The 2017 and 2018 editions of the American College of Cardiology conference were dramatic affairs that put paid to any hope of massive sales acceleration for the newest cholesterol-lowering drugs. This year’s confab looks likely to be less earth-shaking, although incremental data from such projects as Esperion’s bempedoic acid and Amarin’s Vascepa could raise or lower these assets' commercial profiles.
A curious addition to the late-breaking programme is the heart failure project neladenoson bialanate, which Bayer has discontinued. Either this asset's Panache study found something positive or the investigators believe that there is something important to learn from its failure.
Amarin’s triglyceride-lowering treatment Vascepa pulled off one of the bigger surprises of 2018 when it reported positive cardiovascular outcomes data in the Reduce-It trial. Detailed data from that study were presented at the American Heart Association meeting in November but, as is the case in any major cardiovascular trial, there are plenty of sub-analyses that might be used to help tease out the drug’s commercial promise and help physicians and payers understand the real-world benefit of the fish-oil pill.
At ACC, Amarin will release data on total ischaemic events, which were contained within the five and three-point composites that served as the 8,000-patient study’s respective primary and key secondary endpoints (AHA 2018 – Amarin goes hard on Vascepa but questions remain, November 11, 2018).
Given the concerns that emerged in the wake of Amarin’s American Heart Association presentation, additional data could help assuage doubters about Vascepa’s potency. A more pronounced increase in LDL cholesterol levels in the control arm was blamed on the mineral oil pill that served as a placebo, and some critics questioned whether that LDL-raising effect flattered Vascepa's apparent benefit.
In the realm of lipid-lowering agents, Esperion will detail data from the Clear Wisdom trial, its study in patients with high levels of LDL and either atherosclerotic cardiovascular disease or familial hypercholesterolaemia already on maximally tolerated statins. The company toplined the data in October: the primary endpoint of LDL-lowering at 12 weeks was met, with an additional 18% reduction versus statins alone.
Esperion's ACC presentation will give the group an opportunity to provide more detailed data, including a breakdown on the individual components of the major adverse cardiovascular events (MACE) composites, which will be of interest to specialists looking to see if there were any imbalances of concern.
MACE composites evaluate such outcomes as cardiovascular death and nonfatal complications in various ways. Clear Wisdom measured three, four, and five-point MACE; on all of these bempedoic acid scored better than placebo. However, cardiologists and payers would like to see a consistent benefit in all components rather than having one or two drive the difference over placebo.
The inclusion among the ACC late-breakers of the Bayer project, a partial adenosine A1 receptor agonist, is even more intriguing given that the company disclosed data from the Pantheon trial at last year's European Society of Cardiology meeting showing that it did not significantly improve the left ventricular ejection fraction (EF) of heart failure patients with reduced EF.
The company confirmed to Vantage that it had discontinued the project in September.
The phase II Panache trial enrolled 305 patients with preserved EF, and its primary endpoint is the sometimes controversial six-minute walk test. Five doses from 5mg to 40mg daily are being trialled against placebo over 20 weeks. The good news from 427-patient Pantheon study was that no safety concerns were identified at the same doses.
While advances have been made recently in the treatment of heart failure with reduced EF, including the approval of Novartis's angiotensin receptor-neprilysin inhibitor Entresto, the preserved EF population is in need of novel treatments. Notably, the phase III Paragon trial of Entresto in the preserved EF setting is expected to read out this year and, if positive, would give the Swiss group a head-start here (Event – Novartis hopes Entresto can be a Paragon of label expansion, July 30, 2018).
The signs do not look promising for neladenoson, as other adenosine A1 receptor agonists have not fared well in cardiovascular disease. Gilead Sciences’ CVT-510 (tecadenoson), Astellas Pharma’s DTI-009 (selodenoson), and Bayer’s own BAY 68-0496 (capadenoson), have all failed in this space, primarily as atrial fibrillation projects.
Neladenoson bialanate is not the only card Bayer has to play in heart failure. The company also has vericiguat in phase III in the reduced EF population and in phase II in preserved EF patients.
Other highlights from ACC will inlcude new data cuts from the Declare-Timi trial of Astrazeneca's SGLT2 inhibitor Farxiga, which evaluated cardiovascular outcomes in patients with type 2 diabetes, read out positively last September and had more data at the American Heart Association meeting. The ACC late-breaker will focus on heart failure and mortality; the diuretic effects of the SGLT2 class on heart failure has been thought to be a driver of its cardiovascular benefit.
And another sub-analysis will concern the Reveal trial of Merck & Co’s discontinued CETP inhibitor anacetrapib, which showed a small benefit in reducing cardiovascular events, but not enough for Merck to press on. This post-hoc look will consider the impact of the ADCY9 gene on response to anacetrapib, and short of groundbreaking efficacy that prompts Merck to resume development the results will be irrelevant for the big pharma group.
However, they could be highly relevant for Canada’s Dalcor Pharmaceuticals, which is testing Roche’s failed CETP inhibitor dalcetrapib specifically in patients with the AA variant at rs1967309 in the ADCY9 gene. A positive effect in the Reveal sub-analysis could serve as an important read-across to Dalcor's pivotal Dal-Gene trial, which is due to read out in 2021.
Biopharma innovation in the cardiovascular space tends to move more slowly than in other diseases because of the necessary size and length of trials. Eking out a small benefit is often seen as a clinical win, but transforming this into a commercial product that insurers will reimburse is another matter – thus drilling down into such details can count for a lot.
|Key trials at ACC 2019|
|Panache||Neladenoson bialanate in heart failure with preserved ejection fraction||NCT03098979|
|Reduce-It||Vascepa cardiovascular outcomes trial in hypertriglyceridaemia patients||NCT01492361|
|Clear Wisdom||Bempedoic acid in in patients with hyperlipidaemia at high cardiovascular risk||NCT02991118|
|Declare-Timi||Farxiga cardiovascular outcomes trial in type 2 diabetics with established or at high risk of disease||NCT01730534|
|Reveal||Anacetrapib cardiovascular outcomes trial||NCT01252953|