FDA Approves Updated Indication for Sotatercept-csrk (WINREVAIR) in Adult PAH

The US Food and Drug Administration (FDA) has approved an updated indication for sotatercept-csrk (WINREVAIR) in adults with pulmonary arterial hypertension (PAH).1

Announced on October 27, 2025, by parent company Merck, the decision is based on results from the phase 3 ZENITH study. This randomized, double-blind, placebo-controlled trial investigated adding sotatercept-csrk to background therapy, which demonstrated a statistically significant and clinically meaningful reduction in major morbidity and mortality outcome risk in adults with PAH World Health Organization (WHO) functional class (FC) III or IV compared to placebo.1

“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,” Vallerie McLaughlin, MD, Kim A. Eagle MD endowed professor of cardiovascular medicine and director of the Pulmonary Hypertension Program at the University of Michigan, said in a statement. “Results from the pivotal ZENITH trial add to the growing body of data and support the potential for WINREVAIR as a standard of care.”1

Sotatercept-csrk is an activin signaling inhibitor, improving the balance between pro- and anti-proliferative signaling to modulate vascular proliferation. It was initially approved to improve exercise capacity and WHO FC and reduce risks of clinical worsening events, based on the pivotal STELLAR study in March 2024. Sotatercept-csrk is the first activin signaling inhibitor therapy approved for PAH.1

The ZENITH trial enrolled 172 patients, who were randomly assigned in a 1:1 ratio to receive either add-on subcutaneous sotatercept at a starting dose of 0.3 mg/kg before escalating to the target dose of 0.7 mg/kg, or placebo every 21 days. Both arms also received stable maximum tolerated doses of double or triple therapy for PAH. Investigators followed up with patients in the sotatercept group for a median of 10.6 months and with the placebo group for a median of 7.1 months.1

To be included in the study, patients were required to be 18-75 years of age, exhibit symptomatic WHO group 1 PAH or WHO FC III or IV, have a REVEAL Lite 2 score of ≥9, be clinically stable and on stable doses of maximum tolerated double or triple background PAH therapy for ≥30 days before screening, and exhibit a pulmonary artery wedge pressure or left ventricular end-diastolic pressure of ≤15 mm Hg, among other factors. Patients were excluded if they had PAH associated with portal hypertension, HIV, pulmonary vein-occlusive disease, pulmonary capillary hemangiomatosis, or LVEF <45%, among others.2

Ultimately, investigators noted a major decrease in composite death from any cause, lung transplantation, or hospitalization for worsening PAH in the sotatercept arm versus placebo. All-cause mortality rates were 8.1% in the sotatercept arm versus 15.1% in placebo. Lung transplantation occurred in 1.2% of patients in the sotatercept arm and 7% in placebo, while PAH-related hospitalizations occurred in 9.3% of the sotatercept arm and 50% of placebo.2

The most common adverse reactions (≥10% for sotatercept and ≥5% more than placebo) were infections (67.4% versus 44.2%), epistaxis (45.3% versus 9.3%), diarrhea (25.6% versus 17.4%), telangiectasia (25.6% versus 3.5%), and increased hemoglobin (15.1% versus 1.2%), among others. Median exposure duration was longer in the sotatercept group (435 days) than in placebo (268 days).1

“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 of global clinical development at Merck Research Laboratories, said in a statement.1

References

1. Merck. US 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. October 27, 2025. Accessed October 27, 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. Maron B. Sotatercept in high-risk patients with pulmonary arterial hypertension. American College of Cardiology. March 31, 2025. Accessed October 27, 2025. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2025/03/28/02/58/zenith/