ZENITH Trial Findings Could Reshape PAH Treatment, Extending Sotatercept’s Reach

In the phase 3 ZENITH trial, sotatercept (Winrevair; Merck) significantly reduced the risk of death, lung transplantation, or prolonged hospitalization due to worsening pulmonary arterial hypertension (PAH) compared with placebo. The findings were presented at the American College of Cardiology 2025 Annual Scientific Session (ACC.25) by principal investigator Marc Humbert, MD, PhD, dean of the medical school and professor of respiratory medicine at the University Paris-Saclay and Inserm in France, and published simultaneously in The New England Journal of Medicine.

Humbert joined The American Journal of Managed Care^® to discuss the data, which indicated a 76% relative risk reduction in major morbidity and mortality events for patients receiving sotatercept (HR, 0.24; 95% CI, 0.13-0.43; P < .0001), despite being on maximal background therapy. At a median follow-up of 10.6 months, 17.4% of patients on sotatercept experienced serious events, compared with 54.7% in the placebo group.

This transcript was lightly edited; captions were auto-generated.

Transcript

The ZENITH trial was stopped early due to overwhelming efficacy. Can you share the key findings that led to this decision?

It is very important in the ZENITH trial to bear in mind that there was an interim analysis after 59, plus or minus 3, events. Thanks to this interim analysis, it appeared very clear that the primary end point was very much improved on sotatercept as compared to placebo. And based on that and for ethical reasons, the study was terminated. It is really the first time in our field that a phase 3 randomized controlled trial is terminated for efficacy at interim analysis.

Given the success of ZENITH, what are the next steps for sotatercept in terms of regulatory approval and potential clinical use?

It's important to bear in mind that sotatercept is currently approved for PAH, but in some regions, people with advanced PAH are not really in the focus of the label. Thanks to that study, it will certainly be possible to extend the label for patients with advanced PAH and a higher risk of death. Now, there are many studies on sotatercept trying to cover the full landscape of PAH situations, and we know from the first phase 3 trial that this drug is important and improves exercise capacity and delays time to clinical worsening in people with functional class 2 or 3 of PAH. Now we know that it is the case also in people with a high risk of death, and very soon, there will be another study testing sotatercept early in the development of PAH in order to see whether early intervention translates into better outcomes.

Reference

Klein H. Sotatercept reduces risk of death, transplant, or hospitalization in advanced PAH. AJMC. March 31, 2025. Accessed March, 31, 2025. https://www.ajmc.com/view/sotatercept-reduces-risk-of-death-transplant-or-hospitalization-in-advanced-pah