FDA Expands Sotatercept Indication for PAH: A Closer Look at Clinical Impacts

The U.S. Food and Drug Administration (FDA) has approved an expanded indication for WINREVAIR™ (sotatercept-csrk), offering new hope for adults with pulmonary arterial hypertension (PAH, WHO Group 1) at high risk for clinical worsening. The update, announced by Merck in October 2025, incorporates findings from the Phase 3 ZENITH trial, which demonstrated substantial reductions in hospitalization, lung transplantation, and death when WINREVAIR was added to standard PAH therapies.

Already approved in March 2024 based on the pivotal STELLAR study, WINREVAIR now formally carries a U.S. label that recognizes its ability not only to improve exercise capacity and WHO functional class (FC) but also to reduce the risk of major morbidity and mortality events in this patient population.

The ZENITH study, which randomized 172 adults with WHO FC III or IV PAH to either WINREVAIR or placebo alongside background therapy, was stopped early due to overwhelming efficacy. Patients receiving WINREVAIR experienced a 76% reduction in the risk of key clinical worsening events compared to placebo (hazard ratio 0.24; 95% CI: 0.13–0.43; p<0.0001). The composite endpoint included all-cause death, lung transplantation, or hospitalization for PAH lasting ≥24 hours.

Only 17% of patients on WINREVAIR experienced such events, compared to 55% in the placebo group. These numbers mark a dramatic clinical improvement in a disease known for its progressive and life-threatening course, even in patients receiving multi-drug regimens.

WINREVAIR represents a first-in-class therapy targeting activin signaling, a key regulatory pathway implicated in the abnormal vascular remodeling that drives PAH. By rebalancing pro- and anti-proliferative signaling in the pulmonary vasculature, sotatercept helps reduce vascular thickening, improve right ventricular function, and modulate hemodynamics—effects observed in both preclinical and clinical studies.

Patients in ZENITH were already on background PAH therapy, including 72% on triple therapy and 59% receiving prostacyclin infusion. The median time from diagnosis to enrollment was eight years, highlighting the real-world relevance of the study’s findings. Participants had varied PAH etiologies, including idiopathic (50%), connective tissue disease-associated (28%), and heritable PAH (11%).

While WINREVAIR offers substantial benefit, its use is not without risk. The most common adverse events in ZENITH included infections (67%), epistaxis (45%), diarrhea (26%), and telangiectasia (26%). WINREVAIR is associated with increases in hemoglobin and decreases in platelet count, raising concerns for thromboembolic complications or severe bleeding, particularly in patients also receiving prostacyclin therapy or anticoagulants.

As a result, the FDA recommends monitoring hemoglobin and platelet levels before each of the first five doses—or longer if values are unstable—and periodically thereafter. Treatment should not begin if platelet counts are below 50,000/mm³, and clinicians are advised to withhold therapy in the event of serious bleeding. Additionally, WINREVAIR carries warnings related to embryo-fetal toxicity and potential fertility impairment, with recommendations for pregnancy testing, contraception use, and breastfeeding cessation during and after therapy.

For a condition that remains incurable and often fatal, WINREVAIR’s expanded label marks a pivotal moment in PAH treatment. The ZENITH data solidify its role not just as a supportive agent to improve symptoms but as a disease-modifying therapy capable of altering the course of progression.

As the first activin signaling inhibitor approved for PAH, WINREVAIR’s continued evaluation in long-term follow-up studies and broader patient populations will help define its place in treatment algorithms. For now, it stands as one of the most consequential advances for patients with advanced PAH in recent memory—a welcome shift in the trajectory of a devastating disease.