Winrevair Found to Significantly Reduce the Risk of Morbidity and Mortality in Patients with Pulmonary Arterial Hypertension

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Results from the Phase III ZENITH trial show that Merck’s Winrevair (sotatercept-csrk) significantly reduced the risk of major morbidity and mortality events in patients with pulmonary arterial hypertension (PAH, Group 1 PH) World Health Organization functional class (FC) III or IV at high risk of mortality who were on maximum tolerated background PAH therapy. Full data from the study were presented at the American College of Cardiology's (ACC) Annual Scientific Session and Expo and simultaneously published in the New England Journal of Medicine.¹

“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, department of respiratory and intensive care medicine Hospital Bicêtre (AP-HP), University Paris-Saclay and Inserm Unit 999, in a press release. “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.”

The multicenter, double-blind, placebo-controlled ZENITH trial evaluated 172 patients with WHO FC III or IV PAH at high risk of mortality who were on maximum tolerated background PAH therapy. Patients were randomized 1:1 to receive Winrevair, administered every three weeks starting at 0.3 mg/kg and increasing to 0.7 mg/kg, or placebo. The primary endpoint of the study was time to first confirmed morbidity or mortality event, with events defined as all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours. Secondary endpoints included overall survival (OS), transplant-free survival, and several additional measures.

Compared to the placebo, Winrevair lowered the risk of all-cause death, lung transplantation, and PAH-related hospitalization by 76% (HR=0.24; p<0.0001). Only 17.4% of patients in the Winrevair arm experienced a morbidity or mortality event, compared to 54.7% in the placebo group. Merck noted that due to overwhelming efficacy, the trial was stopped early and participants were transitioned to the SOTERIA open-label extension study.

The safety profile of Winrevair was reported to be consistent with data from previous studies. Serious adverse events (AEs) were reported in 53.5% of patients in the WINREVAIR™ group and 64% of patients in the placebo group. Additionally, treatment-related AEs were reported in 65.1% of patients in the Winrevair group and 32.6% of patients in the placebo group. Seven deaths occurred in the Winrevair group, compared to 13 in the placebo group. Common AEs associated with Winrevair were cutaneous telangiectasia, increased hemoglobin, and thrombocytopenia.

In January, Merck announced that due to the overwhelmingly positive results from the ZENITH trial, it was halting the Phase III HYPERION trial. The company stated that stopping the trial early would allow patients continued access to the treatment.²

“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,” said Eliav Barr, SVP, head of global clinical development, chief medical officer, Merck Research Laboratories, in the press release. “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.”

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. Merck. 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/
2. Merck Announces Decision to Stop Phase 3 HYPERION Trial Evaluating WINREVAIR™ (sotatercept-csrk) Early and Move to Final Analysis. Merck. January 30, 2025. Accessed April 1, 2025. https://www.merck.com/news/merck-announces-decision-to-stop-phase-3-hyperion-trial-evaluating-winrevair-sotatercept-csrk-early-and-move-to-final-analysis/