FDA Reviewing Sotatercept-csrk Label Expansion for PAH

An earlier version of this article was published by HCPLive.

The FDA has granted priority review to a supplemental biologics license application (sBLA) to update the US product label for sotatercept-csrk (Winrevair; Merck) to treat pulmonary arterial hypertension (PAH).

Announced on July 2, the sBLA submission was based on positive results from the phase 3 ZENITH trial (NCT04896008), which was the first phase 3 PAH outcomes study to use a primary end point of major morbidity and mortality events. The FDA has set a Prescription Drug User Fee Act 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, in a statement. “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-in-class homodimeric recombinant fusion protein acting as an activin signaling inhibitor.² The drug traps activin A and GDF ligands, recalibrating TGF-β proliferative and antiproliferative pathways to blunt vascular remodeling.

The ZENITH trial was terminated early in response to the overwhelming efficacy displayed in its primary composite end point, with sotatercept demonstrating a 76% reduction in all-cause death, need for lung transplantation, and hospitalization for PAH for at least 24 hours. | Image Credit: Maggie-sora.chatgpt.com

The medication received a priority review from the FDA in September 2023 to treat adults patients with PAH World Health Organization functional class (WHO FC) I disease, as well as breakthrough therapy and orphan drug designations for the 45-mg and 60-mg doses.^3,4 Sotatercept-csrk was first approved in 2024 for the treatment of PAH in adults to increase their exercise capacity, improve WHO FC, and reduce the risk of clinical worsening events.^1,3 That approval was based on results seen in the phase 3 STELLAR trial (NCT04576988), in which patients were assigned 1:1 to receive either sotatercept (n = 163) or placebo (n = 160) every 3 weeks plus background standard-of-care therapy; the primary end point was change in 6-minute walking distance from baseline to week 24.³

The ZENITH trial was a pivotal phase 3 multicenter, double-blind, placebo-controlled evaluation of sotatercept-csrk vs 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 and randomized in a 1:1 ratio to either sotatercept-csrk (n = 86) once every 3 weeks at 0.3 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 (SD) age of 54.4 (14.3) years.⁵

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

“The impressive results from ZENITH demonstrated that patients on Winrevair had a 76% 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, in a statement.⁵ “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.”

References

1. FDA grants priority review for Winrevair (sotatercept-csrk) to update label based on results from ZENITH trial. News release. BusinessWire. July 2, 2025. Accessed July 13, 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. Bonavitacola J. FDA approves sotatercept, first-in-class treatment for adults with PAH. AJMC^®. March 26, 2024. Accessed July 13, 2025. https://www.ajmc.com/view/fda-approves-sotatercept-first-in-class-treatment-for-adults-with-pah
4. Merck receives priority review from FDA for new biologics license application for sotatercept, an activin signaling inhibitor to treat adults with pulmonary arterial hypertension (PAH). News release. Merck. September 23, 2023. Accessed July 13, 2025. https://www.merck.com/news/merck-receives-priority-review-from-fda-for-new-biologics-license-application-for-sotatercept-an-activin-signaling-inhibitor-to-treat-adults-with-pulmonary-arterial-hypertension-pah/
5. 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 July 13, 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/