ACC 2020 – Merck and Bayer face a fight with new heart failure pill

The presentation of vericiguat’s pivotal heart failure study, Victoria, at the American College of Cardiology’s annual meeting this weekend was followed by glowing endorsements from two reviewing physicians. But Merck & Co and Bayer could struggle to translate this acknowledgement into broad commercial use.

True, the study was the first to show a benefit in a specific group of very sick patients, most of whom were already on standard of care. But with Novartis’s Entresto becoming increasingly entrenched, and Astrazeneca’s SGLT2 inhibitor Farxiga poised for approval in the coming weeks, vericuguat will arrive in a competitive market – and certain cross-trial comparisons do not make for flattering reading.

The three pivotal trials of these agents – Paradigm-HF, Dapa-HF and Victoria – all recruited patient with heart failure with reduced ejection fraction (HFrEF); an important differentiation is that Victora enrolled those with the worst prognosis. However, all used the same primary endpoint – a composite of cardiovascular death and hospitalisation for heart failure worsening – which allows a comparison of hazard ratios.

On these measures Victoria looks relatively weak; measures of cardiovascular death or absolute mortality failed to reach significance, with the win on the primary endpoint driven by hospitalisation numbers.

The Victoria trialists obviously anticipated that this comparison would be made: in a paper published in Circulation over the weekend, at the same time as the full results were published in the New England Journal of Medicine, they argued that measures of risk reduction, standardised to fixed times points, made for a better comparison.

“Hazard ratios don’t talk about what burden, or number of events, could be lowered. The absolute risk reduction matters in terms of prevented events during the time,” Lothar Roessig, head of clinical development at Bayer’s cardio-renal division, told Vantage.

This comparison paints vericiguat in a much better light, of course, and it is presumably these data that Bayer and Merck sales reps will be highlighting, should the project win approval.

At the end of the day, however, Merck and Bayer chose to test vericiguat in a sick, high-risk population, and it seems likely that physicians will reserve the drug for this category of patient. If the SGLT2 inhibitors were not on the horizon the prospects might be different, but this class of diabetes drug has mounting evidence of utility in heart failure, as well as huge cardiovascular outcome studies to support their safety.

Over the weekend at ACC a new analysis of Dapa-HF was presented that demonstrated Farxiga’s efficacy regardless of background therapy; should regulatory approvals emerge, Astrazeneca will waste no time trying to establish the drug as a new standard of care. Hazard ratios will no doubt be the focus of its marketing message.

“The general sentiment we gathered was that physicians would continue to start the majority of patients on a standard of care regimen, which will include Entresto in place of angiotensin receptor blockers/ACE inhibitors and an SGLT2, especially for patients with diabetes,” SVB Leerink analysts wrote today in response to the Victoria data.

Still, the fact that vericiguat will likely be kept as an option for high-risk patients should not underestimate the need in this population – hence the recognition that the Victoria study received. And another trial called Vitality, in an even sicker population, is due to read out shortly, and could further prove vericiguat’s worth.

The sellside have relatively modest expectations, however: 2024 sales are seen reaching $560m, against the $4bn that Entresto is forecast to bring in that year, according to EvaluatePharma. When Merck paid Bayer $1bn to access this project back in 2014, along with two other cardiovascular assets, it was probably hoping for bigger things.