Winrevair Reduced Risk of Morbidity and Mortality by 76% in PAH | ACC 2025

Winrevair (sotatercept-csrk) reduced the risk of major morbidity and mortality events in patients with pulmonary arterial hypertension (PAH) by 76% in the phase 3 ZENITH trial. The study found that for patients treated with Winrevair, 17.4% (15 of 86) experienced one or more major morbidity and mortality events, compared with 54.7% (47 of 86) of patients in the placebo arm.

The results were presented today at a late-breaking session at the American College of Cardiology Annual Scientific Session and Expo. The findings were simultaneously published in The New England Journal of Medicine.

Mahesh Patel, M.D.

“These results demonstrated efficacy early in treatment for patients receiving Winrevair, with an increasing benefit throughout the study,” Mahesh Patel, M.D., vice president, global clinical development, Merck Research Laboratories, told Managed Healthcare Executive. “These results, together with the growing body of evidence from the PAH clinical development program, support the practice-changing potential of Winrevair for a broad range of patients with PAH.”

Pulmonary arterial hypertension is a rare, progressive, and life-threatening disease in which blood vessels in the lungs narrow, causing strain on the heart. About 40,000 people in the United States are living with pulmonary arterial hypertension. The five-year mortality rate is about 43%.

Developed by Merck, Winrevair works by inducing cellular changes that are associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.

Winrevair is currently approved in the United States and 40 countries to treat pulmonary arterial hypertension and to reduce the risk of clinical worsening events. In preclinical models, Winrevair induced cellular changes that were associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics. The FDA approved Winrevair in March 2024, and it has a list price of $14,420 per vial.

Winrevair was approved based on 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 ZENITH Trial

In the phase 3 ZENITH trial, 172 patients with more advanced disease were enrolled and randomized to receive either Winrevair or placebo added to current treatment. In total, 124 of the randomized patients (72.1%) were receiving triple therapy and 48 patients (27.9%) were receiving double therapy; 102 patients (59.3%) were receiving prostacyclin infusion therapy.

The primary outcome measure 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 outcome measures include overall survival, transplant-free survival and several additional measures. Patel said that in this trial, the first secondary endpoint of overall survival did not reach the heightened threshold that was required to establish statistical significance at the interim analysis. The ZENITH study included a hierarchical testing strategy, which required that the secondary endpoints be tested in a pre-specified, sequential order.

“The ZENITH trial was designed to investigate the impact of Winrevair in adult patients with WHO FC III or IV pulmonary arterial hypertension at a high risk of mortality. All-cause death, lung transplantation and hospitalization for PAH were chosen as the primary endpoint because they reflect major morbidity and mortality event outcome measures,” Patel said.

The ZENITH trial was stopped early because an interim analysis found that adding Winrevair to background therapy led to a statistically significant and clinically meaningful reduction in morbidity and mortality risk compared with placebo.

No patients treated with Winrevair discontinued treatment due to an adverse event. Treatment-related adverse events (TRAEs) occurred in 65.1% of patients who received Winrevair versus 32.6% of patients who received placebo, and severe TRAEs were observed in 3.5% of the Winrevair group. Adverse events leading to death occurred in five patients (5.8%) in the Winrevair treatment group and 12 patients (14.0%) in the placebo group.

Lung transplantation occurred in one patient treated with Winrevair (1.2%) compared with six patients treated with placebo (7.0%); and hospitalizations for PAH occurred in eight patients in the Winrevair arm (9.0%) compared with 43 patients in the placebo group (50.0%).

The HYPERION Study

In February 2025, it stopped a second study of Winrevair early because of positive results seen in an interim analysis of a separate trial. The phase 3 HYPERION study because an interim analysis of the ZENITH trial and a review of the totality of data from Winrevair, the clinical program to date, showed positive efficacy results, Merck officials said in a news release.

Related: Another Trial of Winrevair Stopped Early Due to Positive Efficacy

Patel said the HYPERION trial used different endpoints because the patients enrolled were newly diagnosed. “This study used time to clinical worsening (TTCW) as measured by the first confirmed morbidity or mortality event as the primary endpoint because this study was evaluating Winrevair plus background therapy in recently diagnosed adults with PAH at intermediate or high risk of disease progression,” he said. “Since these were newly diagnosed patients at a relatively lower risk of mortality, the primary endpoint was different than that of ZENITH.”

Patel said findings from the HYPERION study will be available later this year at a future medical congress.