On October 27, 2025, the U.S. FDA approved an expanded indication for WINREVAIR™ (sotatercept-csrk), Merck’s first-in-class activin signaling inhibitor, for adults with pulmonary arterial hypertension (PAH, WHO Group 1). The update incorporates data from the Phase 3 ZENITH trial and now includes reduction in the risk of clinical worsening events—specifically all-cause death, lung transplantation, and PAH-related hospitalization of ≥24 hours—alongside previously established benefits in exercise capacity and WHO functional class (FC).
The pivotal ZENITH study (NCT04896008) enrolled 172 high-risk PAH patients (74% FC III, 26% FC IV) on maximal background therapy (72% triple therapy, 59% prostacyclin infusion). Randomized 1:1 to WINREVAIR (target dose 0.7 mg/kg subcutaneously every 3 weeks) or placebo, the trial met its primary composite endpoint with a 76% reduction in risk of first major morbidity or mortality event (HR 0.24; 95% CI 0.13–0.43; p<0.0001). Events occurred in 17% (15/86) of WINREVAIR-treated patients versus 55% (47/86) in the placebo arm. Due to this efficacy signal at interim analysis, ZENITH was terminated early, and all patients were offered open-label WINREVAIR.
Originally approved in March 2024 based on the STELLAR trial for exercise capacity and FC improvement, WINREVAIR now carries a broader label reflecting hard outcomes. The drug rebalances vascular proliferation signaling, demonstrating preclinical reversal of right ventricular remodeling and improved hemodynamics. ZENITH reinforces its benefit-risk profile across etiologies (50% idiopathic, 28% connective tissue disease–associated).
Safety remains consistent with prior data. Hemoglobin and platelet monitoring is mandated for at least the first five doses and periodically thereafter due to risks of erythrocytosis (15.1% vs 1.2%) and thrombocytopenia, particularly in patients on prostacyclin infusion. Serious bleeding occurred in 7% of WINREVAIR patients versus 5% on placebo in ZENITH. Common adverse reactions (>5% difference) included infections, epistaxis (45.3%), telangiectasia, diarrhea, and gingival bleeding. Only 1% discontinued WINREVAIR due to adverse events versus 5% on placebo.
Experts, including ZENITH investigator Dr. Vallerie McLaughlin, emphasize that despite optimal standard therapy, PAH mortality remains high; ZENITH data support WINREVAIR as a potential new standard of care. Merck continues long-term follow-up and real-world evidence generation to solidify its role in PAH management.
