FDA Expands Sotatercept Indication for PAH

To improve exercise capacity and World Health Organization (WHO) functional class (FC) and to reduce the risk of clinical worsening events in adults who have pulmonary arterial hypertension (PAH) are now included as approved indications for sotatercept-csrk (Winrevair; Merck), following the FDA’s decision to expand the activin signaling inhibitor’s US product label.¹ The expansion approval is notable for the inclusion of the clinical worsening events, which encompass hospitalization for PAH, lung transplantation, and death.

The injectable therapy is available in doses of 45 mg and 60 mg.

Preceded by a priority review in September 2023, as well as breakthrough and orphan drug designations, sotatercept was first approved by the FDA in March 2024, based on results from the STELLAR trial (NCT04576988).² It was approved by the European Commission in September 2024.³

This newest approval incorporated data from the phase 3 ZENITH trial (NCT04896008), a global, double-blind, placebo-controlled, multicenter, parallel-group clinical analysis of outcomes in 172 adult patients with WHO FC class III (74%) or IV (26%) disease, considered high risk, and who were randomized to either sotatercept plus background PAH therapy (n = 86) or placebo plus background PAH therapy (n = 86). The target dose of sotatercept was 0.7 mg/kg, and treatment for both groups was every 3 weeks. Background PAH therapy consisted of triple therapy in 72%, double therapy in 28%, and prostacyclin infusion in 59%.

The most common PAH etiologies were idiopathic in 50%, associated with connective tissue diseases in 28%, and heritable in 11%. Patients had a mean 8-year gap between diagnosis and study screening, and they were excluded if living with HIV-associated PAH, PAH associated with portal hypertension, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement.

ZENITH was stopped early, in November 2024,⁴ following the release of data showing overwhelming efficacy. Following this move, patients could subsequently receive sotatercept through an open-label long-term follow-up study.

As a background add-on therapy, sotatercept reduced the risk of the primary end point of major morbidity and mortality outcomes by 76% vs placebo (HR, 0.24; 95% CI, 0.13-0.43; P < .0001). Events of all-cause death, lung transplantation, or PAH-worsening hospitalization of 24 hours or more—the ZENITH trial’s composite primary efficacy end point of time to first occurrence—occurred in only 17% of treated patients compared with 55% who received placebo.

Considered a common adverse reaction if seen in 10% or more of treated patients (median exposure, 435 days) and at least 5% of patients who received placebo (median exposure, 268 days), infections (67.4% vs 44.2%, respectively), epistaxis (45.3% vs 9.3%), diarrhea (25.6% vs 17.4%), telangiectasia (25.6% vs 3.5%), increased hemoglobin (15.1% vs 1.2%), rash (10.5% vs 4.7%), erythema (10.5% vs 3.5%), and gingival bleeding (10.5% vs 2.3%) were noted.

For the first 5 doses of sotatercept, monitoring recommendations are for hemoglobin and platelet counts before each dose, but longer if these demonstrate instability. Periodic monitoring is also suggested for potential dose adjustments. There is a risk of hemoglobin increasing and of erythrocytosis, both of which are known to increase the risk of thromboembolic events or hyperviscosity syndrome, and of decreased platelet count, which ups the risk of bleeding. A platelet count of 50,000/mm³ or lower is an indicator to stop treatment.

“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,” said Vallerie McLaughlin, MD, the Kim A. Eagle MD Endowed Professor of Cardiovascular Medicine and Director of the pulmonary hypertension program at the University of Michigan in Ann Arbor, in a statement.¹ “Results from the pivotal ZENITH trial add to the growing body of data and support the potential for [sotatercept] as standard of care.” McLaughlin is also a member of the adult sotatercept steering committee and an investigator in the ZENITH study.

References

1. 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. News release. 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. Bonavitacola J. FDA approves sotatercept, first-in-class treatment for adults with PAH. AJMC^®. March 26, 2024. Accessed October 27, 2025. https://www.ajmc.com/view/fda-approves-sotatercept-first-in-class-treatment-for-adults-with-pah
3. AJMC Contributor. Sotatercept gains European approval for PAH for use with other treatments. AJMC. September 11, 2024. Accessed October 27, 2025. https://www.ajmc.com/view/sotatercept-gains-european-approval-for-pah-for-use-with-other-treatments
4. Winrevair (sotatercept-csrk) reduced the risk of a composite of all-cause death, lung transplantation and hospitalization for pulmonary arterial hypertension (PAH) by 76% compared to placebo in the phase 3 ZENITH trial. News release. Merck. March 31, 2025. Accessed October 27, 2025. https://www.merck.com/news/winrevair-sotatercept-csrk-reduced-the-risk-of-a-composite-of-all-cause-death-lung-transplantation-and-hospitalization-for-pulmonary-arterial-hypertension-pah-by-76-compared-to-placebo-i/