WINREVAIR™ (sotatercept-csrk) Reduced the Risk of Clinical Worsening Events by 76% Compared to Placebo in Patients Recently Diagnosed With PAH on Background Therapy in Phase 3 HYPERION Trial

Results showed the benefits of early initiation of WINREVAIR within the first year after PAH diagnosis

HYPERION results were presented today at ERS 2025 and simultaneously published in the New England Journal of Medicine

RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive results from the Phase 3 HYPERION trial evaluating WINREVAIR™ (sotatercept-csrk) versus placebo (both in combination with background therapy) in recently diagnosed adults with pulmonary arterial hypertension (PAH, WHO* Group 1) functional class (FC) II or III at intermediate or high risk of disease progression. In the study, WINREVAIR reduced the risk of clinical worsening events by 76% (hazard ratio [HR] 0.24 [95% confidence interval [CI], 0.14 to 0.41]; p<0.0001) as measured by a composite endpoint of all-cause death, the need for non-planned PAH-related hospitalization ≥24 hours, atrial septostomy, lung transplantation or PAH deterioration. HYPERION included participants who were within their first year of diagnosis (median seven months and as early as one month), with over 70% of trial participants on double background therapy. In the pivotal Phase 3 study, STELLAR, participants were WHO Group 1, FC II or III at baseline and had an average disease duration of 8.8 years from PAH diagnosis to screening. The safety profile of WINREVAIR was generally consistent with that observed in previous trials. Results from the study were presented today at the 2025 European Respiratory Society (ERS) Congress and simultaneously published in the New England Journal of Medicine.

In HYPERION, there was an early and sustained separation in the Kaplan-Meier curves with treatment benefit observed within six weeks of randomization. Patients on placebo plus background standard of care therapy experienced accumulation of clinical worsening events. Results showed that 10.6% (n=17/160) of patients treated with WINREVAIR compared to 36.9% (n=59/160) in the placebo group experienced at least one clinical worsening event. The treatment effect was consistent across all prespecified subgroups treated with WINREVAIR, including patients with idiopathic PAH, those with connective tissue disease, those on double background therapy, those on triple background therapy and those at intermediate or intermediate-low risk by REVEAL Lite 2 and COMPERA 2.0 risk tools, respectively.

“PAH is a rare condition that can progress quickly making diagnosis and early treatment critically important,” said Dr. Vallerie McLaughlin**, Kim A Eagle MD Endowed Professor of Cardiovascular Medicine and Director, Pulmonary Hypertension Program, University of Michigan in Ann Arbor. “The patients with PAH enrolled in HYPERION were early in their treatment journey, had co-morbidities and were older, which reflects the type of patients we are diagnosing in a contemporary real-world setting. I am encouraged by the compelling results of the HYPERION study demonstrating that initiation of WINREVAIR on top of background therapy within the first year of diagnosis significantly reduces the risk of clinical worsening events compared to placebo.”

"These positive results from HYPERION expand on the body of clinical evidence for WINREVAIR, now including PAH patients within their first year of diagnosis, including those earlier in their treatment journey," said Dr. Joerg Koglin, senior vice president, head of general and specialty medicine, global clinical development, Merck Research Laboratories. “The totality of WINREVAIR data to date continues to reinforce our confidence in its practice-changing potential. We thank the study participants and investigators for their contributions to this important study.”

The safety profile of WINREVAIR in HYPERION was generally consistent with that observed in previous studies. The median duration of follow-up was longer in those receiving WINREVAIR (14.6 months) compared with those receiving placebo (11.5 months). Adverse events occurred in 89.4% versus 90.0% and serious adverse events in 24.4% versus 28.1% of participants in the WINREVAIR and placebo groups, respectively.

WINREVAIR demonstrated statistically significant improvements in two secondary endpoints, including multicomponent improvement and maintenance or achievement of a low REVEAL Lite 2 score. Results showed that 29.4% of patients treated with WINREVAIR met all three criteria of multicomponent improvement (improvement in 6MWD, improvement or maintenance/achievement of NT-proBNP, and improvement in WHO FC or maintenance of WHO FC II) versus 14.6% treated with placebo. An additional secondary endpoint demonstrated 60.1% of patients treated with WINREVAIR maintained or achieved a low REVEAL LITE 2 score (≤5) relative to baseline at Week 24 compared to 47.9% treated with placebo. WINREVAIR did not show statistical significance in achieving or maintaining low risk for a simplified French risk score (SFRS). Subsequent secondary endpoints showed numerical improvements in the WINREVAIR arm (including NT-proBNP, WHO class and 6MWD), but were not formally tested due to the prespecified hierarchical testing strategy.

Earlier this year, the HYPERION trial was stopped early based on a review of the totality of data from the WINREVAIR clinical program at that time, and all patients were offered the opportunity to receive WINREVAIR through the SOTERIA open-label extension study. HYPERION is the third Phase 3 study of WINREVAIR to demonstrate significant efficacy in adults with PAH. The first was the Phase 3 STELLAR study previously presented at ACC.23, followed by the Phase 3 ZENITH study presented at ACC.25. Results from HYPERION will be submitted to regulatory authorities around the world. WINREVAIR is currently approved in more than 54 countries based on the results from the STELLAR study.

*World Health Organization

**Dr. McLaughlin is a member of the adult sotatercept steering committee, an investigator in the ZENITH and HYPERION studies and a paid consultant to Merck.

About HYPERION
The HYPERION study (NCT04811092) is a global, double-blind, placebo-controlled clinical trial to evaluate WINREVAIR when added to background PAH therapy in newly diagnosed intermediate or high-risk PAH patients. Participants who enrolled in the study had a diagnosis of symptomatic PAH (WHO Group 1, classified as FC II [21.3%; 68/320 participants] or III [78.8%; 252/320 participants] within 12 months of study screening. Two patients had a protocol deviation with a time since the diagnosis of PAH of more than 1 year (442 days in one patient in the sotatercept group; 397 days in one patient in the placebo group). Eligible participants had a confirmed diagnosis of PAH in any of the following subtypes: idiopathic PAH (59.4%; 190/320), heritable PAH (5.9%; 19/320), PAH associated with connective tissue diseases (CTD) (30.3%; 97/320), drug- or toxin-induced PAH (2.5%; 8/320), or PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair (1.9%; 6/320), and those at intermediate or intermediate-low risk by REVEAL Lite 2 and COMPERA 2.0 risk tools, respectively. The study excluded patients with PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension, schistosomiasis-associated PAH, pulmonary veno occlusive disease, and pulmonary capillary hemangiomatosis.

The study enrolled 320 study participants over the age of 18, who were randomized in a 1:1 ratio to receive either WINREVAIR or placebo, both on top of background therapy. Participants were at an intermediate to high risk of disease progression and on stable doses of double (72.2%; 231/320 participants) or triple (27.8%; 89/320 participants) background PAH therapies for at least 90 days prior to screening. A majority (83.4%; 267/320 participants) were not on prostacyclin-infusion therapy.

The primary composite outcome measure is TTCW as measured by first confirmed morbidity or mortality event. Clinical worsening events are defined as all-cause death, non-planned PAH worsening-related hospitalization of ≥ 24 hours, atrial septostomy, lung transplantation, and deterioration in six-minute walk test from baseline combined with at least one of the following changes: worsening of WHO FC from baseline, signs/symptoms of increased right heart failure, addition of a background PAH therapy or change in the background PAH therapy delivery route to parenteral.

Secondary outcome measures were assessed relative to baseline at Week 24: proportion of participants achieving multicomponent improvement (consisting of improvement in 6MWD, improvement in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and improvement in WHO FC or maintenance of WHO FC II) as well as additional measures.

About WINREVAIR™ (sotatercept-csrk) for injection, for subcutaneous use, 45 mg, 60 mg
WINREVAIR is FDA-approved for the treatment of adults with pulmonary arterial hypertension (PAH, WHO Group 1) to increase exercise capacity, improve WHO functional class (FC) and reduce the risk of clinical worsening events. WINREVAIR is the first activin signaling inhibitor therapy approved to treat PAH. WINREVAIR improves the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation. In preclinical models, WINREVAIR induced cellular changes that were associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.

WINREVAIR is the subject of a licensing agreement with Bristol Myers Squibb.

Selected Safety Information for WINREVAIR in the U.S.
WINREVAIR may increase hemoglobin (Hgb). Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required.

WINREVAIR may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. Thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Do not initiate treatment if platelet count is <50,000/mm³. Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine whether dose adjustments are required.

In clinical studies, serious bleeding (eg, gastrointestinal, intracranial hemorrhage) was reported in 4% of patients taking WINREVAIR and 1% of patients taking placebo. Patients with serious bleeding were more likely to be on prostacyclin background therapy and/or antithrombotic agents, or have low platelet counts. Advise patients about signs and symptoms of blood loss. Do not administer WINREVAIR if the patient is experiencing serious bleeding.

WINREVAIR may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with WINREVAIR and for at least 4 months after the final dose. Pregnancy testing is recommended for females of reproductive potential before starting WINREVAIR treatment.

Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertility.

The most common adverse reactions occurring in the phase 3 clinical trial (≥10% for WINREVAIR and at least 5% more than placebo) were headache (24.5% vs 17.5%), epistaxis (22.1% vs 1.9%), rash (20.2% vs 8.1%), telangiectasia (16.6% vs 4.4%), diarrhea (15.3% vs 10.0%), dizziness (14.7% vs 6.2%), and erythema (13.5% vs 3.1%).

Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with WINREVAIR, and for 4 months after the final dose.

About PAH
Pulmonary arterial hypertension (PAH) is a rare, progressive and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation. Approximately 90,000 people worldwide are living with PAH. The disease progresses rapidly for many patients. PAH results in significant strain on the heart, leading to limited physical activity, heart failure and reduced life expectancy. The five-year mortality rate for patients with PAH is approximately 43%.

About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA
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Please see Prescribing Information for WINREVAIR (sotatercept-csrk) at http://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_pi.pdf, Patient Information for WINREVAIR at http://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_ppi.pdf, and Instructions for Use for WINREVAIR (1-vial kit, 2-vial kit) at https://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_ifu_1-vial_2-vial_kits.pdf.

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Source: Merck Sharp & Dohme