ACC 2019 round-up – Esperion and Amarin prepare to go it alone

As approval decisions near, further data fail to answer lingering questions about Esperion's bempedoic acid and Amarin's Vascepa.

This year’s American College of Cardiology conference promised incremental updates rather than fireworks. And perhaps Amarin’s investors would have preferred a takeout bid instead of a new analysis from the pivotal Reduce-It trial of its triglyceride-lowering therapy, Vascepa.

For Esperion, full data from the Clear Wisdom trial only confirm that bempedoic acid has a good chance of receiving regulatory approval for reducing LDL cholesterol as an add-on to statins. However, these data do not answer questions about bempedoic acid’s commercial opportunity, which is being squeezed as prices for the more potent anti-PCSK9 antibodies fall. Both companies face the prospect of going it alone in the increasingly tough cardiovascular market.

Clear Wisdom enrolled patients with established cardiovascular disease or familial hypercholesterolaemia on a maximally tolerated statin therapy and in need of additional LDL lowering. 12-week data from this trial were released last year, and at ACC investigators presented results at 12 months showing LDL lowering of 17%, a slight decline from the 18% at 12 weeks. Patients taking statins alone saw their LDL essentially unchanged at 12 weeks, but had a slight decline of 5% at 12 months.

Bempedoic acid has not resulted in the profound LDL reductions seen with the PSCK9 antibodies Repatha and Praluent. In Repatha’s Fourier cardiovascular outcomes trial, in a similar population, a placebo-adjusted change of 57% was seen at 72 weeks.

The 779-patient Clear Wisdom study did not record a statistically significant difference in the number of major adverse cardiovascular events as measured by composite scores of three, four and five points. Looking at individual components of these composite scores bempedoic acid looks numerically better than statins alone on non-fatal myocardial infarctions and coronary revascularisation, although a higher percentage of patients taking bempedoic acid were hospitalised for unstable angina.

This trial was too small to measure cardiovascular outcomes properly, something that could be rectified by the 12,600-patient Clear Outcomes trial, which should complete enrolment later this year.

Tide turns for Amarin 

There was probably an element of selling on the news for Amarin investors today, with few catalysts on the horizon until Vascepa is approved in a broader population. The product is already marketed for a niche use, severe hypertriglyceridaemia, and Amarin plans to file Vascepa with the FDA for mixed dyslipidaemia population by the end of this quarter.  

Still, the lack of a takeover bid so far, despite rumoured interest from Pfizer and, more recently, Novartis, might also have had something to do with a 4% drop in Amarin's stock this morning after an ostensibly positive update from Reduce-It, which suggested that Vascepa could prevent second and third major cardiovascular events, as well as initial ones.

The latest analysis, which Amarin described as “tertiary or exploratory”, found a 30% reduction in the risk of first and subsequent cardiovascular events with Vascepa versus placebo, against a background of statin therapy. Reduce-It originally reported a 25% placebo-adjusted reduction in the risk of a first major adverse cardiovascular event (AHA 2018 – Amarin goes hard on Vascepa but questions remain, November 11, 2018).

In the 8,000-patient study there were 1,606 first cardiovascular events and 1,303 subsequent events. This illustrates the scale of recurrent cardiovascular problems, and should stand Amarin in good stead as it tries to boost uptake of Vascepa.

However, the data did nothing to answer lingering questions about Vascepa’s mechanism, or whether the Reduce-It result had been flattered by a worse performance in placebo subjects, who had received a mineral oil pill. Perhaps these issues are holding back a potential acquirer.

Farxiga focus

Meanwhile, Astrazeneca touted updated ACC guidelines recommending SGLT2 inhibitors, including its own Farxiga, in a primary prevention population of diabetics at risk of cardiovascular disease. But new analyses from its Declare-Timi cardiovascular outcomes trial suggest that much of the benefit was driven by sicker patients.

One prespecified subanalysis presented at ACC today found that the SGLT2 inhibitor reduced the relative risk of major adverse cardiovascular events (MACE) by 16% in patients who had previously had a heart attack. Meanwhile, another discovered that a small group of patients with heart failure with reduced ejection fraction drove a decrease in cardiovascular deaths.

Full data from Declare-Timi were presented at the AHA meeting in November – the trial only found that Farxiga was non-inferior to placebo on the MACE co-primary endpoint, although it did show superiority on its second co-primary, a composite of cardiovascular death or hospitalisation (AHA 2018 – Astrazeneca takes heart from partial Farxiga victory, November 11, 2018).  

Notably, 60% of the patients in Declare-Timi were merely at risk of cardiovascular events, while the rest had had established cardiovascular disease, making the trial's population less sick than outcomes studies of other SGLT2s – something that Astra previously made much of.

Danilo Verge, Astra’s vice-president of global medical affairs, told Vantage he was not concerned about the latest data limiting use of Farxiga to a more severe patient niche.

Farxiga is also in trials in heart failure and kidney disease patients regardless of their diabetic status. And another large clinical programme, called DapaMech, aims to pin down the mechanism that leads to Farxiga’s cardiovascular benefit, something that is still unclear for all the SGLT2s.

Mr Verge said Astra was probably the only company taking this approach; with the SGLT2 inhibitors now an ageing drug class, perhaps this is not a surprise.

Selected upcoming trials of Farxiga
Study Setting Trial ID Primary completion
Define-HF  HF biomarkers/symptom in chronic HF with reduced systolic function  NCT02653482 Jan 2019
Dapa-Card Cardiac function, metabolic efficiency and cardiac fuel handling in T2DM NCT03387683 Apr 2019
Preserved-HF HF biomarkers/symptom in chronic HF with preserved systolic function  NCT03030235 Jun 2019
Dapa-Salt Sodium excretion in patients with impaired renal function +/- T2DM NCT03152084 Jul 2019
Diamond Proteinuria in non-diabetes and kidney diseases  NCT03190694 Jul 2019
Dapa-Maast Insulin sensitivity, energy metabolism and mitochondrial function in T2DM  NCT03338855 Dec 2019
Dapa-HF   CV outcomes in heart failure with reduced ejection fraction NCT03036124 Dec 2019
Dapa-CKD Outcomes in chronic kidney disease NCT03036150 Nov 2020
Deliver CV outcomes in heart failure with preserved ejection fraction NCT03619213 Jun 2021

Bayer's heart failure fail

Finally, data with Bayer’s heart failure project neladenoson bialanate revealed why the German group discontinued all work with it after phase II. The Panache trial in patients with heart failure with preserved ejection fraction was no more successful than the Pantheon study in reduced ejection fraction patients.

The primary endpoint of Panache was the six-minute walk test, and trial investigators detected no significant difference between patients taking five different doses of neladenoson bialanate and those taking placebo. Numerically, patients taking the lower doses of 5mg and 10mg had a greater improvement than those taking higher doses of 20mg, 30mg and 40mg.

Still, at least Bayer has other irons in the fire. Esperion and Amarin's fortunes hinge on how their lead projects perform.

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