After teasing positive top-line results last November, a deeper dive into Merck & Co. and Bayer’s heart failure drug vericiguat helped kick off this year’s scientific meeting of the American College of Cardiology (ACC), presented virtually as a late-breaking trial.
The data were highly anticipated, especially since the two Big Pharma partners decided to continue with clinical testing—and enroll over 5,000 high-risk participants worldwide—after the novel compound missed its primary endpoints in two previous phase 2 studies.
The phase 3 VICTORIA trial saw a 10% drop in a composite rate of cardiovascular deaths and related hospitalizations among patients with recently worsening heart failure and reduced ejection fraction. Compared to placebo, the treatment difference with vericiguat started to become apparent after three months.
With a median follow-up period of 10.8 months, patients showed significant reductions in hospitalizations when looked at specifically, however the reduction in cardiovascular-related deaths alone was not statistically significant.
The study, simultaneously published in The New England Journal of Medicine, said the overall difference between the drug and placebo translated to an absolute risk reduction of 4.2 events per 100 patient-years—or, that it would take about 24 to 28 people treated with vericiguat for one year to prevent one cardiovascular-related death or hospitalization.
“For a group of patients with this form of high-risk heart failure, where other heart failure drugs have rarely been studied, vericiguat provides a significant novel addition to usual treatment,” said the study’s lead author and presenter, Paul Armstrong, a distinguished university professor of medicine at the University of Alberta’s Canadian VIGOUR Centre.
“This is a sick population that has a significant unmet need,” Armstrong added. Of the 6.5 million adults in the U.S. suffering from heart failure, many have decompensating conditions leading to repeat hospital visits, and few options for slowing the progression of the disease.
Vericiguat is a novel guanylate cyclase stimulator designed to boost a cell signaling pathway that helps relax blood vessels and increases blood flow, as well as improves heart muscle function.
Its two phase 2 studies enrolled chronic heart failure patients with reduced ejection fraction and preserved ejection fraction, respectively. Vericiguat didn’t meet either’s primary endpoints measuring the hormone biomarker N-terminal pro B-type natriuretic peptide, or NT-proBNP, which is released by the heart in response to pressure changes and associated with worsening heart failure.
Still, Bayer and Merck felt there were clear dose responses when looking at the studies’ subgroups individually, with vericiguat’s effect sizes on par with clinical trials of other heart failure drugs, according to Merck’s vice president and head of global clinical cardiovascular development, Joerg Koglin. This, as well as the drug’s safety data, pushed the two companies to forge ahead with the larger trial.
“Of course now, seeing the phase 3 results, we felt that it was the right decision,” Koglin said in an interview with FierceBiotech. “But Bayer and Merck were very closely aligned on this … I wouldn’t put it into ‘big gamble’ category.”
“This is not just another chronic heart failure study,” he said. “It is differentiated because it really studied a clinical problem that has not been studied before in other big heart failure trials. It didn’t look at broad chronic heart failure—it specifically focused on what we believed was a huge unmet clinical need.”
Vericiguat’s safety profile included similar rates of serious adverse events compared to placebo, as well as no adverse effects related to electrolytes or kidney function. That gave the study the unique chance to enroll decompensating patients with higher levels of renal impairment at baseline compared to other drugs, Koglin said.
Now, the companies are discussing the VICTORIA data with regulators and expect to finalize plans for follow-up studies over the next six months.
“This study is not only answering questions—does it work, is it safe, and were we able to enroll a unique patient population—but the study also generates a number of additional hypotheses,” he said, which includes vericiguat’s relationship with NT-proBNP.
Patients with lower levels had shown greater treatment effect sizes, but those in the highest quartile at the start of the study trended more toward placebo. “That will be interesting for us to study, to figure out what it means and why, and how it should or should not inform the use of the drug.”
Meanwhile, the ACC’s flagship meeting, presented together with the World Congress of Cardiology, will continue virtually this year after being forced to cancel its in-person plans at Chicago’s McCormick Place due to the spreading coronavirus pandemic. The large annual confabs of the American Association for Cancer Research and the American Society for Clinical Oncology, among several other medical meetings, have also postponed or gone online.
“As a physician-scientist, if you work for three-and-a-half to four years on a program like this, it’s a little bit of a bummer that you’re not able to present the results face-to-face in front of 15,000 cardiologists,” Koglin said. “But it is what it is—and I’m glad that we can still get the data out. And being able to do so with a simultaneous publication in the New England Journal I think will do the trick.”