Winrevair Advanced PAH Trial Stopped Early Due to ‘Overwhelming’ Efficacy

Merck’s new pulmonary arterial hypertension (PAH) medication has posted another batch of promising clinical trial data, bolstering the company’s case that its first-in-class therapy ought to become a major part of the treatment of the debilitating disease.

The company announced late last month that an interim analysis of its phase 3 ZENITH trial of Winrevair (sotatercept) yielded such positive results that the company will stop the placebo-controlled study early and allow all participants access to the medication. The new data add to the evidence that the first-ever activin-signaling inhibitor approved to treat PAH can make a meaningful difference in the lives of people with the disease.

Winrevair was approved by the FDA in March 2024 on the strength of the phase 3 STELLAR trial, in which adults with functional class II or III PAH saw a 41-meter improvement in 6-minute walking distance after 24 weeks of adding sotatercept to background therapy. Trial participants who received Winrevair also saw an 84% reduction in the risk of all-cause death or clinical PAH worsening.

The new study looked specifically at patients with more advanced disease. The researchers randomly assigned 172 patients with functional class III or IV PAH were randomized on a 1:1 basis to receive Winrevair or placebo in addition to background therapy. Participants were also required to score at least 9 on the Registry to Evaluate Early and Long-Term PAH Disease Management(REVEAL) Lite 2.0 risk scale. Such a score indicates high-risk disease.

The primary end point of the trial was the composite outcome measure of time to first confirmed morbidity or mortality event. Qualifying events could include death, lung transplantation, or a hospitalization lasting at least 24 hours and related to PAH worsening.

In the interim analysis, investigators found that adding Winrevair to background therapy led to a statistically significant and clinically meaningful reduction in morbidity and mortality risk compared with placebo. The data prompted an independent data monitoring committee to recommend stopping the trial so all participants could have the opportunity to receive Winrevair as part of the SOTERIA open-label extension study.

Vallerie McLaughlin, M.D.

“This is the first study in PAH in which the interim analysis led to an early conclusion of the study due to overwhelming efficacy,” said Vallerie McLaughlin, M.D., a ZENITH investigator and the director of the pulmonary hypertension program at the University of Michigan, in a press release.

“Winrevair has brought significant optimism to the field, and we thank the investigators and patients for being part of this important study,” McLaughlin said.

The current FDA approval for Winrevair does not restrict access to the drug based on functional class. According to the approval, the therapy is indicated for patients with PAH to increase exercise capacity, improve functional class and reduce the risk of clinical worsening events. A company spokesperson said they plan to submit the ZENITH data to the FDA to evaluate whether this additional clinical evidence supports an expansion of the drug’s indication.

Winrevair works by improving the balance between pro- and anti-proliferative signaling to modulate vascular proliferation, the company explained. In preclinical models, Merck said the therapy induced cellular changes that were associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.

The most common adverse events in the phase 3 trial were headache (24.5%), nosebleeds (22.1%), and rash (20.2%).

Following its FDA approval in March, the therapy has quickly earned similar approvals in 36 countries, including in the European Union. The company said it submitted an application for approval in Japan last month.

Eliav Barr, M.D., Merck’s senior vice president and head of global clinical development, emphasized in the press release that PAH is a progressive disease that comes with a high incidence of morbidity and mortality. He said the ZENITH results underscore the therapy’s “overwhelming efficacy.”

“These findings are impressive, and set a high evidentiary bar for studies of future candidates developed for the treatment of PAH and support the potential of Winrevair to be practice-changing for the management of PAH,” he said.