pfizer seemed unable to allay the concerns of prime minister David Cameron and business secretary Vince Cable.
After numerous “friendly bids” and just as many rejections, Pfizer eventually made a final offer of £69.3 billion ($118 billion) – which was also turned down by AZ, with the company saying it was “inadequate”.
Leif Johansson, AZ’s chairman, did not mince his words, saying: “Pfizer’s approach throughout its pursuit of AstraZeneca appears to have been fundamentally driven by the corporate financial benefits to its shareholders of cost savings and tax minimisation.
“From our first meeting in January to our latest discussion yesterday, and in the numerous phone calls in between, Pfizer has failed to make a compelling strategic, business or value case. The Board is firm in its conviction as to the appropriate terms to recommend to shareholders.”
This did not stymie Pfizer’s desire to move its HQ out of the US, though. The next year it also attempted a ‘reverse takeover’ of Irish Pharma firm Allergan – where, technically, Allergan would acquire the US company and rename itself as Pfizer, allowing Pfizer to have its tax base in Ireland.
At the time $160 billion deal was the biggest ever seen in the pharma sector.
But soon the Obama administration came down hard on such ‘tax inversion’ deals, changing laws such that the deal was no longer attractive to Pfizer.
No signs of slowing down
Despite some setbacks, Pfizer remains one of the biggest pharma companies in the world today. The sheer size of the organisation is mindboggling, totalling well over 100,000 employees. One commentator compared the company’s 38,000 sales reps to “three army divisions”, a sales team that has been immortalised in a Hollywood rom-com of all things – Love and Other Drugs, starring Jake Gyllenhaal and Anne Hathaway.
And with the company becoming one of the first in the world to get a COVID-19 vaccine approved – via its collaboration with BioNTech – it feels like we’re only on the cusp of seeing where the company could head in the future.
Pfizer’s sheer diversity and economies of scale likely mean it will have the power to shape the pharmaceutical industry well into the 21st century. With fingers in every pie, ranging from small molecules to biologics in every clinical area, to stem cells and consumer goods, Pfizer will surely celebrate its 200th anniversary in as strong a position as it spent the last 160 years.
First results of the DiabetRisk study – Over 8% of patients identified with undiagnosed diabetes or pre-diabetes at dental practices
The DiabetRisk study could contribute to early diagnosis of diabetes in thousands of dental patients each year – and in every country worldwide
Simple screening process applied to 1,143 dental patients at 41 dental practices
Patients with the worst cases of periodontal disease are more likely to have prediabetes or diabetes
The first results of a significant new research project, the DiabetRisk study, show the key role dental practices could play in the early detection of diabetes for thousands of dental patients each year – and in every country worldwide according to its researchers.
The findings of the pioneering DiabetRisk study of 1,143 adult patients at 41 dental practices across Spain concluded that a simple screening protocol combining a FINDRISC questionnaire and HbA1c blood test identified 96% of patients with undiagnosed diabetes or prediabetes during a dental visit. Commissioned by the SEPA Research Network of Dental Clinics from the ETEP Research Group at Complutense University of Madrid and sponsored by multinational oral healthcare company, Sunstar, the results of the three-year study have just been released by SEPA (Spanish Society of Periodontology) at a time when people with diabetes are more likely to suffer severe symptoms or complications from the Coronavirus.
Out of 1,143 patients, 97 patients more than 8% were identified with undiagnosed diabetes or prediabetes. The study found that using a FINDRISC (FINnish Diabetes Risk Score) questionnaire completed by each patient alone detected undiagnosed hyperglycemia with 87% accuracy.
The FINDRISC questionnaire evaluated risk factors such as age, consumption of fruit and vegetables, physical exercise, family history of diabetes mellitus. Patients also received a basic periodontal examination. Complementing the questionnaire results with a chair-side HbA1c test – to provide an average blood glucose level for the last two to three months – increased the diagnosis accuracy to 96%.
The study has also corroborated the link that patients with the worst cases of periodontal disease are more likely to have pre-diabetes or diabetes. If a patient suffers from both conditions at the same time there is an increased risk of developing complications from diabetes earlier, since gum disease is an inflammatory disease that can increase systemic inflammation. In turn, this promotes insulin resistance, leading to impaired blood sugar control.
The DiabetRisk study demonstrates that a simple screening protocol combining the FINDRISC questionnaire and an HbA1c blood test is a simple, efficient and affordable way to identify patients with early undiagnosed diabetes or prediabetes during a dental visit. Costs per patient for the screening protocol were approximately 10Euro. Importantly, early detection and treatment of diabetes significantly reduces the risk for cardiovascular morbidity and mortality in patients.
Says David Herrera, chief researcher for the DiabetRisk study and Professor at Complutense University of Madrid: “These findings mean that in at least eight out of every 100 patients who went to a dental practice and had the screening, diabetes or prediabetes was detected.”
“Given the relationship between gum disease and diabetes, dental clinics are an ideal place for the early detection of this metabolic disease as demonstrated by our findings. It’s also widely accepted that while many patients don’t visit their doctor very regularly, a large proportion of the population do visit their dentist, enhancing the role of dental practices as a key ally in promoting general health.”
Comments Dr. Marzia Massignani, head of Scientific Affairs, Sunstar: “We are very pleased to be involved in the DiabetRisk study which has a number of important results and implications for dentists worldwide – and also demonstrates Sunstar’s longstanding commitment to promoting health and in preventing diabetes with dentists.”
For over 30 years, Sunstar has been promoting and supporting research in the bi-directional relationship between oral health and diabetes. SUNSTAR’s founder, Kunio Kaneda, passed away due to a complication of diabetes in his fifties and, as early as 1986, during the SUNSTAR Portside Symposium, Hiroo Kaneda, Kunio’s son, raised the question of a possible link between periodontal disease and systemic diseases. This was the first step towards the recognition of the relationship between oral health and general health.
Interviews on the findings of the DiabetRisk study results are available with Dr Marzia Massignani, head of Scientific Affairs, Sunstar.
SUNSTAR is a multinational company headquartered in Switzerland and founded in 1932 in Osaka, Japan. Today, SUNSTAR is a leading global company in the Mouth & Body Care field, a major presence in the Health & Beauty Care and the Environment & Amenity business fields, and a world leader in the Safety Support & High Technology field. In fiscal year 2019, consolidated net sales of the SUNSTAR Group totalled over 1.3 billion Swiss Francs. The products and services of SUNSTAR are distributed in more than 100 countries, and the company has 4000+ employees worldwide. Under the motto “Always strive to help people everywhere achieve better health and enhance their quality of life”, SUNSTAR continuously provides high-value-added products and services all over the world. www.sunstar.com
Pfizer and BioNTech have filed their COVID-19 vaccine with the European medicines regulator, paving the way for a potential approval before the end of the year.
The filing for a conditional marketing authorisation completed the rolling submission process that began on October 6.
The companies initially filed the nonclinical data and other technical data, followed by emerging clinical trial results.
If the EMA decided that the benefits of the vaccine candidate outweigh its risks in protecting against COVID-19, it will recommend a conditional marketing authorisation that could enable use of the vaccine in Europe by the end of 2020.
The data submitted show a vaccine efficacy rate of 95% in the companies’ phase 3 clinical study, which involved patients without previous infection with the SARS-CoV-2 infection and also people with and without previous infection.
Efficacy was consistent across age, gender, race and ethnicity demographics, with an observed efficacy in adults age 65 and over of more than 94%, the companies said.
The first primary objective analysis was based on 170 confirmed cases of COVID-19. In the trial, BNT162b2 also showed an overall favourable tolerability with no safety concerns reported to date.
Approximately 42% of global participants and 30% of US participants in the phase 3 study have racially and ethnically diverse backgrounds, and 41% of global and 45% of U.S. participants are 56-85 years of age, the companies noted.
The FDA and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) have already begun their reviews and similar rolling submissions have begun in countries including Australia, Canada and Japan.
Despite the fast review, the company insisted that the potential vaccine will be assessed according to the EMA’s normal standards for quality and safety.
The EMA has also confirmed it has received a filing from Moderna, which is producing a rival vaccine based on similar RNA technology.
If approved these vaccines will break new ground as it will be the first time RNA vaccines have been used.
They work by using a short length of genetic code that makes the body produce the “Spike” protein seen on the surface of the SARS-CoV-2 coronavirus.
This encourages the body to produce antibodies that neutralise the virus in the event of an infection.
Japanese drugmaker Eisai has teamed up with UK biotech Wren Therapeutics on an R&D programme seeking drugs for neurodegenerative disorders.
The two companies will focus their efforts on alpha-synuclein, a pathway that has been implicated in disorders such as dementia with Lewy bodies (DLB) and Parkinson’s disease (PD).
DLB and PD are both so-called synucleinopathies, diseases that are characterised by mutations in the SNCA gene coding for alpha-synuclein, leading to the production of misfolded, toxic forms of the protein that clump together and are thought to damage nerve cells.
Wren – a spinout from the universities of Cambridge in the UK and Lund in Sweden – has developed a drug discovery platform that can be used to screen small-molecule drugs to see if they can bind to misfolded proteins and correct their structure, preventing them from aggregating.
It’s a similar concept to interfering with the aggregation of beta-amyloid to form neurotoxic plaques in diseases like Alzheimer’s disease – another of Wren’s research targets.
Under the terms of the agreement, Cambridge-based Wren’s “network kinetics” platform will be deployed alongside Eisai’s drug discovery expertise in neurodegenerative disorders.
Eisai has a long heritage in this area, having been involved in the development of well-established Alzheimer’s drug Aricept (donepezil) and various other drugs for epilepsy, with a late-stage pipeline that includes Biogen-partnered anti-amyloid drug aducanumab, currently under review by the FDA.
“Synucleinopathies such as dementia with Lewy bodies and Parkinson’s disease represent a significant unmet medical need due to the lack of any effective disease-modifying treatments,” said Dr Teiji Kimura, who heads up drug discovery in Eisai’s neurology division.
“The accumulation of alpha-synuclein oligomers with protein misfolding is an important hallmark of these diseases,” he added.
Last summer, Wren raised 23 million in first-round financing to advance its internal R&D in the area of protein-misfolding diseases.
Other companies are also targeting alpha-synuclein, although Eisai and Wren are unusual in that they are seeking small-molecule candidates. Rivals include Roche and Prothera, which have an antibody in late-stage testing, as well as AstraZeneca/Takeda, Biogen, Lundbeck, AbbVie/BioArctic and Denali.
Roche licensed the antibody – called prasinezumab – from Prothera in a $600 million deal that dates back several years. Earlier this year however, the programme had a setback when a phase 2 trial in PD missed the mark.
The partners said the data showed some signs of efficacy, and prasinezumab is now heading for a phase 2b trial as an add-on therapy to standard levodopa therapy in PD.
Biogen has an antibody candidate called cinpanemab (BIIB054) in the phase 2 SPARK trial, due to generate results next year, while Lundbeck started a phase 1 trial in 2018 of Lu AF82422, another antibody, that could read out before year-end.
AZ and Takeda started a first phase 1 trial of their MEDI 1341 antibody in 2017, adding a second earlier this year that is due to run until 2022, while AbbVie’s ABBV-0805 cleared a phase 1 trial but seems to have been sidelined for strategic reasons.
Denali’s project is earlier in development. Its preclinical candidate ATV:aSyn is a bispecific antibody designed to penetrate the central nervous system more effectively, with one end targeting alpha-synuclein and another targeting a transporter in the blood-brain barrier.
Cure Rare Disease’s Rich Horgan discusses the importance of preclinical NAbs screening and helping rare disease patients better understand their eligibility for gene therapies.
Neutralising antibodies (NAbs) present a unique challenge to researchers looking to treat patients with AAV treatment. As AAV is a virus derived from the common cold, the immune system can easily have levels of pre-existing NAbs that will recognise and neutralise AAV, rendering it ineffective.
In serious cases, higher levels of pre-existing NAbs can even cause a dangerous immune reaction when such therapies are administered.
This is particularly pertinent in rare diseases, as a number of gene therapy products use viral delivery methods to deliver the transgene to target organs.
“NAbs are antibodies that are part of the humoral response of the adaptive immune system,” explains Rich Horgan, founder and president of Cure Rare Disease (CRD), a nonprofit biotech developing CRISPR therapeutics for Duchenne muscular dystrophy (DMD). “They defend against foreign pathogens or infectious particles, and are specific to the targeted antigen, neutralising its effect and rendering it no longer pathogenic by binding to it.
“The goal is to not have the body neutralise the therapeutic, and therein lies the issue with NAbs. For gene therapy treatments using viral delivery methods such as AAV, NAbs are an issue that we must all contend with for both initial patient dosing as well as subsequent redosing.
“Our belief is that patients should understand the challenges associated with drug development and how those challenges impact them personally… It is emotionally challenging for patients who must put their faith in the hands of pharma companies”
“Regardless of route of administration, the virus can be identified as a foreign pathogen causing the adaptive immune system to try and eliminate it through NAbs or other means.”
A further issue is that patients can, and do, develop NAbs from environmental exposure. For example, since AAV is derived from a common virus, patients can develop NAbs against AAV from common colds or other infections – and ultimately, even low levels of antibodies can prevent successful transduction of a viral-based therapeutic.
Clinical trials will screen potential patients for NAbs against the delivery vector to understand the level of NAbs present in the patient (known as the titer level) before dosing them with the experimental drug – but there is currently no standardisation for measuring NAb titer levels in a patient, and each pharma company develops their own assay for testing.
“Moreover, there is not a generally agreed upon threshold for a dose/no-dose decision,” says Horgan. “Ultimately, titer levels are related to safety, as dosing a patient who has a higher titer level (however that may be defined) is more likely to trigger an immune response to the treatment, an extreme example being the infamous case of Jesse Gelsinger.
“As additional gene therapy trials advance, it is important that bodies like the FDA begin to standardise NAb measurement assays and acceptable titer levels for inclusion in clinical trials.”
But although companies are able to screen patients in an attempt to avoid complications, only those already in line for clinical studies qualify, even though for many patients it’s critical to know this information in advance as they consider potential trials.
“To date, there hasn’t been a widely available mechanism for patients and patient families to get insight into whether or not they have a significant level of NAb activity other than through enrollment in a clinical trial,” says Horgan.
Because of this, Horgan believes there needs to be more conversations surrounding this issue, and much more education of patient communities regarding the issue of NAbs and the challenges they create towards participation in a gene therapy study.
“Our belief is that patients should understand the broad challenges associated with drug development and how those challenges may impact them personally. While drug development is technically challenging, it is even more emotionally challenging for patients and patient families who must put their faith in the hands of pharma companies to develop effective treatments for their disease.
“Given the rise of many gene therapies, especially those in the rare disease space, neutralising antibodies stand as a significant challenge to the patient community and it is critical that patients understand that a) these neutralising antibodies exist and can potentially prevent patients from participating in a gene therapy clinical trial and b) collaborative development efforts are needed to ensure that patients can get access to life-saving gene therapies if they possess a significant level of NAbs.”
As such, CRD has rolled out a new system to allow patients to get an understanding of where their neutralising antibody levels stand – knowing that these levels may change over time and that medical decisions should not be based on these results.
The system offers community access to preclinical neutralising antibodies screening. CRD enrolls patients into their research study, then sends a patient kit for local blood collection through a lab. Patients are then informed of the research results several weeks later, and are provided genetic counselling to understand and emotionally handle the results.
“We’ve gone to great lengths to provide a high level of counselling as we know, from personal experience, the results are more than data points – they are the hopes and dreams of a family counting on a potentially life-saving gene therapy,” says Horgan.
“Ultimately, we believe that patients should have knowledge of the impact of neutralising antibodies and must advocate for the advancement of technologies so that all patients may be eligible for viral-based therapeutics. Time and access are of the essence.”
Horgan says that the long-term benefits for families who choose to get screened comes from this generated knowledge.
“Knowledge is power. While the information provided does not change the reality of the situation, we hope that it encourages families to ask more questions and to advocate for the development of technologies to enable dosing with a viral-based therapeutic.
“While non-viral gene therapies will someday be possible, leading researchers believe it will be a number of years before this is realistically feasible.
“Moreover, we want to help patients avoid the immense emotional disappointment of a situation where the patient is found to be ineligible for a gene therapy study due to NAbs even though they never knew that NAbs were an issue to begin with.
“By rallying together a community, we can catalyse the development of technologies to enable dosing (and re-dosing) of advanced therapeutics so that all have access.”
About the interviewee
Rich Horgan is the founder and president of Cure Rare Disease. He has a deep passion for Duchenne muscular dystrophy (DMD) and other rare diseases. With a younger brother impacted by DMD, Rich has a strong interest in accelerating promising treatments for the disease. He has formed a collaboration with world-class researchers and clinicians to pioneer the rapid development of customised therapies for Duchenne and other rare diseases.
Genmab has axed development of its pipeline cancer drug enapotamab vedotin after it failed to show enough activity in a proof-of-concept trial.
The drug is an antibody-drug conjugate where a monoclonal antibody is linked to monomethyl auristatin, a cancer-killing “payload”.
It is targeted against AXL, a signalling molecule that is overexpressed in several haematologic and solid malignancies.
Developing enapotamab vedotin formed a major part in the rationale behind the company’s $506 million Nasdaq IPO last year.
Genmab said it will not advance development of the drug after data from expansion cohorts showed it did not meet stringent criteria for proof-of-concept in the early trial.
There was some evidence of clinical activity but this was not “optimised by different dose schedules and/or predictive biomarkers” the company said in a statement.
The company will instead prioritise development of other drugs in its pipeline.
AXL overexpression is thought to drive several cancer processes, including metastasis, tumour angiogenesis, resistance to chemotherapy and targeted agents, and decreased antitumor immune response.
Enapotamab vedotin is fully owned by Genmab and the drug linker technology used for enapotamab vedotin was licensed from Seagen Inc, formerly known as Seattle Genetics.
Jan van de Winkel, CEO of Genmab, said: “We are committed to developing innovative antibody products for patients with cancer, however the data from the enapotamab vedotin expansion cohorts unfortunately does not support moving this product candidate forward.
“This decision will allow us to focus more of our resources and energy on other programs in our robust next-generation antibody therapeutics pipeline.”
AXL is also being targeted by the Norwegian biotech BerGenBio, which has also been looking at using the pathway to fight inflammation seen in COVID-19.
The company’s bemcentinib is under development as a combination and single agent therapy in lung cancer and leukaemia, as well as COVID-19.
It also has an anti-AXL antibody, tilvestamab, which is undergoing phase 1 testing in cancer.
With the prospects for its Alzheimer’s drug aducanumab still up in the air, Biogen has moved to shore up its late-stage pipeline with a $3 billion licensing deal with Sage that adds drugs for depression and neurological disorders.
The licensing agreement gives Biogen rights to Sage’s zuranolone (SAGE-217) for psychiatric disorders including depression, and SAGE-324 for essential tremor and other neurological diseases, which both target the GABAA receptor pathway.
In return Sage gets $1.525 billion upfront – $875 million in cash and a $650 million equity investment – as well as potential milestones of $1.6 billion if both drugs meet their development and commercial targets.
The deal comes as both companies are facing a challenging period. Biogen has invested heavily in its Alzheimer’s candidate aducanumab, but an FDA advisory committee was unimpressed with the company’s rehashed data for the anti-amyloid drug and voted that it didn’t support efficacy.
The FDA may still approve the drug – its reviewer had called some elements of the data persuasive in a briefing document – but even if it does getting payers to stump up for a drug with shaky data could be a challenge, despite the lack of Alzheimer’s therapies.
Meanwhile, Biogen has suffered recent setbacks including the failures of multiple sclerosis candidate opicinumab and a gene therapy for spinal muscular atrophy (SMA) – at a time when its big selling SMA drug Spinraza (nusinersen) is facing increased competitive pressure.
At the same time, Sage has struggled to make headway with its only approved therapy – Zulresso (brexanolone) for postpartum depression (PPD), which has been held back by a cumbersome dosing schedule that requires a 60-hour inpatient infusion.
Zulresso was launched last year but sales in the recent third quarter were just $1.6 million, around the same level as the same period of 2019.
With zuranolone, Biogen gets shared US and exclusive ex-US rights (excluding Japan, Taiwan and South Korea) to a potential first-in-class, once-daily oral drug with a breakthrough designation from the FDA as a treatment for major depressive disorder (MDD).
It has positive results from two pivotal trials – a phase 2 trial in MDD and phase 3 study in PPD – although a second phase 3 PPD trial (MOUNTAIN) failed to meet its primary objective. Biogen and Sage say there will be data readouts from other phase 3 trials in MDD and PPD next year.
The partners are going after three indications for the drug, namely PPD, as a rapid response therapy for MDD, and “as needed” treatment of acute MDD, and down the line will also look at its potential in bipolar disorder and generalised anxiety disorder.
A key characteristic is a rapid onset of action, which could free patients from the need to take antidepressants chronically and “may enhance quality of life and patient adherence”, according to Biogen.
SAGE-324 meanwhile is in phase 2 for essential tremor, a neurological disorder that causes involuntary and rhythmic shaking, and is being explored for other indications like epilepsy and Parkinson’s disease. Biogen gets shared US rights to the drug under the deal, as well as ex-US rights.
Essential tremor is estimated to affect over six million patients in the US, while 17 million Americans have symptoms of depression every year, and those numbers have led analysts to predict potential blockbuster sales for both zuranolone and SAGE-324 if approved.
Shares in Sage dipped after the announcement, with Jefferies analyst Andrew Tsai suggesting that might be because of disappointment that Sage hadn’t held out for potentially more favourable deal terms if zuranolone hits the mark in trials due to read out in 2021.
Despite advances in science and technology, denovo drug development has been a costly and time-consuming process over the past decades.
Given these circumstances, drug repositioning and repurposing has appeared as an alternative tool to accelerate drug development processes by seeking new indications for approved/shelved drugs rather than discovering de novo drug compounds.
The newest computational approach to drug repositioning showing the greatest promise is AI and machine learning. With a drug-repurposing strategy, AI can quickly detect drugs that can fight against emerging diseases (such as Covid-19) as well as existing diseases.
The AI Driven Drug Repositioning & Repurposing Summit will bring together 80+ leaders in repurposing
and pioneers in AI and machine learning to strategize how repurposing can reach its full potential to:
• Improve time and cost savings of drug development
• Leverage the safety advantage in reducing development risk
• Unlock market potential advantage
• Improve return on investment for repurposed drugs
• Explore out-licensing options
This meeting aims to help pharma, biotech and academics stay ahead of the curve in their repurposing endeavors during a period exploding with new technologies. Join cutting-edge discussions with the like of AstraZeneca, BenevolentAI, and Healx, to solve ongoing technical challenges surrounding AI tools in repurposing, understand the delicate risk-reward balance in potential repurposing opportunities and explore lessons learned from AI applications in repurposing during Covid-19.
Featuring 2 days of jam-packed content, this digital summit will provide you with all the information you need to begin implementing AI tools into repurposing projects within your organization. What’s more, our digital platform allows you to take part in live Q&A with the presenters, take a tour of the virtual exhibition, and even join online rooms where you can join targeted interactive discussion groups!
Colchicine, a cheap and readily available anti-inflammatory drug used to treat diseases such as gout, is to be investigated as a potential therapy for COVID-19 in the UK’s ground-breaking RECOVERY trial.
In a statement academics from Oxford University, which is running the trial, said that colchicine will be added to the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial from today.
Colchicine is derived from the autumn crocus and could be an important inclusion in the growing list of drugs that are being used against the disease if results are supportive.
RECOVERY is the world’s largest clinical trial of treatments for COVID-19 and is taking place in 176 hospital sites with over 18,000 patients recruited so far.
At least 2,500 patients are expected to be recruited to RECOVERY and will be randomly allocated to receive colchicine plus usual standard of care.
Results will be compared with at least 2,500 patients who receive the usual standard of care on its own.
Dosage used will be 1000 micrograms for the first treatment, then 500 micrograms every 12 hours for a total of 10 days or until discharge if sooner.
The main outcome the RECOVERY trial will assess is mortality after 28 days. Other outcomes include the impact on hospital stay and the need for ventilation.
Depending on recruitment rates, it is likely to be several months before there is enough evidence to conclude whether colchicine has a significant benefit in COVID-19 patients.
Other treatments being tested on RECOVERY include Roche’s Actemra (tocilizumab), convalescent plasma from donors who have recovered from COVID-19 containing antibodies against the virus, Regeneron’s antibody cocktail REGEN-COV2 and aspirin.
The trial has already shown that the dexamethasone, a cheap steroid, can cut mortality in patients with severe respiratory complications from COVID-19.
RECOVERY has been made possible by the UK’s National Health Service and its ability to coordinate a large clinical trial across the entire country.
Professor Peter Horby, co-chief investigator of the RECOVERY trial, said: “Colchicine is an attractive drug to evaluate in the RECOVERY trial as it is very well understood, inexpensive and widely available. If it works it would be another COVID-19 treatment that could be used immediately worldwide, even in the poorest countries.”
AstraZeneca is to run an additional global trial to test its COVID-19 vaccine at a lower dosage, as the UK regulator begins to review trial data.
The shot, known as AZD-1222, developed in partnership with Oxford University, has dominated the pharma news agenda this week after it hit efficacy targets but appeared short of rivals from Pfizer and BioNTech.
With an overall efficacy of 72%, below the 95% seen with rivals, AZ’s vaccine would have been even weaker had it not been for a stronger potency seen in patients accidentally treated with a half dose followed by a full dose.
Now CEO Pascal Soriot wants to conduct a new test to confirm the 90% efficacy rate of the lower dose regimen, which was stumbled upon because of a manufacturing mistake.
The companies did not disclose the error at the time and there are concerns over their transparency, Bloomberg news reported.
Soriot told Bloomberg: “Now that we’ve found what looks like a better efficacy we have to validate this, so we need to do an additional study.”
This will likely be another international study but could be faster as it will require fewer patients due to the higher efficacy seen with the revised dosing regimen.
The additional trial is unlikely to hold up regulatory approvals in the UK and EU, according to Soriot.
Health secretary Matt Hancock has asked the UK’s regulator the Medicines and Healthcare products Regulatory Agency (MHRA) to begin its review of the vaccine.
The Department of Health and Social Care said the UK could be one of the first in the world to receive the vaccine if authorised.
AZ is set to have up to 4 million doses ready for the UK by the end of the year and 40 million by the end of March.
The government also has pre-ordered 40 million doses of the Pfizer/BioNTech vaccine, which could be more than 90% effective but is harder to store and distribute as it needs to be kept extremely cold to retain its integrity.
AstraZeneca may have tried a positive spin on the trial mistake that led to the accidental discovery of the low dose COVID-19 vaccine regime with the highest efficacy– but the revelation has drawn a mixed response from commentators.
The company’s share price has tumbled since the announcement of the trial results from AZD-1222 at the beginning of the week, reflecting an overall loss of confidence in the company’s handling of the trial.
This was also reflected in numerous press reports that called into question the strength of the findings, particularly in the smaller group of patients who were given the lower dose.
As pointed out by the New York Times, there were fewer than 2,800 volunteers who got the more effective dose, which was accidentally given at half strength followed by a full strength dose 28 days later.
There were more than 23,000 participants in the data from the UK and Brazil, and the numbers used to calculate efficacy are lower than those used by rivals such as Moderna and Pfizer/BioNtech to calculate efficacy.
Pfizer tested its vaccine on more than 43,000 people and Moderna based its findings on more than 30,000 patients.
And then there’s the question of the deviation from the trial protocol that AZ’s research chief Mene Pangalos admitted to earlier this week.
After realising several thousand volunteers had accidentally received the wrong dose, Oxford University academics running the trial decided to press on regardless with the weaker dosing regime, breaking with the predetermined design.
As pointed out by Canada’s CBC, the change was okayed by regulators but nevertheless the stronger effect could still be a statistical quirk.
There was another confounding factor in that none of the people in the low-dose group were more than 55 years old.
Younger people would tend to produce a stronger immune response than older people, which could account for the differing results.
The decision to pool results and give a composite figure from the two dose strengths is another factor that is causing concern.
Moncef Slaoui, who leads the US COVID-19 vaccine programme Operation Warp Speed has told reports that his team are trying to determine what immune response the vaccine produced.
A separate study being conducted in the US may be modified to include the half-dose followed by a full strength booster, said Slaoui, who used to be GlaxoSmithKline’s vaccines chief.
Many reports point out that AZ’s shot has an advantage in that it can be stored in fridges instead of at the ultra-cool temperatures required by those from Moderna and Pfizer.
But trial results from these mRNA-based rivals seem to be much cleaner and could pave the way to faster decisions from regulators, which could be due in the next few days.
COVID-19 is proving to be the perfect storm in terms of the supply of pharmaceutical products. But learning how to overcome the challenges of 2020 will serve the industry well for years to come. As part of our EU Leader series, Christian Pawlu, head of strategy, portfolio and BD&L at Sandoz, told us about how securing supply in a time of crisis will ensure future access, build resilience, and transform relationships.
Since the start of the year, pharmaceutical companies have been riding a rollercoaster of challenges. Pawlu describes a “perfect storm” as the various strands came together to threaten supply chains.
“First, we saw a doubling or tripling of usual demand for a lot of our products. At the same point, there were big worries about supply chains in China.
“Then, as we went further into the crisis, there were some almost protectionist moves in some countries, as they placed or considered export bans on active pharmaceutical ingredients (API).”
Navigating this rapidly evolving landscape presented a challenge, but not an insurmountable one, Pawlu says.
“The industry, and our company in particular, always has business continuity plans in the drawer. But never in recent history have we had to pull out strategies for so many of our products and subsidiaries at the same time and put them into place.”
Daily calls with supply chain colleagues, activating second sources and alternative supply chains, along with strategic API and finished product stockpiling, all contributed to an absence of any major disruptions.
“For us, the crisis was also a reminder of our purpose as a company: to provide and pioneer access to the patient. We were the first company to commit to keeping prices stable for drugs seen as essential treatments for COVID-related symptoms.
“As an industry, we will have to be more honest with ourselves. We’ll be much better able to see where we have a really deliverable message and when we elicit a response, rather than measuring it by the time people spend with the customer”
“We made a commitment early on that we would not want to benefit from any shortages. In addition, we have made a commitment to provide 15 drugs to low-income countries at cost.”
COVID-19 has fundamentally changed the way all sectors work on a day to day basis, but pharma did not have the luxury of time in allowing these changes to bed in.
Within a week, all 100,000 employees at Sandoz and parent company Novartis had transitioned from office to remote working, a process Pawlu describes as relatively “frictionless”.
“The biggest challenge was the interaction with our customers, because we weren’t able to see healthcare providers physically anymore. But, in the end, that turned out to be an opportunity.”
Before the pandemic, Sandoz was able to reach around 15% of its customers digitally, but that has now increased to around 70%.
As people adjusted to connecting digitally, through Zoom, Microsoft Teams, and other video-based software, in their private lives, this expanded into their professional lives, says Pawlu.
“Traditionally, the way we interact with our customers has been a big barrier to conveying messages, particularly in off-patent pharma.”
While using digital channels will not necessarily be easier, it will make companies think differently about how best to interact with healthcare professionals, Pawlu believes.
He says: “The key question we need to ask ourselves is, if we have more access to physicians, how do we want to use it? More reach? More efficiency?
“We are working through this as we speak and are thinking how we complement or even replace the traditional channels, and how we can reach customers we haven’t reached so far. It’s exciting.”
As the industry moves from a face-to-face to digital communication model, it needs a change of mindset, he adds.
“A physical person showing up in a physical office is the old normal.
“As an industry, we will have to be a bit more honest with ourselves. We’ll be much better able to see where we get access, where we have a really deliverable message, and when we elicit a response or an active request for follow up, rather than measuring it by the time people spend with the customer.”
Another change Pawlu hopes is here to stay is the increased communication and collaboration between industry and policy makers.
This is, in part, thanks to a greater appreciation of the importance of resilient supply chains, he says.
“Over the last 30 years, the volume of products produced in Europe versus Asia has flipped. The majority of APIs and an increasing share of FDF is currently being manufactured in Asia,” explains Pawlu, adding that this was driven, particularly in generics, by price.
“I think the balance we need to keep in mind is cost, quality, and resilient supply. You can optimise all three, but you can only maximise two at the same time.
“If you can go for the highest quality and resilient supply, you will have to pay a higher cost, or you do it the other way around – of course we never want to compromise on quality.”
Supply chain issues during the pandemic have brought this argument into sharp focus, and it is now “on the radar” at an international level.
“Sandoz has been in contact with heads of governments across Europe, and I’m extremely happy that this topic has gained so much attention,” he says, adding that the European Commission has committed to developing a continent-wide pharma strategy.
Back in July, Sandoz announced that it had entered a partnership with the Austrian government to keep production of penicillin at the company’s Kundl facility – the last remaining integrated production chain for antibiotics in the western world.
“Austria is something that’s been very visible, but we’re having similar discussions on other product areas with other governments,” Pawlu says.
Ultimately, 2020 has been a challenging time for pharma, but it has also presented a myriad of opportunities to learn and evolve.
For Pawlu, COVID-19 has highlighted how we transform the way the industry works – from manufacturing and supply chains, to sales and detailing – in a way that ensures everyone can access the high quality, affordable medicines they need to live happier, healthier lives.
About the interviewee
Christian Pawlu is the global head, strategy, portfolio and BD&L for Sandoz and a member of the global Sandoz Executive Committee. Christian studied medicine in Germany, Canada and France and is a licenced physician. Before he joined Sandoz, Christian was a start-up entrepreneur. He was a partner at McKinsey & Company where he specialised in pharmaceuticals and medical products with a focus on generic drug manufacturers. Prior to joining McKinsey, Christian was a neuroscience researcher at the university of Freiburg, Germany. Christian is married to a professor of medicine and they have three children.
About the author
Dr Paul Tunnah founded pharmaphorum in 2009, which combines industry leading publications (www.pharmaphorum.com) with a specialist strategy and content marketing/communications consultancy (www.pharmaphorumconnect.com). He is a recognised author, speaker and industry advisor on content marketing, communications and digital innovation, having worked with many of the world’s leading pharmaceutical companies and the broader ecosystem of healthcare organisations.
In June 2020, he became chief content officer for Healthware Group, a next-generation integrated consulting group that operates at the intersection of the transformation of commercial operations and digital health, offering a unique range of services combining design, strategy, communication and innovation with technology and corporate venturing.
Novartis’ pipeline is strong enough to overcome a $14 billion patent cliff as blockbuster drugs face generic competition in the coming years, analysts have said.
Following a briefing with management, a team of analysts led by Peter Welford said that the big Swiss pharma will be propped up by its psoriasis and infectious diseases blockbuster Cosentyx for some time.
Although the drug has lost market share to rivals in psoriasis, there is still more to come from Cosentyx thanks to potential new uses in ankylosing spondylitis, psoriatic arthritis and six new indications.
This will be helped by a new 300mg pre-filled syringe and auto-injector have halved administrations, although there is an intravenous option for administration by doctors treating US Medicare patients.
This is supported by the company’s portfolio of other approved medicines and revenues from its Sandoz biosimilars and generics division.
In the short term, the analysts predict “flattish” Q4 sales, although they noted that the company may benefit from cost savings introduced during the COVID-19 pandemic.
Jefferies expects that the company expects sales of $14 billion could be at risk by 2027 from patent expiries of Tasigna, Promacta, Jakavi, Gilenya and Entresto.
But the analysts said that sales growth will continue despite the headwind thanks to “underappreciated” drugs in the late-stage pipeline.
Four key drugs outlined by Jefferies have combined peak potential of $14 billion – the high lipoprotein cardiovascular disease drug pelacarsen, iscalimab for organ transplant and Sjogren’s syndrome, the rare disease drug iptacopan and the leukaemia drug sabatolimab.
Other important phase 3 drugs that are due to read out are Lu-PSMA in prostate cancer and canakinumab in lung cancer.
The company’s Sandoz division will also chip in with growing sales from its portfolio of biosimilars – cut-price near-copies of established biologic drugs that have been shown to be as safe and effective in rigorous tests and clinical trials.
Uptake of biosimilars in the US has been better than hoped, perhaps aided by hospitals focusing on cost because COVID-19 has curtailed income from surgery.
AstraZeneca’s research chief has said that the more effective dosing regimen of its coronavirus vaccine was discovered by accident.
According to Reuters, the AstraZeneca development team made a minor mistake that made them realise they could significantly boost the success rate of the vaccine, codenamed AZD1222.
Results announced earlier this week showed that by giving a half dose, followed by a full dose a month later, the vaccine’s efficacy could be boosted from 62% to around 90%.
AZ originally planned for trial participants in the UK to receive two full doses but researchers found that certain side effects such as fatigue, headaches or arm aches were milder than predicted.
Mene Pangalos, executive vice-president of biopharmaceuticals R&D at AZ, said: “The reason we had the half dose is serendipity.
“So we went back and checked…and we found out that they had underpredicted the dose of the vaccine by half.”
Researchers decided to continue with the half dose group and administer the second booster shot as previously planned.
Results showed that in the group treated with the half dose, the vaccine was 90% effective, leading to an overall efficacy of 70% across the two dosing schedules.
“That, in essence, is how we stumbled upon doing half dose-full dose. Yes, it was a mistake.”
The error could make all the difference, cutting the amount of vaccine required for a strong therapeutic effect and allowing greater coverage.
Although at 90% effectiveness AZ’s shot would lag slightly behind RNA-based rivals from Pfizer/BioNTech and Moderna, AZD1222 is easier to handle and can be stored in fridges instead of at ultra-cool temperatures.
The revelation means that the stronger regimen could be added to a growing list of medicines discovered by accident – Alexander Fleming famously discovered penicillin after noticing a mould producing the compound was killing bacteria in a petri dish.
Pfizer’s erectile dysfunction drug Viagra was initially trialled as an angina drug before scientists at Pfizer’s laboratory in Sandwich, Kent, stumbled upon its other properties in a story so famous that Spike Lee is to direct a musical about the discovery.
It’s still not clear whether AZ’s vaccine discovery will be celebrated in popular culture as regulators have not yet approved it, but the incident shows the unpredictable nature of drug R&D and that after years of painstaking research good fortune is sometimes needed to get projects over the line.
Merck & Co is to buy US biotech OncoImmune for at least $425m, adding a potential new therapy for COVID-19 to its pipeline.
The pharma company, known as MSD outside North America, will pay the money up front with OncoImmune shareholders receiving further undisclosed milestone payments if certain sales and regulatory goals are achieved.
What attracted Merck & Co’s attention were interim findings of a phase 3 study showing OncoImmune’s CD24c – also known as Saccovid – significantly cut recovery time or progression to death or respiratory failure in patients with severe or critical disease compared with placebo.
Data was based on findings from 203 patients, around 75% of planned population of the trial, which the privately-owned US biotech said is fully recruited.
The pre-specified interim efficacy and safety analyses were performed when 146 patients achieved clinical recovery from COVID-19, a milestone achieved with 203 enrolments.
The trial was opened in April this year and activated in 15 medical centres in the US.
It involved patients requiring oxygen support, including those requiring supplemental oxygen, high flow oxygen, and non-invasive ventilation.
They were randomly assigned into two arms receiving either SOC plus a single dose of Saccovid or standard of care plus placebo.
Saccovid is a first-in-class recombinant fusion protein that targets the innate immune system, which had originally been developed for prevention of graft versus host disease (GVHD) following stem cell transplants in patients with leukaemia.
It has been studied in GVHD in phase 2 clinical trials, and a pivotal phase 3 clinical trial has already begun in GVHD.
In COVID-19 research, Merck & Co is already collaborating with Ridgeback Biotherapeutics to develop an oral antiviral drug, which is in phase 2/3 development.
Merck & Co is also conducting clinical trials to evaluate two COVID-19 vaccine candidates: V590, being developed through a collaboration with IAVI, which utilizes a recombinant vesicular stomatitis vector, and V591 which uses a measles virus as a vector.
AstraZeneca is preparing to file its COVID-19 vaccine with regulators after phase 3 trial results showed it is up to 90% effective.
AZ made the announcement as the UK regulator reportedly gears up to make a decision on the rival vaccine from Pfizer and BioNTech, ahead of counterparts in the US and Europe.
Results from trials conducted in the UK and Brazil showed an efficacy of 90% in 2,741 patients receiving the vaccine as a half dose, followed by a full dose at least one month apart.
Another regimen of the vaccine codenamed AZD1222, given to 8,895 patients showed 62% efficacy when given as two full doses at least one month apart.
The combined analysis shows efficacy of 70% and the company said there were no serious safety events confirmed as related to the vaccine.
AZ said the trial has therefore met its main efficacy goal and will immediately prepare filings to regulators around the world to allow early approval.
It will also seek an Emergency Use Listing from the World Health Organization to make the shot quickly available in low income countries.
AZ made no further reference to the safety scare that caused trials of the vaccine to be halted for several weeks in September.
The AZ vaccine also has a considerable convenience advantage over RNA-based vaccines from Pfizer and Moderna.
The AZ shot can be stored at refrigerator temperatures making distribution much easier, while the vaccines from Pfizer and Moderna require ultra-cool temperatures to prevent their active ingredients from breaking down.
AZD-1222 is based on a weakened cold virus that causes the disease in chimpanzees, which has been modified so that it causes the body to code for the “spike” protein seen on the surface of the SARS-CoV-2 coronavirus that causes COVID-19.
The body produces antibodies against the protein, which neutralise the coronavirus in the event of an infection.
AZ announced the news as reports suggested the UK could approve Pfizer’s rival by the end of the week.
Citing a gated report from the Daily Telegraph, Reuters said the Medicines and Healthcare Products Regulatory Agency could have concluded its review of the shot developed by Pfizer and BioNTech by the end of the week.
This would allow distribution of the vaccine to begin during the first week in December.
Feature image courtesy of Rocky Mountain Laboratories/NIH
2020 has been an exciting year for gene therapies targeting blood disorders. Despite FDA’s recent rejection of BioMarin’s hemophilia gene therapy program, the clinical landscape is progressing quickly with Pfizer and Sangamo kicking off their phase 3 and bluebird bio receiving European approval for their beta-thalassemia candidate.
With pipelines advancing and emerging companies joining the blood disorders field, it is essential for gene therapy developers to communicate and share lessons learned to accelerate their programs to market. The 2nd Gene Therapy for Blood Disorders meeting is taking place in March 2021, focusing on the clinical and commercial challenges of developing gene therapies targeting hemophilia, sickle cell disease and beta thalassemia.
Evaluate the best strategies for a commercial launch in blood disease and optimize your trial design to ultimately transform your clinical candidates into a commercial reality.
The inaugural Gene Therapy Medical Affairs Summit is dedicated to exploring the pivotal internal and external role that Medical Affairs plays in delivering gene therapies to patients.
Industry pioneers from leading pharma and biotech companies at various stages of development and commercialization including Novartis Gene Therapy, Orchard Therapeutics & Bluebird Bio will share how to engage effectively with internal clinical and commercial teams as well as external HCPs, regulators and patient advocates to create a cohesive and streamlined launch strategy for complex, high priced gene therapy products and ultimately work to remove both barriers that exist for access to gene therapies.
Join this definitive, niche conference to delve into the unique Medical Affairs challenges encountered when working with gene therapies, from adapting to the clinical realities of the rare disease space to handling long-term follow up and post-launch scrutiny, equipping you with the insights required to launch gene therapy products more efficiently and effectively than ever before.
This virtual event is set to be a highly interactive and engaging meeting. We fully understand (and quite frankly agree) that a presentation-heavy conference just isn’t up to scratch! As such we have created a new format for this meeting which maximises opportunities for engagement, discussion, and Q&A’s in order for you to get the best value from this meeting.
Just over a year after its first phase 3 trial of its Engensis gene therapy for painful diabetic peripheral neuropathy (DPN) bombed, Helixmith has started dosing patients in a new study.
The South Korean biotech says the DNA plasmid-based therapy has been administered to a patient at Innovative Research of West Florida. The aim is to enrol 152 DPN patients at 15 clinical sites across the US in the study, called REGAiN-1A.
Helixmith has previously suggested that if positive, the new study could support marketing applications for Engensis. It is due to generate results in December 2021, which could lead to filings in 2022.
While most gene therapies in late-stage development target rare diseases, DPN is a relatively common condition and is likely to become even more prevalent as diabetes is becoming more common around the world. It has a lifetime prevalence of around 50% in people with diabetes, with around half of these having pain.
In DPN, prolonged exposure to higher than normal blood sugar levels damages nerves, most commonly in the legs and feet but also in the arms and hands.
At the moment treatment is limited to drugs like gabapentin and pregabalin, which are only palliative and don’t tackle the underlying cause of the condition.
Engensis – also known as VM202 – is a DNA plasmid-based gene therapy that is administered as an intramuscular injection into the calves, delivering a gene coding for human hepatocyte growth factor (HGF).
The hope is that delivery of Engensis to the lower limbs might promote nerve system regeneration and alleviate the pain that often accompanies DPN, whilst also promoting blood vessel growth in the extremities.
In its first 500-patient phase 3 trial, called DPN 3-1, Engensis was no better than placebo at reducing pain scores over the first 90 days of the trial. However Helixmith (formerly known as ViroMed) said that was due to a major mix-up in the study protocol, which undermined the results.
Analysis of samples taken from patients in the placebo group found traces of the VM202 plasmid, suggesting that clinicians may have inadvertently administered the gene therapy to the control group.
There was also a wide variation in the amount of plasmid DNA among the treatment group, which might suggest inaccuracies in the administration of the gene therapy. On the plus side, safety results were in keeping with a benign profile seen in earlier-stage clinical trials.
Helixmith then started a phase 3 extension study in 101 subjects from DPN 3-1 – conducted under a separate protocol – to look at long-term safety and efficacy at 12 months.
That backed up the safety data for the therapy, and also found significant pain reductions compared to placebo after six, nine and 12 months, as well as a trend towards reduced pain at three months.
The primary measure in REGAiN-1A will be a comparison of the average daily pain scores from seven days prior to the first injection, to seven days prior to the six-month visit between both the Engensis and placebo groups.
Secondary efficacy measures include pain reduction at six months compared to placebo, as well as the proportion of patients experiencing a 50% reduction in pain at six months. The therapy will be administered by injection into the calf at day zero, 14, 90 and 104.
Trans-Atlantic biotech venture capital firm SR One has completed its spin-out from GlaxoSmithKline and closed its first fund with $500m in its coffers.
The VC built itself a considerable reputation after it was founded in 1985 and works with entrepreneurs and scientists to build biotechnology companies.
GSK is the largest investor in the independent fund, which said it is the largest first-time VC fund to close in 2020 focused on US and European biotechs.
CEO Simeon George will lead the company’s investment team, bringing more than a decade’s worth of experience in the sector.
George has been with the fund since 2007 and established its San Francisco office in 2010.
He earned his MD and MBA from the University of Pennsylvania School of Medicine/Wharton and BA from Johns Hopkins University.
Previously, he worked in management consulting (Bain & Co.) and investment banking (Goldman Sachs) and has led some of SR One’s highest profile investment deals.
These include CRISPR Therapeutics and Principia Biopharma, which was recently acquired by Sanofi for $3.7 billion, Turning Point Therapeutics, Progyny and Nkarta Therapeutics, which he co-founded.
David Redfern, chief strategy officer at GSK, said: “Since inception, SR One’s mandate has been to deliver financial returns by investing in innovative biotechnology companies.
“Following SR One’s spin-out from GSK and establishment as an independent fund management business, GSK has remained a committed investor in SR One’s new independent fund, alongside a diversified and top tier investor base.
“The close of the fund at the hard cap and its over-subscription by global investors underscore the team’s abilities and strong track record.”
CEO Simeon George said: “Our spin-out from GSK and successful raise of a new independent fund provide a foundation for SR One’s next chapter, enabling us to scale our investment strategy and build upon our track record of success.”
It’s been a busy time for life sciences VC, with the likes of Canaan Partners, Atlas Venture creating new funds amid the investment boom in life sciences amid the COVID-19 pandemic.
The FDA has agreed to expedite development of two rare disease drugs from Sanofi.
The most significant of the two announcements is the Priority Review for avalglucosidase alfa, a potential new therapy for Pompe disease.
The review period will be shortened from the standard ten months to six months or less, and the French pharma said the FDA will make the regulatory decision before May 18th.
These faster reviews are reserved for drugs that could be a significant improvement in safety or efficacy over standard care.
Avalglucosidase alfa is an investigational enzyme replacement therapy designed to improve the delivery of acid alpha-glucosidase (GAA) enzyme to muscle cells.
The FDA will review data from the phase 3 COMET trial in patients with late-onset Pompe disease.
Also in the file will be data from the phase 2 mini-COMET trial testing safety and efficacy in patients with infantile-onset Pompe disease previously treated with standard enzyme replacement therapy, alglucosidase alfa.
European regulators began their review of the data last month.
Pompe disease is caused by a genetic deficiency or dysfunction of the lysosomal enzyme GAA, which results in build-up of complex sugars (glycogen) in muscle cells throughout the body.
The accumulation of glycogen leads to irreversible damage to the muscles, including respiratory muscles and the diaphragm muscle supporting lung function, and other skeletal muscles that affect mobility.
In a separate announcement, Sanofi said the FDA granted Fast Track Designation for its oral investigational Bruton’s tyrosine kinase inhibitor rilzabrutinib, which is in development for immune thrombocytopenia.
Fast Track designation gives developers more support from the FDA for potentially important new drug for serious conditions and can lead to a Priority Review if clinical trial data looks promising enough.
Fast-tracked drugs can also be granted a tentative Accelerated Approval based on earlier data, with a full approval granted on the basis of information from a larger trial.
Sanofi has already begun a phase 3 trial of rilzabrutinib in the disease caused by destruction and impairment of platelet production by the immune system following supportive phase 1/2 results.
Rilzabrutinib is being investigated in a phase 3 trial for pemphigus, an immune mediated disease characterized by blisters in mucous membranes and skin. Sanofi has also begun a phase 2 study in the autoimmune condition IgG4 disease.
The coronavirus vaccine being developed by Oxford University and AstraZeneca produces a strong immune response in higher risk older patients, a study has found.
The phase 2/3 trial results published in The Lancet about the UK-developed shot follow more detailed findings from Pfizer/BioNTech showing that their vaccine protected 94% of adults over 65 years old.
Although both vaccines are not yet approved by regulators, the results are encouraging as older people seem to be most at risk from the virus.
The results from the UK-developed vaccine, codenamed AZD1222, come from a trial in 560 healthy adult volunteers.
Results from the phase 2 component of the trial were published ahead of phase 3 data expected in the coming days or weeks, which will provide a much clearer picture about the vaccine’s safety and efficacy.
Those taking part were assessed to see if they were fit and healthy enough to take part before being assigned to receive either an intramuscular injection of the coronavirus vaccine or a control vaccine.
Booster regimes were given 28 days apart and dosing regimen varied according to age group.
Findings showed that the vaccine, which is based around a weakened chimpanzee cold virus, produced a similar immune response across all age groups and was better tolerated in older adults than in younger adults.
Regulators in the UK and Europe have begun rolling reviews of several coronavirus vaccines, including the Oxford vaccine, but these results will not be enough for them to fully assess its safety and efficacy.
The data needed for that will come from the larger phase 3 trial, which will be reviewed quickly by the regulators in real-time under the rolling review to hasten a decision.
Separate results published by Pfizer yesterday show the vaccine it is developing with Germany’s BioNTech protect around 94% of adults over 65 years old.
The trial involved 41,000 people worldwide, half of whom received the vaccine, with the remainder given a placebo.
These latest figures from the older age group are an improvement on the 90% overall efficacy figures announced in top-line results earlier this month.
Pfizer is reportedly close to filing results with the FDA for an Emergency Use Authorization after gathering the required amount of safety data.
Gilead Sciences has the data it was hoping for in a pivotal trial of lenacapavir, an HIV drug that only needs to be dosed by subcutaneous injection every six months, keeping it on course for regulatory filings next year.
Lenacapavir (previously GS-6207) is the first in a new class of class HIV-1 capsid inhibitor that Gilead is hoping will eventually free patients from the need to take daily oral tablets, although initially it is being developed for patients who are failing their current treatment regimen.
The drug is also a key part of Gilead’s plans to defend its $16 billion HIV franchise from rivals which are also developing long-acting injectables, namely ViiV Healthcare with cabotegravir and Merck & Co’s islatravir (MK-8591).
The 36-patient CAPELLA trial tested lenacapavir in highly treatment-experienced HIV patients who had developed resistant to their current drugs, with virus levels rising as a result.
It found that 21 of 24 (88%) of patients on the capsid inhibitor experienced a 0.5 log10 reduction in viral load after 14 days, compared to two of 12 patients (17%) on placebo.
“We look forward to sharing data from longer-term follow-up of CAPELLA study participants next year and submitting these data for regulatory approval,” said the company’s head of virology Diana Brainard.
The FDA granted breakthrough designation to lenacapavir for the treatment of resistant HIV, which has become a niche part of the overall HIV market thanks to much-improved oral drug regimens in recent years.
In time, Gilead wants in time to extend the use of lenacapavir into additional and much larger indications, including the general HIV-positive population as well as for pre-exposure prophylaxis (PrEP) among people who have sex with HIV-positive partners.
Earlier this year Gilead added a lenacapavir arm to its planned prevention study in women at risk of HIV – which is being carried out to expand the label for Descovy after it was approved with a narrower PrEP indication than Truvada last year.
In parallel, Gilead is also planning to carry out a study of lenacapavir for HIV prevention in men and transgender people who have sex with men.
PrEP is already a big market for HIV drugs like its blockbuster brands Descovy (emtricitabine/tenofovir alafenamide) and Truvada (emtricitabine/tenofovir disoproxil fumarate), which accounted for around $1.5 billion and $3 billion of Gilead’s HIV sales last year.
Descovy’s approved indication excluded people who have receptive vaginal intercourse due to a lack of efficacy data in that population, and Gilead wants to shore up the label quickly as Truvada is facing the loss of patent protection. It is thought that around two-thirds of Truvada’s near-$3 billion in 2019 sales came from use as PrEP.
Expanding the use of lenacapavir into the broader population could be complex however as Gilead will need to find another long-acting drug that can be partnered with it to reduce the risk of resistance to the capsid inhibitor.
GlaxoSmithKline’s HIV joint venture ViiV Healthcare could mount a challenge to Gilead’s HIV pre-exposure prophylaxis (PrEP) medicines after the FDA granted Breakthrough Therapy Designation for its long-acting injectable drug cabotegravir.
In the trial cabotegravir was injected every eight weeks in a formulation that the company hopes will be more appealing than Gilead’s daily Truvada pill.
Offering patients the option of an injection every eight weeks would allow them to take the medicine more discreetly. Trial results show that cabotegravir is more effective at preventing infections than Truvada.
PrEP drugs are taken by HIV-negative people before they have sex and reduce the risk of getting HIV.
The FDA granted the status based on efficacy and safety results of a trial comparing cabotegravir with emtricitabine+tenofovir disoproxil fumarate (FTC/TDF) – the active ingredients in Gilead’s Truvada – in high-risk individuals.
HPTN 08 is, a phase IIb/III randomised, multicentre, double-blinded, clinical trial comparing the two drugs for HIV prevention among 4,566 men who have sex with men and transgender women who have sex with men.
ViiV said the final analysis of HPTN 083 showed the superiority of long-acting cabotegravir, which was 66% more effective at preventing HIV when compared to daily oral Truvada tablets.
Results of the trial were presented at the AIDS 2020 conference in July and the blinded phase of a prevention study in 3,223 sub-Saharan African women was stopped earlier this month after an analysis by the independent safety monitoring board showed cabotegravir was superior to oral FTC/TDF.
Viiv, which is majority owned by GSK with Pfizer and Shionogi as shareholders, plans to use the data from both studies for future filings with regulators.
Breakthrough Therapy status is intended to expedite the development and review of drugs for serious or life-threatening diseases, which may be better than available therapies.
The FDA requires preliminary clinical evidence showing a drug may be a substantial improvement on at least one clinically significant endpoint over available therapies.
It may allow more frequent collaboration with the FDA to discuss a development plan and could pave the way for a faster Priority Review lasting six months.
Gilead has also produced a follow-up to Truvada – Descovy (emtricitabine+tenofovir alafenamide) which is approved by the FDA in PrEP and to help keep the virus at bay in those infected with the virus.
Pfizer is preparing to file its COVID-19 vaccine after a trial reached the safety milestone required by US regulators for emergency use, according to press reports.
The company’s CEO Albert Bourla said that the company is preparing to submit its data to the FDA following last week’s announcement that the vaccine is more than 90% effective, according to an interim analysis of a phase 3 trial.
Bourla was speaking at a virtual conference hosted by the New York Times, without saying when the company expected to file for the Emergency Use Authorization with the FDA.
“We are preparing now for submissions,” said Bourla.
However the company has already said it would have the two months of safety data required by the FDA by the third week of November.
But according to Bloomberg he conceded that there are important questions about the vaccine that remain to be answered, such as how long it remains effective.
“When it comes to how durable the protection could be, this is something we don’t know yet,” he said.
More efficacy results are due soon, he said.
Developed in partnership with Germany’s BioNTech, Pfizer’s vaccine is slightly ahead of a rival from Moderna in development.
Both vaccines are based on mRNA technology but Moderna’s rival seems to be slightly more effective with an efficacy of 94.5%.
Moderna’s shot is also easier to handle, requiring storage at -20C instead of the much more challenging -70C for the Pfizer vaccine.
There are also issues with access to an already available therapy for COVID-19, Eli Lilly’s antibody therapy bamlanivimab, according to reports.
Reuters reported that hospitals in the US are rationing use of the drug because demand is outstripping supply following an EUA from the FDA last week.
The federal government has paid $1,250 per dose for 300,000 doses of bamlanivimab, enough to last for a week at current infections levels, according to Reuters.
COVID-19 has reminded the world how critical infectious disease is, from both a societal and economic standpoint. Cancer is rightly seen as one of the most pressing challenges of our time: but it has not yet caused a multi-trillion hole in the world’s finances.
For the first time in my career developing antimicrobials, I’m hearing more investors enthused by the prospect of investing in companies developing solutions to infectious diseases. We all know COVID-19 has shifted our perspective on a range of things, and in economic terms three developments have underpinned this shift.
First, there is now a wealth of innovation, perhaps more than ever, in antimicrobial design and development (almost all of it being generated by SME businesses). Second, push incentives from government and NGO bodies, particularly the AMR Action Fund, providing $1 billion of investment, are now substantial enough to really fuel that innovation. And third, pull incentives are now in place which are beginning to make an effective commercial case for antimicrobial development.
The NHS/NICE antibiotic subscription model announced earlier this year is potentially the most significant of these developments. The US PASTEUR Act, if enacted, would also pave the way for providing prepaid subscription contracts for antimicrobials in the US, collectively making antimicrobials viable again. Similar subscription models and other market entry reward proposals are being floated in Sweden and elsewhere.
After years of lobbying by the industry, policymakers now accept the need for “pull” models that de-link sales (by volume) from reward; reward being for developing and launching these drugs for when they are needed, not for promoting use. Antimicrobial stewardship is now clearly linked with economic success.
We’ve all heard the bear cases for antibiotics: the bankruptcy of Achaogen, fire sale of Tetraphase and other high-profile problems at antibiotic developers have highlighted the fact that even with the best possible support in the development phase, generating profitable versions of the ‘traditional’ antibiotic classes remains challenging. The decision by Cipla to withdraw Zemdri (plazomicin) from European marketing authorisation, is a sobering reminder that even highly effective antibiotics with proven efficacy are often not considered economically viable.
“We need to keep up the momentum. Although welcome, the pull incentives are the first small steps to creating the economic climate required for very successful commercialisation of antimicrobials.”
But now, just as a communicable disease poses the biggest economic challenge the world has faced in a decade, there are signs that new reimbursement models, alongside a new generation of innovation in development, have changed the rules of engagement.
Innovative and commercial savvy companies are creating platform technologies and diversified portfolios, focusing not only on antibiotics but desperately needed antifungals and antivirals as well.
NovaBiotics is proud to be developing antifungal and antiviral therapies alongside antibacterials, all of which mitigate resistance as they are based on platforms engineered from innate immune effector molecules – harnessing the way the body fights disease versus ‘synthetic’ approaches that introduce new resistance pressure to microbes. We are not alone in developing drugs which are designed to avoid creating antimicrobial resistance.
There’s every reason to believe that by the time these new drugs reach the marketing approval and launch, the reimbursement and commercial landscape will allow for a good economic runway.
We need to keep up the momentum. Although welcome, the pull incentives are the first small steps to creating the economic climate required for very successful commercialisation of antimicrobials. The forthcoming EU Pharmaceutical Strategy can perhaps create conditions to address market failure in antimicrobials and reinvigorate innovation, by taking the right actions. These include support for the SME companies which generate the lion’s share of innovation, better alignment between health systems and drug developers, the targeted use of diagnostics and a regulatory framework based around non-inferiority trials, to name a few.
The UK government, which has already played a leading role in creating a significant pull incentive for developers, is talking about creating an equivalent to DARPA. The UK has some of the world’s most innovative antimicrobial developers so there’s a clear incentive to do this.
This year may be the great awakening of the value of anti-infectives from a social perspective. 2021 could be the year that they demonstrate their economic case. Let’s use Antimicrobial Awareness Week to get that message out.
Lead Pharma has signed a potential 260 million euro ($308 million) deal with Roche to develop small molecule drugs for immune diseases.
The deal will revolve around a single undisclosed drug target and will see the Dutch biotech receive 10 million euros up front from Roche.
Lead will lead the selection of a pre-clinical drug candidate, after which Roche will be responsible for further development and global marketing.
Based in Oss-Netherlands, Lead will be eligible to receive research funding and pre-clinical milestone payments; total potential payments including research, development, regulatory and sales milestones may add up to 260 million euros, plus royalties on worldwide sales.
The biotech’s chief scientific officer Arthur Oubrie said: “Our rigorous target selection process, translational screening cascade, and smart medicinal chemistry have been essential to bring this project to this stage. We are keen to collaborate with our colleagues at Roche to bring this novel approach to patients.”
The company has been working with Sanofi since 2015 on a small molecule targeting ROR gamma, a regulator of T-helper 17 immune cells.
It has already received four milestone payments under this first agreement, which targets autoimmune disorders including common diseases such as psoriasis, rheumatoid arthritis and inflammatory bowel disease.
In March last year Sanofi began a phase 1 clinical trial of the treatment , triggering the most recent payment.
Roche is clearly looking to expand from the cancer beat where it has made most of its money in the last few decades.
Sales of its “big three” cancer drugs Avastin, Herceptin and Rituxan are slipping away because of competition from cheaper biosimilars.
It has had limited success with newer oncology drugs, which have not produced the annual sales of more than $20 billion generated by these drugs at their peak.
Roche last year signed a $792.5 million deal with immune-mediated disease focused Rheos Medicines, based in Cambridge, Massachusetts.
The US biotech got $42.5 million up front, with a further $90 million due in research and pre-clinical development milestones.
The remainder will come from development, regulatory and sales milestones, plus tiered royalties.
Pharmaceutical companies often struggle to actively involve patients in the design phase of clinical trials but doing so can have huge benefits for the sustainability and success of research.
It can help address well established issues with studies, such as patient recruitment and retention, as well as reducing the need for additional trial protocol amendments. Now, patient engagement is becoming even more relevant, with the COVID-19 pandemic heralding a major shift towards remote, virtual and hybrid clinical trial models.
The regulatory issues of how to engage with patient organisations and involve patients in clinical trial design are covered by publications such as the ABPI’s Code of Practice. However, the implementation of these while maintaining compliance with internal company guidelines can prove challenging and can be difficult to navigate without support and guidance.
So, working together with patients, research clinicians and Pfizer, the NIHR has collectively agreed a way in which it can facilitate patient engagement, remain aligned with ABPI and AMRC Codes and help to manage the burden faced by life sciences companies.
This pharmaphorum webinar, held in association with the National Institute for Health Research (NIHR), takes place on Wednesday 16th December, 11:00 GMT / 12:00 CET and will look at how to navigate the compliance pathway to increase patient engagement with clinical trials.
The webinar will also cover:
Building better relationships between pharma/CROs and patient advocates
Improving the design of commercial research by listening to the patient voice
Gaining patient input on marketing and recruitment materials
How the NIHR’s Patient Engagement in Clinical Development service can help
View the webinar* by clicking on the link in the window above or by clicking here.
Sophie Evett is the feasibility lead within the Pfizer Study Optimisation group. She holds a Bachelor’s degree in Biological Sciences and a PhD in Molecular Biochemistry from the University of Reading, UK. Having worked for CROs since graduating, Sophie joined Pfizer in 2011 and has had various roles within the UK and now global groups.
Richard Stephens has survived two cancers, a heart emergency, and continued co-morbidities and late effects. He has participated in four interventional studies and nine others. A patient advocate for two decades, Richard has been involved in the design and delivery of over 30 clinical trials and studies, and has sat on many UK and European strategic bodies, including several roles within NIHR. He works with patient groups and advocates globally, with academics and industry, and with researchers and clinicians. An international key opinion former, Richard is the founding co-editor of the Journal of Research Involvement and Engagement, chairs BBMRI-ERIC’s Stakeholder Forum, and chaired the NCRI Consumer Forum 2012-2019.
Keith Wilson is a former heart patient who has worked on a voluntary basis, over many years with various organisations and researchers, promoting Public and Patient involvement to enhance the clarity of documentation and participation in Research. In 2014 Keith was fortunate to become a full-time salaried patient research ambassador at Liverpool Heart and Chest Hospital Trust. Embedding the patient voice not only in research, but everything they do.
Gareth Powell is a business development officer for the NIHR Clinical Research Network (CRN). Gareth facilitates key discussions between industry and the Clinical Research Network, and is a point of contact for life sciences companies engaging with the Clinical Research Network’s Study Support Service to ensure clinical studies are set up efficiently, and recruit to time and target. Gareth has been with the Clinical Research Network since 2009. Before joining the Business Development and Marketing Team, Gareth previously worked within the Research Delivery Directorate. He was responsible for supporting interactions between the life sciences industry and the NIHR National Speciality Groups across seven therapeutic areas, providing operational support through feasibility, set-up and patient recruitment.
Dominic Tyer, interim managing editor, pharmaphorum [moderator] Dominic Tyer is a trained journalist and editor with 19 years of pharmaceutical and healthcare publishing experience. He serves as interim managing editor at pharmaphorum media, which facilitates productive engagement for pharma, bringing healthcare together to drive medical innovation. He is also creative and editorial director at the company’s specialist healthcare content consultancy, pharmaphorum connect.
The antidepressant fluvoxamine merits further investigation as a potential treatment for COVID-19 according to findings of a preliminary trial.
Findings of the trial involving 152 outpatients showed fluvoxamine, a selective serotonin reuptake inhibitor and sigma-1 receptor stopped clinical deterioration compared with placebo.
All the patients on the US-based trial had confirmed COVID-19 and were randomly assigned to receive either fluvoxamine or placebo, three times daily for 15 days.
Participants were community-living, with COVID-19 symptom onset within seven days and oxygen saturation of 92% or greater, according to study findings reported in the Journal of the American Medical Association (JAMA).
Clinical deterioration occurred in no patients in the 80 in the treatment group and six in 72 from the placebo group, although there was a high drop-out rate with only 109 people completing the trial.
The fluvoxamine group had one serious adverse event and 11 other adverse events, whereas the placebo group had six serious adverse events and 12 other adverse events.
Study authors concluded that there was a lower likelihood of clinical deterioration in patients treated with fluvoxamine than those with placebo.
According to study authors, it is the action against the alpha-1 receptor that could be a potential mechanism of action against the virus.
Early studies of COVID-19 found that hospitalisation most often occurs within eight to 10 days of initially mild to moderate symptoms, according to the team from the Washington School of Medicine that conducted the study.
The receptor is linked to regulation of cytokines that cause the inflammation that leads to the serious symptoms seen in some patients with COVID-19.
Previous studies in rats had shown that because of its action on the receptor, fluvoxamine could reduce inflammation and shock.
Authors conceded that if fluvoxamine is determined to be effective in treating COVID-19, the underlying mechanism of action will need further clarification.
Other anti-inflammatory drugs that could show benefits include colchicine and corticosteroids, authors noted.
Perhaps mindful of the many drugs that have failed to live up to early promise in the disease they added that findings were “extremely fragile” because of the small number of endpoint events.
Factors such as distribution of oxygen saturation confounding the results, authors noted.
“The study is limited by a small sample size and short follow-up duration and determination of clinical efficacy would require larger randomised trials with more definitive outcome measures,” they said.
Feature image courtesy of Rocky Mountain Laboratories/NIH
Moderna is the third group in a week to report encouraging phase 3 data with a coronavirus vaccine, saying today that its mRNA-1273 shot had an efficacy of 94.5% in the 30,000-patient COVE study.
The results set up an emergency use authorisation (EUA) filing in the US “within weeks” according to the company, and the UK government has also said it is now in active negotiations with the biotech to try to claim a share of the supply if approved.
The interim analysis from COVE comes after 95 confirmed cases of COVID-19 among the vaccine and placebo groups in the study, which was carried out by Moderna and the National Institute of Allergy and Infectious Diseases (NIAID) in the US.
That’s the same number of cases that prompted the readout of data from a trial of Pfizer/BioNTech’s BNT162b2 a week ago – another mRNA-based vaccine with a 90% efficacy rate – and rather more than the 20 cases used to give a 92% efficacy measure for Russia’s adenovirus-based Sputnik V candidate.
Pfizer chief executive Albert Bourla was among the first to congratulate Moderna on the encouraging data, tweeting:
I am thrilled to hear the good news coming out of @moderna_tx’s #COVID19 vaccine development program. Our companies share a common goal – defeating this dreaded disease – and today we congratulate everyone at Moderna and share in the joy of their encouraging results.
In COVE, 90 cases of COVID-19 were seen in the control arm, compared to five in the mRNA-1273 group. There were also 11 cases of severe COVID-19 out of the 95 total, all of which occurred in the placebo group.
Moderna and the NIAID have also pointed to spectrum of COVID-19 cases in the study, saying that 15 of the 95 were people aged over 65, while 20 were from diverse communities including Hispanic/Latino, black/African American, and Asian American.
A UK government spokesperson said that “advanced discussions” are ongoing with Moderna to ensure UK access to the vaccine, suggesting that doses would become available in spring 2021 in the UK “at the earliest.”
There will be a queue for early access, however. Moderna said towards the end of last month that it had received $1.1 billion in deposits for mRNA-1273, with 100 million doses destined for the US, 50 million heading to Japan, and 20 million to Canada.
Moderna has previously said it expects to produce and ship around 20 million doses of mRNA-1273 to the US this year – a reduction on earlier estimates. It says it could be able to make 500 million to a billion doses next year.
As with the other two vaccine data readouts there are still a lot of unanswered questions with COVE, including whether it can cut viral transmission rates – including asymptomatic transmission – and how long its protection may last.
As more cases of COVID-19 occur in the ongoing study, Moderna notes that the point estimate for vaccine efficacy could change. Nevertheless, there’s little doubt that having three separate vaccines claiming 90%-plus efficacy is a massive boost to hopes of widespread immunisation in 2021.
“This is a pivotal moment in the development of our COVID-19 vaccine candidate,” said Moderna CEO Stéphane Bancel.
“We look forward to the next milestones of submitting for an EUA in the US, and regulatory filings in countries around the world, while we continue to collect data on the safety and efficacy of the vaccine in the COVE study,” he added.
Gilead and Novo Nordisk have announced drug combinations for the fatty liver disease known as NASH involving the GLP-1 class drug semaglutide have checked out in a mid-stage proof-of-concept study.
The companies said that the trial met its primary safety goal in people with non-alcoholic steatohepatitis (NASH) but stopped short of announcing any further plans for clinical development.
Instead they are “carefully evaluating next steps based on a thorough assessment of data,” according to Novo Nordisk’s senior vice president of global development, Martin Holst Lange.
The five-arm trial tested combinations of Novo’s semaglutide GLP-1 agonist, in various combinations with two Gilead pipeline drugs: the FXR agonist cilofexor and the investigational ACC inhibitor firsocostat.
Semaglutide is the active ingredient in Novo’s weekly injection Ozempic and its daily pill Rybelsus, which are both approved to treat type 2 diabetes.
Results of the 24-week trial involving 108 people with NASH were presented at The Liver Meeting Digital Experience over the weekend.
The trial met its primary endpoint by demonstrating that in people with NASH and mild to moderate fibrosis, all regimens were well tolerated.
The most common adverse events (AEs) were gastrointestinal. Minimal pruritus (itching) was observed in people treated with cilofexor.
Across all groups, 5–14% of people discontinued any trial treatment due to AEs.
Exploratory efficacy endpoints assessing biomarkers of liver health at 24 weeks in post-hoc analyses showed statistically significant improvements in liver fat levels and liver injury in the combination arms versus semaglutide alone.
Although liver stiffness measured and enhanced liver fibrosis score declined in all groups, statistically significant differences between groups were not observed.
Gilead and Novo are among a group of companies searching for therapies for NASH, which has for years been predicted to be a source of billions of dollars in revenue for big pharma.
But finding a drug that works against the disease has proved tricky: the FDA rejected Intercept Pharmaceuticals’ FXR agonist obeticholic acid in NASH in July after deciding its benefits would not outweigh its risks.
Although the REGENERATE study showed obeticholic acid increased the likelihood of at least a one-stage improvement in fibrosis without worsening of NASH, it failed to meet another endpoint of improvement in NASH without worsening fibrosis.
Gilead added frisocostat and cilofexor to its pipeline after acquiring them from Nimbus Therapeutics and Phenex Pharmaceuticals, respectively.
The California biotech’s other big hope in NASH selonsertib is yet to produce convincing results in late stage clinical trials.
Johnson & Johnson has begun a second phase 3 trial of its potential COVID-19 vaccine, including sites in the UK, testing whether it works as a two-dose regimen.
The company’s Janssen pharmaceuticals and vaccines unit has already begun the ENSEMBLE study testing the single-dose vaccine and plans to enrol up to 60,000 participants worldwide.
It has now begun the two-dose regimen trial ENSEMBLE 2 trial, which will run in parallel with the first ENSEMBLE and will recruit up to 30,000 people worldwide.
The company acknowledged that a single-dose vaccine with a good safety profile would have significant benefit but is assessing other dosing regimens as well to see if they work better in the long term.
ENSEMBLE 2 study is a randomised, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of a two-dose vaccine regimen versus placebo in adults 18 years old and older.
Patients may or may not have stable comorbidities associated with an increased risk for severe COVID-19.
The study will assess efficacy of the investigational vaccine after both the first and second dose to evaluate protection against the virus and potential incremental benefits for duration of protection with a second dose.
Janssen is testing the vaccine in countries with high infection rates, such as Belgium, Colombia, France, Germany, the Philippines, South Africa, Spain, the United Kingdom and the United States.
In the UK, ENSEMBLE 2 is being conducted in collaboration with the UK National Institute for Health Research (NIHR).
There are 11 vaccines in late stage-development, according to the World Health Organization, including the Pfizer/BioNTech shot, which is more than 90% effective according to top-line clinical trial results announced last week.
BioNTech’s co-founder professor Ugur Sahin told the BBC’s Andrew Marr show that if it is approved by regulators, the vaccine’s impact will significantly kick in over summer, leading to resumption of normal life by next winter.
A new post-hoc analysis from Novo Nordisk of their SUSTAIN 6 and PIONEER 6 studies into semaglutide is looking to help ‘individualise’ treatment for diabetes patients by better predicting their cardiovascular lifetime risk. We spoke to lead study investigator, Utrecht University’s Dr Jan Westerink, to find out how he sees the results being used in daily practice.
The heightened risk of cardiovascular disease remains a pressing concern for type-2 diabetes patients, and one that many healthcare systems have not quite got a handle on yet.
Dr Jan Westerink, assistant professor of internal medicine, University Medical Center, Utrecht, believes that one issue is that the guidelines for addressing cardiovascular risk are too rigid, and don’t take into account each patient’s individual circumstance.
“People always say that patients and doctors should share decision making and discuss treatments with one another, but in reality, most of us just follow the guidelines.
“The problem is, if you have a high risk of cardiovascular disease, the guidelines might suggest that you are given statins and told to take them for the next 50 years, with no discussion at all.”
But Dr Westerink believes there needs to be more room for nuance and an understanding of lifetime risk.
“If you start taking a diabetes treatment with cardiovascular benefits whilst you’re relatively young, you will benefit more than a person who started taking it in their 70s.
“It’s like starting a savings account; if you start young then the benefits will be a lot greater than if you started at a higher age.”
“By using the results of the analysis on individual patient cases, we can show that with the use of semaglutide added to standard of care, some patients will have less than one year’s worth of benefits, and some patients will have more than two years. The mean benefit there would be 1.7 years, but it’s very different for each individual patient.”
But current guidelines do not always take into account this type of reasoning.
Applying a new model
To help understand the lifetime risk of developing CVD and how diabetes drugs like semaglutide can affect this for individual patients, Novo Nordisk conducted a post-hoc analysis by applying the Diabetes Lifetime-perspective prediction (DIAL) of cardiovascular risk model to data from two of Novo Nordisk’s phase 3 trials into semaglutide – SUSTAIN 6 and PIONEER 6.
This model was specifically developed for use in people with type 2 diabetes for lifetime risk prediction of cardiovascular events as well as the years free from cardiovascular disease gained from an intervention.
It was based on data from 389,366 people with type 2 diabetes in the Swedish National Diabetes Registry and externally validated across multiple geographical regions.
Prediction models like this are recommended to help prediction and prevention of cardiovascular disease by leading cardiology associations, including the European Society of Cardiology (ESC).
“As a lifetime risk model, it estimates your life expectancy without cardiovascular disease, whilst also taking into account that you have a risk of dying from other causes,” Westerink, who was lead investigator of the analysis, says.
The two studies included 6,480 people with type 2 diabetes with high cardiovascular risk aged between 50-90 years.
The analysis showed that the addition of semaglutide to standard of care may extend life without a cardiovascular event, such as heart attack or stroke, in people with type 2 diabetes and high cardiovascular risk for up to 3 years, with the average being 18 months.
The results also showed a 20% risk reduction in ten-year risk of experiencing cardiovascular events for participants receiving semaglutide compared to standard of care alone.
With semaglutide, the average number of years during which participants did not experience a cardiovascular event was extended by 7-35 months across all age groups (50 – 90 years), with the greatest benefit seen in people aged between 50 -65 years and with high cardiovascular risk.
The team then took the MACE hazard ratio from the trial cohort – 0.76 – and applied it to patient-level lifetime risk of cardiovascular disease events derived from the DIAL model. From that, they were able to calculate the return on investment from lifetime use of semaglutide for individual patients.
For example, for a specific patient, a 61-year old man with type 2 diabetes and a history of cardiovascular disease, the DIAL model showed that adding semaglutide to standard of care reduced the 10-year risk of having a cardiovascular event by 21% and provided almost two-and-a-half years (29 months) free of cardiovascular events.
“What we found is that, as expected, if you have a large population and you calculate absolute benefits in all those individual patients and you make a histogram, you can see that they have a very wide distribution,” says Dr Westerink.
“Although there’s an average hazard ratio of 0.76 and a 20% risk reduction when looking at every patient, not everybody’s got to benefit to the same extent.”
“By using the results of the analysis on individual patient cases, we can show that with the use of semaglutide added to standard of care, some patients will have less than one year’s worth of benefits, and some patients will have more than two years. The mean benefit there would be 1.7 years, but it’s very different for each individual patient.”
Dr Westerink hopes that insights like this could lead to recommendations for diabetes treatment becoming more personalised, based on each individual patient’s lifetime risk.
He adds that the most important aspect of this approach is its simplicity and logic.
“I’ve never met anybody who doesn’t understand the concept when they hear it,” he says. “The only problem at the moment is that it’s not what doctors are taught to do. Everybody feels that they shouldn’t give older patients certain kinds of drugs, or that they shouldn’t just tell young people to improve their lifestyle and not medicate them at all. In reality, we know that’s not really how it’s supposed to work, and that’s what makes this approach so logical.”
Dr Westerink hopes that eventually this approach will be included in international guidelines, although he acknowledges that changing practice will take “a different way of thinking” from doctors. For example, they might be required to do more in-depth interviews with patients to be able to accurately predict risk.
Westerink adds that individualising treatment in this way could ultimately lead to higher adherence.
“It lets the patient take the lead in their own treatment and lets them know exactly why they are taking a drug,” he says.
About the interviewee
Jan Westerink studied medicine at Utrecht University (1997-2003). During his training as an internist-vascular physician, he carried out three years of doctoral research and obtained his doctorate in 2012 as a result of research focused on the harmful effects of belly fat and the postprandial phase. Since 2013 he has been working as an internist-vascular physician at UMC Utrecht. There is a special interest in vascular diseases in patients with type 2 diabetes mellitus in both care and research.
Today, the University of Exeter and Medicines Discovery Catapult (MDC) announce their strategic partnership to accelerate medicines Research & Development (R&D), creating value for the sector and enhancing translational skills.
MDC is the national centre for technology, innovation and adoption for medicines R&D and, in collaboration with the University of Exeter and its ground-breaking researchers, will maximise the impact and value of basic medical research, to the ultimate benefit of patients. Importantly, this partnership also produces a post-COVID blueprint for academic-Catapult collaboration to drive UK productivity.
To discover new medicines, high quality research must be translated into new drug candidates or technologies through an industrial process of refinement and structured experimentation. This combination of academic endeavour with industrial rigour is critical to produce assets that can be adopted by industry or funded by venture capital. Sharing skills and experience across these two disciplines is also key to how translation can be dramatically improved across UK institutions at this time of exceptional challenge.
Coupling the world-class research at Exeter with MDC’s industry skills, cutting-edge discovery platforms, data technologies and access to its national networks ensures promising innovations are identified, independently validated and packaged so that industry and funders are able to adopt them, with clear benefits to the entire community.
Activities of focus for the partners can be broadly categorised as follows:
Identifying research that can be supported at its earliest stages
Developing identified innovation into an independently validated proposition, allowing investors and pharmaceutical partners to join projects with confidence
Embedding industry standard drug discovery thinking and knowledge at the point of ideation, creating better medicines of the future
Identifying and developing new mechanisms to sustain the development of these medicines, through novel funding mechanisms and partnerships
Prof. Neil Gow FRS, Deputy Vice-Chancellor (Research and Impact) of the University of Exeter, says:
“This exciting partnership offers much for both parties. It will enable our researchers to take their novel ideas beyond the stage where academic inspiration transitions into translational applications. For Medicines Discovery Catapult, we hope this will deepen the well of creative ideas that their expertise can support.
“I look forward to seeing both partners achieve their goals – making a difference and enabling us to translate research well beyond the lab, into real-world impact. This pioneering partnership will create a blueprint for accelerating innovation, enabling our research to have meaningful benefits on people’s health and wellbeing.”
Professor Chris Molloy, Chief Executive Officer at Medicines Discovery Catapult says:
“This partnership is the realisation of a faster route for innovative research to reach the clinic. It is also a paradigm for how universities and industrial translators can each do what they are best at, and maximise national impact – now and into the future.
“This shared-skills, co-operative approach tackles a deep structural issue head on and ensures the best ideas see the light of day at pace and scale for the benefit of patients and the UK economy.
“Access to our skills, technology and networks at a critical stage of medicines discovery means we and the University of Exeter can develop future medicines as well as future wealth creating academic translators.”
Dr. Tony Soteriou, Director for Commercialisation of Research, UKRI says:
“UK Research and Innovation works in partnership with universities, research organisations, businesses, charities, and government to create the best possible environment for research and innovation to flourish.
“The partnership between the University of Exeter and Medicines Discovery Catapult exemplifies this spirit, unblocking one of the major bottlenecks in translation and commercialisation. It capitalises on the excellent work performed by leading academics and ensures it reaches industry in a format that is ready to attract onwards funding and investment.”
Collaboration between the two organisations was initiated and facilitated by Dr. Jehangir Cama, David Whitehouse and Prof. Krasimira Tsaneva-Atanasova, members of the Wellcome Trust funded ‘Translational Research Exchange @ Exeter’ (TREE).
Joint events were hosted pre-COVID-19 at Exeter’s flagship Living Systems Institute to identify early stage innovation, which subsequently initialised several projects involving University of Exeter academic staff, pre-spin out companies and industry specialists at MDC to create independently validated propositions and thus accelerate their development to clinic.
The announced formal agreement of a strategic partnership between the University and MDC will now further strengthen and develop the collaboration, delivering a new paradigm for University-Catapult cooperation and translational science in the UK.
UCB has made a new foray into the gene therapy space, buying fellow Belgium-based company Handl to get control of its adeno-associated virus (AAV) capsid delivery platform and two research programmes in neurodegenerative diseases.
The mid-sized pharma group has also signed a collaboration with Florida, US-based Lacerta Therapeutics, adding more AAV capsids – well established as a staple for delivering gene therapy sequences – as well as another gene therapy candidate.
Like many other pharma companies, UCB has been building a presence in gene therapy as the sector gathers momentum with more therapies getting regulatory approval.
The company says that is part of a shifting focus from “symptomatic treatments to disease modification and eventually towards a cure.”
In 2018, it bought Element Genomics – a spin-out of Duke University in the US – to add genome-editing technologies, and has also been growing its internal exercise at its Boston R&D hub, although so far it hasn’t advanced and gene therapies into clinical development.
Earlier this year, UCB also bought a 47-acre UK R&D campus from Eli Lilly, saying it intends to develop it as a hub for R&D in “gene therapies, translational medicine and antibody discovery.”
It is also in the process of constructing a €300 million biological manufacturing facility at its site in Braine l’Alleud, Belgium, to ensure the supply of medicines in clinical development.
“A vast array of diseases are amenable to gene therapy and UCB is embracing this modality to expand its capabilities and ultimately transform the lives of patients with severe diseases,” said the company in a statement.
It added that AAV-mediated gene therapy can “drive a fundamental change in how diseases are treated with the ability to remove or add disease-related proteins with a single treatment.”
Leuven-based Handl was formed last year by Prof Michael Linden – formerly vice president of gene therapy at Pfizer – and Florent Gros, who has held executive positions at Nestlé, Pasteur Merieux Connaught and Novartis.
Handl’s technology portfolio stems from licensing deals with Prof Linden’s former employer King’s College London, as well as Belgium’s KU Leuven, the Centre for Applied Medical Research in Spain, and the University of Chile.
UCB hasn’t revealed how much it is paying for Handl, or indeed the terms of its alliance with Lacerta, a University of Florida spin-out which also focuses on central nervous system diseases and will contribute research and manufacturing expertise.
Handl has also tapped into the development and manufacturing capabilities at Novasep, a contract manufacturing organisation (CMO) also based in Belgium.
Under the terms of that agreement, Novasep will develop and manufacture AAV vectors and supply drug substances to support Handl’s preclinical and clinical studies.
Swiss startup Synendos Therapeutics has raised CHF 20 million (almost $22 million) in first-round financing that will be used to develop its endocannabinoid drugs for central nervous system disorders.
The Basel-based biotech – which was incubated in Switzerland’s BaseLaunch accelerator – is concentrating on developing a new class of small-molecule drugs for anxiety, mood and stress-related disorders.
Synendos says the cash will allow it to take its lead product SYT-510 through preclinical and proof-of-concept clinical development. It comes shortly after the company secured a CHF 1 million grant from the Swiss government’s innovation agency Innosuisse.
The company was founded as a spin-off of the University of Bern and Swiss research institute NCCR TransCure in April 2019, and is focused on the development of a new class of drugs that work on endocannabinoids, a type of neurotransmitter that bind to the receptors in the brain targeted by cannabinoid compounds.
Endocannabinoids are involved in regulating various physiological and cognitive processes, according to Synendos.
The company has developed selective endocannabinoid reuptake inhibitors (SERIs), which enhance the activity of the neurotransmitters at the junctions between neurons. The programme stems from research carried out at Bern by co-founders, Professor Jürg Gertsch and Dr Andrea Chicca.
Along with SYT-510, the company has identified two other backup compounds from a screening process that started with more than 12 million candidates. It has also received funding from the European Commission to develop SYT-510 as a treatment for post-traumatic stress disorder.
“It has been 25 years since a new drug was approved for the treatment of neuropsychiatric disorders,” according to Chicca, who serves as chief executive of the biotech. “This highlights the urgent need for new safe and effective treatments in this area.”
Synendos isn’t the only company exploring the potential of the endocannabinoid system. Another is Corbus Therapeutics of the US, although its interest is mainly in drugs for inflammatory and fibrotic diseases rather than CNS.
Among the companies looking at interacting with the endocannabinoid pathway for CNS diseases are Inversago Pharma, Abide Pharma (now part of Lundbeck) and Neuritek Therapeutics.
The Series A was co-led by Kurma Partners and Sunstone Life Science Ventures, with BERNINA BioInvest, Schroder Adveq, High-Tech Gründerfonds, Lichtsteiner Foundation, Essential Investments, Zürcher Kantonalbank and private investors also taking part.
“We are very pleased to have attracted such a strong syndicate of world-class investors,” added Chicca. “In the validation of our science, they bring much more than just financing and will enable us to work towards reaching a clinical inflection point with an efficient and clearly-defined path.”
Boehringer Ingelheim and South Korea’s Bridge Therapeutics have decided to axe their collaboration over a potential new drug for idiopathic pulmonary fibrosis (IPF), BBT-877.
The German pharma had hoped the drug would be a successor to Ofev (nintedanib), which is one of its most important drugs and is approved for the potentially fatal lung-scarring disease.
Signed in July last year, Boehringer paid 45 million euros up front and the deal would have been worth up to 1.1 billion euros in milestone payments if trials had worked out plus royalties.
While the companies gave no further details about why the partnership came to an abrupt halt, the German pharma announced earlier this year that it was concerned about the drug’s potential toxicity. Bridge said that it still plans to continue developing BBT-977 to treat IPF.
At the time the agreement was signed, BBT-877 was in phase 1 development but shares in Korean biotech tanked in August when Boehringer announced that BBT-877 would need additional testing.
This delayed a phase 2 trial and at the time Bridge acknowledged it was possible that the German pharma would return rights.
Boehringer had wanted to conduct two further toxicity tests following results from preclinical trials.
Following the cancellation of the tie-up, Bridge will regain all rights to BBT-877, which is also in development for other fibrotic diseases.
CEO James Lee said: “After receiving and reviewing data and dossiers, we will closely work with regulatory authorities to clarify future development plans and necessary studies to initiate human trials in the future.”
BBT-877 was originally discovered by Korea’s LegoChem Biosciences and licensed to Bridge Biotherapeutics in 2017.
It works by inhibiting autotaxin, a protein discovered in the early 1990s that is an important enzyme for generating the lipid-signalling molecule, lysophosphatidic acid.
Founded in 2015, Bridge’s clinical pipeline includes BBT-401, a first-in-class Pellino-1 inhibitor for ulcerative colitis.
It is also developing BBT-176, a potent targeted cancer therapy for non–small cell lung cancer (NSCLC). Bridge is resident at Johnson & Johnson’s JLABS facility in Shanghai.
In the second positive piece of COVID-19 vaccine news in a week, Russia’s Sputnik V candidate has been shown to be 92% effective at the interim point of a 40,000-patient study.
The preliminary assessment is based on 20 coronavirus cases split between the vaccinated and placebo arms of the study at 21 days, according to a press statement issued this morning by the Gamaleya Institute which developed the shot and the Russian Direct Investment Fund (RDIF).
They say the positive interim results will be followed by “mass vaccination in Russia against COVID-19 in the coming weeks.” The country has had more than 1.8 million confirmed coronavirus infections, and just over 31,000 deaths.
The readout from the study comes at a point when 20,000 people have been given the first of the two-dose regimen for the adenovirus-based vaccine, and 16,000 have had the second. There were no unexpected adverse events as yet, with most side effects injection site reactions or minor flu-like symptoms.
Sputnik V has already been approved in Russia ahead of the phase 3 trial results, getting a green light in August on the strength of early-stage data in 100 patients. Since then, around 10,000 people have received it and monitoring of those subjects “confirmed vaccine efficacy at a rate of over 90%,” according to the statement.
The update comes just a couple of days after BioNTech and Pfizer reported a 90% efficacy rate at 28 days with their mRNA-based candidate BNT162b2 from an evaluation of 94 cases in a phase 3 trial involving 43,538 subjects.
In both these cases only the top-line data is available, and medical experts are waiting anxiously for a full look at the data sets, to see for example if the vaccines are able to reduce the rate of severe COVID-19, prevent asymptomatic infection with SARS-CoV-2, and cut viral transmission rates.
It’s also not clear how well they work in different patient populations, such as older people, children and different ethnic backgrounds, and how long protection will last.
The Gamaleya Institute and RDIF says they will follow up all patients in the study for six months, after which final results will be reported. In the meantime, phase 3 trials of Sputnik V are also underway in Belarus, United Arab Emirates and Venezuela, with a phase 2/3 study on the go in India.
Russia’s minister of health Mikhail Marushko hailed the results, saying they show Sputnik V is “an efficient solution to stop the spread of coronavirus infection, а preventive healthcare tool, and this is the most successful path to defeat the pandemic.”
Requests for more than 1.2 billion doses of Sputnik V have already come in from over 50 countries, according to the RDIF, which says it has contracts in pace that will allow production of 500 million doses of V vaccine outside Russia every year.
In other news, the 60,000-patient ENSEMBLE trial of Johnson & Johnson’s coronavirus vaccine candidate has started to resume in Europe after a suspension caused by an unexplained illness in a test subject in October. The trial was cleared to restart in the US a few days later.
Meanwhile, Brazilian regulator Anvisa has suspended clinical testing of a shot being developed by China’s Sinovac Biotech after a “severe adverse incident” – reported to be fatality – in the phase 3 CoronaVac trial being conducted in the country.
The study is also being conducted in Turkey and Indonesia, but dosing hasn’t been suspended int those countries, according to a BBC report.
As part of our series looking at how pharma companies have adapted to the pandemic, Shannon Rush, leader of Eli Lilly & Co’s diabetes business unit in Northern Europe, tells pharmaphorum how the company is working to support diabetes care in the UK amid the pandemic.
As COVID-19 turned the world on its head, healthcare services for people living with long-term conditions like diabetes, came under a huge strain.
With the NHS advising that the virus could have a worse effect on people with diabetes, Eli Lilly & Co knew it needed to help physicians keep services running.
“From a business unit standpoint, the first thing we did was to connect with clinicians and ask how we could help,” Shannon Rush told pharmaphorum. “I needed to get a pulse of how we could add value.”
The company decided to develop a series of virtual webinars to support physicians with COVID-19. The first part focused on how healthcare systems could triage patients with diabetes and COVID-19.
“We looked at how will you need to assess them? How does it affect the medications they are on? What things would you do differently?” she said.
The next part tackled how to virtually assess patients and initiate different medications. “We really just flipped everything on its head. We had to adapt to what our customers need from us right now and that is helping them handle a co-morbidity illness during an acute healthcare crisis.”
Offering the webinars from across the organisation only two weeks after conceiving the idea was a proud moment, says Rush. “We are still offering it as obviously this is our new reality – we won’t be going back to the days of clinicians seeing as many people face-to-face.”
“I think the innovation of how we live, how we’re able to interact from a healthcare setting, I think it’s something that will live beyond COVID-19. For me, it is just the sheer impact of how we all adapted, not just the healthcare system, in general, to really respond”
While the pandemic accelerated plans, digital education is something Eli Lilly had always planned to do. Ensuring compliance across the company was also a challenge.
“That is our North Star, we want to make sure we’re doing things in a compliant way. Again, it was another cross-functional effort across our entire organisation to make sure that we were able to interact virtually in the right way,” says Rush.
“It seems like it’s common sense, but as we see, there are more challenges to it, sometimes, than not. We had a general upskilling, as well, in diabetes to helps advance the treatment during this, as well.”
Population health tools
Eli & Lilly diabetes also worked with the NHS, to create a population health management tool. The tool PARM (ProActive Register Management) Diabetes allows for clinical commissioning groups (CCGs) to stratify the risk and opportunities to treat specific populations and review analytics on different cohorts living with illnesses. The tool organises practice-level patient data to show how well patients are managing their condition, identify any potential issues as well as those who need critical or urgent attention, and can predict who may need input from a diabetes specialist in the future.
“That’s another way we’ve been able to help beyond the day-to-day patient care. The data stays within the CCG but it helps them to look at their organisation and the ones they serve.”
For Eli Lilly, it opens partnership opportunities for different resources that could help CCGs once their population needs are assessed. This support across the healthcare value is important for the company, Rush says.
“Obviously right now we do not have direct opportunities for direct patient feedback, but via clinicians the main thing we kept hearing is they wanted stability. Patients wanted the reassurance that even while COVID-19 was in this acute phase they could still manage their health effectively.”
PARM Diabetes aims to provide this stability. “For some there is comfort in knowing that, obviously, everybody was doing the right thing to manage COVID-19 but not forgetting there were opportunities for those living with diabetes and other illnesses to continue to manage as they would.”
Despite the severity and devastation of COVID-19, Rush believes there has been some “shining lights” coming out of it.
“I think the innovation of how we live, how we’re able to interact from a healthcare setting, I think it’s something that will live beyond COVID-19. For me, it is just the sheer impact of how we all adapted, not just the healthcare system, in general, to really respond.”
Recently, Brittany Erana, MPM, Vice President of PPD® Digital; and Niklas Morton, MSc, Senior Vice President of PPD® Digital, spoke with leaders of Science 37, Medable, and Takeda in an online forum about how the industry is shifting to focus on decentralized trials. They then took questions from attendees regarding their experiences and best practices […]
As the death toll from COVID19 inexorably mounts, Pfizer and BioNTech have announced that their COVID-19 vaccine candidate is more than 90% effective at countering the disease in an interim analysis.
The companies said they will be ready to file the vaccine with the FDA in the third week of November once they have enough safety data to meet the regulator’s requirements.
Top-line results come from a phase 3 trial of the candidate known as BNT162b2 and an evaluation of 94 cases from the trial of 43,538 patients.
The case split between vaccinated individuals and those who received the placebo indicates a vaccine efficacy rate above 90%, at seven days after the second dose, the companies noted.
This means that protection is achieved 28 days after the initiation of the vaccination, which consists of a 2-dose schedule.
The companies cautioned that as the study continues, the final vaccine efficacy percentage may vary.
The independent data monitoring committee that conducted the interim analysis said that there had been no serious safety concerns identified.
It recommended that the study continues to collect additional safety and efficacy data as planned.
Results will be discussed with regulators worldwide and the European Medicines Agency has already begun its rolling review of data to hasten a decision on the clinical trial dossier.
The phase 3 clinical trial of BNT162b2 began at the end of July and has enrolled 43,538 participants to date, 38,955 of whom have received a second dose of the vaccine candidate as of November 8, 2020.
Around 42% of global participants and 30% of U.S. participants have racially and ethnically diverse backgrounds.
The vaccine is based on a strand of messenger RNA – a short segment of genetical material that codes for the “Spike” protein found on the surface of the coronavirus.
These cause the body to produce antibodies that neutralise the SARS-CoV-2 virus in the event of an infection.
Last month the companies aid that they are already producing hundreds of thousands of shots each day should the vaccine get approved.
However it remains to be seen whether countries such as the US and UK, which have ordered millions of shots, will be able to organise a mass vaccination programme after failing to implement track and trace measures that could also slow the spread of the disease.
Pfizer’s CEO Albert Bourla said: “Today is a great day for science and humanity. The first set of results from our Phase 3 COVID-19 vaccine trial provides the initial evidence of our vaccine’s ability to prevent COVID-19.
“We are reaching this critical milestone in our vaccine development program at a time when the world needs it most with infection rates setting new records, hospitals nearing over-capacity and economies struggling to reopen.
“With today’s news, we are a significant step closer to providing people around the world with a much-needed breakthrough to help bring an end to this global health crisis. We look forward to sharing additional efficacy and safety data generated from thousands of participants in the coming weeks.”
The vaccine is one of 47 in clinical development, according to the World Health Organization, showing several shots developed in China and a rival from the UK’s AstraZeneca are also close to reading out late-stage clinical results.
The pharma industry has developed vaccines for COVID-19 in record-breaking time after scientists from China published details of the SARS-CoV-2 virus shortly after the outbreak began in January.
Feature image courtesy of Rocky Mountain Laboratories/NIH
Sanofi’s attempt to take on Roche with a ground-breaking approach to treating haemophilia has hit a setback after the company voluntarily placed its late-stage trials of fitusiran on hold because of safety issues.
The news that phase 3 development has been put on hold was not announced by the French pharma, but in a joint statement from three haemophilia patient groups.
Sanofi’s management has highlighted fitusiran, a potential competitor to Roche’s haemophilia A drug Hemlibra, as one of the most important drugs in its pipeline.
Fitusiran is being developed for haemophilia A and B in partnership with RNA interference (RNAi) specialist Alnylam – but has already been affected by safety issues.
Alnylam temporarily halted a phase 2 trial in 2017 after a blood clot killed a patient but research resumed in late 2017 after the FDA and Alnylam agreed on new clinical risk mitigation measures.
In a joint statement the World Federation of Hemophilia, the European Haemophilia Consortium and the National Hemophilia Foundation said Sanofi had voluntary put the full development programme on hold “due to the identification of new adverse events”.
In a research note a team of analysts from Jefferies said that fitusiran is unlikely to make difference to Sanofi’s bottom line but could be a “key catalyst to invigorate belief” in the company’s drug pipeline.
According to Jefferies the trial was put on hold to allow investigations of “non-fatal thrombotic events” on 30 October.
Jefferies said it remains unknown if these events are treatment-related or reflect existing illnesses in patients.
The safety events were perhaps compounded by COVID19, which has been associated with abnormal blood clotting in some serious cases.
In the note the Jefferies team led by Peter Welford said that “a setback would likely be perceived negatively for sentiment, particularly as belief in the pipeline is beginning to be built.”
This is likely a reference to Sanofi’s success with Dupixent (dupilumab), developed in partnership with Regeneron for disease including asthma and eczema, which has helped revive the company’s fortunes since a first approval in 2017.
Alnylam’s RNAi technology uses small interfering RNA molecules to target strings of defective RNA molecules in cells, preventing them from coding disease-coding proteins.
COVID-19 has sparked a flurry of research and discoveries are being made at an unprecedented rate – but patient participation cannot and should not be left behind in the rush, say leading voices.
SARS-CoV-2 has demonstrated both the strengths and the weaknesses of the life sciences ecosystem, and it is now up to the sector to learn and to lead.
While trials of COVID-19 vaccines and treatments have accelerated at a hitherto unimaginable rate, work in other conditions has been halted and paused, both of which could hinder future progress, said Aisling Burnand, chief executive of the Association of Medical Research Charities (AMRC).
“In a race of frantic, unprecedented change with challenges none of us have faced before, patient and public involvement has felt pushed aside.”
“Research has stopped, and what has gone ahead has felt rushed, with little listening,” she said during the first session of this year’s Pioneering Partnerships conference, organised by the Association of the British Pharmaceutical Industry (ABPI), the National Institute for Health Research (NIHR), and the AMRC.
As we turn the research tap back on, the sector must do everything it can ensure the patient voice gains rather than loses importance, said the speakers.
“One of the consequences of the system commissioning lots of urgent COVID-19 research was that, to a certain extent, patient and public involvement got bypassed. For various reasons it was too difficult or time consuming to do when everybody was in a frightful rush”
In April, 73% of clinical trials were stopped, and, as of early October, more than 40% were still on hold.
Aisling said we were “unlikely” to reach pre-COVID levels of non-SARS-CoV-2 clinical research before August 2021, even without the looming second wave. It means that without a cross-sector plan to get trials back up a running, a decade of research could be lost to the COVID-19 crisis.
Baroness Nicola Blackwood, Conservative MP and chair of Genomics England, agreed, and said that unlocking what we have learned from research during the pandemic so far would help move the NHS from a “sick care service to a healthcare service”.
“COVID-19 has transformed the way clinical trials are run. Our research ecosystem responded to the crisis with a pace and effectiveness that few other nations were able to match,” said Baroness Blackwood.
“UK researchers sourced streamlined regulatory processes, had better communication with patients and clinicians, and we saw some much more sensible approaches to risk. This sped up the development of new COVID treatments, without sacrificing safety.”
But the crisis also brought some of the system’s weaknesses into sharp focus, said NIHR director Jeremy Taylor.
“One of the consequences of the system commissioning lots of urgent COVID-19 research was that, to a certain extent, patient and public involvement got bypassed. For various reasons it was too difficult or time consuming to do when everybody was in a frightful rush,” he said.
“Patient and public involvement turned out to be less embedded than we thought, so I think COVID has been a bit of a shock to the system. It’s made us think that maybe we have been a little bit too complacent.”
The virus, which has disproportionally affected people from Black, Asian and minatory ethic (BAME) communities had also highlighted a lack of diverse voices, and the urgent need to address clinical trial representation and health inequalities, he said.
“We need more BAME voices around the table. We need younger people, and we need people from excluded communities.”
Regardless of what the health system is faced with, Dr Richard Torbett, chief executive of the ABPI, said that “we can’t ignore our collective responsibility to make sure we conduct ethical research”.
“We need to continue advocating the importance of having the patient voice right at the heart of everything that we do.”
Building on the positives
Aisling said we needed to build upon the positives, pointing to the increased public awareness around the process, language, and importance of clinical research.
More people have volunteered for trials than ever before and thousands are monitoring their health on a daily basis.
The sector must seize this opportunity to build back better and stronger, the speakers agreed.
Said Baroness Blackwood: “We need to look honestly at the areas where the crisis has brought sharp relief, and what needs to be improved.
“If we don’t take this chance, we risk losing what is a golden moment to make our clinical research landscape fit for the next generation.”
It was a sentiment echoed by Dr Torbett, who said the UK government needed to take “urgent action” to develop a sustainable, safe, restart plan for non-COVID clinical research.
“It is incredibly important to ensure all patients have the opportunity to be involved and engaged with research. That needs to be a principle that carries right the way through this,” he said.
“I really feel that we’ve got a head of steam right now with multiple stakeholders, particularly in this country, who really understand the value of medical research. We have a genuine opportunity to lead here.”
In response to the COVID-19 pandemic, the ABPI has published a summary of its advice to the pharmaceutical industry on working with patients and the public. Click here for more information.
Swedish biotech Calliditas has announced plans to file its rare disease drug Nefecon with the FDA early next year following positive results from a phase 3 clinical trial.
The company has been developing Nefecon to treat the primary IgA nephropathy, a rare disease that affects the kidney but is caused by overproduction of antibodies produced in the lining of the small intestine, for which there are no approved medications.
Approval by the FDA would give Calliditas a clear shot at the market for the disease affecting 130,000-150,000 people in the US, although US biotech Aravive has a potential competitor in mid-stage clinical development.
Calliditas said part A of the global phase 3 NeflgArd clinical trial has met its target, measuring the effect of Nefecon versus placebo in patients with the disease known as IgAN for short.
Nefecon is a formulation of the established immunology drug budesonide, which targets the Peyer’s patches that are over-active in patients with IgAN.
The antibodies produced as a result lodge in the kidneys, causing severe complications.
The trial met its primary objective of demonstrating a statistically significant reduction in urine protein creatinine ratio (UPCR) or proteinuria after nine months of treatment with 16 mg of Nefecon compared to placebo, with significant continued improvement at 12 months.
The primary endpoint analysis showed a 31% mean reduction in the 16 mg arm versus baseline, with placebo showing a 5% mean reduction versus baseline, resulting in a 27% mean reduction at 9 months of the 16 mg arm versus placebo.
The 199-patient trial also met the key secondary endpoint showing a statistically significant difference in estimated glomerular filtration rate or eGFR after 9 months of treatment with Nefecon compared with placebo.
The eGFR endpoint showed a treatment benefit of 7% versus placebo at nine months, reflecting stabilisation in the treatment arm and a 7% decline of eGFR in the placebo arm.
Collectively the efficacy data from nine months treatment with 16 mg of Nefecon indicated a significant and beneficial effect on key factors correlated to the progression to end stage renal disease (ESRD) for IgAN patients, the company said.
The results indicate that Nefecon was generally well-tolerated and were consistent with the known safety profile of Budesonide. The number of withdrawals in the trial was significantly less than what was seen in the Phase 2b NEFIGAN trial.
Calliditas plans to file for an accelerated approval based on these early results with the FDA in the first quarter of 2021.
A filing for a conditional approval with the European Medicines Agency will follow in the second half of next year.
If approved, Calliditas aims to market Nefecon for IgAN by itself in the US and through collaborations in other regions.
Both of these approvals will require confirmatory data from a larger set of patients for the drug to remain on the market permanently.
Calliditas is led by CEO Renee Aguiar-Lucander and has funded development of Nefecon following an $81m IPO in 2018.
Aguiar-Lucander said in a statement: “Calliditas has been a pioneer in IgAN for many years and we are excited to be the only company to have reported out a positive phase 3 trial in this indication. This result brings hope to thousands of patients who today have no approved treatment alternatives.”
Novo Nordisk has agreed to buy Emisphere Technologies for $1.8 billion, as it continues its quest to develop diabetes medicines that can be taken as pills.
Copenhagen-based Novo Nordisk already markets Rybelsus (semaglutide), a version of its GLP-1 class drug that can help to control blood sugar levels in patients with type 2 disease.
But the company has tried and failed to produce insulin that can be taken orally – this proved unfeasible due to the high doses of the hormone that were needed for absorption through the gut.
The two companies have been working together since 2007 and Emisphere’s technology is already used under a licence agreement in the formulation for Rybelsus.
Novo will buy all outstanding shares in Emisphere for $1.35 billion plus royalty obligations owed to MHR Fund Management, Emisphere’s largest shareholder, for $450 million.
Chief scientific officer Mads Krogsgaard Thomsen told Reuters in an interview: “I don’t think we will ever completely get rid of the needles.”
“We have been making injection drugs for a hundred years, but we just have to admit that if we want patients to get treatment quickly in order to optimise the long-term course of the illness, then it requires tablets if possible,” he said.
Novo said it plans to make “substantial investments” into the platform and has around a hundred scientists at its headquarters refining the tablet technology.
He added: “By further developing the technology, we hope in the future to produce the medicine cheaper than we do now, thus allowing us to penetrate more markets and give broader access to diabetes drugs.”
Novo launched Rybelsus in the UK in September after it won backing from the cost-effectiveness body NICE.
After EU approval in April Novo said it had priced Rybelsus at parity with rival GLP-1 drugs in the UK, and NICE will not perform a single technology appraisal as a result, allowing the company to begin negotiations in England and Wales to get the drug included on NHS formularies.
Novartis’ Ilaris (canakinumab) has failed to produce results in a phase 3 trial, which tested whether it could improve COVID-19 patients’ survival chances without need for mechanical ventilation.
The company is trying to repurpose the drug used in rare inflammatory diseases such as juvenile arthritis for COVID-19, to see if it could relieve the extreme immune reaction that can prove fatal after infection with coronavirus.
But results from the CAN-COVID trial showed that Ilaris also missed an important secondary goal of reduced COVID-19 mortality compared with standard therapy.
In the trial involving 454 patients in the US, Russia and Europe, the primary endpoint of survival without the need for mechanical ventilation was 88.8% for canakinumab plus standard care compared with 85.7% for placebo plus standard care.
The key secondary endpoint was to reduce the COVID-19-related death rate during the four week period after trial treatment.
While the data trended in Ilaris’ favour against both targets, the effect seen was not marked enough to be statistically significant.
Novartis noted that the results from this trial do not affect Ilaris’ licensed indications or other trials and the safety profile was comparable to placebo plus standard of care.
An interim analysis will be submitted to a peer-reviewed journal in the coming weeks.
The company said the focus in COVID-19 moves to Jakavi/Jakafi (ruxolitinib), which is in a phase 3 trial and is another attempt to repurpose an already approved drug – Jakafi is already approved in indications including myelofibrosis.
Novartis is also working with Molecular Partners to develop therapies based on genetically engineered proteins known as DARPins.
These are small proteins that are created in the lab but mimic the effect of antibodies and could be used to neutralise the SARS-CoV-2 coronavirus that causes COVID-19.
There have been countless efforts to repurpose existing drugs to fight COVID-19, with the most successful arguably being dexamethasone.
The cheap steroid has been shown to reduce inflammation caused by the disease in the UK’s large RECOVERY trial, which is testing several already licensed drugs against COVID-19.
COVID-19 has been a shock to the system for every industry, not least pharma, but the sector is already looking at new ways to build resilience for the future.
Kevin Nikitczuk, INTIENT Network lead at Accenture, notes that collaboration and innovation are two of the key aspects that allow pharma to be ready for (hopefully unlikely) future situations akin to the pandemic.
“With COVID-19, the industry has realised that they need to accelerate and expedite everything they do – from identifying new targets to executing clinical studies to getting drugs onto the market.”
The sharing of knowledge has already been critical in the industry’s collaborative efforts to expedite a COVID-19 vaccine, and Nikitczuk believes that this open approach should extend beyond research into the software and data tools pharma uses every day.
A current problem, he notes, is that each of the many steps on this path requires different software tools – and most companies are using myriad different platforms within their organisation.
Part of this is an issue with unproductive competition – which can sometimes be a road blocker for innovation, particularly when proprietary technology is custom-built by niche players or developed in-house.
But it’s also true that over recent years – and especially during the course of the pandemic – the pace of technological growth in pharma has exploded, meaning there are more possible solutions available than ever, including more patient-facing technology such as telemedicine.
“We have some partners providing very similar tools to each other, and that’s okay, because we want to provide clients with options… I think that helps foster collaboration and encourages a little bit of healthy competition – which is always good for science”
This fragmented landscape creates issues for pharma.
“If, for example, regulations change or new standards for processing data come out, companies are going to face difficulties if they don’t have the proper infrastructure to quickly pivot out their software with new tools,” Nikitczuk says.
“Because of that, they may miss out on getting their products to patients in time.”
Nikitczuk believes that open, cross-company collaboration will be key to building flexibility and, ultimately, resilience against these difficulties.
Accenture, for example, decided to take its previously siloed platform products in areas as diverse as research, clinical studies and patient support and bring them under one umbrella.
The resulting INTIENT Platform brings together multiple third-party tools to allow continuity and flow of data across software and companies, whilst also facilitating insights delivered by artificial intelligence.
Rahul Kabra, INTIENT’s Europe lead, says he hopes the platform will streamline and accelerate collaboration across an entire product life cycle.
“We have partners providing patient facing capabilities in the form of medical devices or tools to enhance adherence. We also have partners providing the backend technology to secure personal data or manage workflows.
“Pharma and external partners can now use all these tools under one, end-to-end platform.”
In fact, Nikitczuk notes that clients themselves had a large role to play in pushing for a joined-up approach – showing that the spirit of collaboration in the industry is putting to rest any concerns that competition will continue to be a barrier.
“Our clients started pointing out that even though they were subscribed to several of our platforms, these tools weren’t talking to each other, and everything was still siloed.
“We took their advice and worked with them to bring these platforms together onto one end-to-end solution. Then we started working on bringing third-party vendors in. It’s been really great to see the collaborations blossom.”
To further this, Accenture is encouraging clients to develop their own software tools or bring their existing niche partners into the ecosystem and strengthen its capabilities.
It is also further encouraging open collaboration by keeping the platform solution-agnostic.
“We have some partners providing very similar tools to each other, and that’s okay, because some clients have a preference for certain vendors, and we want to be able to showcase that and provide clients with options.
“I think that helps foster collaboration and encourages a little bit of healthy competition – which is always good for science.”
Another reason for this approach is the fact that, traditionally, trying to get a software solution into a pharma company has been quite an endeavour.
“First you have to navigate procurement, which can be inhibitive for smaller start-ups. Even well-established firms struggle to get new products installed in large companies or even single departments which can be a time- and resource-intensive activity. We want to make this process incredibly fast.”
Nikitczuk adds that the more this partnership ecosystem and infrastructure is built up, the easier it will be to get future solutions onto the platform and into pharma companies.
Kabra adds that, as with pharma companies sharing knowledge to develop COVID-19 vaccines, he hopes that open collaborations like this in software will allow life science companies to take advantage of the collective intelligence of independent vendors who have poured all their time, energy, and passion into developing solutions – which, in turn, will enable the industry to push boundaries and accelerate innovation.
“By being more open, the industry can allow companies the flexibility to test and implement new, potentially game-changing technologies,” Kabra says.
“We might even see the days of laborious, expensive, and inefficient procurement and implementation processes become a thing of the past.”
This is part of the draw of true open collaboration – when different companies are aligned to the same goals, processes that once took months to do can be done in days, or even less.
“As the biopharma landscape grows and evolves, we must continue to uncover new insights and innovative uses for data,” says Kabra. “By doing so, we develop new opportunities to raise the standard and personalisation of patient care and accelerate treatments to market.”
Luckily, it seems that the industry is more than ready to be truly collaborative and drive this collective mission forward.
To learn more about how Accenture is bringing companies together, click here.
About the interviewees
Kevin Nikitczuk is a senior principal within Accenture’s Life Sciences, leading the network partnerships for the INTIENT platform. Kevin has an in-depth working knowledge of life science R&D after years of laboratory and corporate experience within the pharmaceutical, biotechnology, and medical devices fields. Kevin earned a PhD in Immuno-Oncology from Rutgers University and has published peer-reviewed articles on his work and holds several patents.
Rahul has over 25 years’ experience in technology strategy, innovation, global partnerships and solution development. He has previously held positions as a Strategy Lead for Accenture’s Products Group, and as the Ecosystem and Ventures Lead for Accenture Technology. Rahul holds a degree in Computing from City University London, and an MBA from Henley Business School.
Accelerate the Bench to Bedside Development of Novel CAR Immunotherapies for Safe, Effective & Affordable Advanced Therapies
With CAR-TCR therapies on the cusp of achieving global approval, there are still many bottlenecks that are preventing this from becoming the ‘sell-out’ therapy that the field had hoped for.
The CAR-TCR Summit Europe (16th-18th February 2021) will unravel the technical challenges across R&D, translation, scale and delivery to provide your team with the platform to learn, collaborate and gain actionable insights to advance your therapy for clinical and commercial success.
This year’s focused agenda will delve into the technical bottlenecks encountered in every stage of the CAR-TCR drug development cycle, providing more comprehensive analysis from 55+ expert speakers across 3 streams of content including:
Research & Development Track:
Explore the emerging CAR-X landscape with Glycostem & Carisma Therapeutics
Breach the solid tumour microenvironment with Refuge Biotech & Atara Biotherapeutics
Optimise target identification with Celyad & Anocca AB
Investigate next-generation gene engineering techniques with Precision Biosciences
Develop ‘off-the-shelf’ platforms with Leucid Bio
Provide a mechanistic rationale for combination therapies with Agenus & Ziopharm Oncology
Discuss ‘gold standards’ and innovations in assay development GlaxoSmithKline & bluebird bio
Understand and minimise toxicity with Kite: A Gilead Company & The NHS
Manufacturing & Commercialisation Track:
Advance automation for cheaper, faster manufacturing with Gracell Biotechnologies & Glycostem
Gain regulatory guidance to initiate clinical trials in Europe from MHRA & Norwegian Medicines Authority
Maximise real-world evidence for value demonstration, and innovative reimbursement models with Janssen
Expedite batch release and maintain high-quality products with Novartis & Immatics
Provided by Elligo Health Research Clinical research faces a dilemma that has historically plagued the industry: the lack of diversity in research. The underrepresentation of different races, genders, and classes is largely due to the fact that most trials exclusively enroll white males with easy access to participate. According to a 2019 article in JAMA […]
As an influential panel of FDA-appointed experts prepares its verdict on Biogen’s Alzheimer’s drug, a little known China-based pharma is hoping to succeed where big name rivals have failed and develop a drug that is effective against the disease.
For almost two decades there has been no progress with new therapies for Alzheimers – the last new drug approved by the FDA was Forest’s Namenda (memantine) in 2003 and this only helps to relieve symptoms rather than tackling the root cause of the condition.
Since then the story of Alzheimer’s research has been one of expensive failures as experimental drugs, mainly targeting the amyloid plaques found in the brains of people with the disease, failed to stop or slow cognitive decline in clinical trials.
As Biogen hopes to change the narrative with aducanumab and a new analysis of a phase 3 trial initially written off as a failure, Shanghai Green Valley Pharmaceutical is beginning US trials of a radically different approach to treating the disease.
Green Valley’s drug known as GV-971 is a type of sugar extracted from brown algae and does not work directly on the brain at all: it tackles imbalances in the gut’s bacteria population that researchers believe may cause the brain inflammation leading to Alzheimer’s or Parkinson’s disease.
Last year China’s National Medical Products Administration (NMPA) became the first national regulator to approve the drug and the FDA gave the nod for US trials to begin earlier this year.
According to Bloomberg the first patient has been enrolled in a trial that the company hopes will show the cognitive improvements seen in the China-based trial that convinced the NMPA to approve GV-971.
The latest trial has been delayed because of the coronavirus pandemic but will enrol up to 2,046 people across China, the US and Europe, with the first 600 expected to sign up in the next six months.
Bloomberg noted that Green Valley needs the trials to win over sceptics who have questioned the authenticity of the data used by the NMPA for approval.
There is also confusion about why Green Valley has succeeded where the big western pharma companies have failed.
Whether Biogen gets the vote on Friday that could convince the FDA to approve aducanumab, or Green Valley succeeds with its trial, the prize for a drug that sets new standards in Alzheimer’s is huge.
A new Alzheimer’s drug would open up a market worth up to $30 billion in the US alone according to a Sanford C Bernstein & Co analysis cited by Bloomberg.
It’s unlikely that big pharma will be put off research, even if Biogen and Green Valley’s drugs are added to the ever-growing list of trial failures.
Novartis’ injectable migraine prevention antibody Aimovig has been shown to be more effective than topiramate – a go-to oral therapy for people with chronic migraine – in a head-to-head trial.
The HER-MES trial found that Aimovig (erenumab) was more effective at preventing migraine attacks and also better tolerated than topiramate, a generic epilepsy drug which is known to have side effects like sleepiness, dizziness, diarrhoea and nausea.
In the 777-patient study, fewer patients on Novartis’ drug discontinued treatment due to side effects, while more of them met the objective of a 50% reduction in the number of days in a month they had a migraine compared to high-dose topiramate.
Topiramate also needs to be taken twice a day, while Aimovig is given as an injection once a month and is available in a self-injector pen device. Both drugs can take up to three months for their effect on migraine prevention to fully kick in.
Novartis recorded Aimovig sales of $108 million in the first nine months of 2020, a rise of 44% on the same period of 2019, and says it is the most prescribed drug in the CGRP inhibitor class with 480,000 patients using it worldwide.
Quarterly sales have however fallen from a strong launch in 2018, and the drug can’t seem to generate the momentum needed to meet blockbuster sales expectations voiced during its development.
Part of that is the entry into the market of CGRP rivals, with three injectable drugs (Teva’s Ajovy and Eli Lilly’s Emgality) and one six-monthly infusion (Lundbeck’s Vyepti) now jostling for position in the migraine prevention market.
Meanwhile, two oral CGRP inhibitors – AbbVie’s Ubrelvy and BioHaven’s Nurtec – have been launched for the on-demand treatment of acute migraine attacks. These don’t compete with Aimovig and the other prevention therapies directly, but are raising the profile of the CGRP class among migraine sufferers and their doctors.
This year of course there have also been access issues caused by the coronavirus pandemic that have had a particularly big impact on neurology prescribing, as well as a continued challenge in persuading doctors to switch to the new class from older drugs like topiramate and AbbVie/Allergan’s Botox.
It’s estimated that CGRP drugs have only penetrated 15% of the migraine prevention market, and that’s why the HER-MES results are so important to Novartis.
“These results further emphasise its potential to provide significant relief from migraine with an infrequent dosing compared with the oral treatment,” said Estelle Vester-Blokland, the company’s global head of neuroscience medical affairs.
The company has exclusive rights to the sell Aimovig outside the US, where Amgen records sales, with the exception of Japan. Novartis and Amgen are however locked in a legal battle over marketing rights to the drug.
Professor Jean-Pierre Boissel outlines the urgent need for disruptive R&D approaches that can tackle the search for COVID-19 treatments more effectively.
It may not be appropriate to use the word ‘failure’ when summarising the utility of clinical trials in the search for a curative or preventative treatment for disease. For the purposes of this text, let us assume that ‘success’ and ‘failure’ will be used in reference to the objective of clinical trial designers: to obtain sufficient evidence that a treatment under evaluation is of benefit to patients.
SARS-Cov-2, responsible for the COVID-19 infection, rarely kills those who are infected, but unfortunately, the number of deaths caused by the virus now exceeds 1.2 million worldwide and continues to increase despite the global public health measures that have been put in place. As time goes on, the number of individuals requiring access to intensive care facilities exceeds capacity. The main measure available to fight against the spreading of the virus, social distancing, is becoming ever more difficult to bear.
Compared to the number of deaths and the millions of those infected with COVID-19, the number of patients included in randomised clinical trials, the only type of investigation able to provide the necessary evidence for the safety and efficacy of potential new treatments, is ridiculous: less than 10,000 in total for the Recovery and Discovery trials, for which we have initial data, plus an equivalent number for a US NIH trial, a WHO study, and trials launched in China or by the industry.
Despite hundreds of trials on their way there are only a dozen drugs being tested currently with reduction of death as endpoint and yet there are as many as 150 drugs already on the market for other related indications and hundreds more that could potentially have a role to play, targeting the viral proteins, the virus interactions with the target cells or on the human systems that are solicited by the infection.
“Most of the trials are underpowered to demonstrate efficacy on mortality and long-term consequences of the disease… It is not surprising there is no recommended drug treatment for COVID-19, except dexamethasone and remdesivir, despite little evidence that this drug reduces mortality”
If, as it is likely, it will be necessary to combine drugs to obtain a cure, and even personalize these combinations to individuals, the number of ongoing or completed trials appears insignificant compared to the scale of the disease. However, in vitro or binding-based efficacy insight needs to be confirmed by reliable clinical evidence, as shown by the outcomes of COVID-19 trials with remdesivir and hydroxychloroquine.
Most of the trials are underpowered to demonstrate efficacy on mortality and long-term consequences of the disease. The scale of the impact of COVID-19 dwarfs the clinical data obtained to date so it is probably not surprising there is currently no recommended drug treatment for COVID-19, except dexamethasone and, in some countries, remdesivir, despite little evidence that this drug reduces mortality.
We have ‘half-successes’ such as dexamethasone for Recovery, which might only be effective in subgroups of patients, and still needs to be confirmed by at least one other trial, or ‘half-failures’ such as Discovery, the complexity of which is poorly suited in the context of caring for severely ill patients hospitalised in intensive care units. Recruitment into trials is difficult, or outcomes are uninformative as with remdesivir, or like the hydroxychloroquine trial in China, inadequately powered. Even Solidarity, the WHO trial, is some way from yielding strong data.
The only relatively well-argued result we have today is the ineffectiveness of hydroxychloroquine, which was predictable. Also, evidence in favour of a reduction of mortality with lopinavir/ritonavir is elusive. Evidence regarding efficacy of remdesivir on mortality is awaited, the NIAID trial results published recently did not show a statistically significant reduction of mortality
At this rate, how many years might it take, unless luck or serendipity strikes, to test all the options and finally find a cure for the most severe patients?
The picture is hardly more promising for vaccines: the number of approaches, difficulty in finding patients in which to carry out pivotal trials, irrelevant choice of endpoints … the outlook is far from promising.
There are many reasons as to why so few eligible patients are being recruited into clinical trials even though infection numbers are high. The exhortation by the late Thomas C Chalmers to “randomise the first patient” which would translate into the best ethical behaviour by doctors has never been put into practice. If it had been applied to COVID-19, at the very least 2,000 molecules or combinations could have been tested so far against mortality: taking 200 as an average number of endpoints per trial (quite a large number indeed!) and the death toll today. However, this is pure speculation since the story of randomised clinical trials which began more than half a century ago shows us that Chalmers’ words are, sadly, wishful thinking.
The traditional approach to R&D, with its high failure rate, is not acceptable when it comes to COVID-19: the expected time to efficient treatment or vaccine (ETETV) is unbearable compared to the rate of growth of the burden of the disease. Repurposing existing drugs with prior evidence of PK and safety for the potential treatment of COVID-19 only marginally improves the inefficient series of decision-making stages in the traditional R&D process
There is therefore an urgent need to turn to a disruptive approach, modeling and simulation (M&S), to make efforts to tackle COVID-19 more efficiently.
The M&S approach should be integrative, from the molecular level to the clinical and population outcomes. It should be conceived both as a proof of concept tool and a MIDD (Model Informed Drug Development, to use the FDA jargon) tool for potential treatments, including vaccines, and combinations of drugs. It will allow inefficacious treatments to be dropped earlier, sparing time, resources and patients. Also, as a knowledge integrator, enabling the assimilation of large amounts of knowledge that scientists will gather on the virus and the disease. Once the model is achieved and validated, simulations to test hundreds of treatments or vaccines can be run in parallel by sponsors in a just couple of days.
For COVID-19, this can be achieved through a series of connected modules:
the SARS-cov2 virus, its dissemination dynamics, entry into the cell, replication, interactions between viral intracellular activities and energy metabolism, the regulation and phenotype and age-related distribution of ACE2, the infected cell fate;
the systems level and responses (innate and adaptive immune system, inflammation, complement, vascular system and coagulation;
alveolar and gas exchange changes and dynamics of organ irrigation changes;
dynamics of organ failure (heart, gut, kidney, nervous system);
patient level and clinical outcomes, including chronic lung fibrosis and chronic fatigue syndrome;
population level (ways and dynamics of viral penetration, role of social connections, social context, Covid-19 prevention measures).
An M&S approach will enable the prediction of major impairments due to COVID-19. Not only death, but also the chronic fatigue syndrome (‘Long COVID’) which is a major burden for some patients.
Eventually, the model could help to individualise treatment for patients.
About the author
Professor Jean-Pierre Boissel is co-founder and chair of the scientific advisory board, Novadiscovery.
Jean-Pierre is a cardiologist by training. He was until recently an Emeritus Professor of Clinical Pharmacology at the University of Claude Bernard Lyon 1, and has been a scientific director at the French Institute for Health and Medical Research (Inserm), advisor to the General Surgeon and is still a member of a number of scientific societies in Europe and the United States.
Ireland-based Fountain Healthcare Partners has raised another €125 million ($131 million) for its third life sciences fund – 25% ahead of its target – and says it will pump most of the money into European therapeutics and medical device companies.
The latest cash injection adds to the €118 million initially raised by Fountain Healthcare for the fund in May 2019, and brings the total value managed by the company above the €300 million mark. The third fund is now closed.
The specialist life sciences venture capital shop – which has offices in Dublin and New York – said Japanese drugmaker Kyowa Kirin took part in the latest funding round, joining domestic and international institutional investors.
Three companies have already received investment from Fountain Healthcare’s third fund. That includes include France’s Inotrem, which is developing nangibotide in phase 2 testing for septic shock, and Dublin-based Priothera, which is developing immuno-oncology drug mocravimod in phase 2b/3 for acute myeloid leukaemia (AML) in partnership with Kyowa Kirin.
Another beneficiary is Dublin biotech Mainstay Medical, which recently claimed FDA approval for its ReActiv8 device for chronic lower back pain.
All told, Fountain Healthcare expects to make up to 10 investments in “predominantly private life science companies” with its third fund, mainly in Europe but also in the US.
The VC’s first two funds supported early-round financings some prominent emerging biotechs, including inflammatory disease biotech Inflazome, which was sold to Roche in September in a €380 million deal. Inflazome’s lead drugs inzomelid and somalix – both NLRP3 inhibitors – have cleared phase 1 testing.
Others included UK women’s health player KaNDy – snapped up by Bayer for $425 million upfront a few weeks ago – as well as drug delivery specialist Chrono Therapeutics and Opsona, focusing on autoimmune and inflammatory diseases, solid organ transplantation and oncology.
Dr Manus Rogan, co-founder and managing partner at Fountain Healthcare and a former executive at GlaxoSmithKline and Elan, said the company’s investment strategy “focuses on building a balanced portfolio of companies with complementary risk and return profiles within the life science sector.”
Bristol-Myers Squibb could be on the verge of a major coup in psoriasis after its deucravacitinib pill outperformed Amgen’s rival Otezla.
BMS had to sell off Otezla (apremilast) as a condition of its merger with Celgene and made Amgen pay $13.4 billion in cash for the popular pill treatment, which is not quite as effective as injections such as J&J’s Stelara (ustekinumab) but more convenient.
The reason why competition regulators were concerned about Otezla was BMS’ deucravacitinib, which was in Bristol’s pipeline when the $74 billion merger was being finalised last year.
Also known as BMS-986165, BMS was developing the drug as a potential best-in-class oral therapy with a different mechanism of action and cleaner safety profile.
Latest phase 3 results show that BMS may have played a blinder by getting a eye-watering price for Otezla while retaining the better asset: deucravacitinib has outperformed placebo in the POETYK PSO-1 phase 3 trial and met several secondary goals showing it outperformed Otezla while showing a safety profile similar to that seen in phase 2.
Results from the trial testing deucravacitinib in patients with moderate to severe disease showed more patients achieving 75% skin clearance compared with placebo at week 16.
Using a global scale, doctors scored more patients on deucravacitinib as clear or almost clear compared with placebo, meaning the trial’s other main endpoint was met.
BMS said deucravacitinib also beat Otezla on the 75% skin clearance score and the global doctors’ assessment.
BMS added that the overall safety profile of deucravacitinib in the POETYK PSO-1 trial was consistent with previously reported phase 2 results, where there was little to differentiate placebo and treatment groups.
Results of an almost identical phase 3 study, POETYK PSO-2 are due in the first quarter of next year and phase 2 findings will be presented at the American College of Rheumatology conference later this week.
Deucravacitinib has a different mechanism of action than other psoriasis drugs on the market – it is a tyrosine kinase 2 inhibitor that changes intracellular signalling and is also in development for several other inflammatory and immune diseases.
Merck & Co’s CEO Kenneth Frazier has warned that the drugs and vaccines in the pipeline to combat COVID-19 may not be enough to swiftly end the pandemic.
Speaking to CNBC, Frazier said that the drugs and vaccines to treat COVID-19 are not a “silver bullet” solution to the pandemic, meaning people are likely to be wearing masks and practicing social distancing measures well into 2021
He told CNBC’s Squawk Box: “I don’t see the therapeutics that we have – or the vaccines that are coming – as a silver bullet.
“I would say certainly well into 2021 we’ll still be trying to observe these public health measures.”
Frazier said he is “very optimistic that in the near future” there will be positive results coming from late-stage clinical trials for COVID-19 vaccines and therapeutics.
A potential vaccine is unlikely to be widely available for people until mid-2021, Frazier noted.
It’s expected that vaccines will only work in around 70% of cases and Dr Anthony Fauci, White House coronavirus adviser, said that the likelihood of a highly effective COVID-19 vaccine providing coverage in around 98% of people is slim.
Frazier added: “The natural history of viruses is that they don’t go away.
“I don’t think we should tell people that they can expect to give up on those public health measures anytime soon.”
US-based Merck & Co is developing two separate potential COVID-19 vaccines, one from the Australian vaccine manufacture Themis that it acquired in July and with scientific non-profit organisation IAVI.
However the company known as MSD outside North America is well behind the leaders in the COVID-19 vaccine race, which according to the World Health Organization are phase 3 candidates from China’s Sinovac and Sinopharm, followed by the UK’s AstraZeneca.
Frazier made his comments as the US sees a deadly surge of the coronavirus just as voters go to the polls to decide whether incumbent Republican president Donald Trump stays on for another four years, or is replaced by his Democrat rival Joe Biden.
Trump’s handling of the pandemic has been a focus point in the campaigns for the White House, with nearly 9.4 million confirmed cases and 231,000 deaths attributed to the disease.
COVID-19 vaccines could be approved and available early next year in the UK ahead of European countries, after its national regulator began its own rolling reviews of shots from AstraZeneca and Moderna.
AstraZeneca has confirmed that the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) has begun a fast-track rolling review of its AZD1222, the COVID-19 vaccine it developed in conjunction with Oxford University.
This followed last week’s news that the MHRA has begun a parallel rolling review of a rival from Moderna.
The rolling review allows for a real-time assessment of the clinical data from clinical trials, accelerating a process that normally takes around a year to complete using the centralised European regulatory system.
Using the MHRA could allow the UK to make regulatory decisions on COVID-19 vaccines ahead of the European system, where medicines and vaccines are first reviewed by the CHMP scientific committee before being passed on to the European Commission.
But a source close to process told pharmaphorum that it is “eminently possible” that the MHRA could reach its conclusions ahead of its European counterparts as the country reaches the end of the Brexit transition period.
A spokesperson for the MHRA said that from 1st January, it will have new powers to approve medicines, including vaccines including “greater flexibility to do this faster, while maintaining the highest standards of safety, quality and effectiveness.”
The spokesperson said: “The MHRA will evaluate the data rigorously on the quality, safety and effectiveness of COVID-19 vaccines to reach a scientifically robust independent opinion if an earlier authorisation is necessary before the EMA (European Medicines Agency) authorises a product.”
“Patient safety is our top priority. The independent Commission on Human Medicines will advise the UK government on the safety, quality and effectiveness of any potential vaccine. No vaccine will be deployed in the UK unless stringent standards have been met through a comprehensive clinical trial programme”
Representatives of the MHRA used to sit on the CHMP but no longer participate as a result of Brexit, leaving the UK to make its own decisions on medicines regulation should it choose to do so.
According to the source, COVID-19 vaccines could be available in early January depending on the length of time it takes for trial data to be published and shared with regulators.
COVID vaccines are being developed at warp speed, with the development and review process that normally takes up to a decade to complete compressed into less than a year after research began at the end of January.
The MHRA’s approach to the AZ and Moderna vaccines also paves the way for similar fast reviews to rivals from the likes of Pfizer/BioNTech and Novavax, which the UK government also has on order and are reaching the end of the clinical trial process.
The news comes as the country prepares for another national lockdown, which will disrupt business and limit people’s freedoms for at least another month.
A vaccine is seen as a potential way out of the cycle of lockdowns that have already caused severe hardship across the UK, which is one of the countries worst hit by COVID-19.
An AstraZeneca spokesperson told pharmaphorum: “Results from the late-stage trials are anticipated later this year, depending on the rate of infection within the communities where the clinical trials are being conducted. It is then up to the regulatory bodies to review and make approval decisions based on this data, as quickly as possible.
“The EMA announced in October that its CHMP had started a ‘rolling review’ of data for AZD1222, the first COVID-19 vaccine to be evaluated under these arrangements. We confirm the MHRA’s rolling review of our potential COVID-19 vaccine.”
Regeneron’s coronavirus antibody cocktail therapy against COVID-19, famously used to treat president Donald Trump, has hit a safety issue after independent safety experts recommended it should not be given to high-risk patients in a late-stage clinical trial.
It’s the latest blow for antibody therapies against COVID-19 after Eli Lilly last week announced it won’t resume a trial in hospitalised patients, after National Institutes of Health researchers concluded it wouldn’t help.
Regeneron said an Independent Data Monitoring Committee (IDMC) from the REGN-COV2 trial said that based on an unspecified safety signal and an “unfavourable risk benefit profile” the committee recommends a modification to the trial protocol.
The IDMC recommends further enrolment of patients requiring high-flow oxygen or mechanical ventilation be placed on hold pending collection and analysis of further data from those already on the trial.
Regeneron remains blinded to the data and is implementing the recommendations.
The company has also informed the FDA, which is reviewing REGN-COV2 data for a potential Emergency Use Authorization in patients with mild-to-moderate outpatients at high risk for poor outcomes.
The data is also being shared with the independent committee monitoring the RECOVERY trial in the UK, which is testing the drug cocktail in hospitalised patients.
REGN-COV2 is split into four cohorts – patients on low-flow oxygen, patients not requiring oxygen, patients on high-flow oxygen and patients on mechanical ventilation.
The spotlight has been on antibody therapies for COVID-19 after it emerged early last month that Trump was treated with the Regeneron combination.
Regeneron’s therapy is based on two antibodies the company has developed to neutralise the virus.
The rationale is that by having a double therapy, the chances of the virus developing resistance to both parts of the drug are reduced.
AstraZeneca is to begin phase 3 trials of a long-acting antibody therapy combination in the US and other countries in the coming weeks, to prevent infection happening and as therapy for those already infected.
GlaxoSmithKline’s Nucala (mepolizumab) last month became the first and only biologic treatment approved in the US for Hypereosinophilic Syndrome (HES).
It’s part of the company’s focus on eosinophil-driven diseases, and ahead of that regulatory milestone I spoke with Tiffany Robinson-Smith, global medical affairs lead for biologics at GSK, about eosinophils and why they’re an important element of her company’s research programmes.
We also spoke in this episode of the podcast about some of the research challenges GSK faces with eosinophils and where they fit into the pharma company’s current product portfolio.
Already a major player in gene therapy, Novartis has swooped on US startup Vedere Bio in a $280 million deal that builds its position in inherited eye diseases that can lead to blindness.
Incubated by Atlas Ventures, Cambridge, Massachusetts Vedere has been flying under the radar since it was founded in 2019 to develop adeno-associated virus (AAV) based gene therapies for ocular diseases, but didn’t escape the beady eye of Novartis.
The Swiss pharma group already sells one gene therapy for inherited retinal diseases (IRDs) – Luxturna (voretigene neparvovec) – for which it licensed ex-US rights from Spark Therapeutics (now part of Roche) in 2018.
Novartis’ big move in the gene therapy market came when it bought AveXis for $8.7 billion in the same year to add spinal muscular atrophy therapy Zolgensma (onasemnogene abeparvovec), which has made $1 billion in sales since launch last year.
Earlier this year, the group also signed a licensing deal with Dyno Therapeutics for its AAV capsid-based gene delivery technology, also focused on ocular disease which remains one of Novartis’ core drug development targets despite the spin-off of the Alcon eyecare division in 2019.
Shortly after, Novartis teamed up with Sangamo in a deal focused on the adjacent gene therapy discipline of gene silencing, targeting neurodevelopmental disorders like autism.
The Vedere acquisition includes $150 million upfront and $130 million in potential milestones, and expands Novartis position in ocular disease gene therapy with an AAV delivery platform as well as rights to light-sensing proteins that can be delivered to cells in the retina.
It also gets two preclinical-stage development projects. One focusing on IRDs – a wide range of genetic retinal disorders caused by mutations in some 250 genes that are marked by the loss of photoreceptor cells and progressive vision loss. IRDs affect around 2 million people worldwide.
The second is looking at geographic atrophy, an advanced form of ‘dry’ age-related macular degeneration (AMD) that affects around 5 million people around the world and has no approved medical treatments.
While gene therapies like Luxturna are aimed at preventing progressive vision loss, Novartis thinks it could go a step further with the Vedere platform and attempt to restore vision that has already been lost – something that the company’s scientific founders have achieved in animal models.
Combining the light-sensing proteins and AAV platform has the potential “to vastly expand the number of patients who could be treated for vision loss due to photoreceptor death,” according to the company.
When delivered to retinal cells, the proteins stimulate them to sense and transmit information to the visual processing centres in the brain, bypassing cells that have already degenerated.
With exclusive data from Freedom of Information (FOI) requests sent to the National Institute for Health and are Excellence (NICE), Leela Barham takes a look at the trend in early engagement with the UK’s HTA body.
In 2009, NICE was one of the first health technology assessment (HTA) agencies to offer the opportunity for early scientific advice, at a cost. The fees range from £20,000 to £75,000 per project. They are based on cost-recovery.
The idea behind this service is help companies understand the agency’s point of view on evidence; the gaps and how to fill them before the appraisal. Ultimately the idea is to help companies achieve patient access.
The NICE scientific advice service includes a standard approach (taking around 18 weeks) and an express scientific advice service (taking around 12 weeks). The standard approach offers the most in-depth option. Companies ask questions through the service, often on:
Clinical trials, design and analysis
Quality of life data
Economic analyses (modelling, extrapolation, resource use and costs)
The service is popular; over the eleven years it’s been used on average almost 18 times each year although take-up has varied over time (see figure 1).
“Getting advice with NICE as part of the dialogue with others has proven to be more popular than talking to the agency alone. It’s not clear how far advice from NICE alone is a substitute for getting advice as part of a bigger conversation”
Figure 1: NICE early scientific advice projects, 2009/10 to 2019/20
Source: Data from NICE FOI responses. Note the light service has been incorporated into the standard service. Light was previously aimed at small and medium sized enterprises.
Since 2009 the agency has added further charged-for services; in 2015 NICE added the Office for Market Access (OMA). OMA can offer a safe harbour for discussions with NICE, NHS commissioners and other stakeholders. This has proven popular too and has seen a steady increase in safe harbour meetings held over time (figure 2).
Figure 2: NICE OMA safe harbour meetings, 2016/17 to 2019/20
Source: Data from NICE FOI responses.
By 2017, NICE added the Preliminary Independent Model Advice (PRIMA) service. PRIMA is a way to get the agency to check health economic models, taking either 12 weeks for the standard service, or eight weeks for an express service. The service was used twice in 2017/18, four times in 2018/19 and three times in 2019/20 according to FOI responses from NICE.
There are good reasons to want to engage PRIMA. Researchers analysed single technology appraisals completed in 2017 by NICE, looking specifically at technical errors and validation processes reported on the economic models submitted by companies. Only two STAs (5%) had no reported errors. Four STAs had more than ten errors (10%). That prompted Jeanette Kusel, director at NICE Scientific Advice, to highlight on LinkedIn the importance of the PRIMA service for checking models prior to submission.
Engaging with NICE, regulators and other HTA agencies
There are also other services that NICE can be part of in providing early advice. The agency has been a popular choice as part of the EUnetHTA early dialogue offer and has also been one of the HTA agencies taking part in EMA-multi-HTA early dialogues. With Brexit though, NICE has set up a concurrent scientific advice service for when companies want advice from EMA and the UK body at the same time. The latest option is with NICE and the Canadian Agency for Drugs and Technology in Health (CADTH) together. The NICE-CADTH service was launched in 2019. It’s not had long enough to really get a track record, even more so when COVID-19 saw CADTH temporarily suspend the service.
Getting advice with NICE as part of the dialogue with others has proven to be more popular than talking to the agency alone (see figure 3). It’s not clear how far advice from NICE alone is a substitute for getting advice as part of a bigger conversation with others. It’s likely though that hearing from NICE on their own will give a depth of advice that might not be possible in the limits of a meeting held with several other voices in the conversation.
Figure 3:NICE early scientific advice projects alone and with others, 2009/10 to 2019/20
Source: Data from NICE FOI responses. Note: EMA-HTA includes NICE concurrent services delivered in parallel to EMA-multi-HTA dialogue.
What is the impact?
It is clear that the services to secure NICE advice are popular. The agency has a few testimonials on their website to support that. For example, for their scientific advice service, it quotes from a project feedback questionnaire:
“I truly value this Scientific Advice service… It creates fantastic opportunities for global drug development teams to better understand reimbursement hurdles and evidence requirements for timely market access. Great job!”
For PRIMA, the agency quotes Peter Wheatley-Price, market access and pricing director at Takeda UK, who said: “The Takeda team highly regarded the quality of the PRIMA reports and model review documentation. We appreciated the PRIMA team’s engaging and flexible approach at this pivotal stage in development and look forward to using the service as part of our model development efforts going forward.”
Yet it’s hard to know what difference they are making in terms of evidence strategies –what evidence will now be generated, and importantly for efficiency, what evidence won’t be generated because it won’t be valuable to the agency and payers in the UK – and ultimately, NICE recommendations. The services aren’t staffed by those who make the decisions later and it isn’t clear if Appraisal Committee members know if a company has sought advice, what that advice was, and whether it was acted upon by the company. There is a question over pull, through.
NICE has, so far, kept the details of which companies and which products have sought advice close to their chest. The various services offered are confidential and aren’t legally binding on both sides. Yet that doesn’t seem to explain why they can’t routinely release statistics about take-up of their services – it would be a real indicator of value if companies go back repeatedly for different products across their portfolios – nor why they can’t release details in the final guidance on whether advice was sought.
EMA does put into the public domain if a company has sought scientific advice and when. EMA keeps the details of the discussion out of the public domain. There is clear evidence that EMA scientific advice improves the chances of marketing authorisation.
Whilst companies who have sought advice from NICE will know the difference it has made or not, those companies who have yet to engage with the agency could be more likely to, if they know it can make a difference.
About the author
Leela Barham is researcher and writer who has worked with all stakeholders across the health care system, both in the UK and internationally, on the economics of the pharmaceutical industry. Leela worked as an advisor to the Department of Health and Social Care on the 2019 Voluntary Scheme for Branded Medicines Pricing and Access (VPAS).
The US government said it will buy 300,000 doses of Eli Lilly’s COVID-19 therapy bamlanivimab for $375 million if the drug gets Emergency Use Authorisation (EUA) – despite the fact its effectiveness has been called into question.
The initial agreement is for delivery over the two months following an EUA, and provides the option for the government to purchase up to an additional 650,000 vials through 30 June 2021.
Lilly filed for emergency use authorisation (EUA) of bamlanivimab for the treatment of recently diagnosed mild to moderate COVID-19 illness in high-risk patients in early October.
The US has said that patients will have no out-of-pocket costs for the medicine – echoing a promise by Lilly CEO Dave Ricks – although healthcare facilities may charge a fee for the product’s administration.
The federal government, in partnership with state health departments, is developing a government allocation program for bamlanivimab.
Ricks has said that the company “must work with global health systems to ensure equitable access to our medicine at a fair price”.
“Our goal is to ensure that Lilly antibody treatments are available to patients who need them, no matter where they live.
“As long as supply of neutralising antibodies is constrained, we believe the only way to ensure equitable access is for Lilly to contract directly with governments and pan-national philanthropic organisations. These institutions are best positioned to direct our antibody treatments to the patients who need them most.”
He added that treatment allocation will be based on unmet medical needs globally and that equitable government pricing will be tiered based on a country’s ability to pay.
But the news might be dampened somewhat by this week’s announcement that no more patients will be treated with bamlanivimab in a trial run by the National Institute of Allergy and Infectious Diseases (NIAID), as results to date suggest it is unlikely to be effective.
The ACTIV-3 study was comparing bamlanivimab (also known as LY-CoV555 or LY3819253) and placebo when added to therapy with Gilead Sciences’ Veklury (remdesivir), which is already approved to treat COVID-19 requiring hospitalisation.
According to Lilly, the NIAID took its decision on the strength of trial data which indicated that bamlanivimab – an antibody that neutralises the SARS-CoV-2 coronavirus – was unlikely to help hospitalised patients recover from advanced-stage COVID-19.
The drugmaker stressed however that other trials of its drug in COVID-19 are still continuing, and it pointed out that the earlier BLAZE-1 study of bamlanivimab showed a reduced rate of hospitalisation in patients treated with the antibody in the outpatient setting.
It also said it “remains confident…that bamlanivimab monotherapy may prevent progression of disease for those earlier in the course of COVID-19.
ACTIV-3 is a substudy of a larger, 10,000-patient trial that is putting a series of COVID-19 drugs through their paces, and Lilly’s drug is the only arm to include an antibody targeting SARS-CoV-2. In each case, 300 patients are enrolled initially before a decision is taken whether to expand the trial to 1,000 subjects.
In a statement, the NIAID said enrolment of patients into the bamlanivimab was paused on 13 October after 326 had been recruited, “out of an abundance of caution”, and terminated on 26 October.
There were no safety issues – the decision was “driven by lack of clinical benefit for LY-CoV555,” according to the agency – and the patients will continue to be followed for 90 days’ follow-up.
The NIAID is also running another study of Lilly’s antibody, ACTIV-2, which involves outpatients with mild-to-moderate COVID-19 symptoms, and that is continuing as planned.
BLAZE-1 is also continuing – looking at bamlanivimab alone and in combination with etesevimab (LY-CoV016) another Lilly antibody targeting SARS-CoV-2 – and the company is also running the BLAZE-2 trial of bamlanivimab as prophylaxis against COVID-19 in nursing home residents and staff.
Catabasis has conceded defeat with its Duchenne muscular dystrophy drug edasalonexent, pulling the plug on the drug after a phase 3 trial echoed the results of a failed mid-stage study.
The PolarisDMD study failed across the board, leaving Catabasis with no choice but to abandon the drug, including an ongoing open-label extension study from an earlier failed trial in the muscle-wasting disease.
That decision leaves the Cambridge, Massachusetts biotech with a preclinical-stage drug for cystic fibrosis and just over $52 million in cash as it considers its future.
Shares in Catabasis lost two-thirds of their value in after-hours trading as investors reacted to the news, and the biotech said it was bringing in advisors to explore its options. Analyst Hartaj Singh at Oppenheimer said there is now “a lack of clarity on the way forward.”
Edasalonexent is an oral NF-kB inhibitor that works differently to approved DMD drugs like Sarepta’s Exondys 51 (eteplirsen) and NS Pharma’s Viltepso (viltolarsen) which target specific DMD mutations.
It has been in clinical testing since 2011 – Catabasis’ first clinical candidate – and had been billed as a drug that could be used in patients regardless of the underlying cause of their DMD, and tackle three separate consequences of DMD – slowing muscle wasting, preserving cardiac function, and reducing bone fractures. Phase 2 data looked weak, but Catabasis ploughed on with phase 3 after convincing itself there were signs of efficacy.
As it turned out, edasalonexent failed to improve the primary endpoint in PolarisDMD, change from baseline in the North Star Ambulatory Assessment, as well as the secondary measure of timed function tests, compared to placebo.
Edasalonexent is also the second big failure for Catabasis, which was forced to abandon its previous lead drug CAT-20154 for high cholesterol in 2016 after it flunked a phase 2 trial programme.
“We are deeply saddened and disappointed by the results of our Phase 3 PolarisDMD trial,” said Jill Milne, Catabasis’ CEO.
“I want to sincerely thank all of the boys, their families and caregivers, investigators and the trial sites that participated in and enabled this programme,” she added.
The disappointing result comes as three potential gene therapies for DMD that could tackle the underlying genetic cause of the disorder are making their way through clinical development.
Those are Solid Biosciences’ SGT-001 – which recently restarted a phase 1/2 trial that had been placed under a clinical hold by the FDA while adverse events were investigated – as well as Pfizer’s PF-06939926 and Sarepta Therapeutics/Roche’ SRP-9001, which are both heading towards phase 3 testing.
Eli Lilly says no more patients will be treated with its COVID-19 therapy bamlanivimab in a trial run by the US National Institute of Allergy and Infectious Diseases (NIAID), as results to date suggest it is unlikely to be effective.
The ACTIV-3 study was comparing bamlanivimab (also known as LY-CoV555 or LY3819253) and placebo when added to therapy with Gilead Sciences’ Veklury (remdesivir), which is already approved to treat COVID-19 requiring hospitalisation.
According to Lilly, the NIAID took its decision on the strength of trial data which indicated that bamlanivimab – an antibody that neutralises the SARS-CoV-2 coronavirus – was unlikely to help hospitalised patients recover from advanced-stage COVID-19.
The drugmaker stressed however that other trials of its drug in COVID-19 are still continuing, and it pointed out that the earlier BLAZE-1 study of bamlanivimab showed a reduced rate of hospitalisation in patients treated with the antibody in the outpatient setting.
It also said it “remains confident…that bamlanivimab monotherapy may prevent progression of disease for those earlier in the course of COVID-19.
Lilly filed for emergency use authorisation (EUA) of bamlanivimab for the treatment of recently diagnosed mild to moderate COVID-19 illness in high-risk patients.
ACTIV-3 is a substudy of a larger, 10,000-patient trial that is putting a series of COVID-19 drugs through their paces, and Lilly’s drug is the only arm to include an antibody targeting SARS-CoV-2. In each case, 300 patients are enrolled initially before a decision is taken whether to expand the trial to 1,000 subjects.
In a statement, the NIAID said enrolment of patients into the bamlanivimab was paused on 13 October after 326 had been recruited, “out of an abundance of caution”, and terminated on 26 October.
There were no safety issues – the decision was “driven by lack of clinical benefit for LY-CoV555,” according to the agency – and the patients will continue to be followed for 90 days’ follow-up.
The NIAID is also running another study of Lilly’s antibody, ACTIV-2, which involves outpatients with mild-to-moderate COVID-19 symptoms, and that is continuing as planned.
BLAZE-1 is also continuing – looking at bamlanivimab alone and in combination with etesevimab (LY-CoV016) another Lilly antibody targeting SARS-CoV-2 – and the company is also running the BLAZE-2 trial of bamlanivimab as prophylaxis against COVID-19 in nursing home residents and staff.
Analysing real-world health data could help overcome the bias towards men in traditional medical research, says Sensyne Health’s Dr Lucy Mackillop.
Collecting and analysing anonymised patient data has the potential to generate valuable insights that can catalyse research, lead to improved patient care, and power the development of new treatments.
Being able to analyse large data sets can provide a better understanding of how some patients will respond to a treatment or predict who may develop a disease based on data collected during clinical care.
Medical research has often focused on men, meaning that the insights gained have not always been reflective of how women would react to a treatment or disease. Women are likely to have different symptoms to men for the same illness and do not necessarily have the same reactions to certain drugs or respond to the same doses as a male counterpart.
Therefore, it is important to increase the collection and analysis of women’s health data so better insights can be gained for supporting their care.
“The effect of failing to include women proportionately in clinical trials may have consequences for the quality of medical care women receive, with therapies, doses and risk assessment tools being tailored to the male population”
The impact of underrepresenting women
Research from the Allen Institute for Artificial Intelligence found that over the past 25 years, although women have made up nearly half (49%) of participants across drug trials, for many types of disease the proportion of female participants did not match the gender breakdown of real-world patients. In trials for cardiovascular, HIV, kidney disease and digestive diseases, women have especially been underrepresented.
The effect of failing to include women proportionately in clinical trials may have consequences for the quality of medical care women receive, with therapies, doses and risk assessment tools being tailored to the male population. The use of real-world medical data from women may change this – and more broadly, ensure that representative samples of data are used for the disease or issue.
What we can learn during pregnancy
As well as collecting more representative samples of data from women for conditions like cardiovascular disease, accurate data collected during pregnancy could offer a valuable information.
This is because typically, ‘real-world’ medical data is collected from patients who are ill. However, pregnancy is a unique time when large quantities of data are collected in otherwise ‘healthy’ women.
Pregnancy can also act as a cardiometabolic stress test for women and reveal underlying susceptibilities to conditions such as diabetes or hypertension.
Therefore, by analysing the data collected during a woman’s pregnancy, clinicians can view a window into future health risks and understand who is most at risk. This helps develop better preventative strategies and also prioritises care.
Research has found that the environment in which a baby grows has a significant impact on its health throughout its life. This means that being able to improve the way we care for pregnant women through collecting and analysing data can also significantly influence the health of their offspring.
While collecting data from patients is important in development of new treatments, clinical research, and patient care, there must be a greater focus on ensuring that women are well represented in trials.
For pregnant women in particular, the information that their medical records can offer must be recognised, and databases that can be used to support the improvement of care and outcomes has the potential to provide important insights.
About the author
Dr Lucy Mackillop is a consultant obstetric physician at Oxford University Hospitals NHS Foundation Trust; honorary senior clinical lecturer, Nuffield Department of Women’s and Reproductive Health, University of Oxford; and chief medical officer at Sensyne Health.
Learn more about the detailed patient points and associated physician data available from OffTheShelf. View our infographic. http://bit.ly/evidera-offtheshelf Highlights about OffTheShelf™: Understanding the market trends, market behavior, and competition when developing oncology therapies is critical to optimize market access and product uptake OffTheShelf™ provides access to oncology and hematology patient chart data in 48 hours […]
Bayer is making clear its ambitions in cell and gene therapy with a $4 billion acquisition of US biotech Asklepios BioPharmaceutical, also known as AskBio.
AskBio’s portfolio includes pre-clinical and clinical stage candidates for the treatment of neuromuscular, central nervous system, cardiovascular and metabolic diseases.
Through the acquisition, Bayer will gain full rights to the company’s gene therapy technology and manufacturing platforms, including AskBio’s adeno-associated virus (AAV)-based platform, which has already demonstrated applicability across different therapeutic areas.
The company’s most advanced programmes are in Pompe disease – a rare genetic disease causing buildup of a sugar molecule inside cells – Parkinson’s disease and congestive heart failure.
Under the terms of the agreement, Bayer will pay $2 billion, with a further $2 billion marked out for potential success-based milestone payments.
According to the company’s statement, some 75% of the potential success-based milestone payments are expected to be due during the course of the next five years and the remaining amount late thereafter.
Last year Bayer fully acquired another cell therapy company, BlueRock Therapeutics – which was created in 2016 via a joint venture between Bayer and Versant Ventures, and is also working on Parkinson’s Disease therapies.
Like with BlueRock, Bayer says it wants AskBio to operate on an “arm’s-length basis” to “persevere its entrepreneurial culture as an essential pillar for nurturing successful innovation”.
Reuters reports that AskBio and BlueRock will exchange information and collaborate but will each operate as independent companies. In light of this, AskBio’s five main owners have pledged to remain with the firm.
“We are staying on board because of the unique structure that Bayer has provided,” said CEO and co-founder Sheila Mikhail. We’ll have the ability to make our science decisions.”
Cell and gene therapy is viewed as one of the most promising areas in pharma, with several biotech and big pharma firms making plays in the area.
These therapies offer new treatment options for many currently untreatable diseases, particularly genetic diseases caused by a single genetic defect.
AskBio has licensed some of its experimental drugs to external partners, such as Pfizer, which recently won fast-track designation in the US for a Duchenne Muscular Dystrophy candidate, PF-06939926, that was invented by AskBio.
Bayer’s blockbuster ambitions for diabetic kidney disease (DKD) drug candidate finerenone look a lot firmer with the publication of data from the phase 3 FIDELIO-DKD trial.
Bayer teased the top-line result from the study back in July, providing the first clue that its sizeable investment in the finerenone programme could pay off, but kept the data under wraps other than to say the drug met the dual objectives of reducing renal and cardiovascular events in patients with type 2 diabetes and chronic kidney disease.
Now, the 5,734-patient study has been presented at the Kidney Week 2020 congress and simultaneously published in the New England Journal of Medicine, and the data look solid.
A second ongoing phase 3 trial – called FIGARO-DKD – is concentrating primarily on cardiovascular endpoints but also includes aptietnsd with earlier-stage kidney disease and has a read out due next year.
Bayer is eyeing regulatory filings before the end of 2020 on the back of the FIDELIO-DKD results, which would set up a clash with SGLT2 inhibitors, drugs for diabetes that are also emerging as promising therapies for DKD.
That includes Johnson & Johnson’s Invokana (canagliflozin) – already approved for diabetic kidney disease – as well as AstraZeneca’s Farxiga (dapagliflozin) which showed positive results in the DAPA-CKD trial in both diabetic and non-diabetic subjects just last week.
Finerenone – billed as a first-in-class non-steroidal, selective mineralocorticoid receptor (MR) antagonist – reduced the risk of kidney disease progression or renal death by 18% when added to the highest tolerated dose of standard therapy in FIDELIO-DKD.
The drug also cut cardiovascular outcomes – including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke or hospitalisation for heart failure – by 14%.
“Overactivation of the mineralocorticoid receptor contributes to inflammation and fibrosis in the kidneys and heart, which represents an unmet medical need,” said lead investigator Prof George Bakris of University of Chicago Medicine.
“The results with finerenone are highly relevant for these patients who currently have limited options,” he added.
There is also a huge number of them. Diabetes is the leading cause of kidney failure, and there are estimated to be almost 850 million people worldwide with chronic kidney disease (CKD).
If approved, finerenone would enter a market in which J&J is struggling to overturn the lingering impact of black-box warnings over amputation risks with Invokana that were dropped in the summer. The drugmaker sees kidney disease as its route to growth after a couple of years of declining sales, and is promoting the new use strongly.
AZ meanwhile is on a roll with Farxiga, with the new data in CKD building on recent data for the drug in heart failure that is helping to drive sales growth, although patent expirations and the threat of generic competition are looming.
Bayer is also eyeing a heart failure indication for finerenone, and now has a phase 3 trial in heart failure with preserved ejection fractions (HFpEF) in play that if successful would unlock a hitherto untapped market with no approved drugs.
Moderna is close to completing its phase 3 trial of COVID-19 vaccine candidate mRNA-1273 after completing recruitment of the 30,000 subjects in the trial.
It’s also revealed that more than 25,000 of them have already received the second dose of the shot in the COVE study, putting it in contention to be the first coronavirus vaccine company to be ready to file for emergency use authorisation in the US.
As with all COVID-19 vaccines, Moderna will need two months of safety data following the final vaccine dose before it will be able to file for an EUA, but the milestone puts it just behind Pfizer and BioNTech in the race to that objective with a possible filing date in early December.
Shares in the company climbed nearly 5% after the announcement continuing an upwards trend that means the stock is now trading at almost four times its value at the start of the year.
The latest milestone follows a rolling reviews of mRNA-1273 in Canada, which allow the country’s regulator to start reviewing data as it becomes available, and Moderna is now gearing up to file via similar mechanism in Europe.
Moderna shared demographic data from the study at an FDA committee meeting today which showed that it included some of the groups most at risk from COVID-19.
That includes 7,000 people aged over 65 and more than 5,000 younger people with chronic diseases that make them more likely to get severe symptoms like diabetes and obesity, while around a third of subjects of African American, Hispanic/Latin and Asian descent.
Last month, Moderna said it was slowing enrolment in COVE to “ensure the representation of…communities of colour, ” and on that measure it seems to have an advantage over Pfizer/BioNTech’s BNT162b2 vaccine, which completed phase 3 recruitment in mid-September but has only 25% ethnic minorities.
Studies have suggested that that black and minority ethic people are at higher risk of dying from COVID-19 than the rest of the population.
We would like to thank the participants in the Phase 3 COVE study as well as the investigators and our partners at clinical trial sites, including our partners from @PPDCRO and the @NIHpic.twitter.com/JT5vahDv4Z
The study – funded with the help of $955 million of US government money – is comparing two 100 µg doses of mRNA-1273 given by intramuscular injection 28 days apart to a matched placebo, and the primary endpoint is the prevention of symptomatic COVID-19 disease 14 days after the second administration.
Like Pfizer/BioNTech and other coronavirus vaccine developers, Moderna has committed to ensuring that it has full safety and efficacy data available before filing for an EUA.
If COVE is positive and mRNA-1273 gets approved, Moderna has said it is on track to deliver up to 500 million doses per year, and possibly up to a billion doses per year beginning in 2021, thanks to a manufacturing collaboration with Lonza.
Initially supplies will be much more limited of course, and the US has already placed orders for 100 million doses of mRNA-123 in a $1.5 billion deal agreed in August.
Hopes that antibody-laden plasma taken from recovered COVID-19 patients could lessen the severity of the disease in others have taken a knock.
The 464-subject PLACID trial – carried out in India – found that the use of so-called convalescent plasma was unable to prevent progression to severe disease or reduce mortality in people hospitalised with moderate COVID-19.
The finding comes after the US issued an Emergency Use Authorisation (EUA) for convalescent plasma in August, despite opposition from some medical experts who said it was premature as the safety and efficacy of the approach had not been established in human testing.
The approval also came amid a spat between the FDA and President Trump, who had accused the agency of impeding progress on coronavirus therapies, and was followed by an embarrassing data gaffe by agency head Stephen Hahn during a press conference announcing the EUA.
Some countries, including the UK, have been collecting and stockpiling convalescent plasma in the hope that it can be deployed quickly to patients if it proves effective in clinical trials.
Now however, it looks like those who advised caution may have had good cause. While it’s worth pointing out that PLACID was an open-label rather than a double-blind study, the trial investigators claim it “approximates convalescent plasma use in real-life settings”.
Studies have shown convalescent plasma from COVID-19 survivors contains antibodies with potent antiviral activity, but there are a lot of unanswered questions about use in patients, including the levels of antibodies needed to be effective, the timing of plasma donation and treatment and the types of patents most likely to respond.
Writing in the British Medical Journal, the authors – led by Anup Agarwal of the Indian Council of Medical Research in New Delhi – say that while prior studies have suggested that convalescent plasma can reduce viral load, the time patients need to spend in hospital, and death rates, that wasn’t the case in their trial.
The primary outcome – progression to severe disease or all-cause mortality at 28 days – was seen in 19% of patients receiving plasma plus standard supportive care, compared to 18% of those in the control arm on supportive care alone.
There were some beneficial effects, including shorter times to resolution of symptoms like shortness of breath and fatigue, but plasma therapy didn’t seem to improve biomarkers for the runaway inflammation that is associated with COVID-19 requiring hospitalisation.
In an editorial accompanying the study, Elizabeth Pathak of the Women’s Institute for Independent Social Enquiry in Maryland, US, said that as the study wasn’t blinded, it was possible that patients who knew they were getting plasma might expect to feel better, and so reported improvements in symptoms.
She also points out that convalescent plasma isn’t without risks – in fact, the FDA specifically warns about the risks of blood clots with the therapy, particularly in older patients and those with cardiovascular risk factors.
Interesting take on the PLACID Trial. I agree with most of it. Were enough early pts included? Ongoing trials will add useful information, but big effect of CP seems unlikely. Convalescent plasma is ineffective for covid-19 https://t.co/QgUo32lUbg
Other studies of convalescent plasma are still ongoing, including the UK RECOVERY trial which has already shown the benefits of the steroid dexamethasone in adults with COVID-19, as well as the failure of the antiviral combination lopinavir-ritonavir.
Convalescent plasma is one of three other therapies being put through their places in the study.
Is a century-old vaccine a ‘game-changer’ for COVID-19? Anita de Waard from Elsevier and Radoslav Kirkov from Estafet tells us how a hackathon is harnessing data science to look beyond the hype and seek definitive clinical evidence.
Today, the notion of ‘data science’ has permeated almost every area of society. Words like machine learning, artificial intelligence and deep learning have entered the everyday business lexicon. From government agencies to online retailers, a ‘big data strategy’ is a must-have. This year, as the COVID-19 pandemic has spread, there has been increased talk of statistics, modelling, predictive analytics, and using data to solve the serious issues we face.
But often, what purports to be data science is actually just a random correlation between different data sets. The phrase ‘data science’ is often used to represent any form of data analysis, however rudimentary, and regardless of whether it is based on scientific understanding. Given the amount of faith we increasingly put in algorithms to make decisions on our behalf, whether in our hospitals, our courts, or our education system, we need a much deeper understanding of how these correlations are drawn, and what they are based on, in order to apply data science for good.
This is especially true in the search for effective therapies to fight COVID-19, and a vaccine. Speed is truly of the essence, but at the same time, the integrity of the science underpinning any clinical recommendations must be maintained. With so many research projects, collaborations and clinical trials taking place in an attempt to limit and prevent the virus, we have to be clear on how decisions are being made and what the data behind an apparent breakthrough is really telling us.
“In a worst-case scenario, misplaced hype could lead to a sudden rush to buy doses of the BCG vaccine. In nations where TB is widespread, this could put many lives at stake”
Understanding the link between COVID-19 and the BCG vaccine
A good example of this phenomenon is the sudden hype around the Bacillus Calmette–Guérin (BCG) vaccine, which is primarily used against tuberculosis (TB). This century-old vaccine came to prominence recently, when a number of early ecological studies (those which study population factors in epidemiology) seemed to show a strong correlation between receiving the vaccine and having immunity against COVID-19.
Some studies suggested the link was a “game-changer” and a “silver bullet”. The studies claimed to show a strong correlation between the BCG vaccination and protection against COVID-19, but closer examination revealed a tenuous correlation, from which clear conclusions can’t be drawn. Indeed, the World Health Organization said that, “Such ecological studies are prone to significant bias from many confounders, including differences in national demographics and disease burden, testing rates for COVID-19 virus infections, and the stage of the pandemic in each country.”
The world-leading TB researcher Prof. Madhukar Pai was also quick to warn of the serious limitations with this approach and the need to be cognizant of confounding variables. In a worst-case scenario, misplaced hype could lead to a sudden rush to buy doses of the BCG vaccine. For developed nations with low TB rates, this would have little impact. But in nations where TB is more widespread, such as India, the potential implications of a sudden shortage of BCG vaccine could put many lives at stake.
The aim now must be on providing stronger clinical trial evidence of the link between the BCG vaccination and incidence of COVID-19, to enable data-led decisions to be made. There are clear shortcomings with current ecological studies, which take aggregated data and look to make inferences at an individual level. If the data are not representative or confounders are not taken into account, the results will be inaccurate.
Establishing an evidence-backed link
The only way to truly understand the correlation between COVID-19 and the BCG vaccine is to conduct randomised trials combined with deep analysis of existing data. To that end, Estafet and Elsevier have initiated a two-stage hackathon. The groups are working together with the BCG World Atlas team, which is led by an infectious disease specialist at the University of Ottawa, Dr Alice Zwerling. The BCG Atlas is an open-source database of global BCG vaccination policies and practices, founded in 2011.
Many of the aforementioned ecological studies were based on data from the BCG Atlas, so the first stage of the hackathon aimed to augment and improve the Atlas; with additional data and health records available on BCG vaccinations. These have been found through natural language processing (NLP) methods. With thirty volunteers globally, including judges, organisers, and data gatherers, prizes were awarded to those deemed to have extended the data most. The winner was Dimitrina Zlatkova of Sofia University, who contributed 57 additional data points, followed by developer Marouane Benmeida of Morocco who added 33 additional data points.
The hackathon now moves to stage two, where the volunteers will seek to answer a series of questions, such as whether the BCG vaccination is causally related to reduced COVID‐19 mortality, or if other factors like lockdowns and average age of the population are responsible for the different mortality rates. If the BCG vaccination does reduce COVID-19 mortality, what are the key factors. For example. how long does the immunity from BCG last after that vaccination? Does the strain of BCG vaccination impact immunity? The team is now looking for more volunteers to get involved as the hackathon progresses. Once complete this most valuable insights from the task will be shared with the ongoing BCG COVID-19 clinical trials.
Data science for good
When it comes to COVID-19, data science will certainly be critical – but it is the blend of scientific understanding and technical acumen through data science that is vital.
It is a job for all of us engaged in data science projects – whether in academia or commercial or government research – to stem the hype. It is important to assess the veracity of a claim before accepting any conclusions, and empower the public to do the same. This habit of mind is important not only in the development of treatments and vaccinations, but paramount to establishing a broad public trust in data-led decision making.
About the authors
Anita de Waard is VP research collaborations at Elsevier and Radoslav Kirkov is technology director at Estafet.
Sarepta chief commercial officer Bo Cumbo has left to head up gene therapy venture – AavantiBio – with $107 million in backing from his former employer and three high-profile life sciences investors.
Rare disease specialist Sarepta is putting up $15 million of that first-round financing, with the remainder coming from Perceptive Advisors, Bain Capital Life Sciences, and RA Capital Management.
The new company – headquartered in the Boston area – is drawing on the gene therapy expertise of University of Florida researchers Barry Byrne and Manuela Corti.
It is focusing its initial efforts on the development of a gene therapy for Friedreich’s ataxia (FA), a rare, inherited neuromuscular disease caused by mutations in a gene called FXN that leads to impaired muscle coordination, as well as problems with the heart and central nervous system.
Earlier this year, three-year-old AavantiBio was awarded a $1 million grant from the US Muscular Dystrophy Association (MDA) to start producing the gene therapy, due to start a phase 2 trial later this year.
Cumbo’s eight years of experience at Sarepta – which sells exon-skipping therapies for Duchenne muscular dystrophy (DMD) and is thought to be at the forefront of developing a gene therapy for the disease – should have prepared him well to take AavantiBio’s lead programme forward.
He has previously worked as vice president of sales at Vertex Pharma, and had various commercial roles at Gilead Sciences. Commenting on the latest role, Cumbo said AavantiBio has “a unique opportunity to change the lives of those living with FA and other rare diseases”.
Sarepta CEO Doug Ingram said that Cumbo “built a first-in-class rare disease commercial organisation and has made tremendous contributions to Sarepta”.
He went on: “We look forward to continuing to work with Bo as he builds a strong AavantiBio team and advances therapies to treat FA and other rare diseases.”
FA affects about 1 in 50,000 people in the US, according to the MDA, but is considered to be a great target for gene therapy because it is linked only to mutations in the FXN gene.
That means replacing the defective gene with a working copy should – or correcting it in situ – could stop the disease in its tracks. FA typically starts in childhood, affecting males and females, but AavantiBio has said it intends to test its therapy in both paediatric and adult patients.
The disease varies in severity depending on the FXN mutation and whether the patient has one or two copies, but typically patients will be confined to a wheelchair within 10 to 20 years of diagnosis. Around 15% of cases are spotted after age 25.
There’s no approved therapy for FA yet, although one is on the horizon. Reata Pharma had been gearing up to file for approval of omaveloxolone as an FA treatment before the end of the year, but said recently it may need to run a second trial of the drug after discussions with the FDA.
Unlike a one-shot gene therapy, omaveloxolone would require continuous dosing to maintain its effects.
Roche may not be the first company that comes to mind for a COVID-19 treatment, but the Swiss firm is taking a big swing at the market to rival Gilead’s remdesivir.
The company has joined forces with Atea Pharmaceuticals to develop, manufacture and distribute Atea’s investigational oral direct-acting antiviral AT-527.
AT-527 works by blocking the viral RNA polymerase enzyme needed for viral replication.
It is currently being studied in a phase 2 clinical trial for hospitalised patients with moderate COVID-19. Phase 3 trials are expected to start in Q1 2021, and will test the drug outside of the hospital setting.
If successful, this would make it the first oral treatment option for COVID-19 for patients that are not hospitalised.
If the drug is approved, Atea will be responsible for distributing it in the US, with the option to request Genentech’s support, and Roche will distribute in the rest of the world.
“The ongoing complexities of COVID-19 require multiple lines of defence,” said Bill Anderson, CEO of Roche Pharmaceuticals. “By joining forces with Atea, we hope to offer an additional treatment option for hospitalised and non-hospitalised COVID-19 patients, and to ease the burden on hospitals during a global pandemic.”
“In jointly developing and manufacturing AT-527 at scale, we seek to make this treatment option available to as many people around the world as we possibly can.”
Roche has been studying its already-approved anti-inflammatory drug Actemra (tocilizumab), branded as RoActemra in some countries, to see if it can cut the chances of COVID patients needing a ventilator.
Until now results have been disappointing – in July the COVACTA trial failed after it showed that Actemra could not improve clinical status in patients with COVID-19.
But the findings of the latest phase 3 study, EMPACTA, could change that after Roche said it plans to share results with the FDA and other regulators to get its label expanded on the basis of the latest results.
Roche has also developed a COVID antibody test, with CEO Severin Schwan branding the state of testing at the start of the pandemic as a “disaster”.
“Some of these companies, I tell you, this is ethically very questionable to get out with this stuff,” Schwan told reporters in a quarterly results conference call.
“It’s a disaster. These tests are not worth anything, or have very little use,” he added.
French biotech SparingVision has raised 44.5 million euros ($52.7 million) to develop its gene therapy for a rare ocular disease.
The round was led by 4BIO Capital and UPMC Enterprises with Jeito Capital and Ysios Capital joining.
Current investors Bpifrance and Foundation Fighting Blindness also participated.
In a statement, the company said funds will be used to further develop SparingVision’s SPVNo6, for treating all forms of the rare eye disease retinitis pigmentosa.
SPVN06 is a proprietary, mutation-agnostic, AAV gene therapy consisting of one neurotrophic factor and one oxidative stress reducing enzyme which, acting together, aim to slow or stop the degeneration of photoreceptors.
Loss of photoreceptors leads to blindness in RP, one of the most common inherited retinal diseases that affects two million patients worldwide. There is currently no treatment approved for RP patients independently of their genetic background.
The financing will support manufacturing of a first clinical batch of the product, regulatory activities and a first human study scheduled to start next year.
The Paris-based company intends to further expand its management team and begin operations in the US. SparingVision announced the appointment of Stephane Boissel as CEO of the company. Boissel was previously executive vice president of corporate strategy at gene editing biotech Sangamo Therapeutics.
Prior to that, he was CEO of TxCell, the CAR-Treg company sold to Sangamo in 2018.
He has also headed up the molecular diagnostic company Genclis and was executive vice president and chief financial officer of Innate Pharma and Transgene.
Earlier this year, Oxford Biomedica and Sanofi ended a partnership focused on rare eye diseases including retinitis pigmentosa.
Sanofi handed back rights to two ophthalmology gene therapies, one of which is in development for retinitis pigmentosa.
The UK biotech said in June that it would start an internal review of the two gene therapies.
Merck & Co has built more momentum behind its attempt to depose Pfizer’s blockbuster pneumococcal conjugate vaccine Prevnar 13, with two new phase 3 trials backing its rival shot V114.
The two trials are both in adult subjects, a group that has been driving growth of Prevnar 13 in the last few years, and showed that V114 stimulated immune responses to all 15 pneumococcal serotypes included in the vaccine.
In the PNEU-PATH and PNEU-DAY studies, dosing with V114 was followed a year later by a shot of Merck’s older polysaccharide-based Pneumovax 23 vaccine, and showed that the combination was protective in the over-50 and under-50 adult age groups, respectively.
US-based Merck already has phase 3 data in hand backing the safety and efficacy of V114 in children as well as non-inferiority to Prevnar 13 for the serotypes the two vaccines share. It reiterated its plans to file for approval of the vaccine before the end of the year in the US.
Prevnar 13 – which as its name suggests covers 13 serotypes – is the world’s top-selling vaccine, adding almost $6 billion to Pfizer’s top-line last year thanks to its dominant position in the paediatric pneumococcal shot market.
Added to that, it’s not due to lose patent protection until 2026, when analysts predict it could make more than $7 billion, although it’s worth noting that growth has been pegged back so far in 2020 as a result of the pandemic lockdowns.
Merck is hoping to trump its rival with 15-valent V114, as it provides protection against two serotypes – 22F and 33F – that aren’t included in Pfizer’s product. It also provides an opportunity to expand its position in the adult pneumococcal disease market, where Pneumovax 23 is still widely used.
“Pneumococcal disease in adults is on the rise globally, in part driven by disease-causing serotypes not targeted by the currently available pneumococcal conjugate vaccine,” said Merck’s chief medical officer Roy Baynes.
“These data provide important information about the potential for V114 followed by Pneumovax 23 [which is] included in more than 90% of age-based adult pneumococcal immunization programmes globally,” he added.
Pfizer isn’t resting on its laurels however, and is preparing to defend its Prevnar franchise, reporting positive clinical results with a 20-serotype follow-up – called PF-06482077 or 20vPnC – that it also thinks could be ready for filing before the end of the year.
As a backup it has also been developing a 7-serotype shot that would provide the same breadth of cover as 20vPnC when combined with Prevnar 13.
Pneumococcal disease is caused by Streptococcus pneumoniae, and includes non-invasive illnesses like pneumonia, sinusitis and middle ear infections, as well as invasive diseases like meningitis.
It can be particularly problematic in young children under two and adults aged over 65, as well as people with compromised immune systems.
AstraZeneca’s COVID-19 vaccine trial could be ready to resume this week in the US after a seven-week hiatus while the FDA completed its review of a serious illness, according to reports.
Citing four sources, Reuters said that the FDA is about to allow the large-scale trial of the shot to resume after it was put on hold on 6 September when a participant in the UK fell ill.
AZ has not confirmed the nature of the illness because of concerns over patient privacy, but according to press reports the person developed the rare spinal inflammatory disorder transverse myelitis.
Reuters said its sources were briefed on the matter but asked to remain anonymous but said the trial could resume later this week.
It is unclear how the FDA characterised the disease that caused the stoppage and the regulator has so far declined to publicly comment on the matter.
The FDA is requiring trial researchers to add information about the incident to consent forms signed by study participants, one of the sources told Reuters.
UK regulators allowed the trial to resume a week after it was put on hold – according to Reuters’ sources this was because there was “insufficient evidence to say for certain” that it was not related to the vaccine.
The Medicines and Healthcare products Regulatory Agency (MHRA) recommended that vaccinations should continue but with close monitoring of the affected person and other participants.
The FDA has publicly stated the importance of safety data for COVID-19 vaccines – they will be given to healthy individuals and there is very little tolerance for any side effects.
The regulator has said manufacturers must have at least two months’ worth of safety data before filing a COVID-19 vaccine, amid concerns that the Trump administration may attempt to rush approval ahead of the US election on 3rd November.
As Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, pointed out to Reuters, regulators have to weigh whether a rare side effect is vaccine-related and could occur again.
Transverse myelitis occurs at a rate of one in 200,000 people and he noted it would be unusual to see it in a trial of 9,000 people.
But other viruses including West Nile and polio can trigger the condition, as well as physical trauma.
Regulators in Brazil, India and South Africa have also allowed trials to resume.
Until the safety issue AstraZeneca had been a frontrunner in the race to produce a vaccine for COVID-19.
Johnson & Johnson has voluntarily put a trial of its potential rival vaccine on hold because of a safety issue.
According to the World Health Organization, there are 44 candidate vaccines in clinical trials, with three shots developed in China listed as most advanced followed by the AZ vaccine.
The war of words between Donald Trump and his top infectious diseases expert Dr Anthony Fauci has intensified as the president’s handling of the coronavirus pandemic comes under increasing scrutiny.
CNN reported that on a campaign call a “frustrated and at times foul-mouthed” Trump ranted about how people are tired of hearing about the pandemic, adding Fauci is a “disaster” and been around for “500 years”.
Fauci has been head of the government-funded National Institute of Allergy and Infectious Diseases (NIAID) since 1984 and is a member of the White House’s coronavirus task force.
According to CNN Fauci was being awarded the National Academy of Medicines first-ever Presidential Citation for Exemplary Leadership in a virtual ceremony at the time of the call.
CNN was given access to the call by a source.
Trump reportedly said during the call on Monday from his hotel in Las Vegas: “Fauci is a disaster. If I listened to him, we’d have 500,000 deaths,” later adding it would be 700,000 or 800,000 although he could present no evidence to support the claim.
The president has been criticised for failing to observe social distancing precautions at campaign rallies after contracting and recovering from COVID-19 a few weeks ago.
Trump is trailing in the polls to rival Joe Biden, with his handling of the pandemic becoming a major issue. To date, COVID-19 has killed more than 215,000 Americans.
Fauci and Trump have been at odds during the last few months with the relationship souring particularly over an advert where the president implied that the NIAID chief endorsed the president’s handling of the crisis.
Fauci disputed the ad, saying his words were taken out of context and asked for the advert to be taken down.
According to CNN, Trump has also been eschewing advice from the coronavirus task force and stopped attending meetings – favouring counsel from radiologist Dr Scott Atlas instead.
The radiologist has undermined the importance of masks and other mitigation practices, contrary to mainstream scientific opinion.
The UK government has signed a contract to develop a controversial COVID-19 human challenge trial, where participants will be deliberately infected in a controlled environment with coronavirus to test whether a vaccine is effective.
Contract research organisation (CRO) hVIVO, a subsidiary of Open Orphan, has signed the contract with the UK government to develop the trial model.
This will involve manufacture of the challenge virus and the first-in-human characterisation study for the virus.
The characterisation study, which is expected to be completed in May 2021, still needs ethical and regulatory approval.
It is designed to assess the minimum dose of the virus required, before moving on to the next stage when a vaccine will be administered.
The study will be sponsored by Imperial College London and conducted by hVIVO at The Royal Free Hospital’s specialist research unit in London, under the scrutiny of highly trained scientists and medics.
hVIVO will also be expanding its clinical operations in London to conduct the trial.
It’s not clear which vaccine will be involved in the study – there are several in the last stages of clinical development and the UK government has orders for candidates from AstraZeneca, Pfizer/BioNTech, Novavax, Valneva, Sanofi/GSK and Johnson & Johnson.
No financial details of the contract with hVIVO were disclosed.
Challenge trials are controversial because of the risks involved with infecting patients with a potentially lethal virus, although with the SARS-CoV-2 coronavirus these could be managed as most people develop mild symptoms and those at high risk of a serious infection are relatively easy to identify.
hVIVO is already known for its challenge studies in other infectious diseases, which are conducted a 24-bedroom quarantine clinic with onsite virology, providing individually isolated rooms and connected to a specialist laboratory facility.
Open Orphan, which comprises of two commercial CRO services business hVIVO and Venn Life Sciences, has been working on several coronavirus challenge study models and expects to be busy over the next few months helping several pharma and biotech companies test their vaccines.
Anyone interested in being contacted and provided with details about future COVID-19 human challenge study research may leave their contact details at www.UKCovidChallenge.com.
The World Health Organization has been keeping tabs on the development of vaccines since the start of the pandemic and says there are now 44 in clinical development.
The three most advanced are being developed in China where the pandemic is thought to have originated, followed by a candidate from Oxford University and AstraZeneca in the UK.
Feature image courtesy of Rocky Mountain Laboratories/NIH
Pfizer said it will wait until after the US election to file its COVID-19 vaccine with the US regulator, as it waits for important safety data to become available.
The vaccine is being developed by Pfizer and development partner BioNTech and will wait until late November to make its application with the FDA.
In a letter published on its website Pfizer may have the data to say whether the vaccine is effective this month, based on the findings of the ongoing 40,000 person clinical trial.
But CEO Alfred Bourla cautioned that the safety data will only be ready in the third week of November.
There have already been two safety scares in COVID-19 vaccine trials – Johnson & Johnson earlier this week put its phase 3 trial on hold because of an undisclosed illness in a patient.
A US trial of AstraZeneca’s shot is also on hold after a similar incident, although studies in other parts of the world have restarted.
As vaccines will be given to healthy individuals, regulators have far less tolerance for adverse events.
There are further concerns that political interference during the election build-up could undermine the credibility of a mass vaccination programme.
Bourla said: “So let me be clear, assuming positive data, Pfizer will apply for Emergency Authorization Use in the US. soon after the safety milestone is achieved in the third week of November.”
Despite the concerns of scientists president Donald Trump has said that there would be a vaccine available before the election on 3rd November and is hoping that approval could be the “October Surprise” that could boost his popularity ahead of the vote.
Rival Moderna has said it could apply for an Emergency Use Authorization for its rival vaccine as soon as November.
The European Medicines Agency has already started a rolling review of the Pfizer/BioNTech and AstraZeneca vaccines.
In the age of artificial intelligence, no trial data should be going to waste. Findacure’s Rick Thompson looks at how these technologies could bring us closer to treatments for underserved rare diseases.
The repurposing of drugs is becoming more common, especially in the field of rare diseases. In the past, repurposing has mostly been driven by academics looking for new possibilities in generics. Now, as part of lifecycle management, pharmaceutical companies are looking more closely at drugs they have on their shelves. These might be licensed drugs that could hold potential for a patent extension, or drugs which failed efficacy trials for an intended indication.
In the quest to repurpose a drug for a rare condition, there is a need to look at any and all available data. The wealth of published scientific literature forms one crucial source of data, with the ever-expanding pool of ‘omic data forming another.
A third pool of clinical evidence is formed by trial data, which will probably only be considered through the published literature. By definition, however, trial master files represent a much richer and more detailed source of data on a drug and how it performs. Published literature tends to catalogue successful clinical trials, but value can also lie in a trial that did not lead to a positive and viable outcome: the data it produced could still provide evidence for repurposing. For instance, provided a drug has not failed a trial on safety, the side effects it caused in one population could constitute on-target effects in another.
With large datasets crucial to gaining an understanding of rare diseases and opening the door to drug development, digital technology is proving transformative. It enables careful collation and organisation of information, but the innovations of artificial intelligence (AI) are now taking things further, facilitating the effective analysis and interrogation of big data to create new treatment hypotheses.
“Patient associations are working to develop registries (some using wearable technologies or apps) and natural history studies, which means that ever-greater volumes of data are being produced”
These techniques make the production of and access to high-quality data on rare diseases the gateway to treatment identification, and so are proving more crucial than ever for organisations in pharma.
Digitised, rigorously controlled data lends itself to techniques of processing and analysis which characterise both drug discovery and drug repurposing.
Raw text can be analysed by Natural Language Processing (NLP) techniques which form connections between studies that could otherwise take thousands of hours of human time to identify.
When combined with analyses of ‘omic approaches, and an appropriate level of disease-specific knowledge from patient groups, you can create a powerful resource for the identification of new treatment hypotheses for rare diseases – and an opportunity to address severe unmet needs.
Findacure is a charity that works directly with rare disease patient groups to help them grow and professionalise. Over the last five years we have focused on the power of drug repurposing for rare genetic diseases. It is estimated that, worldwide, just 400 treatments are licensed for 7000 known rare conditions, which tend to be determined by a very specific genetic factor.
As a consequence, most patients are being left with no hope of a treatment in their lifetime. Luckily, patient associations are working to fill the void by uniting patients and driving research forward for their conditions. Many are working to develop registries (some using wearable technologies or apps) and natural history studies, which means that ever-greater volumes of data are being produced.
This drive to generate data on and interest in their condition – along with the collated knowledge of their community’s lived experience of rare disease – can prove transformative to the treatment landscape. We are now seeing patient associations involved in several collaborative efforts that are identifying drugs which, as candidates for repurposing, stand to deliver treatments to rare disease patients more quickly and cheaply.
In 2020, the pharmaceutical industry has not by any means proved immune to the disruption caused by COVID-19. But, as in other industries, the pandemic has accelerated the process of digital transformation that was already underway.
A recent survey of more than 200 life sciences professionals, conducted on behalf of digital archiving specialists Arkivum, found 70% of respondents saying that COVID-19 has triggered a change in the way clinical trials will be conducted. There can be no doubt that digital technology will play a key role in that change. The survey reports that over 90% of sponsors and CROs have already adopted an eClinical application to improve study execution and data collection in live trials.
When a trial is completed, the valuable and extensive data it has produced must be archived – an exercise crucial both to regulatory compliance and to any future efforts at repurposing. 70% of sponsors reported that they use a digital archive rather than the traditional paper-based option, and 45% of respondents cited the role that clinical trial data plays in finding new indications and formulations. Yet at the same time, 38% of sponsor organisations described their ability to access archived clinical data and records as ‘extremely or very inadequate’.
This percentage rose to 65% amongst QA, compliance, legal and regulatory professionals. Moreover, just 31% of life sciences organisations seem to run a digital archive of sufficient sophistication to ensure that data can be managed in accordance with the FAIR data principles.
These were established to further scientific study through keeping data Findable, Accessible, Interoperable and Re-usable – all key attributes when it comes to exploring the new potential of an existing drug.
In the search to repurpose drugs, readier, more reliable access to archived trial data – including trials that produced negative results – can clearly prove highly beneficial.
If data has been well stewarded before and after it reaches the archive, and if its integrity has been maintained through careful curation, it facilitates the application of AI techniques. Natural language processing can be used in conjunction with, say, analysis of ‘omic-level data and patient group insights in order to work through the problems and side effects encountered in the full spectrum of trials. This can open the way to repurposing for different populations, and to new approaches to the design of clinical trials.
The success of these endeavours will also be favoured by the availability of comprehensive rare disease registries which collate patient-level data on disease natural history while also bringing together a pool of patients who could participate in trials.
Meanwhile at the pre-competitive stage of drug development, researchers are adopting a more open, collaborative approach to data. Now is the time to enable further collaboration by increasing access to historical data and releasing its full value. Success in finding treatments for rare disease is above all the product of collaboration, as technological innovation complements and amplifies a compassionate, patient-centred approach.
In all this, it is worth remembering that the people who participate in clinical trials – especially in the field of rare disease, where recruitment of patients is a particular challenge – would appreciate knowing that their participation will have a lasting value, whatever the outcome of the trial.
Trial participants take on a burden by putting in time, effort, hope and commitment. They also put themselves at some degree of risk whenever they take an experimental drug. In the field of rare diseases, trial participants are hoping to help the next generation of patients even more than themselves.It is crucial to maximise the potential value of data they are helping the professionals to collect.
With repurposing on the table, and improved access to all trial data, we can better unlock this potential.
About the authors
Dr Rick Thompson is CEO of Findacure, a UK charity dedicated to building the rare disease community to drive research and develop treatments.
Tom Lynam is head of Marketing at Arkivum, specialists in digital preservation of valuable data in life sciences and global scientific institutions.
Gilead’s Veklury (remdesivir) has failed to produce an effect on hospital stay and mortality in COVID-19 patients in a large global trial, casting doubt on previous supportive study findings.
The results from the World Health Organization’s large Solidarity trial are yet to be peer reviewed but were posted online on a preprint server.
Interim findings from Solidarity, which involved more than 11,000 patients in more than 30 countries, contradict those from the manufacturer in a US study.
Solidarity is testing the effects of four potential drug regimens including remdesivir, hydroxychloroquine, the anti-HIV combination lopinavir and ritonavir, and interferon.
According to the study the regimens have little or no effect on length of hospital stay or 28-day mortality, the WHO said.
All other three options have already been shown to be ineffective, but the data from remdesivir is a surprise given the previous trial results used to support its Emergency Use Authorization from the FDA.
Earlier this month data from the US-based ACTT-1 trial study showed Veklury resulted in five days’ faster recovery in patients hospitalised with COVID-19.
There was a non-statistically significant trend towards a reduction in mortality, with the effect being more pronounced in patients who were on low-flow oxygen at baseline.
A spokesperson for Gilead told Reuters: “The emerging (WHO) data appears inconsistent, with more robust evidence from multiple randomised, controlled studies published in peer-reviewed journals validating the clinical benefit of remdesivir.
“We are concerned the data from this open-label global trial has not undergone the rigorous review required to allow for constructive scientific discussion, particularly given the limitations of the trial design.”
The WHO said that Solidarity provides a platform that could be used to quickly test emerging treatments.
WHO chief scientist Soumya Swaminathan said that the trial model could be used to test new therapies including monoclonal antibodies and newer antiviral drugs.
In a separate development, Spain’s Pharmamar said it is planning a phase 3 pivotal trial of its Aplidin (plitidepsin) in COVID-19, after an early stage study showed the drug seems to be safe and reduces viral load in infected patients.
Pharmamar specialises in developing medicines that take their inspiration from compounds found in the sea and had been focused on oncology until the pandemic began.
Sanofi will shortly start human trials of a second coronavirus vaccine, developed with US biotech Translate Bio, after reporting that it stimulated antibodies against SARS-CoV-2 in preclinical testing.
The French drugmaker’s Sanofi Pasteur vaccines division says it is planning a phase 1/2 trial of the mRNA-based vaccine, called MRT5500, before the end of the year. It started human testing of a protein subunit vaccine with partner GlaxoSmithKline last month.
There are already three other RNA-based vaccines in trials for COVID-19 from Moderna, Pfizer/BioNTech and CureVac, out of 42 candidates in clinical development, according to the World Health Organization’s latest update.
Among these, Pfizer/BioNTech’s BNT162b2 looks like it could claim the lead among the late-stage COVID-19 vaccine programmes, after safety issues halted trials of rival shots from Johnson & Johnson and AstraZeneca.
Data from a 195-patient phase 1 trial of BNT162b2 were published in the New England Journal of Medicine this week, showing that the shot stimulated neutralising antibodies to SARS-CoV-2 at a level similar or greater than those found in people who have recovered from infection with the virus.
Another vaccine – called BNT162b1 – was also effective in stimulating an antibody response but was associated with more systemic side effects, according to the trial investigators.
In preclinical testing involving mice and non-human primates, two doses of MRT500 also elicited a strong neutralising antibody response against SARS-CoV-2 that according to Sanofi were significantly higher than those observed in COVID-19 patients.
Sanofi and Massachusetts-based Translate Bio started to work together on the mRNA vaccine programme in March, and expanded the effort in June to include all infectious disease areas after identifying promising lead candidates.
Under the expanded deal, Translate stands to receive $425 million in upfront payment and Sanofi common stock, plus up to $1.9 billion in milestone payments, providing another endorsement of the potential for mRNA to generate vaccines.
Russia approves second shot
Sanofi is one of the signatories of a pledge by nine leading companies in the race to develop a COVID-19 vaccine that they will only apply for approval after phase 3 studies have been completed and their candidates have been thoroughly tested.
Russia however has forged ahead with its controversial approach to the pandemic by approving a second SARS-CoV-2 vaccine based on only preliminary human testing, just three months after clearing the Gamaleya Institute’s Sputnik V shot on similarly scant data.
The latest – called EpiVacCorona – was developed by the Vektor State Research Center of Virology and Biotechnology and has been cleared on the strength of clinical testing in just 100 subjects, according to local media reports.
Russian president Vladimir Putin announced the latest approval on state television. adding to concern that Russia has been rushing vaccines to approval in order to claim political capital.
Both the approved vaccines are now in phase 3 trials involving tens of thousands of patients, but results from those are not expected until mid-2021. Regardless, Russia has said it had accepted orders for 200 million doses of Sputnik V from Brazil, India and Mexico.
Russia is the world’s fourth-most affected country by the coronavirus pandemic with a total of 1.37 million cases and a little over 23,000 deaths.
Chinese inactivated vaccine safe
Also this week, A Chinese COVID-19 vaccine based on inactivated coronavirus has been shown to be safe and stimulate an antibody response in a preliminary 640-patient phase 1/2 trial has been published in The Lancet Infectious Disease journal.
Developed by the Beijing Institute of Biological Products, the BBIBP-CorV vaccine was given as a two-dose regimen and was found the be safe across a broad age range – from 18 to 80 – and stimulated a neutralising antibody response in all immunised subjects by day 42, the final day of follow-up.
Antibody levels were lower in older recipients, however. The authors said the results were encouraging, but it is not possible to say yet whether the vaccine will be protective against SARS-CoV-2 infection.
There is growing evidence that the coronavirus may be able to re-infect patients, and a new instance of a second infection has been confirmed in the US.
It is the fifth confirmed reinfection worldwide after at least four other cases were confirmed in Belgium, the Netherlands, Hong Kong and Ecuador.
The latest case was recorded in the Lancet Infectious Diseases journal and involved a 25 year-old man with no known immune disorders or underlying conditions.
Although the authors said further research was needed, they said the findings suggested previous exposure may not confer immunity and that people should comply with control measures.
The second infection of the patients from Washoe County, Nevada, was more severe than the first and resulted in hospitalisation and oxygen support.
The man tested positive for the virus in April this year and later tested negative on two separate occasions.
Genetic sequencing of the virus showed the man was infected twice by different strains of the SARS-CoV-2 virus.
Authors suggested that more research was needed to find out low immunity could last, suggesting that the man may have developed more serious symptoms the second time round after receiving a higher dose.
The second strain encountered may have been more virulent than the first, researchers suggested.
Other new discoveries about the novel virus include a link with permanent hearing loss, which occurred in a 45 year-old man who contracted the disease in the UK.
It’s the first such case to emerge with the coronavirus, although sudden hearing loss can follow other viral infections including flu.
The BMJ Case Reports journal said that steroid drugs could help avoid hearing damage if they were given early enough.
The patient had asthma and was admitted to a London hospital with COVID-19 symptoms and was transferred to intensive care after struggling to breathe.
After being put on a ventilator and treatment with several drugs the man began to recover after around 30 days.
But a week after the breathing tube the patient experienced tinnitus followed by sudden hearing loss in his left ear, with tests suggesting the loss was linked to damage to the auditory nerve rather than blockage in the ear canal.
While steroid treatment has mitigated the damage, the man was left with some irreversible hearing loss.
Feature image courtesy of Rocky Mountain Laboratories/NIH
Evidera’s multidisciplinary team of data scientists, epidemiologists, and statisticians offer a host of fit-for-purpose solutions to address your most challenging research questions. Learn more: http://bit.ly/RWEsolutions Offerings include: Database study designs Hybrid study designs LiveTracker®, a cloud-based platform delivering real-world data in real time Data Science Applications Real-World Data Networks, such as REWARD, an innovative EMR […]
Eli Lilly’s Olumiant (baricitinib) has a significant effect on recovery from COVID-19 when combined with Gilead Veklury (remdesivir), according to a large trial backed by funding from the US government.
The findings came from additional safety and efficacy data harvested from the US National Institute of Allergy and Infectious Diseases’ (NIAID) ACCT-2 trial.
Results in hospitalised adults with COVID-19 infection also showed a numerical decrease in death – 35% – in patients treated with the combination therapy, which was more pronounced in patients receiving oxygen.
Lilly said that mortality rate seen on the combination was 5.1%, compared with 7.8% in patients treated with remdesivir alone.
In patients receiving oxygen the combination reduced mortality rate by 60% at day 29, was 43% in certain subgroups.
No new safety signals were observed for patients treated with Olumiant and results will be peer reviewed soon, the company added.
Lilly is continuing talks with the FDA around the potential for an Emergency Use Authorisation for Olumiant, which has been approved since 2018 in the US to treat rheumatoid arthritis.
However because of the well-known side effects associated with Olumiant, which may increase the risk of blood clots that can cause deep vein thrombosis and pulmonary embolism, it’s likely that the drug will be reserved for use in only very sick COVID-19 patients.
The drug works by inhibiting janus kinase (JAK1 and JAK2), which has the effect of reducing the activity of the immune system.
This is important because the more extreme symptoms seen in serious cases of COVID-19 are caused when the virus causes the body’s immune system to over-react.
Several drugs have been trialled to counter the inflammation and damage to organs that this can cause, such as dexamethasone, a cheap steroid that was found to work against COVID-19 in the UK’s large RECOVERY trial.
Feature image courtesy of Rocky Mountain Laboratories/NIH
Delayed diagnosis, lack of awareness, and a limited evidence base – Aarskog syndrome faces all the challenges of rare diseases everywhere. But a new study hopes to kick start a revolution in understanding.
For five years, Michelle Erskine faced a succession of closed doors and disbelief as she struggled to convince someone that all was not well with her son.
Eventually, after undergoing five operations in as many years, he was seen by a Consultant Ophthalmologist with knowledge of the condition and was placed on the road to an Aarskog syndrome diagnosis.
“When I saw it in black and white, I just burst into tears,” says Michelle, founder of the Aarskog Foundation, which recently marked Aarskog Awareness Week from 29 September to 4 October.
“Up until then, I was unable to convince anyone that something was wrong. We kept going to the nurse and the GP, but we were never referred to a paediatrician. No one would listen.”
The rare, X-linked genetic condition is characterised by short stature and facial, limb and genital abnormalities and was first described in 1970.
Michelle, who had recognised similarities between her son and two of her brothers, who had never been diagnosed, set up the Facebook page that eventually evolved into the foundation 12 years ago.
“I wanted to start a conversation and give people a space where they would be listened to. But from that, I wanted to formalise things – if all we do is talk as a group then nothing will ever get done”
Together with two fellow ‘Aarskog mums’ who had started social media pages around the same time, she had soon made contact with around 100 people from four countries around the world.
“I just wanted to start a conversation and give people a space where they would be listened to, so that no other mother would feel alone again. We were talking about the characteristics of the condition, advising people on how to speak to a GP, when to get a referral, etc.,” says Michelle.
“But from that, I wanted to formalise things – if all we do is talk as a group then nothing will ever get done. As my mum used to say: ‘if you do what you’ve always done, you’ll get what you’ve always got’.”
The Aarskog Foundation was established in 2017 and was given charitable status the following year. The objective, Michelle says, was to ensure families like hers received the support they needed.
“I wanted to change the dynamic, I wanted to raise awareness of the condition, and I wanted to help people to get a diagnosis,” says Michelle, who has published a six-step care plan pathway, which includes when to ask for a referral to a geneticist, on the foundation’s website.
As with many rare diseases, part of the problem families come up against when seeking care is a lack of solid evidence.
It is thought that around one in 25,000 people live with the condition, but the characteristics vary from person to person.
Most experience some form of cognitive difficulty, and some develop psychosocial problems related to short stature and feelings of social isolation.
The physical impact of Aarskog is extremely wide ranging. Michelle’s son, who is now 22, needed operations for undescended testicles and a bilateral hernia before his fifth birthday, for example.
“The challenge we have with Aarskog syndrome is that the medical literature hasn’t extensively addressed the natural history and the spectrum of symptoms,” she says. “Although the advancements in sequencing technologies have enabled the genetic confirmation of this disease, an effort to understand the genetic basis of this multitude of symptoms is still due.”
“For instance, all our children are on the autistic spectrum in one form or another. Still, there is a considerable lack of literature discussing the variability and etiopathogenesis of the autism spectrum disorder in Aarskog syndrome.”
Because Aarskog is an X-linked genetic condition affecting predominantly males, women have traditionally been considered asymptomatic carriers. However, Michelle believes that around 80% of the mothers she speaks to have an inflammatory disease such as rheumatoid arthritis or ankylosing spondylitis that should be evaluated for any association with this syndrome.
“Women have traditionally been considered asymptomatic carriers – but Michelle believes that 80% of the mothers she speaks to have an inflammatory disease such that should be evaluated for any association with Aarskog syndrome”
“We are not aware of so many aspects of this disease because they have not been researched adequately,” she says.
“Because this disease is so rare and there is no cure yet, it is not seen as important by researchers and physicians. This is what I want to change. I want people to have a system that they can rely on and be supportive”
Natural history study
To this end, Michelle’s foundation has just started working with two medical geneticists to identify and delineate the syndrome’s novel characteristics. This human history study project will use data from the foundation’s patient registry.
“This study will primarily use the data to understand the natural history of the disease phenotype so that we can help the patients and families with better care of their ailments.
“At the moment, there is information about this disease, but it’s neither concise nor comprehensive in nature.”
The human history study, which is being funded by the foundation and its supporters, will feed into gene reviews, an international point-of-source for inherited disorders. The team hopes that this study’s scope will also shed light on the gene’s impact on the women who carry it in addition to an elaborative genotype-phenotype correlation.
The two research projects, Michelle says, will start to build the evidence base.
“This condition causes so much pain for families. I hope the research encourages clinicians to look into this further so that they can better inform people about the condition and put people on better management pathways,” she concludes.
To contribute to the cost of the studies, click here
Exploring Rare Diseases is produced in partnership with Cambridge Rare Disease Network (CRDN). CRDN is building a vibrant network of patients and stakeholders to share knowledge and foster innovation that leads to better diagnosis, treatment and support for those living with a rare disease
Shares in Amgen were down nearly 7% after close of trading yesterday after the company’s heart failure drug omecamtiv mecarbil disappointed in a large phase 3 trial.
Take a look at Amgen’s portfolio and it becomes apparent how important this potential new drug is: the company is relying on its ageing inflammatory diseases drug Enbrel for a large chunk of its revenue.
It is also hoping to steal market share from rivals with biosimilars, which are comparatively cheaper versions of biologic drugs.
Psoriasis drug Otezla is also bringing in the bucks – but Amgen paid $13.4 billion for this after Celgene was forced to sell it as a condition of its merger with Bristol-Myers Squibb.
Amgen looks in need of fresh home-grown revenues, but investors don’t think these will come from omecamtiv mecarbil, based on the findings of the phase 3 GALACTIC-HF trial.
The trial met its primary endpoint by demonstrating a statistically significant effect to reduce cardiovascular death or heart failure events compared with placebo in patients treated with standard care.
But there was no reduction in the secondary endpoint measuring only cardiovascular death in the trial, which with 8,256 patients with reduced ejection fraction in 35 countries is one of the largest phase 3 cardiovascular outcomes studies in heart failure ever conducted.
Adverse events, including major ischemic cardiac events, were balanced between treatment arms, Amgen said.
With such a large cohort of subjects, Amgen and partners Cytokinetics and Servier have nowhere to hide – they cannot claim the trial was not powered to produce a result against this important secondary endpoint measuring the impact on mortality.
Merck & Co and Bayer are trying to develop a rival heart failure drug in patients with reduced ejection fraction, vericiguat, but that has also produced similar results, scoring against a composite measure of deaths and hospitalisation but failing to outperform placebo at reducing deaths.
Developed by Cytokinetics, omecamtiv mecarbil is a cardiac myosin activator that works by increasing interactions between filaments in the heart muscle to improve its pumping.
Amgen has been working on the drug with Cytokinetics since 2006, and Servier bought European rights in 2013.