Key takeaways
Early trial termination for efficacy signals strong clinical benefit: The ZENITH trial was halted ahead of schedule due to overwhelming efficacy, underscoring the importance of robust interim analyses and data monitoring planning.
Priority review highlights regulatory momentum: The FDA’s acceptance and expedited review of Merck’s sBLA for Winrevair reflects how strong clinical outcomes can accelerate labeling updates and access pathways.
Background therapy integration remains critical: ZENITH and STELLAR both evaluated Winrevair on top of standard PAH therapies, reinforcing the operational complexity of combination trial designs and the need for careful therapy management at trial sites.
The FDA has accepted and granted priority review for a new supplemental Biologics License Application (sBLA) from Merck to update Winrevair’s (sotatercept-csrk) product label.1
This submission by Merck is based on positive outcomes from the Phase III ZENITH clinical trial (NCT04896008). The study evaluated Winrevair for the treatment of patients with pulmonary arterial hypertension (PAH).
Unmet need in PAH population remains a key focus
In a press release, Joerg Koglin, MD, PhD, senior vice president, global clinical development, Merck Research Laboratories, said: “We are pleased that the FDA has accepted our sBLA for WINREVAIR and granted a priority review to consider an update to labeling for WINREVAIR to include the impressive results of ZENITH. 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. 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.”
ZENITH trial halted early due to overwhelming efficacy
Merck initially shared data from the ZENITH trial in March.2 Due to overwhelming efficacy demonstrated in the primary endpoint of composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening PAH, Merck ended the study early. According to the company, ZENITH is the first Phase III study in PAH stopped early by an independent data monitoring committee for overwhelming efficacy.
- In ZENITH, Winrevair met the primary endpoint by achieving a 76% reduction in the risk of a composite of all-cause death, lung transplantation, and hospitalization.
- For patients treated with Winrevair, only 17.4% experienced one or more major morbidity and mortality events compared to 54.7% in the placebo arm.
- As a result of the study being ended early, the key secondary endpoint of overall survival did not reach its heightened mark that was required to establish statistical significance at the interim analysis.
In a press release announcing the positive results from ZENITH, Marc Humbert, MD, PhD, department of respiratory and intensive care medicine Hospital Bicêtre (AP-HP), University Paris-Saclay and Inserm Unit 999, said: “The ZENITH study represents the first PAH clinical trial with a primary endpoint comprised entirely of major outcome measures—all-cause death, lung transplantation and hospitalization for PAH. Winrevair had a significant and clinically meaningful impact on the composite of these outcomes, and together with the growing body of evidence from the clinical development program, these data support the practice-changing potential of Winrevair for a broad range of patients with PAH.”
ZENITH study design and long-term extension plans
- The ZENITH study is a global, double-blind, placebo-controlled clinical trial to evaluate WINREVAIR when added to maximum tolerated background PAH therapy in adult patients with WHO functional class III or IV PAH at high risk of mortality.
- There were 172 participants enrolled and randomized 1:1 to receive either Winrevair plus background PAH therapy or placebo plus background PAH therapy.
- In addition to the primary endpoint previously mentioned, the study’s key secondary endpoints included overall survival as well as transplant-free survival.
- Following completion of the ZENITH trial, patients were offered to receive Winrevair as part of the open-label, long-term extension study, SOTERIA (NCT04796337).
Background: Winrevair’s initial FDA approval in 2024
Winrevair was approved by the FDA in March 2024 for the treatment of adults with PAH, WHO Group 1, to increase exercise capacity, improve WHO functional class, and reduce the risk of clinical worsening events.3
The approval was based on positive results from the Phase III STELLAR trial (NCT04576988), in which Winrevair, when added to background therapy, increased six-minute walk distance from baseline by 41 meters at 24 weeks and reduced the risk of death from any cause or PAH clinical worsening events by 84% versus background therapy alone.
References
1. FDA Grants Priority Review for WINREVAIR™ (sotatercept-csrk) to Update Label Based on Results From ZENITH Trial. News release. Merck. 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. Merck Shares Results from Phase III Clinical Trial of Winrevair in Pulmonary Arterial Hypertension. Applied Clinical Trials. April 1, 2025. Accessed July 2, 2025. https://www.appliedclinicaltrialsonline.com/view/merck-results-phaseiii-clinical-trial-winrevair-pulmonary-arterial-hypertension
3. FDA Approves Merck’s WINREVAIR™ (sotatercept-csrk), a First-in-Class Treatment for Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1). News release. Merck. March 26, 2024. Accessed July 2, 2025. https://www.merck.com/news/fda-approves-mercks-winrevair-sotatercept-csrk-a-first-in-class-treatment-for-adults-with-pulmonary-arterial-hypertension-pah-who-group-1/
