NHS patients in England will be among the first in the world to receive Gilead’s Tecartus cancer cell therapy for certain types of lymphoma, after the company’s specialist Kite unit struck a deal with NICE.
Marketed as Tecartus (autologous anti-CD19-transduced CD3+) in Europe, the drug was approved in the EU in December for adults with relapsed or refractory mantle cell lymphoma after two or more lines of systemic therapy including a Bruton’s tyrosine kinase (BTK) inhibitor.
It has been approved in the US since July last year and like other CAR-Ts the one-time therapy is expensive at $373,000 a shot in the US.
NICE said in guidance that the treatment can be considered for those with relapsed or refractory mantle cell lymphoma, after treatment with drugs such as AbbVie/Janssen’s Imbruvica (ibrutinib).
Kite has signed a managed access agreement with NHS England that allows for funding via the Cancer Drugs Fund (CDF) at a commercially confidential discount, so more data can be collected for NICE’s cost-effectiveness calculations.
While in most cases reimbursement from the CDF results in regular NHS funding in the long run, manufacturers must usually produce convincing overall survival data before NICE gives this the go-ahead.
But as Bristol-Myers Squibb found out earlier this month with its Opdivo immunotherapy in head and neck cancer, NICE is prepared to say “no” in the absence of the required data after a period of funding on the CDF.
NICE said in a statement that it is looking for further data on progression-free survival, overall survival and age when treatment with Tecartus starts.
This will help reduce uncertainty in evidence while NHS is used on NHS patients.
The NHS has ten providers around the country which will be able to offer this treatment option.
Many parts of the country continue to experience pressures on critical care services, that are required for the administration of a CAR-T therapy and patients can travel to centres further afield to receive their treatment if necessary, NICE said.
There is no standard treatment for adults, who are usually in their 70s, with relapsed or refractory mantle cell lymphoma after a BTK inhibitor. A combination of rituximab, bendamustine and cytarabine (R BAC) is the most common treatment option.
Around 100 patients each year could be treated with this CAR-T therapy.
NHS England has been leading the way with funding of CAR-T (Chimeric Antigen Receptor T-cell) therapies after it became an early adopter of Novartis’ Kymriah the first approved drug from this class in September 2018 in acute lymphoblastic leukaemia (ALL).
CAR-T therapies are made by harvesting a patient’s T-cells, genetically engineering them to target cancer cells and reintroducing them into the body.
Women with newly-diagnosed advanced ovarian cancer have a new treatment option in England after NICE recommend interim funding for GlaxoSmithKline’s Zejula (niraparib) in final guidance.
Zejula competes with AstraZeneca/Merck & Co’s PARP inhibitor class rival Lynparza (olaparib) but in this case it has an advantage in this maintenance therapy use as it can be used regardless of whether the BRCA mutation is present.
GSK estimates that around 3,000 people could benefit annually from the decision covering advanced high-grade epithelial ovarian cancer, fallopian tube or primary peritoneal cancer, who have completed and shown a response to platinum-based chemotherapy.
The drug will be paid for by the Cancer Drugs Fund, which provides interim funding until further data can be gathered that can help NICE with its cost-effectiveness calculations.
This indication is supported by data from the phase 3 PRIMA study, which enrolled patients with newly diagnosed advanced ovarian cancer following a complete or partial response to platinum-based chemotherapy regardless of biomarker status.
The primary endpoint in PRIMA was progression-free survival (PFS) analysed sequentially first in patients with BRCA-like mutations, then in the overall population.
Results showed Zejula significantly improved PFS regardless of biomarker status – in patients with homologous recombination deficiency (HRd) mutations, Zejula resulted in a 57% reduction in risk of disease progression versus placebo.
In the overall population there was a 38% reduction in the risk of disease progression or death compared with placebo.
However NICE usually requires overall survival data before making decisions on long-term funding NHS funding.
As a result, the cost-effectiveness body has decided to use the CDF until GSK has the required survival data, it said in the guidance document.
In a managed access agreement with NICE, GSK has agreed an confidential discount to the list price of £4,500 for 56 100mg capsules, excluding VAT. Zejula pills are taken three times daily.
Poly-(ADP-ribose) polymerase (PARP) inhibitors are targeted therapies that work by exploiting cancer cells’ tendency to use a back-up system to keep control of mutations in their DNA.
By interfering with this process PARP inhibitors cause cancer cells to self-destruct as genetic defects mount, while leaving healthy tissue unaffected.
With a new year comes the opportunity to think ahead for the market access landscape for the coming year. 2020 was a big year for market access initiatives in the UK, many of which are only just starting, and their impact will come through in 2021 and beyond. Looking back at key market access news from the last year, Leela Barham takes stock of what the next twelve months could bring for UK market access.
Whilst regulatory approval is only a starting step on market access, the UK has made steps to put the UK on the priority list for companies seeking marketing authorisation. The UK joined two initiatives in October 2020 that should bear fruit in the future: Project Orbis and the Access Consortium.
Project Orbis is coordinated by the US Food and Drug Administration and includes Canada, Australia, Switzerland, Singapore and Brazil and focuses upon review and approval of cancer treatments that offer promise. The Access Consortium includes some of the same players – Australia, Canada, Switzerland and Singapore – and looks more broadly at securing patient access to high-quality, safe and effective medicines. The ABPI has seen these as another way to help the UK deliver faster access.
The promise of faster market access
Announced in December 2020, and beginning from 1 January 2021, the new licensing and access pathway (ILAP) at the Medicines and Healthcare Regulatory products Agency (MHRA) offers the chance – for a fee – for faster access for medicines that meet the criteria for the scheme. Criteria include that the condition is life-threatening or seriously debilitating or there is a significant patient or public health need.
“The UK has sought to provide incentives for development of new antibiotics by offering a volume neutral deal, also termed a Netflix approach”
Additional criteria include being an innovative medicine, such as an advanced therapy medicinal product (ATMP), significant new indication or a treatment for a rare disease or other special populations such as neonates, children, elderly and pregnant women and aligning with priorities of the UK, be that from the chief medical officer, the Department of Health and Social Care (DHSC) or those from the UK’s Life Sciences Sector Deal.
What is probably most exciting about ILAP is the bringing together of expertise from the MHRA with that of key HTA agencies NICE and the Scottish Medicines Consortium (SMC), as well as NHS England and NHS Improvement (NHSE&I), and, of course, patients too. It’s the first time that all these agencies are working together (much else draws on what has been available for some time; early advice and in parallel between NICE and MHRA).
2021 will reveal just how the ILPA will be operationalised and whichever product will be the first to go through the Innovation Passport stage – a new designation as part of ILAP – will help everyone understand how the criteria for the passport will apply in practice. It’ll also reveal just what the Target Development Profile (TDP) living document will cover and how it can evolve over time. This rolling review features is also another new element on offer under ILAP.
The Netflix approach
Antibiotics are vital to modern health care, yet there have been warnings for years that the economics at play simply don’t incentivise the development of new antibiotics; new antibiotics should be kept in reserve to limit antibiotic resistance and aren’t likely to be used in large volumes. The lack of new antibiotics is a problem when the existing antibiotics stop working.
The UK has sought to provide incentives for development of new antibiotics by offering a volume neutral deal, also termed a Netflix approach. In June 2017, NICE and NHSE&I launched a novel payment approach; offering up to £100 million to companies developing and marketing novel antibiotics based on the value of their products, regardless of volume sold.
2021 will see NICE trialling their adapted HTA approach for assessing the value of new antimicrobials. This will not only interest companies researching and developing new antibiotics, but other countries who will want to see whether the UK approach could work for them too. Where NICE leads, others will want to learn and adapt from.
Key access commitment due to report in VPAS
The UK has a unique approach to managing the pricing of branded medicines through the 2019 Voluntary Scheme for Branded Medicines Pricing and Access (VPAS). The deal balances affordability commitments that benefit the UK government – where NHS spend on branded medicines cannot go above a pre-agreed level – with access commitments to industry.
A key commitment in the deal is to reach the upper quartile of uptake in relation to comparator countries for the five highest health gain categories of treatments. A timeline is set for hitting this too; it should be met during the first half of the scheme. That makes it a target for June 2021. Whilst there isn’t a timeline against it, there is also a commitment for the Department of Health and Social Care, NHSE&I and the industry association, the Association of the British Pharmaceutical Industry (ABPI) to better understand national and international variation on uptake and where that is unwarranted.
Realistically it’s seems unlikely that the timetable for the upper quartile target can be met. That’s because so far, based on desk research, there doesn’t appear to be a public list of the five highest health gains, and meeting minutes from operational reviews of the scheme suggest discussions have faced difficulties in agreeing them. It’s difficult both from a methods side (which countries, which treatments, etc) as well as data and time; COVID-19 has been a higher priority for many staffers involved. Expect a delay that may even see this reporting in 2022.
More change at NICE
2020 saw NICE consult on a variety of changes and set out plans on cross-cutting market access issues.
NICE started 2020 with the January publication of their principles; essentially a framework for how the agency goes about its work – from working on national priority areas through to publishing their work and updating as necessary.
NICE followed these in March 2020 with their final statement of intent on increasing the use of health and social data in their guidance. The statement covers one of the buzz phrases in market access – ‘real world data’ – and signals a greater willingness for NICE to consider its use in their work. The agency will keep working on how this will be implemented during 2021; this can only help, as much in the statement is aspirational and there’s not a great deal of clarity on exactly what NICE will accept, or not, as the case may be.
In June 2020, NICE let industry know about their changes to the process used in Single Technology Appraisals (STAs), moving from technical reports from Evidence Review Groups (ERGs) – independent academics – to present issues. That allows for easier engagement but also offers companies a right to reply to ERGs. With this change applied from STAs starting in May 2020, 2021 should see more companies seeing the difference. Efficiencies are the gain NICE hopes to see and that ties in with commitments to make NICE faster set out in VPAS. NICE hadn’t yet reached their targets according to metrics set out in July 2020 relating to appraisals up to Q1 of 2020, so 2021 could see NICE really getting to grips with getting faster.
NICE kept up the pace of consulting in 2020, setting out proposals to change the selection of treatments for evaluation in October 2020. The aim is for simplification as well as confirming promises made in VPAS that NICE will appraise all new active substances and significant new indications.
Arguably the most important consultation from NICE in 2020 was a six week consultation on the evidence and considerations for changing their methods, including those used in Technology Appraisals. According to experts at market access consulting firm, Bresmed, the changes being tabled that are likely to have a high potential impact include the removal of End of Life criteria to be replaced with a severity modifier, a change to the discount rate from 3.5% to 1.5% as well as greater emphasis on real world data.
Yet there is still more work for NICE and all stakeholders who will want to shape the final changes, as the agency plans to consult for another six weeks from February to March 2021 as well as consult with stakeholders on the draft programme manual which will encompass the reformed methods in June to July 2021.
The final changes won’t bear fruit for a little more time; implementation will be for treatments assessed from October 2021. This will also be when changes to selection processes will be implemented too. Companies are going to need to keep refining their inputs to NICE as they consult as well as run scenarios and review strategies to make the most of any opportunities for treatments that will be reviewed under the new approach.
Less clear is the ‘what and when’ of changes to the criteria that determine which treatments are reviewed through the NICE Highly Specialised Technologies (HST) programme, another area that NICE is reviewing. This is of interest as it offers a wider set of value components to be considered, as well as more flexibility on the cost-effectiveness threshold, for ultra-orphan treatments.
It’s likely NICE will set out details on this review during 2021. However, anyone hoping that the door will be open for the rarer end of common treatments could be disappointed as NICE say that they want to make the criteria clearer and more specific but not increase, or decrease, the number of HST topics. NICE is funded to do three a year.
NICE, building on their international links, was one of seven agencies who took part in the first ever World Evidence-based Healthcare Day in October 2020. We can expect to hear more on the global initiative in 2021. It’s also likely that their 2020 agreement with Colombia’s IETS will start to bear fruit, shaping how HTA is done in Colombia.
Pulling all this work together will also be a test of NICE’s 2020 appointed chief executive Gillian Leng. She’ll likely bring a steady hand to the consultation and the next steps, reflecting her over 13 years at NICE. 2021 could see big changes that should provide opportunities for faster NICE appraisals but as ever, the devil is in the detail and the full impact won’t be possible to see until a number of treatments have gone through the new methods and processes.
Medicines and Medical Devices Bill and a new Innovative Medicines Fund
The Medicines and Medical Devices Bill is still going through Parliament and should become law in 2021. It’s part of the legal homework necessitated by the UK leaving the EU and covers a range of regulatory issues.
The importance of the Bill from a market access perspective is not however just about regulation but has also seen discussion of the establishment of an Innovative Medicines Fund. Whilst a proposed amendment to the Bill on establishing such a fund was withdrawn during December 2020, the discussions in the House of Lords suggested that NHSE&I and NICE will be engaging during the first quarter of 2021 on the fund.
The fund will replace the Cancer Drugs Fund (CDF), and widen the treatments that can be funded on an interim basis. The CDF as it has been run from 2016 helps generate evidence for treatments that have the potential to be cost-effective but face uncertainties that can be addressed through evidence generation. It’s proved to be a key enabler for market access for cancer drugs and many – although not all – drugs funded under the CDF have gone on to go into routine commissioning, although often with a hefty price cut. Just how the Innovative Medicines Fund will work is something to watch as it may provide new access opportunities previously not available.
More change ahead in 2022
There will be yet more change in the future with major shakeups expected in the way NHS England is structured, with the potential to abolish Clinical Commissioning Groups (CCGs) and Integrated Care Systems to be put on a statutory footing in 2022. That means much planning could be on the cards and, as ever, a need for the pharma industry to keep up to date and ensure that they’re engaging with those that matter for access on a local level.
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).
NICE has rejected Bristol Myers Squibb’s immunotherapy Opdivo as a second-line treatment for head and neck cancer in first draft guidance, unconvinced by evidence unearthed during a three-year NHS trial period.
In its latest guidance, NICE said that clinical trial data gathered so far and real-world evidence did not convince about the cost-effectiveness of Opdivo (nivolumab) in this use.
It said that Opdivo seems to produce a survival benefit in metastatic squamous cell carcinoma of the head and neck (SCCHN) compared with one of three possible standard therapies.
But there was too much uncertainty around the results and one of the comparators, the chemotherapy docetaxel, is already used as a standard treatment on the NHS.
As a result, NICE said there were doubts over the long-term survival benefit of Opdivo in this indication.
Cost-effectiveness estimates are likely to exceed the £30,000 per QALY threshold above which NICE considers drugs to be a waste of NHS resources.
While the manufacturer can submit further evidence following this first draft guidance, there is a chance interim funding could be discontinued if NICE comes to the same conclusions in final draft guidance.
Opdivo is currently available to NHS patients in England on the Cancer Drugs Fund after NICE agreed to fund it through the CDF in October 2017.
Following an initial rejection earlier that year, NICE asked (BMS) to submit a proposal for interim CDF reimbursement which could pay for Opdivo until stronger clinical data emerges and improves the argument that it is cost-effective.
BMS sweetened the deal with a commercially-confidential price cut and provided further information that convinced NICE to grant CDF funding.
Opdivo is a monoclonal antibody that binds to the PD-1 receptor, blocking its interaction with the PD-L1 and PD-L2 proteins.
This releases an immune response, allowing T-cells to interact with the cancer cells and destroy them.
Opdivo competes in several different cancer indications with a growing number of rival checkpoint inhibitors, although Merck & Co’s Keytruda (pembrolizumab) has become standard care in many indications and is the biggest seller in its class.
NICE will be consulting on its decision until 28th January.
Just a few weeks after its EU approval for heart failure, AstraZeneca’s Forxiga has been backed by NICE for this use by the NHS in England and Wales.
Forxiga (dapagliflozin) – originally developed as a type 2 diabetes drug – is the first SGLT2 inhibitor to be approved for the treatment of symptomatic chronic heart failure with reduced ejection fraction (HFrEF) in adults with and without diabetes.
It got a green light for this use in the EU in early November and in the US in May, with the new indication helping to drive third-quarter sales up by a third to $525 million.
Approval for Farxiga was based on positive results from the phase 3 DAPA-HF trial, which showed Farxiga achieved a statistically significant and clinically meaningful 26% reduction of death or hospitalisation for heart failure compared with placebo.
Today, NICE issued draft guidance which recommends Forxiga as an option for treating symptomatic HFrEF in adults if used as an add-on to standard drugs, which would make around 260,000 additional people eligible for treatment with the drug.
Novartis’ Entresto (sacubitril/valsartan) is also used to treat HFrEF, an indication which propelled it to sales of almost $2 billion last year.
According to NICE, while there are no head-to-head trials comparing Entresto and Forxiga, AZ’s drug “is likely to be as effective as [Entresto] at reducing the risk of death from heart disease
AZ’s rivals Eli Lilly and Boehringer Ingelheim meanwhile are also attempting to develop their SGLT2 inhibitor Jardiance (empagliflozin) for heart failure. They suffered a setback a year ago when the drug failed to improve exercise ability in two phase 3 studies, but bounced back with the results of the EMPEROR-Reduced study in July.
GlobalData has said that heart failure could add billions to the sales of the two SGLT2 inhibitors, particularly if they also claim approvals in heart failure with preserved ejection fraction (HFpEF), a larger patient population. It says Farxiga will reach peak sales of $9 billion in 2028, with Jardiance forecast to reach $4.6 billion, assuming a launch for HFrEF in 2021.
AZ is also putting Forxiga through its paces in heart failure in combination with other drugs, including its mineralocorticoid receptor modulator AZD9977 and selective endothelin A antagonist zibotentan (also known as AZD4054), with mid-stage trials on the go.
Meanwhile, heart failure is just one area into which AZ is hoping to expand Forxiga before its patents start to expire in the coming years. It’s also looking at chronic kidney disease (CKD), and has picked up a breakthrough designation from the FDA for this indication.
Forxiga was the first medicine to significantly prolong survival in patients with CKD, either with or without diabetes, in the DAPA-CKD trial.
NHS England is to grant immediate access to AstraZeneca’s cancer drug Calquence (acalabrutinib) for certain patients with chronic lymphocytic leukaemia (CLL) after NICE backed it in first draft recommendations.
NICE recommended regular NHS funding for Calquence in CLL who are considered high-risk due to 17p deletion or TP53 mutations.
It is also recommended for adults with CLL who have had at least one previous treatment and only if AbbVie and Janssen’s class rival Imbruvica (ibrutinib) is their only suitable treatment option.
NHS England is granting access via an interim funding arrangement with AstraZeneca, which will end 30 days after publication of positive final guidance, after which treatment will be funded by routine commissioning budgets.
However the guidance has rejected Calquence for a third group of patients with untreated, non-high risk CLL who are unsuitable for treatment with chemotherapy.
AZ said it will provide further data analyses for continued discussions with NICE about this group of patients.
Calquence was approved in CLL by the EMA last month as monotherapy or in combination with Roche’s Gazyvaro (obinutuzumab).
In CLL, too many blood stem cells in the bone marrow become abnormal white blood cells, and these have difficulty in fighting infections.
As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells, and platelets. This could result in anaemia, infection, and bleeding.
B-cell receptor signalling through Bruton’s tyrosine kinase (BTK) is one of the essential growth pathways for CLL.
In B-cells, BTK signalling results in the activation of pathways necessary for growth: proliferation, trafficking, chemotaxis, and adhesion.
Calquence binds selectively to BTK, inhibiting its activity.
This is the second recommendation of a therapy for CLL in the space of a month – in November it recommended AbbVie/Roche’s chemotherapy-free option of Venclyxto (venetoclax) and Gazyva.
NICE’s decision allows for a 12-month fixed duration treatment option based on data from the phase 3 CLL14 trial.
A heart monitor developed by iRhythm has become the first product to be endorsed by NICE in a pilot project covering digital health technologies.
In new guidance, the health technology assessment (HTA) agency has recommended iRhythm’s Zio XT service for detecting abnormal heart rhythms – provided NHS organisations that deploy it collect evidence of its benefits.
The wearable electrocardiogram (ECG) patch and associated software has been tested for its ability to detect atrial fibrillation (AF) in high-risk patients, with investigators reporting higher rates of diagnosis and more use of potentially life-saving anticoagulant therapy among users, but also increased demand on healthcare resources.
Zio XT has been recommended by NICE as an option for people with suspected cardiac arrhythmias who would benefit from ECG monitoring for longer than 24 hours, as a lighter, discreet alternative to Holter monitoring, which requires patients to wear several electrodes as well as a bulky monitor.
iRhythm’s device is waterproof, so can even be taken into the shower – an important consideration as it is used for up to two weeks, day and night.
NHS patients will have access to Zio XT for three years while more data is collected to address “evidence gaps about its benefit”, according to NICE. After that period, NICE will look at the new evidence before making a final recommendation.
Assuming NHS trusts take up the tech, it could be available for more than 150,000 people in the UK, according to the HTA. As it stands, there are more than 1.2 million people with diagnosed AF in the country, and another 500,000 are thought to be undiagnosed.
People with AF are more likely to suffer a stroke, and the risk is much higher in people who are unaware they have the heart rhythm disorder.
Monitoring patients for up to 14 days means that more data from each patient will be available to review, potentially improving its ability to spot arrhythmias.
At the end of the monitoring period, users remove the patch and send it via freepost for analysis using artificial intelligence algorithms, with the findings forwarded to their clinician.
Currently 12 hospital trusts across England are evaluating the Zio XT service, which costs £265 per patient, according to NICE, which says it is likely that Zio XT will be cost saving – or at least similar in cost – to Holter monitoring.
“Throughout the COVID-19 pandemic we have seen a number of cardiac patients avoiding hospitals and suffering in silence, even when experiencing serious conditions such as strokes,” said iRhythm’s EMEA vice president Justin Hall.
“This has led to a backlog of patients requiring care, putting additional pressure on medical staff and services,” he added. “Services like Zio can help ease this backlog, offering clinically-validated services remotely.”
Earlier this year, iRhythm won a UK government AI in Health and Care Award for Zio XT, securing funding to trial the service in selected sites across the country over the next three years.
Two months after rejecting Pierre Fabre’s Braftovi for a rare form of metastatic colorectal cancer (mCRC), NICE has changed its mind, and now says the drug can be funded by the NHS in England, Wales and Northern Ireland.
The cost-effectiveness agency has backed the combination of Braftovi (encorafenib) and Eli Lilly’s Erbitux (cetuximab) as a second-line treatment option for BRAF V600E mutated mCRC after an improved access deal – which generally means a discount on its list price.
The pairing of the BRAF inhibitor and anti-EGFR antibody was approved by the EMA in June on the back of the BEACON CRC trial, which showed a median overall survival of 9.3 months for the two-drug regimen and 5.9 months for patients in the control group, who received standard second-line chemotherapy. The duo also reduced the risk of death by more than a third (39%) compared to the control arm.
The green light made it the first and only targeted, chemo-free regimen licensed in Europe specifically for patients with BRAF V600E-positive mCRC, and came shortly after the combination was approved by the FDA for the same indication.
NICE turned down Braftovi/Erbitux in September, acknowledging the clinical benefits of the regimen but saying it was too expensive.
The agency also said the comparative chemo regimens used in BEACON CRC weren’t generally used in NHS clinical practice, so it was forced to rely on unreliable indirect comparisons in its modelling.
At the time, patient organisation Bowel Cancer UK said the decision was a big disappointment, as “treatment options for the one in ten people diagnosed with bowel cancer who have a BRAF V600E mutation are currently extremely limited.”
The charity’s chief executive – Genevieve Edwards – welcomed the change of heart by NICE. “We worked closely with clinicians to submit evidence to the NICE consultation on the benefits of the combined therapy, and are really pleased that today’s announcement offers new hope to patients,” she said.
In the UK, over 42,000 people are newly diagnosed with colorectal cancer each year, and around a quarter have tumours that have already metastasised to other parts of the body at diagnosis.
BRAF mutations are thought to occur in approximately 8% to 12% of patients with mCRC, and are associated with a poor prognosis.
“Conventional cytotoxic chemotherapy is associated with suppression of the immune system in many ways, and so this chemotherapy-free option is particularly pertinent in the current COVID-19 climate,” said BEACON CRC investigator Dr Harpreet Wasan.
“Historically, these patients generally have worse outcomes and a poor prognosis, when treated with standard, cytotoxic chemotherapy,” he added. “Today’s recommendation offers a significantly better option in their disease management.”
BEACON CRC also included another three drug arm – Braftovi, Erbitux, and MEK inhibitor Mektovi (binimetinib) from Array Biopharma (now part of Pfizer). That wasn’t able to improve survival any more than the two-drug arm however so wasn’t submitted for approval.
UK cost-effectiveness agency NICE has said that Eli Lilly’s Emgality can be made available through the NHS for migraine prevention, the second drug in the CGRP inhibitor class to achieve that milestone.
The decision means that with two CGRP antibodies now cleared for migraine prevention, the first drug in the class to be approved in Europe – Novartis’ Aimovig (erenumab) – has fallen further behind its rivals in getting access to the UK market.
NICE has backed Emgality (galcanezumab) as a once-monthly injection to prevent migraine attacks in people with episodic or chronic migraine who suffer at least four days with a migraine headache per month, and who have tried at least three prior preventative medicines.
That puts Emgality ahead of Teva’s Ajovy (fremanezumab), which picked up a positive opinion from NICE earlier this year but is only recommended for use in chronic migraine sufferers who have 15 or more headache days a month for more than three months, with at least eight of those having features of migraine.
It also puts Lilly’s drug ahead of Aimovig, which has been rejected twice by NICE although the agency has agreed to take another look at the application after an appeals panel ruled that its technology appraisal committee had failed to consider all of the evidence about the cost-effectiveness for the drug.
NICE said Ajovy was an option for around 10,000 people in the UK in guidance issued in June, but Lilly says many more patients are eligible for its drug – around 144,000 people with episodic migraine and 59,000 people with chronic migraine.
The decision is based on trials comparing Emgality with placebo which showed that the antibody halved the number of monthly migraine headache days for up to 40% of adults with migraine who had previously tried three or more prior medicines, such as Allergan’s Botox (botulinum toxin type A) or topiramate.
Gemma Jolly of medical charity the Migraine Trust said NICE’s recommendation is “wonderful news for people living with this very painful and debilitating neurological condition [as] both chronic and episodic migraine patients across England and Wales will be able to access an effective drug on the NHS.”
The CGRP inhibitors have performed well in clinical trials, but so far commercial success has been limited, despite blockbuster sales predictions ahead of their approval.
First-to-market Aimovig generated sales of $108 million in the first nine months of 2020 for Novartis, which records ex-US sales, while Amgen booked $274 million from the drug in the US in the same period.
Aimovig is said to be the most prescribed anti-CGRP drug worldwide with more than 480,000 patients prescribed the drug worldwide. In the same period, Lilly reported sales of $253 million for Emgality, and Teva made $98 million from Ajovy.
Novartis is hoping for a bounce to Aimovig sales from the HER-MES trial reported earlier this month, which showed it was more effective than topiramate – a go-to oral therapy for people with chronic migraine – in a head-to-head trial.
There’s more competition jostling for position however, following the approval of Lundbeck’s Vyepti (eptinezumab), an intravenous drug that only needs to be administered four times a year.
Lilly has a real opportunity to build momentum behind Emgality in England and Wales, but will have to wait until next year before it hears from NICE’s counterpart in Scotland, the Scottish Medicines Consortium (SMC). Aimovig was cleared for use by NHS Scotland last year, with Ajovy given a green light in January 2020.
As regional vice president for Northern Europe & Australia, Simon Lem led the digital launch of Vertex Pharma’s novel cystic fibrosis drug Kaftrio. He tells pharmaphorum about embracing digital change and the need for innovative reimbursement solutions.
For Vertex, COVID-19 accelerated a digital transformation much needed for the patients they serve.
As the leading developer of novel drugs to treat cystic fibrosis (CF) the Boston-based company has always taken a very focused approach.
“For CF, you have a proportion of the population predominantly quite young and tech-savvy. They do not want to be coming into the hospital,” Lem tells pharmaphorum. “There was already a direction of the clinical community to be having these interactions or helping patients manage their disease virtually. COVID-19 sped up all of that.”
With COVID-19 posing an added risk to people with CF, Vertex was “even more motivated” to secure its supply chain and access to drugs. In June 2020, NHS England swiftly approved a reimbursement deal for Vertex’s fourth CF drug Kaftrio meaning the medicine would be accessible for doctors and eligible patients in England from the day (in August 2020) it received licensing from the European Commission, with the medicine being accessible by eligible patients in Scotland, Wales and Northern Ireland soon after. The drug has since launched digitally.
“I never thought that in my career, I would see a launch of a significant product without having a face to face interaction with a customer, but it has worked. Early results are positive, it hasn’t changed the mission,” says Lem.
Like other pharmaceutical companies, Vertex still faces challenges with reimbursement and market access. The agreement for Kaftrio followed a long battle with NHS England to make the company’s three other cystic fibrosis medicines available.
“It’s one thing if you can develop an innovative medicine, but then you’ve got to get it to patients for it to be useful… that is challenging for many healthcare systems.”
“The challenge we face is universal to any biotech company. You are operating in multiple different countries with multiple different healthcare systems, multiple different cultures and all the different ways they approach, reimbursement, or engagement,” explains Lem.
“It’s one thing if you can develop an innovative medicine, but then you’ve got to get it to patients for it to be very useful and I think that is challenging for many healthcare systems, particularly ex-US where you have finite and limited budgets. You also have very well-established long-term health technology, appraisal systems.”
The speedy nature of Kaftrio’s approval is encouraging for how reimbursement could look in the future, says Lem. Working flexibly with NHS England and NICE, Vertex managed to ensure patients got access to the drug on the day of licensing.
“I don’t know of many examples where that’s happened before if any, but primarily it was about taking a step back and asking what we had learned from our ongoing discussions and how we could bring those forward into the next step of the negotiations.”
Engaging with the health system as early as possible and working flexibly was key to the success, he adds. “It has to be more collaborative. Especially if you move into things like gene therapies.”
UK’s opportunity for change
The UK government also has an opportunity now to speed up the process, Lem says. “I think sometimes other healthcare systems have looked at the UK as the ones that are playing catch up, and there is a less flexibility to change, but I think the UK could lead the way with this. We saw with our CF medicines; they can do it if all parties are motivated to do it.”
A more flexible approval process would also benefit patients within the UK. “Sometimes patients in the UK only get access to medicines much later than other European countries. I think there needs to be innovation, flexibility, and open communication with all parties involved in in the process including the HTA system and the health authorities.”
A bigger challenge for healthcare systems in future will be deciding reimbursement for curative medicines. “We’re at a very embryonic stage across the pharmaceutical industry. There’s going to have to be even more collaboration, even more flexibility and even more talking at a far earlier stage than we’ve done previously.”
Starting his pharma career as a sales rep, Lem has worked across the industry in management and marketing roles. He notes how business practice has changed significantly over the years. “Now we are far more focused on individual patients and individual prescribers and that has changed how you go about doing the businesses. It is far more personalised, and that’s down from a key account manager’s perspective to even reimbursement.”
Vertex’s focus for now is on being less of “a one-franchise organisation” and diversifying its portfolio. The company is investigating new medicines for serious diseases with key unmet needs.
“We want to treat the underlying cause of the disease,” says Lem. “It will be interesting seeing how that pipeline pans out and the impact that that will have on the business.”
Expanding into new diseases areas will require a different approach from the organisation, says Lem, but presents an exciting new challenge. Having worked at Vertex for nine years, he says that no day is the same as the day before.
“I can tell you what I am doing today is not the same as what I was doing this time last year. I think it’s a really exciting journey because we’re doing stuff so rapidly and having such a big impact that and we go into new disease areas.”
However, the goal to find a cure for CF remains core to the company.
“People say to me, ‘Are you happy? Patients have got the medicines. It’s over and done with.’ I say, no, it is not – there is still a lot of work to do for CF. We brought four medicines to the market. Yet there’s still work to be done.
“We’ve got medicines with the potential to treat up to 90% of people with CF, but the other 10% still don’t have a medicine. Until that 10% have got a medicine, the game’s not over.”
Previously-untreated patients with hepatocellular carcinoma (HCC), a common form of liver cancer, will have an immunotherapy-based treatment option after NICE gave the nod to NHS funding of Roche’s Tecentriq and Avastin combination therapy.
The decision by NICE comes shortly after Tecentriq (atezolizumab) and Avastin (bevacizumab) was approved by the European Commission as a first-line treatment for adults with advanced or inoperable HCC, becoming the first and only immunotherapy regimen approved in Europe for this patient group.
Approval was based on findings of the phase 3 IMbrave 150 study, which showed an improvement in overall survival compared with Bayer’s Nexavar (sorafenib), one of the standard treatments for previously-untreated liver cancer along with Eisai’s Lenvima (lenvatinib).
NICE’s final appraisal document notes that patients receiving the dual regimen “live longer and have longer before their disease progresses than people who have sorafenib” and it is a cost-effective use of NHS resources.
It is the first treatment to be approved in Europe for over a decade that has improved overall survival for people with previously untreated advanced or unresectable HCC.
HCC accounts for 90% of all liver cancer cases and there are around 5,900 new cases in the UK every year. The disease is also becoming more common – Roche says the incidence of HCC is projected to rise by 38% to 15 cases per 100,000 people by 2035.
“Tecentriq, in combination with Avastin, is the only cancer immunotherapy treatment, approved by NICE for this indication,” said Gemma Boni, head of liver cancer at Roche Products Ltd.
“We hope that it can help further improve overall survival rates, while having a generally manageable safety profile, compared to what is already achieved,” she added.
The Tecentriq/Avastin combination is crucial to Roche’s immuno-oncology franchise, and along with HCC has also been approved to treat non-squamous non-small cell lung cancer (NSCLC).
Sales of Tecentriq sales rose 64% to around $2.2 billion in the first nine months of this year, but Avastin has started to succumb to biosimilar competition, shrinking 22% to a little over $4 billion in the same period.
Cablivi gets green light for aTTP
NICE’s recommendation that Sanofi’s Cablivi (caplacizumab) can be covered by the NHS, is also a big step forward for patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder that can be fatal without prompt treatment.
Cablivi is the first treatment specifically approved for aTTP in 30 years, and the only therapy approved for people experiencing an acute aTTP episode. NICE has backed the drug after rejecting it earlier this year due to an “improved commercial arrangement” with Sanofi – in other words a price discount.
Cablivi was also recommended for NHS use by the Scottish Medicines Consortium (SMC) in September.
aTTP is a rare disease where blood clots form in small blood vessels throughout the body, limiting the flow of oxygen to organs, such as the brain, kidney and heart. NICE’s appraisal document says that Cablivi, combined with plasma exchange and immunosuppression, reduces time to bring blood platelet levels back to normal.
Sanofi welcomed the positive recommendation, but said access to Cablivi had been delayed by procedural issues at NICE.
As a treatment for an ultra-rare disease, Cablivi was initially supposed to be considered within the Highly Specialised Technology (HST) process, but was assessed under the Single Technology Appraisal (STA) process.
The STA does not consider the concerns around long-term follow-up and management, which are a well-known issue in evaluating medicines for ultra-rare diseases, says the company, which claims this delayed access to the drug.
“We now hope that the forthcoming NICE Methods Review and Innovative Drugs Fund consultation will fix the ongoing barriers for patients,” commented Deborah Lough, head of rare blood disorders UK & Ireland at Sanofi Genzyme.
NICE estimates that more than 100 people each year will be eligible for treatment with Cablivi.
The UK’s drug cost-effectiveness body NICE has launched a public consultation, presenting the case for change about how it assesses medicines, medical devices and diagnostics.
NICE has been assessing medicines for 21 years using the Quality Adjusted Life Year (QALY) – the cost to ‘buy’ a patient a year of quality life – as its main methodology.
Big pharma was never going to be happy about the existence of a body like NICE, which is designed to drive down prices paid by the taxpayer-funded NHS, by far and away the largest payer in the UK.
While industry has begrudgingly found ways to work with NICE to get drugs to the UK market, there have been numerous occasions where manufacturers have felt short-changed by the process and in some cases seen drugs failing to get funding on technicalities.
It’s still true that most drugs are eventually funded after a NICE assessment.
But the consensus is that despite tweaks to the system over the years, reform is needed to keep apace with developments in fields such as cancer.
NICE uses the Cancer Drugs Fund to provide interim reimbursement for cancer drugs that require more survival data and allows more flexibility for drugs used at the end of life.
And the cost-effectiveness threshold of £30,000 per QALY has not moved since NICE began, meaning that manufacturers’ wiggle-room on pricing has been constantly squeezed by inflation.
NICE’s consultation will ask whether additional factors should be included in decision-making, such as the severity of a condition and how health technologies can reduce health inequalities.
It is also asking whether there should be more flexibility in rare diseases, where generating evidence is difficult.
NICE wants feedback on how it assesses highly innovative technology, or those with potentially large benefits where risks could be managed.
The consultation will cover the role of evidence gathered outside clinical trials, such as real-world evidence and how NICE could refine its approach to measuring health-related quality of life in different circumstances.
NICE’s consultation follows an internal review of its number-crunching following commitments made in the voluntary pricing scheme that the government agreed with industry last year.
Steve Bates, chief executive of the Bioindustry Association said: “The proposed changes to NICE’s methods published today send an important signal to the innovative biotech sector that the UK is serious about ensuring access to new medicines.
“We are very encouraged by the focus on removing significant barriers to access, which puts the UK on a new footing, setting the benchmark for health technology appraisals – particularly around modifiers, uncertainty and discounting. It will help ensure both that industry can continue to deliver innovative medicines and that patients can access them.”
Novo Nordisk’s Saxenda has been recommended by NICE as a treatment for obesity, ending a 10-year drought in new drug therapies for weight management.
The cost-effectiveness agency for England and Wales has recommended Saxenda (liraglutide) as a treatment option for people with a body mass index (BMI) of 35 or more, and who are also pre-diabetic with a high risk of developing cardiovascular disease because of risk factors such as high blood pressure or high cholesterol levels.
NICE tuned down the GLP-1 agonist earlier this year, but changed its stance after Novo Nordisk offered a confidential discount to the NHS.
Saxenda – which comes as prefilled self-injection pen – will be used as part of a programme based on a reduced-calorie diet and increased physical activity, according to NICE, and treatment should be discontinued if patients don’t lose at least 5% of their body eight within 12 months.
“Our independent committee was presented with clinical evidence which showed that people lose more weight with liraglutide plus lifestyle measures than with lifestyle measures alone,” said Meindert Boysen, NICE’s deputy chief executive.
“Liraglutide may also delay the development of type 2 diabetes and cardiovascular disease and this is the main benefit of treatment,” he added. It will be prescribed in secondary care, by a specialist multidisciplinary tier 3 weight management service.
Denmark-based Novo Nordisk said there are 13 million obese people in England with obesity, placing them at risk not only of diabetes and heart disease but also severe COVID-19 symptoms if infected with SARS-CoV-2.
The NICE recommendation coincided with Novo Nordisk’s third quarter results statement, which showed modest 3% growth for Saxenda in the first nine months of the year to DKK 4.2 billion ($661 million), held back by the impact of the pandemic on patients accessing healthcare.
That also put a brake on Novo Nordisk’s other products, which are mainly use for chronic diseases like diabetes, although it said a “gradual recovery” occurred in the third quarter. All told, sales grew 7% in the nine months to just under DKK 95 billion ($14.9 billion).
Saxenda continues to develop a dominant position in obesity pharmacotherapy however, and Novo Nordisk said the drug currently has a market share of 63% worldwide.
The company’s GLP-1 agonists for diabetes grew strongly, thanks to its once-weekly injectable Ozempic (semaglutide) which grew 119% to DKK 15 billion ($2.35 billion), overtaking Novo Nordisk’s older Victoza (liraglutide) product which requires dosing by injection every day.
Ozempic is squaring off in the market against Eli Lilly’s Trulicity (dulaglutide), which grew 22% to $3.57 billion in the same period.
Novo Nordisk also recorded DKK 1 billion ($156 million) in sales for its new oral formulation of semaglutide – Rybelsus – which started to roll out this year.
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).
As recently as June, NICE was minded not to back routine NHS of MSD’s Keytruda as a first-line treatment for advanced head and neck cancer, but it has had a partial change of heart on the drug after the company submitted new data.
Just-published draft final guidance from the cost-effectiveness agency gives a green light for NHS use of Keytruda (pembrolizumab) as a monotherapy for adults with untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) whose tumours express the biomarker PD-L1.
The decision makes Keytruda the first checkpoint inhibitor to be recommended for this use by NICE, according to MSD, which is known as Merck & Co in North America.
NICE hasn’t backed use of the checkpoint inhibitor in combination with chemotherapy however, a decision that the Institute of Cancer Research (ICR) says is disappointing as its experts think there are patients who would benefit more from the combination rather than Keytruda on its own.
The verdict is also at odds with that of the Scottish Medicines Consortium (SMC), which backed both monotherapy and combination use of Keytruda in this setting last month.
ICR would like to see the Keytruda combination available via the Cancer Drugs Fund (CDF), which covers the cost of cancer drugs until confirmatory data is available, for a period of two years in order to allow new evidence to be collected.
NICE however says that while it can support use of Keytruda on its own as the drug is more effective than standard treatments, the cost of using it in combination with platinum chemotherapy and 5-FU “are higher than NICE normally considers an acceptable use of NHS resources”.
ICR’s position is that the decision highlights a major problem with cancer immunotherapies, namely a lack of good tests to determine who will benefit from them.
In this case, biomarker tests like PD-L1 alone “fail to give clinicians a clear-cut indication of who will benefit from immunotherapy – and, critically, who requires pembrolizumab alone and who needs the combination of pembrolizumab and chemotherapy,” it points out.
PD-L1 testing is a “good starting point”, according to ICR’s experts, but “does not allow for the more nuanced approach that is permitted in Scotland and in much of the rest of the world”.
“The partial approval leaves patients in England behind much of the world when it comes to accessing this game-changing treatment,” commented Prof Kevin Harrington of The Royal Marsden, who led the UK arm of the KEYNOTE-048 trial that supported approval of Keytruda in first-line HNSCC.
“The evidence for the benefit of pembrolizumab in combination with chemotherapy in recurrent head and neck cancer is clear – and I would urge NICE and the manufacturer to work together to find a way for patients to access the range of treatment options they deserve,” he added.
The NICE has issued FAD which is based on the P-III ICARIA-MM trial assessing isatuximab + pom-dex vs pom-dex in patients prior treated with 3L treatment and at least 2L therapies including lenalidomide and a proteasome inhibitor with RRMM in 307 patients with RRMM
The study demonstrated that the combination regimen demonstrated a reduction in risk of disease progression or death in adults by 40%, mPFS (11.5 vs 6.5), well-tolerated with no increase in treatment discontinuation
Isatuximab is a mAb that binds to a specific site on CD38 and is now available to eligible patients through the NHS Cancer Drugs Fund. Isatuximab is the first mAb approved in EU to be used in combination with pom-dex for RRMM
Click here to read full press release/ article | Ref: Sanofi | Image: Bloomberg
Eli Lilly is to buy the private biotech Disarm Therapeutics, which is working on a new class of disease-modifying drugs for neurological diseases, in a deal worth up to $1.36 billion.
Massachusetts-based Disarm is focused on treatments for diseases caused by axonal degeneration, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis.
Disarm has discovered novel, potent SARM1 inhibitors and is advancing them into preclinical development for diseases including peripheral neuropathy as well as ALS and MS.
Axonal degeneration is a common yet unaddressed occurrence in a range of neurological diseases and is known to cause severe sensory, motor and cognitive symptoms.
Disarm’s scientific founders, Dr Jeffrey Milbrandt and Dr Aaron DiAntonio of Washington University School of Medicine in St Louis, discovered that the SARM1 protein is a central driver of axonal degeneration. Disarm’s SARM1 inhibitors are designed to directly prevent the loss of axons.
Lilly will pay $135m million up front for Disarm and shareholders may be eligible for up to $1.225 in further payments if certain goals are met if the big pharma develops and markets medicines resulting from the acquisition.
There will be no change to Lilly’s earnings per share guidance as a result of the deal.
While there are limited treatment options for ALS, the market for MS drugs is increasingly crowded with a range of different options including oral and injected medicines.
Roche has demonstrated the commercial potential for MS drugs after its Ocrevus (ocrelizumab) became a blockbuster after just a year on the market following its launch in 2017.
Migraine drug gets NHS funding
Lilly has also made some progress with its already-marketed neurology drug Emgality (galcanezumab), after NICE okayed NHS funding in final draft guidance applying to England and Wales.
NICE has already recommended Teva’s rival Ajovy (fremanezumab) this year, although it has rejected Novartis’ Aimovig (erenumab) despite an appeal from the manufacturer.
All the drugs come from the calcitonin gene-related peptide (CGRP) class of drugs, which patients inject to reduce the likelihood of attacks occurring.
NICE’s latest guidance recommends Emgality for preventing migraine in adults who have at least four migraine days each month and where at least three previous preventive treatments have failed.
This is the same point in the treatment pathway as Ajovy, but patients will have to experience at least 15 migraine days each month to be eligible for Teva’s drug.
UK cost-effectiveness agency NICE has backed Novartis’ Mayzent for secondary progressive multiple sclerosis (SPMS), after turning it down earlier this year in draft guidance.
The change of heart means Mayzent (siponimod) becomes the first oral disease-modifying therapy to be recommended for NHS use in SPMS patients with active disease, defined as relapses or evidence of active inflammation of neurons on imaging.
Secondary progressive disease can occur after the relapsing/remitting stage of the disease, where patients experience fewer or no relapses but find their disability is increasing.
In June, NICE said it wasn’t able to support the use of Mayzent because there was limited clinical evidence for its benefits in SPMS, and it was not persuaded by the cost-effectiveness modelling submitted by Novartis.
Now, a consultation period and a new commercial agreement with Novartis to supply the drug at a discount on its £1,643.72 monthly list price means that around 38,000 people with SPMS across the UK could get access to the drug – which the MS Society charity says is “a huge step forward” for patients.
The NICE judgment for England and Wales follows a positive verdict from the Scottish Medicines Consortium (SMC) a few days ago. In Northern Ireland, the Department of Health reviews NICE guidance before deciding on use of a new drug.
Mayzent provides a treatment option to many people living with MS where once there was none, according to the MS Society, which said that people transitioning from relapsing/remitting MS to SPMS “have faced an immensely difficult challenge – being forced to go from having a range of treatments available to them, to severely limited choices.”
At the same time, for some people living with the secondary progressive form of the disease who are able to take beta interferons – currently given by injection – Mayzent provides a less intrusive choice, according to the charity.
Historically, the diagnosis of SPMS with active disease has often been delayed or avoided due to uncertainty around disease progression, as well as the lack of any effective treatment, says Novartis.
“We are working closely with the NHS to ensure eligible patients can start benefiting from siponimod as soon as possible,” said Chinmay Bhatt, managing director for Novartis Pharma UK, Ireland & Nordics.
Mayzent has the same mechanism of action as Novartis’ older drug Gilenya (fingolimod), which is approved for RRMS but not SPMS.
The drug was approved in Europe in January based on the 779-patient phase 3 EXPAND trial which showed that it significantly reduced the risk of disease progression, including physical disability and cognitive decline.
In a subgroup of Mayzent-treated patients with active disease, the data showed that the risk of three-month and six-month confirmed disability progression was significantly reduced, by 31% and 37% respectively, compared with placebo.
“By slowing down disability progression and improving cognition, siponimod has the potential to allow people to carry on working, remain independent and stay connected with family and friends,” commented David Martin, chief executive of the MS Trust patient organisation.
“More broadly, we hope that the availability of this new treatment will lead to a greater focus on services for progressive MS which would benefit a much wider group of people,” he added.
NICE has recommended regular NHS funding for Roche’s Polivy in certain lymphoma patients in final draft guidance, overturning a previous rejection.
The new guidance recommends Polivy (polatuzumab vedotin) in combination with rituximab and bendamustine, for adults with diffuse large B-cell lymphoma (DLBCL), in second line when patients cannot have a stem cell transplant.
Around 4,800 people in England have DLBCL and around 530 of these will be eligible for the treatment.
NICE had rejected the treatment in previous draft guidance, but Roche has since offered an “updated commercial agreement” – likely a further confidential price cut – and offered further analyses relating to long-term survival data.
This has swayed NICE, which says it considers Polivy to be a cost-effective use of NHS resources.
NICE cited clinical trial evidence showing that in 40 patients treated with Polivy combination it caused cancer to become undetectable in around 40% of the cohort, compared with around 18% of the 40 patients treated with rituximab and bendamustine alone.
While NICE conceded there is uncertainty in the long-term data on remission, the evidence also suggested the combination treatment may increase progression-free survival and overall survival compared with rituximab and bendamustine.
DLBCL accounts for two in five non-Hodgkin’s lymphoma (NHL) cases in the UK. It is an aggressive disease that progresses rapidly, with a significant negative impact on the quality of life of patients.
Delivered intravenously every three weeks, the average cost of a course of the combination treatment is £50,416 at its list price, but the company offered the NHS a confidential discount.
Final guidance is expected to be published next month.
Pia Ballschmieter, haematology franchise lead, Roche Products Limited said: “People with relapsed or refractory diffuse large B-cell lymphoma have limited treatment options, especially those who are not candidates for haematopoietic stem cell transplant.
“We are proud to have collaborated with the clinical community and NICE to ensure that, from now on, people are able to benefit from Polivy, which represents a step forward in the treatment of this disease.”
Polivy is a first in class antibody drug conjugate, which targets the CD79b protein expressed on the majority of B-cells that cause NHL.
It binds to CD79b and delivers a cytotoxic agent resulting in cell death.
New research looks at the factors that speed up and slow down HTA appraisals for rare disease medicines across Europe.
Rare diseases drugs have always faced challenges when it comes to HTA approvals, even as governments bring in more regulatory policies that make their path through assessment easier.
Several factors make it difficult for HTA bodies often to assess orphan drugs, including a lack of robust trial data due to difficulties in finding patients, the absence of randomised controlled trials, the use of surrogate endpoints, and the lack of active drug comparators.
A new analysis from consulting firm CRA has honed in on the different challenges faced in four EU markets – England, France, Germany and Scotland – and looked at how manufacturers can increase the chances of a successful appraisal.
The research analysed more than 70 EMA-approved rare disease therapies and compared reimbursement recommendations from the regulatory bodies in each country, to see how HTA decisions potentially prolonged time to reimbursement.
The results show that HTAs for orphan drugs can vary widely across Europe, causing inconsistencies in evidence requirements and recommendations.
Rates of approval
The study reviewed all 80 European Medicines Agency (EMA) authorised drugs receiving an orphan designation between 1 January 2013 and 31 December 2019, analysing their HTA outcomes and time to reimbursement across France, Germany, England and Scotland.
A comparative analysis was then conducted on the 71 approved drugs that achieved a negotiated price in at least one of the four markets.
Germany had the highest approval rate of orphan drugs at 98% – however most of these recommendations (73%) were awarded a ‘non-quantifiable benefit’ rating, the automatic rating for an orphan drug, which shows the regulator did not see any benefit compared to comparator products (see graph 1). The authors also note that orphan drug trials with higher p values and surrogate endpoints are often accepted for assessment in the country.
A more favourable outcome from the German regulator took on average 1.4 times longer to achieve a final negotiated price (708 versus 510 days).
Graph 1: Assessment of the HTA outcome in France, Germany, England and Scotland of all orphan drugs that obtained an EMA approval between 2013-2019. N above each bar equals the number of drugs reviewed by the respective HTA body. Source: CRA Analysis
France and England had comparable approval rates (92% and 91%, respectively); however, France reviewed almost twice the number of orphan drugs over the period of analysis (67 versus 35). Only 19% of the orphan drugs in France were awarded an Amelioration du Service Médical Rendu (ASMR) rating of V, which indicates no improvement in medical benefit. Drugs with an ASMR IV-V rating were reimbursed in 427 days, compared to 585 days for products with ASMR I-III (see Graph 2).
Graph 2: Comparison of the time to reimbursement (days) for EMA orphan drugs approved from 2013- 2019. Orphan drugs were reimbursed in at least one of the selected markets (N = 70). N within each bar equals the number of drugs with each outcome reviewed by the respective HTA body. Source: CRA Analysis
In England, two key mechanisms were often used to achieve approval: label restrictions or a patient access scheme (PAS).
Over one third (37%) of orphan drugs appraised by NICE only achieved approval in a positioning or population that was restricted versus the full regulatory approved label. Companies that accepted such restrictions saw faster approval time compared to no drugs with restrictions (407 versus 505 days).
Meanwhile, although introducing a PAS improved the chance of approval, the analysis suggests that it actually delays the overall appraisal time (523 versus 311 days).
Scotland had the highest rate of non-approval for orphan drugs. Thirty-three percent of drugs reviewed were not accepted, despite specific modifiers in place for rare disease products, including the incorporation of the patient voice through the country’s Patient and Clinician Engagement (PACE) meetings – which were included in 74% of orphan drug submissions between 2013-2019.
Improving HTA outcomes
The authors conclude that while the various concessions and modifiers introduced by different governments have a positive impact on minimising rejections and accelerating approval times, there are still challenges in capturing the full value of orphan drugs within the HTA process.
“Achieving more favourable outcome ratings, avoiding restrictions, or addressing uncertainty with a PAS all lead to prolonged appraisal times,” the authors say. “Manufacturers are therefore still required to consider carefully their HTA launch strategy and complement this with additional evidence generation and engagement from a wider stakeholder group.”
The authors outline several approaches companies can take to improve the chances of success in orphan drug approvals and overcome the challenge of having limited data and evidence available.
One approach is to agree methods for ongoing real world data collection post-launch with HTA bodies.
They add that “creative” solutions to real world evidence collection could help, such as developing apps for patients and HCPs.
Meanwhile, it is also important to strive for wider engagement with the rare disease community and other stakeholders.
Listening to views from patients and HCPs can help with processes like Scotland’s PACE meetings – but more indirect forms of stakeholder engagement may also improve HTA outcomes, as the value-added services provided to these stakeholders can be leveraged during negotiations.
“For example, Galafold, an enzyme replacement therapy for Fabry’s disease, is primarily differentiated from existing treatments by providing a reduction in administrative burden,” the authors say. “Despite this, Galafold was able to achieve an ASMR IV in France, recommendation by NICE, and was accepted for restricted use in Scotland.”
They note that the perception of Galafold’s value may have been improved by the additional value-added services the manufacturer, Amicus Therapeutics, offered to a wider stakeholder group
For example, Amicus reimbursed amenability tests for patients with unknown mutations that could be referenced against Galafold’s amenability table via a physician support website. This service was accepted in the NICE evaluation as something which avoided additional resource implications for the NHS.
For more information contact the report’s authors:
NICE has said a combination of Merck KGaA’s Bavencio and Pfizer’s Inlyta should be available as a first line option for kidney cancer patients for NHS patients in England.
The cost-effectiveness body okayed interim reimbursement from the Cancer Drugs Fund (CDF) in final guidance for adults with advanced renal cell carcinoma.
NICE said that the therapy could be made available to around 1,600 patients per year in England.
The cost-effectiveness body noted clinical trial data showing that the combination of Bavencio (avelumab) and Inlyta (axitinib) improved progression-free survival for an average of five months compared with Pfizer’s Sutent (sunitinib).
Sutent was first recommended in this indication by NICE as long ago as 2009.
NICE said that final trial results including overall survival data are not yet available, but said the drug has the potential to be cost-effective.
The combination therapy will be available via the CDF on an interim basis at a confidential discounted price.
Bavencio is administered by a drip every two weeks and Inlyta is taken as a pill twice a day.
There are other NICE-recommended alternatives in first-line kidney cancer such as Novartis’ Votrient (pazopanib) and Bristol-Myers Squibb’s immunotherapy combination of Opdivo (nivolumab) and Yervoy (ipilimumab) is also available.
Meindert Boysen, deputy chief executive and director of the centre for health technology evaluation at NICE, said: “The committee heard from patient representatives that having more first line treatment options for advanced renal cell carcinoma would be welcomed, as it would allow for more individualised treatment plans to better control the disease.
“We’re therefore pleased that, because of the joint working between the two companies, NHS England and NHS Improvement and NICE, eligible patients with advanced renal cell carcinoma will be able to access this combination therapy from today on the CDF, while more clinical data is collected.”
However the news was not so good for Kyowa Kirin – NICE rejected the Japanese pharma’s Poteligeo (mogamulizumab) in first draft guidance for mycosis fungoides, a type of non-Hodgkin’s lymphoma affecting the skin causing red patches or plaques that progress to skin tumours.
It also rejected Poteligeo for the closely related Sezary syndrome, which is caused by cancerous T-cells in the blood and lymph nodes.