Sotatercept Reduces Risk of Major Morbidity, Mortality for Pulmonary Arterial Hypertension

Sotatercept-csrk (Winrevair) reduced the relative risk of major morbidity and mortality events for patients with pulmonary arterial hypertension (PAH) at high risk of mortality. The results were presented as a late-breaking oral presentation at the American College of Cardiology’s Annual Scientific Session and Expo 2025.¹

Patients with pulmonary arterial hypertension (PAH) received the maximum tolerated dose of background therapy with sotatercept or the placebo to the therapy. | Image Credit: Uladzislau - stock.adobe.com

“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,” Marc Humbert, MD, PhD, professor in the department of respiratory and intensive care medicine at the University Paris-Saclay, said in a news release.¹ “Winrevair had a significant and clinically meaningful impact on the composite of these outcomes, and together with the growing body of evidence from the clinical development program, these data support the practice-changing potential of Winrevair for a broad range of patients with PAH.”

In the phase 3 trial, investigators included patients who were receiving the maximum tolerated dose of background therapy and added sotatercept or the placebo to the therapy every 3 weeks. Patients were excluded if they had pulmonary hypertension WHO groups 2, 3, 4, or 5, a baseline systolic blood pressure of less than 85 mmHg at screening, and a history of restrictive or congestive cardiomyopathy. The primary end point included composite death from any cause, lung transplantation, or hospitalization for 24 or more hours for worsening PAH. Secondary end points included overall survival (OS) up to 31 months, transplant-free survival up to 31 months, percentage of patients who experienced a mortality event up to 31 months, percentage of participants who improved in WHO functional class up to 31 months, change from baseline in mean pulmonary artery pressure at week 24, change from baseline in cardiac output at week 24, and change in EuroQoL-5 Dimensions Scale 5 Levels index score at week 24.^2,3

At a median follow-up of 10.6 months, investigators found that the primary end point was reduced by 76% for patients on sotatercept compared with the placebo. Furthermore, 17.4% of patients treated with sotatercept experienced 1 or more major morbidity and mortality events compared with 54.7% in the placebo group. Because the trial was discontinued early due to overwhelming efficacy, the key secondary end point of OS was not reached.¹

“The impressive results from ZENITH demonstrated that patients on Winrevair had a 76% risk reduction in the composite of all-cause death, lung transplantation, and hospitalization for PAH compared to placebo, with improvement observed early in treatment and increasing benefit throughout the study,” Eliav Barr, MD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, said in the news release.¹ “These results led to the ZENITH study being the first PAH clinical trial stopped early due to overwhelming efficacy, representing an important milestone in clinical research with promise for the PAH community.”

The full results were published in the New England Journal of Medicine.³

REFERENCES

1. 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 in the phase 3 ZENITH trial. News release. March 31, 2025. Accessed April 1, 2025. https://www.businesswire.com/news/home/20250331242477/en/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-in-the-Phase-3-ZENITH-Trial

2. A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/​ZENITH) (ZENITH). ClinicalTrials.gov identification: NCT04896008. Updated March 25, 2025. Accessed April 1, 2025. https://clinicaltrials.gov/study/NCT04896008

3. Humbert M, McLaughlin VV, Badesch DB, et al. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. N Engl J Med. Published online March 31, 2025. doi:10.1056/NEJMoa2415160