Merck, known as MSD outside of the United States and Canada, today announced the first presentation of results from the Phase 3 ZENITH trial evaluating WINREVAIR™ (sotatercept-csrk) compared to placebo in adults with pulmonary arterial hypertension (PAH, Group 1 PH) WHO* functional class (FC) III or IV at high risk of mortality who were on maximum tolerated background PAH therapy. At a median follow-up of 10.6 months (range, 0.3-26.1), WINREVAIR reduced the relative risk of major morbidity and mortality events (the composite of all-cause death, lung transplantation and PAH worsening-related hospitalization of ≥24 hours) by 76% (HR=0.24 [95% CI, 0.13-0.43]; p<0.0001 [1-sided]) compared to placebo. For patients treated with WINREVAIR, 17.4% (n=15/86) experienced one or more major morbidity and mortality events, compared with 54.7% (n=47/86) of patients in the placebo arm. The safety profile of WINREVAIR in ZENITH was generally consistent with that observed in previous studies.
These results were presented today as a late-breaking oral presentation at the American College of Cardiology’s Annual Scientific Session and Expo (ACC.25) and simultaneously published in the New England Journal of Medicine. These results follow Merck’s announcement in November 2024 that, based on the recommendation of an independent data monitoring committee, the ZENITH study was stopping early due to overwhelming efficacy, and study participants were offered the opportunity to receive WINREVAIR through the SOTERIA open-label extension study.
“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 Dr. Marc Humbert, Department of Respiratory and Intensive Care Medicine Hospital Bicêtre (AP-HP), University Paris-Saclay and Inserm Unit 999. “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 impressive results from ZENITH demonstrated that patients on WINREVAIR had a 76 percent 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. 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.”
Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories
In this trial stopped early due to overwhelming efficacy demonstrated in the primary endpoint, the key secondary endpoint of overall survival did not reach the heightened threshold (p<0.0021) that was required to establish statistical significance at the interim analysis (HR=0.42 [95% CI, 0.17-1.07]; p=0.0313]). Subsequent secondary endpoints showed numerical improvements in the WINREVAIR arm, but were not formally tested due to the prespecified hierarchical testing strategy.
ZENITH is the second Phase 3 study of WINREVAIR to demonstrate efficacy in adults with PAH. The first was the Phase 3 STELLAR trial previously presented at ACC.23. Results from the ZENITH trial will be shared with regulatory authorities around the world. WINREVAIR is currently approved in more than 40 countries based on the results from the STELLAR trial.
Merck announced in January 2025 that the Phase 3 HYPERION study evaluating WINREVAIR when added to background PAH therapy in newly diagnosed patients with PAH FC II or III at intermediate or high risk of disease progression was stopping early and moving directly to final analysis. The decision to stop the HYPERION study prior to its scheduled completion and offer patients the opportunity to receive WINREVAIR through the SOTERIA open-label extension study was based on the positive results from the interim analysis of the ZENITH trial and a review of the totality of data from the WINREVAIR clinical program to date. Findings from the HYPERION study will be available later this year and presented at a future medical congress.
Study design and additional data from the ZENITH trial
The ZENITH trial (NCT04896008) is a pivotal Phase 3 multicenter, double-blind, placebo-controlled trial evaluating WINREVAIR versus placebo for the treatment of adult patients with WHO FC III or IV PAH at high risk of mortality who were on maximum tolerated background PAH 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.
The trial enrolled 172 participants receiving the maximum tolerated background PAH therapy, who were randomized in a 1:1 ratio to receive either WINREVAIR (n=86) once every 3 weeks at a dose of 0.3 mg/kg at visit 1 and a dose of 0.7 mg/kg thereafter or placebo (n=86). The study population characteristics were: mean [±SD] 54.4 ± 14.3 years of age; 87% white; and 77% female. 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. Additionally, 25.6% of patients in the WINREVAIR arm and 30.2% in the placebo arm had PAH associated with connective-tissue disease. Demographic and baseline characteristics were similar between the WINREVAIR and placebo groups.
When examined as standalone outcomes, each component of the primary composite endpoint was directionally consistent with the overall treatment effect. There were seven deaths in the WINREVAIR arm (8.1%) compared with 13 in the placebo arm (15.1%); lung transplantation occurred in one patient treated with WINREVAIR (1.2%) compared to six patients treated with placebo (7.0%); and hospitalizations for PAH occurred in eight patients in the WINREVAIR arm (9.0%) compared to 43 patients in the placebo group (50.0%). Individual patients could experience one or more component.
The safety profile of WINREVAIR was generally consistent with that observed in previous studies. In the ZENITH trial, no patients treated with WINREVAIR discontinued treatment due to an adverse event. Serious adverse events occurred in 53.5% of patients treated with WINREVAIR versus 64.0% in the placebo arm. Treatment-related adverse events (TRAEs) occurred in 65.1% of patients who received WINREVAIR versus 32.6% of patients who received placebo, and serious TRAEs were observed in 3.5% versus 2.3% of patients, respectively. Bleeding events occurred in 62.8% of patients treated with WINREVAIR versus 34.9% treated with placebo (mostly non-serious epistaxis and gingival bleeding). There was a 1.1% difference in the risk of serious bleeding events (5.8% versus 4.7%, respectively), which were similar between treatment groups. 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. Adverse events that occurred more frequently with WINREVAIR versus placebo were cutaneous telangiectasia (25.6% versus 3.5%), increased hemoglobin (12.8% versus 1.2%) and thrombocytopenia (14% versus 8.1%).
All participants who have completed the ZENITH trial were offered the opportunity to receive WINREVAIR as part of the open-label, long-term extension trial, SOTERIA (NCT04796337), consistent with that trial’s eligibility criteria.
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