Merck Reports Clinical Positive Phase 3 HYPERION Trial Results for WINREVAIR™ (sotatercept-csrk) in Newly Diagnosed Pulmonary Arterial Hypertension Patients
Merck known as MSD outside the United States and Canada, today announced encouraging findings from the Phase 3 HYPERION trial evaluating WINREVAIR™ (sotatercept-csrk) compared with placebo in adults recently diagnosed with pulmonary arterial hypertension (PAH, WHO Group 1) who were classified as functional class (FC) II or III and at intermediate or high risk of disease progression. Both treatment arms were administered in combination with standard background therapy.
The HYPERION study demonstrated that WINREVAIR significantly reduced the risk of clinical worsening events by 76%, with a hazard ratio (HR) of 0.24 (95% confidence interval [CI], 0.14 to 0.41; p<0.0001). The composite endpoint used to measure clinical worsening included all-cause mortality, unplanned PAH-related hospitalizations lasting 24 hours or more, atrial septostomy, lung transplantation, and PAH disease progression.
HYPERION enrolled participants who were within their first year of diagnosis, with a median disease duration of seven months and some patients enrolled as early as one month after diagnosis. More than 70% of participants were receiving double background therapy at the time of enrollment, reflecting contemporary real-world treatment patterns. This contrasts with the pivotal Phase 3 STELLAR study, in which patients had an average disease duration of 8.8 years from initial diagnosis to study screening. The safety profile of WINREVAIR observed in HYPERION was generally consistent with prior trials. Results from the trial were presented at the 2025 European Respiratory Society (ERS) Congress and simultaneously published in the New England Journal of Medicine.
Early and Sustained Efficacy Observed
The Kaplan-Meier curves in HYPERION indicated an early and sustained separation between the WINREVAIR and placebo groups, with treatment benefits emerging within six weeks of randomization. Among participants receiving placebo alongside background therapy, clinical worsening events accumulated steadily over the study period. Specifically, only 10.6% (17 of 160) of patients receiving WINREVAIR experienced at least one clinical worsening event, compared with 36.9% (59 of 160) in the placebo group.
The efficacy of WINREVAIR was consistent across all prespecified subgroups. This included patients with idiopathic PAH, those with PAH associated with connective tissue disease, individuals receiving double or triple background therapy, and patients stratified by REVEAL Lite 2 and COMPERA 2.0 risk assessment tools, regardless of intermediate or intermediate-low risk categories.
Expert Perspective on Early Intervention
“PAH is a rare condition that can progress rapidly, making early diagnosis and intervention crucial,” said Dr. Vallerie McLaughlin, Kim A. Eagle MD Endowed Professor of Cardiovascular Medicine and Director of the Pulmonary Hypertension Program at the University of Michigan in Ann Arbor. “The patients enrolled in HYPERION were early in their treatment journey, often had comorbidities, and were older, reflecting the typical profile of patients we see in clinical practice today. The study’s results are compelling, showing that initiating WINREVAIR in combination with background therapy within the first year of diagnosis substantially lowers the risk of clinical worsening events compared with placebo.”
Dr. Joerg Koglin, senior vice president and head of general and specialty medicine, global clinical development at Merck Research Laboratories, added, “The positive outcomes from HYPERION extend the growing body of clinical evidence supporting WINREVAIR. This includes patients newly diagnosed with PAH and those early in their treatment course. Taken together with data from previous trials, WINREVAIR continues to demonstrate potential as a practice-changing therapy in PAH management. We are grateful to the patients and investigators who contributed to this pivotal study.”
Safety Profile Consistent with Previous Trials
The safety profile of WINREVAIR in HYPERION was generally aligned with prior clinical experience. The median duration of follow-up was 14.6 months for patients receiving WINREVAIR compared with 11.5 months for those on placebo. Adverse events occurred in 89.4% of patients in the WINREVAIR arm versus 90.0% in the placebo arm, while serious adverse events were reported in 24.4% and 28.1% of patients, respectively. These findings suggest that WINREVAIR is generally well tolerated in the context of early PAH treatment.
Secondary Endpoints Show Clinically Meaningful Improvements
WINREVAIR also demonstrated statistically significant improvements in two key secondary endpoints. The first, a multicomponent improvement endpoint, assessed improvement in six-minute walk distance (6MWD), improvement or maintenance/achievement of NT-proBNP levels, and improvement or maintenance of WHO functional class. In the WINREVAIR group, 29.4% of patients met all three criteria, compared with 14.6% in the placebo group.
The second secondary endpoint involved maintaining or achieving a low REVEAL Lite 2 score (≤5) at Week 24 relative to baseline. In this assessment, 60.1% of patients treated with WINREVAIR achieved or maintained a low-risk score compared with 47.9% of placebo-treated patients. WINREVAIR did not reach statistical significance in maintaining or achieving a low-risk status using the simplified French risk score (SFRS). Additional secondary endpoints, including NT-proBNP, WHO functional class, and 6MWD, showed numerical improvements in the WINREVAIR arm but were not formally tested due to the prespecified hierarchical testing strategy.
Trial Stopped Early to Offer Open-Label Extension
Earlier in 2025, the HYPERION trial was stopped early following a review of the totality of data from the WINREVAIR clinical program. This decision allowed all participants the opportunity to continue receiving WINREVAIR through the SOTERIA open-label extension study. HYPERION represents the third Phase 3 trial demonstrating significant efficacy of WINREVAIR in adults with PAH. The first, STELLAR, was presented at ACC.23, and the second, ZENITH, was presented at ACC.25.
Regulatory Path Forward and Global Approvals
Based on the HYPERION results, Merck plans to submit data to regulatory authorities worldwide to support approval for use in recently diagnosed PAH patients. WINREVAIR is currently approved in more than 54 countries for PAH treatment, supported primarily by results from the STELLAR study. The expanding clinical dataset, now including early-diagnosed patients, underscores the potential of WINREVAIR to transform the management of PAH and provide meaningful clinical benefit across diverse patient populations.
The HYPERION trial provides robust evidence that early intervention with WINREVAIR, in combination with background therapy, can substantially reduce the risk of clinical worsening in patients recently diagnosed with PAH. The treatment effect was rapid, evident within six weeks, and sustained over the follow-up period, with a favorable safety profile consistent with previous studies. The study reinforces the importance of timely diagnosis and early initiation of targeted therapy in PAH, while contributing to a growing body of evidence supporting WINREVAIR as a potentially transformative therapy in the management of this progressive and life-threatening disease.
