Sotatercept

WINREVAIR significantly reduced the risk of major morbidity and mortality events, the primary endpoint, in adults with PAH (Group 1 PH) WHO* functional class (FC) III or IV at high risk of mortality who are on maximum tolerated background PAH therapy ZENITH results presented today at ACC.25 as a late-breaking oral presentation and simultaneously published in the New England Journal of Medicine RAHWAY, NJ, USA I March 31, 2025 I Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the first presentation of results from the Phase 3 ZENITH trial evaluating WINREVAIR™ (sotatercept-csrk) compared to placebo in adults with pulmonary arterial hypertension (PAH, Group 1 PH) WHO* functional class (FC) III or IV at high risk of mortality who were on maximum tolerated background PAH therapy. At a median follow-up of10.6 months (range, 0.3-26.1), WINREVAIR reduced the relative risk of major morbidity and mortality events (the composite of all-cause death, lung transplantation and PAH worsening-related hospitalization of ≥24 hours) by 76% (HR=0.24 [95% CI, 0.13-0.43]; p<0.0001 [1-sided]) compared to placebo.For patients treated with WINREVAIR, 17.4% (n=15/86) experienced one or more major morbidity and mortality events, compared with 54.7% (n=47/86) of patients in the placebo arm. The safety profile of WINREVAIR in ZENITH was generally consistent with that observed in previous studies. These results were presented today as a late-breaking oral presentation at the American College of Cardiology’s Annual Scientific Session and Expo (ACC.25) and simultaneously published in the New England Journal of Medicine . These results follow Merck’s announcement in November 2024 that, based on the recommendation of an independent data monitoring committee, the ZENITH study wasstopping early due to overwhelming efficacy, and study participants were offered the opportunity to receive WINREVAIR through the SOTERIA open-label extension study. “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,” said Dr. Marc Humbert, Department of Respiratory and Intensive Care Medicine Hospital Bicêtre (AP-HP), University Paris-Saclay and Inserm Unit 999. “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.” “The impressive results from ZENITH demonstrated that patients on WINREVAIR had a 76 percent risk reduction in the composite of all-cause death, lung transplantation and hospitalization for PAH compared to placebo, with improvement observed early in treatment and increasing benefit throughout the study,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “These results led to the ZENITH study being the first PAH clinical trial stopped early due to overwhelming efficacy, representing an important milestone in clinical research with promise for the PAH community.” In this trial stopped early due to overwhelming efficacy demonstrated in the primary endpoint, the key secondary endpoint of overall survival did not reach the heightened threshold (p<0.0021) that was required to establish statistical significance at the interim analysis (HR=0.42 [95% CI, 0.17-1.07]; p=0.0313]). Subsequent secondary endpoints showed numerical improvements in the WINREVAIR arm, but were not formally tested due to the prespecified hierarchical testing strategy. ZENITH is the second Phase 3 study of WINREVAIR to demonstrate efficacy in adults with PAH. The first was the Phase 3 STELLAR trial previously presented at ACC.23. Results from the ZENITH trial will be shared with regulatory authorities around the world. WINREVAIR is currently approved in more than 40 countries based on the results from the STELLAR trial. Merck announced in January 2025 that the Phase 3 HYPERION study evaluating WINREVAIR when added to background PAH therapy in newly diagnosed patients with PAH FC II or III at intermediate or high risk of disease progression was stopping early and moving directly to final analysis. The decision to stop the HYPERION study prior to its scheduled completion and offer patients the opportunity to receive WINREVAIR through the SOTERIA open-label extension study was based on the positive results from the interim analysis of the ZENITH trial and a review of the totality of data from the WINREVAIR clinical program to date. Findings from the HYPERION study will be available later this year and presented at a future medical congress. Study design and additional data from the ZENITH trial The ZENITH trial ( NCT04896008 ) is a pivotal Phase 3 multicenter, double-blind, placebo-controlled trial evaluating WINREVAIR versus placebo for the treatment of adult patients with WHO FC III or IV PAH at high risk of mortality who were on maximum tolerated background PAH therapy. The primary outcome measure was time to first confirmed morbidity or mortality event, with events defined as all-cause death, lung transplantation or PAH worsening-related hospitalization of ≥24 hours. Secondary outcome measures include overall survival, transplant-free survival and several additional measures. The trial enrolled 172 participants receiving the maximum tolerated background PAH therapy, who were randomized in a 1:1 ratio to receive either WINREVAIR (n=86) once every 3 weeks at a dose of 0.3 mg/kg at visit 1 and a dose of 0.7 mg/kg thereafter or placebo (n=86). The study population characteristics were: mean [±SD] 54.4 ± 14.3 years of age; 87% white; and 77% female. In total, 124 of the randomized patients (72.1%) were receiving triple therapy and 48 patients (27.9%) were receiving double therapy; 102 patients (59.3%) were receiving prostacyclin infusion therapy. Additionally, 25.6% of patients in the WINREVAIR arm and 30.2% in the placebo arm had PAH associated with connective-tissue disease. Demographic and baseline characteristics were similar between the WINREVAIR and placebo groups. When examined as standalone outcomes, each component of the primary composite endpoint was directionally consistent with the overall treatment effect. There were seven deaths in the WINREVAIR arm (8.1%) compared with 13 in the placebo arm (15.1%); lung transplantation occurred in one patient treated with WINREVAIR (1.2%) compared to six patients treated with placebo (7.0%); and hospitalizations for PAH occurred in eight patients in the WINREVAIR arm (9.0%) compared to 43 patients in the placebo group (50.0%). Individual patients could experience one or more component. The safety profile of WINREVAIR was generally consistent with that observed in previous studies. In the ZENITH trial, no patients treated with WINREVAIR discontinued treatment due to an adverse event. Serious adverse events occurred in 53.5% of patients treated with WINREVAIR versus 64.0% in the placebo arm. Treatment-related adverse events (TRAEs) occurred in 65.1% of patients who received WINREVAIR versus 32.6% of patients who received placebo, and serious TRAEs were observed in 3.5% versus 2.3% of patients, respectively. Bleeding events occurred in 62.8% of patients treated with WINREVAIR versus 34.9% treated with placebo (mostly non-serious epistaxis and gingival bleeding). There was a 1.1% difference in the risk of serious bleeding events (5.8% versus 4.7%, respectively), which were similar between treatment groups. Adverse events leading to death occurred in five patients (5.8%) in the WINREVAIR treatment group and 12 patients (14.0%) in the placebo group. Adverse events that occurred more frequently with WINREVAIR versus placebo were cutaneous telangiectasia (25.6% versus 3.5%), increased hemoglobin (12.8% versus 1.2%) and thrombocytopenia (14% versus 8.1%). All participants who have completed the ZENITH trial were offered the opportunity to receive WINREVAIR as part of the open-label, long-term extension trial, SOTERIA ( NCT04796337 ), consistent with that trial’s eligibility criteria. 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. 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 40,000 people in the U.S. 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 . SOURCE: Merck

New data unveiled Monday showed that Merck’s Winrevair can significantly cut the risk of death, lung transplantation and hospitalization in patients with a rare form of high blood pressure in the lungs, potentially providing a boost to sales. The data come from a study that was stopped early for overwhelming efficacy in November . However, this early halt meant that a secondary endpoint looking at deaths alone faced a higher bar and did not meet statistical significance. It is now unclear whether Winrevair, which was approved for pulmonary arterial hypertension (PAH) around a year ago , will be able to get a specific mortality claim on its label as the company had previously hoped. What is clear is that the trial, named ZENITH, scored a huge success on its primary endpoint. Winrevair, an injected activin receptor fusion protein, reduced a composite of all-cause death, lung transplantation and hospitalization for PAH by 76% compared with placebo. Of those given Merck’s drug, 17.4% experienced one or more of these major morbidity and mortality events, versus 54.7% of those given placebo. ZENITH enrolled 172 adults with advanced PAH who were at high risk of mortality and were on maximum tolerated background therapy. This finding, presented at the American College of Cardiology’s Annual Scientific Sessions, is important because Winrevair’s approval was based on softer endpoints, including improving patients’ exercise capacity and symptoms. Evidence of a more concrete effect on patients’ health could extend the drug’s reach. “Four to five weeks after initiation of [Winrevair] there’s already a detectable difference in deaths, hospitalization and lung transplant between both groups,” Joerg Koglin, senior VP of global clinical development at Merck, told Endpoints News . “That’s an endpoint that was never tackled by any other PAH drug development program,” he added. However, the crucial secondary endpoint of overall survival was not met. There were seven deaths in the Winrevair arm compared with 13 in the placebo arm, but the statistical threshold here was set at a p-value of 0.0021, a harder bar to hit than the more usual 0.05. Koglin said that this tougher standard was a statistical necessity when interim analyses are used. The actual p-value for mortality at the interim point was 0.0313. “If we would’ve seen that p-value at the end of the study, of course that would’ve been significant,” he said. When examined individually, the other components of the composite endpoint also favored Merck’s drug, though again the company was unable to claim statistical significance. One Winrevair patient had a lung transplant compared with six in the placebo arm, and eight patients in the drug group were hospitalized for PAH versus 43 — half the patients — in the placebo group. Safety was consistent with earlier studies, such as the STELLAR trial which led to Winrevair’s approval. The group will submit the ZENITH data to the FDA and other agencies, and Koglin said that “one of the discussions with regulators would be if the survival benefit should be spelled out more clearly in the label.” Whether a mortality benefit is added to the label or not, sales could see an uptick. With Winrevair, Koglin said, “you see an impact on hard endpoints and there is no other program out there that ever has shown a similar effect. It will be a strong argument for a physician to consider [Winrevair] for a given patient.” Merck confirmed that it does not anticipate a price increase for Winrevair even if the drug does receive a label update. Winrevair was one of the two main products behind Merck’s $11.5 billion acquisition of Acceleron in 2021 . The drug had sales of $419 million last year. The other main reason for the Acceleron deal was the blood disorder therapy Reblozyl, which sold $371 million in 2024. Winrevair sales will have to grow if Merck is to make its money back.