FDA Grants Priority Review to Merck’s WINREVAIR™ Based on Landmark ZENITH Trial Showing Dramatic Reduction in Morbidity and Mortality in PAH Patients
Merck (NYSE: MRK), operating as MSD outside the U.S. and Canada, has announced a significant regulatory milestone for its pulmonary arterial hypertension (PAH) treatment, WINREVAIR™ (sotatercept-csrk). The U.S. Food and Drug Administration (FDA) has accepted for review a new supplemental Biologics License Application (sBLA) and granted it priority review status, seeking to update the U.S. label of WINREVAIR based on compelling new evidence from the Phase 3 ZENITH trial.
The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of October 25, 2025.
This latest submission builds on WINREVAIR’s earlier 2024 approval for adult patients with PAH (Group 1 pulmonary hypertension), where it was shown to improve exercise capacity, World Health Organization (WHO) functional class, and reduce the risk of clinical worsening.
The new sBLA is anchored in results from the ZENITH study—one of the most rigorously designed and consequential Phase 3 trials in PAH to date. This trial was the first in its therapeutic area to use a composite primary endpoint consisting solely of major morbidity and mortality events, such as all-cause death, lung transplantation, or PAH-related hospitalization of at least 24 hours. Notably, the study was halted early following a recommendation by an independent data monitoring committee, citing overwhelming efficacy.
The topline results are compelling: WINREVAIR achieved a 76% relative risk reduction in the primary composite outcome versus placebo. Importantly, the treatment effect emerged early in the course of therapy and continued to increase over time. The safety profile observed in ZENITH was consistent with previous studies of WINREVAIR, bolstering confidence in its long-term use.
“This priority review designation reflects the transformative potential of WINREVAIR for patients living with PAH,” said Dr. Joerg Koglin, Senior Vice President of Global Clinical Development at Merck Research Laboratories. “Despite existing therapies, many PAH patients remain at substantial risk. We believe WINREVAIR, backed by the ZENITH trial’s outcomes, represents a pivotal advancement for a broad population of patients.”
ZENITH (NCT04896008) was a double-blind, placebo-controlled trial that enrolled 172 participants with WHO functional class III or IV PAH considered to be at high mortality risk, as defined by a REVEAL Lite 2.0 risk score of 9 or greater. Patients were randomized 1:1 to receive either WINREVAIR or placebo, both in combination with maximum-tolerated background therapy.
Exclusion criteria for the trial included PAH associated with HIV or portal hypertension, as well as any diagnosis of pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. The trial’s design ensured the patient population was both homogenous and clinically high-risk, enhancing the robustness of the findings.
Following the trial, eligible participants were invited to enroll in the SOTERIA long-term extension study (NCT04796337), allowing continued access to WINREVAIR while further evaluating its long-term safety and efficacy.
WINREVAIR is the first FDA-approved activin signaling inhibitor for PAH. The drug works by rebalancing signaling pathways that regulate vascular remodeling, with the goal of reducing pro-proliferative responses in pulmonary blood vessels. In preclinical models, it has been shown to reduce vessel wall thickness, partially reverse right heart remodeling, and improve overall hemodynamics.
The product was developed under a licensing agreement with Bristol Myers Squibb.
U.S. Safety Profile
Despite its benefits, WINREVAIR carries several safety considerations. It may increase hemoglobin levels, posing risks such as erythrocytosis, which can lead to thromboembolic events. Platelet counts may also decrease, heightening bleeding risk, particularly in patients on prostacyclin therapy or antithrombotics. Serious bleeding events occurred in 4% of WINREVAIR-treated patients versus 1% on placebo.
Pregnancy risk is another consideration—WINREVAIR may cause fetal harm and impact fertility in both males and females. Women of reproductive age are advised to use effective contraception and undergo pregnancy testing before starting treatment.
The most common adverse events seen in trials included headache (24.5%), epistaxis (22.1%), rash (20.2%), telangiectasia (16.6%), diarrhea (15.3%), dizziness (14.7%), and erythema (13.5%)—all occurring at higher rates than in placebo-treated patients.
Breastfeeding is not recommended during treatment and for four months after the final dose, due to the potential for serious adverse effects in nursing infants.
The PAH Landscape
Pulmonary arterial hypertension is a rare but serious condition, affecting an estimated 40,000 individuals in the U.S. It is marked by high blood pressure in the arteries of the lungs due to narrowing or obstruction of small pulmonary vessels, causing progressive right heart failure. PAH patients often experience profound limitations in physical activity, and the disease is associated with a five-year mortality rate of approximately 43%, underscoring the urgent need for more effective treatments.
With the inclusion of ZENITH data in the WINREVAIR label now under FDA review, Merck is poised to further solidify its role as a leader in the PAH space. The company has already achieved regulatory approvals for WINREVAIR in more than 45 countries, based initially on results from the STELLAR trial.
If approved, the updated U.S. label for WINREVAIR could expand its reach and reinforce its position as a cornerstone therapy in the management of PAH—offering new hope to thousands of patients facing a challenging and often deadly disease.
