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
WINREVAIR significantly reduced the risk of major morbidity and mortality events, the primary endpoint, in adults with PAH (Group 1 PH) WHO* functional class (FC) III or IV at high risk of mortality who are on maximum tolerated background PAH therapy
ZENITH results presented today at ACC.25 as a late-breaking oral presentation and simultaneously published in the New England Journal of Medicine
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,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “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.”
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 [
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;
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 (
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
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.
About WINREVAIR™ (sotatercept-csrk) for injection, for subcutaneous use, 45 mg, 60 mg
WINREVAIR is FDA-approved for the treatment of adults with pulmonary arterial hypertension (PAH, WHO Group 1) to increase exercise capacity, improve WHO functional class (FC) and reduce the risk of clinical worsening events. WINREVAIR is the first activin signaling inhibitor therapy approved to treat PAH. WINREVAIR improves the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation. In preclinical models, WINREVAIR induced cellular changes that were associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.
WINREVAIR is the subject of a licensing agreement with Bristol Myers Squibb.
Selected Safety Information for WINREVAIR in the
WINREVAIR may increase hemoglobin (Hgb). Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required.
WINREVAIR may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. Thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Do not initiate treatment if platelet count is <50,000/mm3. Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine whether dose adjustments are required.
In clinical studies, serious bleeding (e.g., gastrointestinal, intracranial hemorrhage) was reported in
WINREVAIR may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with WINREVAIR and for at least 4 months after the final dose. Pregnancy testing is recommended for females of reproductive potential before starting WINREVAIR treatment.
Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertility.
The most common adverse reactions occurring in the phase 3 clinical trial (≥
Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with WINREVAIR, and for 4 months after the final dose.
About PAH
Pulmonary arterial hypertension (PAH) is a rare, progressive and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation. Approximately 40,000 people in the
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Please see Prescribing Information for WINREVAIR (sotatercept-csrk) at http://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_pi.pdf, Patient Information for WINREVAIR at http://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_ppi.pdf, and Instructions for Use for WINREVAIR (1-vial kit, 2-vial kit) at https://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_ifu_1-vial_2-vial_kits.pdf.
*World Health Organization |
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