Boehringer, Lilly’s Jardiance ties to match AZ’s Farxiga with heart failure label

Boehringer and Eli Lilly have moved closer to a heart failure indication for their SGLT2 inhibitor Jardiance, as the FDA starts a fast-track review of the drug in its first use beyond diabetes.

The US regulator is looking at data from the EMPEROR-Reduced trial of Jardiance (empagliflozin), which found that the drug achieved a 25% reduction in the combined primary endpoint of cardiovascular death or hospitalisation compared to placebo.

Lilly and Boehringer claim almost 60% market share for Jardiance among SGLT2 drugs used to treat type 2 diabetes, driving blockbuster sales for the brand.

It was the top-selling drug in the SGLT2 inhibitor class in 2019, with sales of almost $3 billion, helped by side-effect problems that have afflicted first-to-market rival Invokana (canagliflozin) from Johnson & Johnson.

However its rivals – which also include AstraZeneca’s Farxiga (dapagliflozin)  – have moved more swiftly into areas like heart failure and chronic kidney disease (CKD) which have made large numbers of new patients eligible for treatment with the class.

The new FDA review – covering Jardiance as a treatment for adults with heart failure with reduced ejection fraction (HFrEF) in patients with and without diabetes – is Lilly and Boehringer’s first chance to fight back.

Farxiga won FDA approval for adults with HFrEF in May 2020, which helped to drive its third-quarter sales up by a third to $525 million. AZ picked up EU approval for the same indication the following November.

Lilly and Boehringer will be hoping for a swift FDA review so that Jardiance will not fall too far behind its competitor in the heart failure category, and that looks likely as the benefit in HFrEF increasingly appears to be an SGLT2 class effect.

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 this year. The bulk of those sales will come from HFpEF, however,  as in this form of heart failure there is a huge unmet need and no approved therapies.

Boehringer and Lilly are waiting for the results of the EMPEROR-Preserved later in 2021, while AZ should also Farxiga in the DELIVER trial in HFpEF, with additional data on both HFrEF and HFpEF due from the DETERMINE study, before year-end.

Meanwhile, EMPEROR-Reduced also showed a slowdown in the rate of decline in kidney function among patients with HFrEF, an effect that Lilly and Boehringer are exploring in the CKD patient population in the EMPA-KIDNEY trial due to generate results in 2022.

Invokana was the first mover among the SGLT2 drugs in the kidney area, winning FDA approval towards the end of 2019 for diabetic kidney disease. After a couple of years of declining sales due to concern about a risk of lower limb amputation, Invokana managed a 25% gain to $224 million in third-quarter 2020.

Farxiga meanwhile has already been filed for CKD on the back of the DAPA-CKD trial, with a verdict due in the second quarter.

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FDA rejects Novartis’ cholesterol drug after factory inspection issue

Novartis’ cholesterol drug inclisiran has hit a speed bump with the FDA, which has rejected the potential blockbuster because a manufacturing facility has yet to be inspected.

Matters appear to have been complicated by the pandemic and the travel disruption that it has caused, which is preventing an FDA team from visiting the plant in Europe.

In a statement the Swiss pharma said that the FDA has not raised any concerns about the safety or efficacy of the drug, which Novartis added to its pipeline after buying The Medicines Company for $9.7 billion late last year.

A first-in-class treatment discovered by Alnylam and then licensed to The Medicines Company, the drug is being developed for treatment for hyperlipidaemia in adults who have elevated low-density lipoprotein cholesterol (LDL-C) while being on a maximum tolerated dose of a statin therapy.

The FDA was due to make a regulatory decision on inclisiran by Wednesday but this has been delayed because of the unresolved “facility inspection-related conditions”.

Novartis said it will receive these requirements at the European manufacturing facility within 10 business days.

The FDA has not yet conducted a facility inspection and the FDA will set out a schedule if it deems one necessary, once safe travel may resume.

The European Commission has already approved the drug under the brand name Leqvio earlier this month following backing from the CHMP regulatory committee.

Inclisiran is a small interfering RNA (siRNA) therapy that works by inhibiting PCSK9 – the same target as Amgen’s Repatha (evolocumab) and Sanofi/Regeneron’s Repatha (alirocumab) – but is dosed only twice a year rather than every month.

Novartis hopes that the drug will make an impact where these antibody drugs have failed, with Repatha and Praluent lacking sales momentum despite being on the market for more than five years.

Payers had deemed the drugs to be too expensive and even price cuts failed to expand their use.

In January, Novartis and NHS England forged a pact to accelerate access to inclisiran for primary prevention of cardiovascular disease.

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Entresto set for big sales hike after FDA panel endorsement

Novartis’ Entresto is on course to become the first drug to be approved in the US for a form of heart failure that is notoriously hard to treat effectively, despite missing the mark in a phase 3 trial.

An FDA advisory committee 12 to 1 in favour of approving Entresto (sacubitril/valsartan) for heart failure with preserved ejection fraction (HFpEF), which accounts for around half of all heart failure cases but proves highly resistant to drug treatment. In HFpEF, the heart muscles pump normally but the organ is too stiff to fill properly.

Entresto is already approved to treat heart failure with reduced ejection fraction (HFrEF), caused by the heart muscles not pumping effectively, and has revitalised the treatment of patients with this form since its launch in 2015.

After a slow start, it has grown to become a $1.7 billion product last year, and that represented a surge from around $1 billion in 2018 revenues.

Analysts have predicted that approval in HFpEF – which affects around 3 million people in the US alone – could more than double Entresto’s sales, perhaps driving them as a high as $5 billion a year. There’s also plenty of upside in HFrEF as three out of four eligible patients are still not being treated with the drug, according to Novartis.

The prospect of adding HFpEF to Entresto’s label looked shaky last year however, when the drug missed its primary objective in the phase 3 PARAGON-HF trial.

The 4,822-patient study missed statistical significance for a composite primary endpoint of reducing cardiovascular death and total heart failure hospitalisations by 13% compared with valsartan alone, but only by a whisker, and Novartis has been upbeat since about the chances of approval.

The published data from the study suggested that the drug performed better in women, people with structural abnormalities in the left ventricles of their hearts, and those with very low ejection fractions – the amount of blood pushed out of the heart each beat.

The positive vote by FDA advisors came after the FDA reviewer acknowledged the narrow miss for statistical significance and pointed to the pressing need for a drug treatment for HFpEF.

The agency’s own expert said that “various pre-specified and post-hoc analyses suggest that sacubitril/valsartan compared to valsartan reduces HF events” in HFpEF, and of course Entresto’s long track record of safety stands in its favour.

While the FDA doesn’t have to follow its advisory committee’s advice it generally does, and Novartis is now eyeing approval of Entresto in HFpEF in the first quarter of 2021.

The main question now is exactly how the FDA will word the label if it approves the drug, with panellists debating the use of ejection fractions percentages to guide treatment with little agreement.

PARAGON-HF in included patients with left ventricular ejection fraction (LVEF) of 45% or more, but earlier studies have suggested the drug can have a benefit in people with scores below 40%.

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Amgen shares down as heart failure drug disappoints in phase 3 trial

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.

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RHYTHM AI cleared for large trial of atrial fibrillation mapping tool

UK-based RHYTHM AI is to go ahead with a larger clinical trial of its artificial intelligence (AI)-driven system, which could be used as a treatment for atrial fibrillation without the need for medication.

Antiarrhythmic drugs are standard therapy but they often only work for around 18 months, after which time a catheter ablation procedure is necessary to isolate the cause of the electrical abnormality that is the cause of the disease.

The ablation procedure works by using small burns to isolate the vein causing the irritation that is disrupting the electrical pathways in the heart.

RHYTHM AI’s STAR Mapping uses novel computer algorithms to identify the causes of atrial fibrillation, using 3D mapping equipment to inform the ablation procedure.

The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has given the go-ahead for the company to proceed with its ‘ROCSTAR’ clinical trial to further test the system as a potential treatment for persistent AF.

The company said that in a single centre study published in May last year, 80% of patients treated in a single procedure using STAR Mapping were free of AF without use of anti-arrhythmia drugs at an average of 18.5 months follow up.

This compares with a study showing 48% of patients from AF at 18 months follow-up without use of anti-arrhythmic drugs using standard 3D mapping technology.

RHYTHM AI will expand the research, using a multi-centre clinical trial designed to be a ‘real-world’ evaluation of the STAR Mapping System as a potential treatment for patients undergoing cardiac ablation procedure for persistent AF.

The randomised trial will recruit 177 patients in up to 15 UK centres and follow the patients to evaluate freedom from AF at 12 months follow up.

A control group of 59 patients will receive the standard pulmonary vein isolation ablation procedure, while a study group of 118 patients will receive a pulmonary vein isolation procedure by guided further ablation using STAR Mapping.

The primary goals are freedom from AF without anti-arrhythmia drugs at 12 months and response to STAR guided ablation during the procedure – either a slowing or termination of AF.

Clinical development of the system got off the ground last year when the company announced the closure of a £2.15m financing round.

This was led by an affiliate of Rinkelberg Capital Ltd, a private wealth management firm based in London, as well as investment from founders.

Developed at the city’s St Bartholomew’s Hospital, the system was developed by a team including London-based cardiologist Richard Schilling.

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Regeneron’s cholesterol drug evinacumab claims February FDA date

The FDA has started a speedy review of Regeneron’s ANGPTL3-targeting antibody evinacumab for a rare, inherited disorder that dramatically raises the risk of heart disease.

The cholesterol-lowering drug has been classed as a breakthrough therapy for homozygous familial hypercholesterolaemia (HoFH) by the FDA, which is due to deliver a decision on the marketing application by 11 February after a truncated six-month review.

HoFH affects around 1,300 people in the US, says the biotech, and raises cholesterol levels in the blood to very high levels. As a consequence, people with the condition can develop cardiovascular disease very early, even in childhood in some cases, despite aggressive treatment with cholesterol-lowering drugs like statins and PCSK9 inhibitors.

Evinacumab (formerly REGN1500) was developed after scientists discovered that people with genetic profiles that reduced ANGPTL3 gene activity had significant lower levels of LDL cholesterol, and a decrease in the risk of developing heart disease,

If approved, it will sit alongside Sanofi-partnered PCSK9 inhibitor Praluent (alirocumab) – which has underperformed since its launch in 2015 – in Regeneron’s emerging cardiovascular franchise.

The ANGPTL3 antibody has been filed for approval in the US and Europe on the back of the phase 3 ELIPSE trial, which tested the antibody in 65 HoFH patients already being treated with statins, PCSK9 inhibitors and other drugs like ezetimibe.

Adding in Regeneron’s antibody resulted in a 49% drop in cholesterol levels from the start of the study compared to patients sticking with their current therapy alone, according to results presented earlier this year at the American College of Cardiology’ congress in March.

The FDA awarded evinacumab breakthrough status in 2017 on the strength of phase 2 data which also showed that the antibody could achieve impressive 50% reductions in LDL cholesterol, as well as cutting blood lipids like triglycerides, in HoFH patients.

There’s no data showing that the drug can reduce progression to heart disease yet, but it’s widely believed that cutting blood lipids can reduce that risk.

Not all patients with HoFH are the same however as there are multiple genes involved in the disease, including those for LDL receptors, apolipoprotein B and PCSK9.

Crucially, Regeneron’s drug seems to work even in so-called ‘null-null’ patients, which have very low levels of receptors that remove LDL cholesterol from the blood and so progress to cardiovascular complications very quickly.

Evinacumab may not be so significant commercially however, at least in the near term, although it will likely be able to command higher pricing than Praluent due to the rarity of HoFH. Analysts put peak US sales in the region of $200 million to $400 million.

Once tipped as blockbusters, Praluent and a rival PCSK9 drug from Amgen – Repatha (evolocumab) – have struggled to gain sales momentum in the much larger population of people with other forms of high cholesterol, and have yet to crack the $1 billion sales threshold, even when their sales are combined.

They now also face the threat of competition from Novartis PCSK9 rival inclisiran, which offers much less frequent dosing.

Evinacumab is expected to be a smaller product, thanks to the tiny population affected by the ultra-rare indication, although Regeneron will be able to detail using the same salesforce that sells Praluent, reducing the cost of rollout if approved.

The biotech is also running trials that could end up expanding its use into patients with heterozygous familial hypercholesterolaemia (HeFH) – a less severe inherited disorder – as well as for patients with non-inherited forms of high cholesterol who can’t meet treatment targets with a statin and PCSK9 inhibitor.

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