FDA Expands Indication for Merck’s Winrevair in Pulmonary Arterial Hypertension

The FDA has approved an expanded indication for Merck’s Winrevair (sotatercept-csrk) in the treatment of pulmonary arterial hypertension (PAH).¹

Winrevair Found to Lower Risk of Clinical Worsening Events in Pulmonary Arterial Hypertension

The regulatory action, based on findings from the Phase III ZENITH trial (NCT04896008),² updates the label to include evidence that adding Winrevair to background therapy lowers the risk of clinical worsening events such as hospitalization, lung transplantation, and death in adults with PAH.

“For patients with PAH, the risk of serious events such as hospitalization, transplantation or death remains unacceptably high despite being maximally treated with traditional therapies,” Zenith trial investigator Vallerie McLaughlin, MD, Kim A Eagle MD Endowed Professor of Cardiovascular Medicine and director, Pulmonary Hypertension Program, University of Michigan in Ann Arbor, said in a press release. “Results from the pivotal ZENITH trial add to the growing body of data and support the potential for Winrevair as standard of care.”¹

Previous FDA Approval and Clinical Development of Winrevair

• Winrevair is an activin-signaling inhibitor that attaches to activin A and other TGF-β superfamily ligands, which has been found to improve the balance between antiproliferative and proproliferative signaling to alter vascular proliferation.
• In turn, this action lowers inflammation and inhibits the proliferation of endothelial and smooth muscle cells in diseased vasculature, leading to thinner vessel walls, a partial reversal of right ventricular remodeling, and improved hemodynamics.³
• The FDA approved Winrevair in March 2024 for adults with PAH, marking the first activin signaling inhibitor therapy to gain approval for the treatment of PAH.⁴
• The approval was based on findings from the Phase III STELLAR trial (NCT04576988), in which Winrevair was found to increase six-minute walking distance from baseline by 41 meters at week 24, with an 84% reduction in the risk of death and potential worsening of the condition.⁵

Trial Design and Efficacy Outcomes From ZENITH

• The global, double-blind, placebo-controlled, multicenter, parallel-group ZENITH trial enrolled 172 adult patients with PAH WHO functional class (FC)III or IV who have an elevated risk of mortality.
• Patients were randomly assigned in a 1:1 ratio to receive Winrevair at a target dose of 0.7 mg/kg (n=86) plus background PAH treatment or placebo (n=86) plus background PAH treatment administered administered subcutaneously once every three weeks.
• The trial’s primary efficacy endpoint was time to first confirmed major morbidity or mortality event, defined as all-cause death, lung transplantation, or hospitalization due to worsening of PAH for ≥24 hours.

Phase III ZENITH Trial Shows 76% Reduction in Major Morbidity and Mortality

• Results demonstrated a statistically significant and clinically meaningful 76% decrease in the risk of major morbidity and mortality outcomes in adults with PAH WHO FC III or IV vs. placebo (HR: 0.24; 95% CI: 0.13, 0.43; p<0.0001).
• Composite primary efficacy endpoint events were reported in 15 patients administered Winrevair (17%) compared to 47 patients in the placebo cohort (55%).
• Based on efficacy findings for the primary endpoint, investigators stopped the ZENITH trial early at the interim analysis, with patients given the chance to receive Winrevair as part of an open-label long-term follow-up study.

“This approval represents another step forward in our mission to deliver on the promise of Winrevair, an activin signaling inhibitor with an indication recognizing its impact to adult patients with PAH on the risk of clinical worsening events, including death, lung transplantation and PAH hospitalization,” Joerg Koglin, MD, senior vice president, global clinical development, Merck Research Laboratories, said in the press release.¹

References

1. U.S. FDA Approves Updated Indication for WINREVAIR™ (sotatercept-csrk) in Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1 Pulmonary Hypertension) Based on Phase 3 ZENITH Study. Merck. News release. October 27, 2025. Accessed October 28, 2025. https://www.merck.com/news/u-s-fda-approves-updated-indication-for-winrevair-sotatercept-csrk-in-adults-with-pulmonary-arterial-hypertension-pah-who-group-1-pulmonary-hypertension-based-on-phase-3-zenith-study/

2. A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/​ZENITH) (ZENITH). ClinicalTrials.gov. Updated August 22, 2025. Accessed October 28, 2025. https://clinicaltrials.gov/study/NCT04896008

3. Winrevair. Prescribing information. Merck & Co, Inc; 2024. Accessed October 28, 2025. https://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_pi.pdf

4. FDA Approves Merck’s WINREVAIR™ (sotatercept-csrk), a First-in-Class Treatment for Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1). Merck. March 26, 2024. Accessed October 28, 2025. https://www.merck.com/news/fda-approves-mercks-winrevair-sotatercept-csrk-a-first-in-class-treatment-for-adults-with-pulmonary-arterial-hypertension-pah-who-group-1/

5. A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/​A011-11)(STELLAR). ClinicalTrials.gov. Updated September 19, 2024. Accessed October 28, 2025. https://clinicaltrials.gov/study/NCT04576988