FDA Expands Approval of Sotatercept-Csrk for Pulmonary Arterial Hypertension

The FDA approved an update to the product label for sotatercept-csrk (Winrevair; Merck), a 45 mg and 60 mg injection for the treatment of adults with pulmonary arterial hypertension (PAH) to improve exercise capacity and World Health Organization (WHO) functional class (FC). The expanded approval of the activin-signaling inhibitor is aimed at reducing the risk of clinical worsening events, such as hospitalization for PAH, lung transplantation, and death, based on results from the phase 3 ZENITH trial (NCT04896008).^1,2

“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 in Ann Arbor, and investigator in the ZENITH study, said in a news release. “Results from the pivotal ZENITH trial add to the growing body of data and support the potential for [sotatercept] as standard of care.”¹

What is PAH?

PAH is a broader condition of pulmonary hypertension, which is high blood pressure in the lungs. Individuals with PAH experience increased pressure in the vessels caused by obstruction in the small arteries in the lungs, along with other reasons, according to the American Lung Association. Symptoms may not be present in the early stages of the disease but could later develop as the condition progresses. The most common symptoms include increased shortness of breath, fatigue, edema, dizziness and fainting spells, chest pain, heart palpitations, and lips and fingers turning blue. Currently, there is no cure for PAH, but treatment can be used to slow the progression of the disease.³

Understanding Sotatercept-Csrk for PAH

Sotatercept is marked as the first activin signaling inhibitor approved for PAH treatment. The injection works by restoring balance between pro- and anti-proliferative signaling to regulate vascular proliferation. In preclinical studies, the investigators noted that it led to thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.¹

The FDA previously approved sotatercept in March 2024 for the treatment of PAH based on the phase 3 STELLAR trial (NCT04576988), which evaluated the efficacy and safety of the drug compared with placebo in combination with background standard-of-care therapies at 24 weeks. Results demonstrated that sotatercept combined with background therapy increased the 6-minute walking distance by 41 meters at week 24. The combination also significantly improved key secondary outcomes, reducing the risk of death and clinical worsening events by about 84% compared with background therapy alone.^4,5

ZENITH Clinical Trial Data Supporting Sotatercept’s Expanded Indication

A total of 172 adult participants with PAH were included in the global, double-blind, placebo-controlled, multicenter, parallel-group ZENITH clinical trial, which assessed sotatercept compared to placebo in reducing the risk of clinical worsening events among adults at high risk of mortality.¹

Participants were randomly assigned at a 1:1 ratio to receive a target dose of 0.7 mg of sotatercept plus background PAH therapy or placebo plus background PAH therapy, subcutaneously once every 3 weeks. The results demonstrated that adding sotatercept to background therapy significantly reduced the risk of major morbidity and mortality by 76% in adults with PAH WHO FC 3 or 4 compared to placebo (HR: 0.24; 95% CI: 0.13, 0.43; p<0.0001). Primary end point events, including death, lung transplantation, or OAH-related hospitalizations, occurred in 17% of sotatercept-treated patients compared to 55% of patients receiving placebo.¹

The most common adverse events with sotatercept included infections, epistaxis, diarrhea, telangiectasia, increased hemoglobin, rash, erythema, and gingival.¹

The study authors noted that the trial was stopped early due to sotatercept’s significant efficacy, and patients were offered to receive the treatment in an open-label extension study.¹

“This approval represents another step forward in our mission to deliver on the promise of [sotatercept], 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, and an investigator in the ZENITH study, said in a news 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. 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. A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/​ZENITH) (ZENITH). National Library of Medicine. Updated August 22, 2025. October 27, 2025. https://clinicaltrials.gov/study/NCT04896008

3. Treating and Managing PAH. American Lung Association. Updated August 1, 2025. Accessed October 27, 2025. https://www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-arterial-hypertension/treating-and-managing

4. A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/​A011-11)(STELLAR). National Library of Medicine. Updated September 19, 2024. Accessed October 27, 2025. https://www.clinicaltrials.gov/study/NCT04576988

5. Gallagher A. FDA Approves Sotatercept-csrk for Pulmonary Arterial Hypertension. March 27, 2024. Accessed October 27, 2025. https://www.pharmacytimes.com/view/fda-approves-sotatercept-csrk-for-pulmonary-arterial-hypertension