ZENITH Shows Sotatercept Reduces Mortality, Transplant Risk in PAH, with Vallerie Mclaughlin, MD

Sotatercept could be a life-saving therapy for high-risk patients with pulmonary arterial hypertension (PAH), according to the ZENITH trial.

Approved in 2024 based on the STELLAR trial, which demonstrated its effects on exercise capacity, the ZENITH trial details statistically significant 76% reduction in relative risk for the primary outcome of all-cause mortality, lung transplantation, or hospitalization for worsening PAH.

“The ZENITH study represents the first PAH clinical trial with a primary endpoint comprised entirely of major outcome measures – all-cause death, lung transplantation and hospitalization for PAH,” said Marc Humbert, MD, PhD, Department of Respiratory and Intensive Care Medicine Hospital Bicêtre (AP-HP), University Paris-Saclay and Inserm Unit 999.

Presented at the American College of Cardiology (ACC) 2025 Annual Scientific Sessions, the phase 3 ZENITH trial evaluated the efficacy of sotatercept as an add-on therapy for patients with PAH at high risk of death. Per trial protocol, all 172 participants were receiving the maximum tolerated dose of background therapy and were randomly assigned to receive sotatercept at starting dose of 0.3 mg/kg that was escalated to 0.7 mg/kg or placebo every 3 weeks.

The primary outcome of interest was a composite of all-cause mortality, lung transplantation, or hospitalization for worsening PAH, assessed using a time-to-first-event analysis. The trial was terminated early due to the efficacy findings from a prespecified interim analysis.

Data from ACC.25 suggested at least 1 primary endpoint event occurred among 17.4% of patients in the sotatercept group compared to 54.7% among the placebo group (Hazard Ratio [HR], 0.24; 95% CI, 0.13 to 0.43; P <.001). When examining individual components of the outcome, investigators found death from any cause was reported in 8.1% of the sotatercept group and 15.1% of the placebo group (HR, 0.42; 95% CI, 0.17 to 1.07). Investigators noted this did not meet the criterion for significance at the interim analysis, which had a required P value less than .0021, and was not tested in subsequent secondary outcomes.

Investigators also pointed out use of sotatercept was associated with a reduction in risk for lung transplantation (1.2% and 7.0%; HR, 0.34; 95% CI, 0.15 to 0.78) and hospitalization for worsening PAH (9.3% vs. 50.0%).

For more on these results and how they inform the potential of sotatercept, check out our interview from ACC.25 with study investigator Vallerie McLaughlin, MD, professor of medicine and director of the Pulmonary Hypertension Program in the Division of Cardiovascular Medicine at the University of Michigan.

Relevant disclosures for McLaughlin include Bayer, Merck, Janssen Pharmaceuticals, Corvista, and others.

References:

Humbert M, McLaughlin VL, Badesch DB. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. New England Journal of Medicine. Published online March 31, 2025. doi: 10.1056/NEJMoa2415160

Merck. WINREVAIR^TM (sotatercept-csrk) Reduced the Risk of a Composite of All-Cause Death, Lung Transplantation and Hospitalization for Pulmonary Arterial Hypertension (PAH) by 76% Compared to Placebo in the Phase 3 ZENITH Trial - Merck.com. Merck.com. Published March 31, 2025. Accessed April 1, 2025. https://www.merck.com/news/winrevair-sotatercept-csrk-reduced-the-risk-of-a-composite-of-all-cause-death-lung-transplantation-and-hospitalization-for-pulmonary-arterial-hypertension-pah-by-76-compared-to-placebo-i.