Merck’s WINREVAIR Achieves Primary Endpoint in Phase 3 HYPERION Trial for Pulmonary Arterial Hypertension in Newly Diagnosed Adults
Merck, operating as MSD outside the United States and Canada, has announced a significant clinical milestone in its ongoing commitment to improving treatment options for patients with pulmonary arterial hypertension (PAH). The company revealed positive topline results from its Phase 3 HYPERION study evaluating WINREVAIR™ (sotatercept-csrk), an investigational first-in-class activin signaling inhibitor, in adults with recently diagnosed PAH. These findings represent a pivotal advancement in the treatment of this rare, progressive, and life-threatening disease.
Study Overview and Population
The HYPERION study was designed to assess the efficacy and safety of WINREVAIR when used in combination with standard background therapy, compared to placebo, in adult patients recently diagnosed with pulmonary arterial hypertension. Participants were classified as WHO Group 1 PAH, functional class (FC) II or III, indicating moderate to severe disease at either intermediate or high risk of clinical deterioration. Enrollment was limited to individuals who had received a PAH diagnosis within the previous 12 months.
Notably, more than 70% of patients enrolled in HYPERION were receiving dual background therapy—typically a combination of an endothelin receptor antagonist (ERA) and a phosphodiesterase type 5 (PDE5) inhibitor—highlighting the study’s focus on optimizing outcomes in a real-world therapeutic context.
Primary Endpoint and Clinical Results
The HYPERION trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful reduction in the risk of time to clinical worsening (TTCW). This was evaluated using a robust composite endpoint that included all-cause mortality, non-planned PAH-related hospitalization lasting over 24 hours, atrial septostomy (a surgical intervention to reduce right heart pressure), lung transplantation, or progressive clinical deterioration of PAH symptoms.
According to Merck, the addition of WINREVAIR to background therapy resulted in a meaningful improvement in patient outcomes, particularly in delaying disease progression and reducing the risk of severe clinical events. These data underscore the therapeutic potential of WINREVAIR when introduced early in the course of disease.
The safety profile observed in the HYPERION study was consistent with findings from previous WINREVAIR trials, with no new safety concerns identified. The treatment was generally well tolerated, and adverse events aligned with the known effects of the drug class and prior studies.
Building on a Strong Foundation: STELLAR and ZENITH
HYPERION represents the third Phase 3 clinical trial of WINREVAIR to deliver compelling efficacy results in patients with PAH. It follows two earlier landmark studies: STELLAR and ZENITH.
The STELLAR trial, presented at the American College of Cardiology’s 72nd Annual Scientific Session (ACC.23), focused on a broader PAH population and demonstrated that WINREVAIR significantly improved exercise capacity, as measured by the 6-minute walk distance, as well as multiple secondary endpoints. STELLAR was instrumental in securing regulatory approvals in more than 45 countries.
ZENITH, the second pivotal Phase 3 trial, presented at ACC.25 earlier this year, further validated WINREVAIR’s effectiveness in a different patient population—primarily composed of individuals with more advanced disease who had been receiving treatment for a longer period. In that study, most patients were on triple therapy, underscoring WINREVAIR’s ability to deliver benefits even in heavily treated cases.
HYPERION now adds another important piece to the evidence base by showing that initiating WINREVAIR in recently diagnosed patients—many of whom were only on dual therapy—can yield substantial improvements in clinical outcomes. This trial effectively broadens the therapeutic scope of WINREVAIR, demonstrating its applicability across a wide spectrum of PAH patients, from newly diagnosed to those with established treatment histories.
Early Termination Based on Positive Interim Data
In January, Merck announced that the HYPERION trial had been stopped early following a recommendation from the data monitoring committee. This decision was based on the interim efficacy results from the ZENITH trial, combined with a favorable overall assessment of the totality of evidence from the WINREVAIR clinical program. Upon termination of the trial, all participants in HYPERION were offered the opportunity to transition into the ongoing SOTERIA open-label extension study, allowing continued access to WINREVAIR and enabling longer-term follow-up on safety and efficacy.
Expert Commentary: A New Era in PAH Management?
The announcement of HYPERION’s success has generated optimism among pulmonary hypertension specialists, clinicians, and the broader PAH community. Dr. Vallerie McLaughlin, the Kim A. Eagle MD Endowed Professor of Cardiovascular Medicine and Director of the Pulmonary Hypertension Program at the University of Michigan, emphasized the importance of early and effective intervention in managing PAH.
“PAH is a progressive and debilitating disease with a poor prognosis that can be difficult to diagnose and treat,” said Dr. McLaughlin. “Patients often struggle for years to find a treatment plan that helps manage the disease, so it’s critical to provide new options earlier in the treatment journey. The HYPERION study demonstrated that WINREVAIR on top of background therapy met its primary outcome measure of reduction in the time to clinical worsening events in adults who have been recently diagnosed with PAH. WINREVAIR has brought significant optimism to patients, their families, and investigators. We thank all study participants for being part of this important study.”
Dr. Joerg Koglin, senior vice president and head of general and specialty medicine at Merck Research Laboratories, echoed this sentiment, stressing the broad potential impact of the therapy.
“To date, the strong clinical profile of WINREVAIR, a first-in-class activin signaling inhibitor, had been primarily established through previous studies in a prevalent patient population comprised of patients that were several years into their treatment journey,” he said. “These positive results from HYPERION expand on the body of clinical evidence now including recently diagnosed adults, supporting the practice-changing potential of WINREVAIR in a broad spectrum of PAH patients, including those earlier in their treatment journey. We look forward to presenting these data to the scientific community at a future medical meeting.”
Regulatory Outlook and Next Steps
Merck plans to present detailed data from the HYPERION study at an upcoming medical congress later this year. The company also intends to submit the results to regulatory authorities to further support label expansions and updated treatment guidelines.
With approvals for WINREVAIR already secured in more than 45 countries based on the STELLAR trial data, the addition of HYPERION’s findings could pave the way for earlier use of the drug in clinical practice, potentially shifting the treatment paradigm for PAH toward earlier intervention with disease-modifying therapies.
The positive topline results from the HYPERION study mark a critical milestone in Merck’s PAH research program and reinforce the clinical value of WINREVAIR across various stages of disease. By demonstrating a significant reduction in the time to clinical worsening in a newly diagnosed population, WINREVAIR has the potential to reshape how clinicians approach treatment for this complex and life-threatening condition.
Merck’s commitment to advancing cardiovascular and pulmonary medicine is once again underscored by its strategic investment in novel therapies like WINREVAIR. With additional data and regulatory milestones on the horizon, the company is poised to bring new hope to patients living with pulmonary arterial hypertension worldwide.
