FDA Accepts Application for Sotatercept-csrk Label Expansion in PAH

The US Food and Drug Administration (FDA) has granted priority review to a supplemental Biologics License Application (sBLA) aiming to update the US product label for sotatercept-csrk (WINREVAIR)to treat pulmonary arterial hypertension (PAH, Group 1 PH).

Announced by parent company Merck on July 2, 2025, the sBLA submission was based on positive results from the phase 3 ZENITH trial. ZENITH was the first phase 3 PAH outcomes study to use a primary endpoint of major morbidity and mortality events. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of October 25, 2025.1

“There remains a significant unmet medical need for patients living with PAH who, despite being on background therapy, remain at higher risk of morbidity and mortality,” said Joerg Koglin, MD, senior vice president, global clinical development, Merck Research Laboratories. “The FDA’s Priority Review designation acceptance of our sBLA reinforces our confidence in WINREVAIR for a broad range of patients and represents a critical step toward advancing the treatment of PAH.”1

Sotatercept-csrk is a first-of-its-class homodimeric recombinant fusion protein acting as an activin signaling inhibitor. Granted Breakthrough Therapy Designation by the FDA in March 2024, the drug traps activin A and GDF ligands, recalibrating TGF-beta proliferative and antiproliferative pathways to blunt vascular remodeling.2

Sotatercept-csrk was first approved in 2024 for the treatment of PAH in adults, to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events.1

The ZENITH trial was a pivotal phase 3 multicenter, double-blind, placebo-controlled evaluation of sotatercept-csrk versus placebo to treat adult patients with WHO FC III or IV PAH at high risk of mortality who were on maximum tolerated background PAH therapy. A total of 172 patients were enrolled in the trial; they were then randomized in a 1:1 ratio to either sotatercept-csrk (n = 86) once every 3 weeks at .3 mg/kg at visit 1 and 0.7 mg/kg thereafter, or placebo (n = 86). The study population was 77% female and 87% white, with a mean age of 54.4 (Standard deviation, 14.3) years.3

ZENITH was terminated early in response to the overwhelming efficacy displayed in its primary composite endpoint; compared to placebo, sotatercept-csrk demonstrated a 76% reduction in all-cause death, lung transplantation, and hospitalization for PAH ≥24 hours. Additionally, the safety profile was consistent with previous studies.1

“The impressive results from ZENITH demonstrated that patients on WINREVAIR had a 76 percent risk reduction in the composite of all-cause death, lung transplantation and hospitalization for PAH compared to placebo, with improvement observed early in treatment and increasing benefit throughout the study.” said Eliav Barr, MD, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “These results led to the ZENITH study being the first PAH clinical trial stopped early due to overwhelming efficacy, representing an important milestone in clinical research with promise for the PAH community.”3

References

1. Merck Research Laboratories. FDA Grants Priority Review for WINREVAIR (sotatercept-csrk) to Update Label Based on Results From ZENITH Trial. BusinessWire. July 2, 2025. Accessed July 2, 2025. https://www.businesswire.com/news/home/20250702111344/en/FDA-Grants-Priority-Review-for-WINREVAIR-sotatercept-csrk-to-Update-Label-Based-on-Results-From-ZENITH-Trial

2. Miranda AC, Cornelio CK, Tran BAC, Fernandez J. Sotatercept: A First-In-Class Activin Signaling Inhibitor for Pulmonary Arterial Hypertension. J Pharm Technol. Published online February 22, 2025. doi:10.1177/87551225251317957

3. Merck Research Laboratories. 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. March 31, 2025. Accessed July 2, 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/