WINREVAIR™ (sotatercept-csrk) Reduced the Risk of a Composite of All-Cause Death, Lung Transplantation and Hospitalization for Pulmonary Arterial Hypertension (PAH) by 76% Compared to Placebo in the Phase 3 ZENITH Trial

Rhea-AI Summary

Merck (NYSE: MRK) announced groundbreaking results from the Phase 3 ZENITH trial of WINREVAIR™ for pulmonary arterial hypertension (PAH). The study demonstrated a 76% reduction in the risk of major morbidity and mortality events compared to placebo in adults with PAH WHO functional class III or IV at high risk.

At median follow-up of 10.6 months, only 17.4% of WINREVAIR-treated patients experienced major events versus 54.7% in the placebo group. The trial was stopped early due to overwhelming efficacy. Key outcomes included:

• Deaths: 8.1% WINREVAIR vs 15.1% placebo
• Lung transplantation: 1.2% WINREVAIR vs 7.0% placebo
• PAH hospitalizations: 9.0% WINREVAIR vs 50.0% placebo

The safety profile remained consistent with previous studies, with no treatment discontinuations due to adverse events. WINREVAIR is currently approved in over 40 countries based on previous STELLAR trial results.

Positive

• 76% reduction in major morbidity and mortality events
• Significant reduction in PAH hospitalizations (9% vs 50%)
• Lower death rates compared to placebo (8.1% vs 15.1%)
• First PAH trial stopped early due to overwhelming efficacy
• No treatment discontinuations due to adverse events

Negative

• Key secondary endpoint of overall survival did not reach statistical significance
• Higher rate of bleeding events in treatment group (62.8% vs 34.9%)
• Increased adverse events in treatment group (65.1% vs 32.6%)

Insights

Clinical Research Specialist

The Phase 3 ZENITH trial results for WINREVAIR represent an exceptional clinical breakthrough in pulmonary arterial hypertension treatment. The 76% reduction in the composite of mortality and major morbidity events is remarkable, particularly in high-risk WHO functional class III/IV patients already on maximum background therapy.

This trial stands out for three crucial reasons: First, it's the first PAH trial stopped early for overwhelming efficacy, a rare occurrence signaling extraordinary results. Second, it used hard clinical endpoints (death, transplantation, hospitalization) rather than surrogate markers. Third, each component of the primary endpoint showed consistent benefit, with hospitalizations for PAH reduced from 50% to just 9% in the treatment arm.

While the secondary endpoint of overall survival didn't reach the heightened statistical threshold required at interim analysis, the directional benefit was clear (HR=0.42). The safety profile remained consistent with previous studies, with manageable side effects primarily including non-serious bleeding events and telangiectasia.

Most significantly, these results expand on the already-established efficacy from the STELLAR trial that led to approvals in 40+ countries, now demonstrating compelling benefit in higher-risk patients. The early stopping of another Phase 3 study (HYPERION) suggests a pattern of strong efficacy across PAH patient populations, potentially establishing WINREVAIR as a practice-changing foundation therapy for this severe condition.

Pharmaceutical Equity Analyst

Merck's WINREVAIR just delivered what pharmaceutical companies dream of: a trial stopped early due to "overwhelming efficacy" with a 76% risk reduction in hard clinical endpoints. For context, achieving a 30-40% reduction would typically be considered successful in PAH trials.

This represents a significant commercial opportunity strengthening Merck's cardiovascular/pulmonary portfolio. PAH requires lifelong therapy, and with WINREVAIR already approved in 40+ countries from previous trials, these results should expand its label to higher-risk patients and drive adoption among physicians.

The commercial value of these results is magnified by several factors: First, PAH patients with functional class III/IV have few effective treatment options, creating significant unmet need. Second, demonstrating efficacy in patients already on maximum tolerated therapy positions WINREVAIR as an additive treatment on top of existing regimens. Third, the consistent benefit across mortality and hospitalization endpoints provides compelling evidence for payers.

Additionally, the early stopping of the HYPERION trial in newly diagnosed patients suggests efficacy across the PAH spectrum, potentially making WINREVAIR foundational across treatment paradigms. While exact market sizing wasn't disclosed, specialty drugs for severe conditions like PAH typically command premium pricing, and WINREVAIR's demonstrated clinical benefits position it for strong market uptake and reimbursement support.

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, N.J.--(BUSINESS WIRE)-- 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 of 10.6 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 was stopping 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.

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 (e.g., 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 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.

Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA
This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2024 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

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.

*World Health Organization

 

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Source: Merck Sharp & Dohme

FAQ

What were the main results of Merck's (MRK) ZENITH trial for WINREVAIR?

WINREVAIR reduced major morbidity and mortality events by 76% compared to placebo, with only 17.4% of treated patients experiencing events versus 54.7% in placebo group.

How did WINREVAIR impact hospitalization rates in the MRK ZENITH study?

PAH-related hospitalizations occurred in only 9% of WINREVAIR-treated patients compared to 50% in the placebo group.

What safety concerns were reported for WINREVAIR in Merck's ZENITH trial?

Common side effects included bleeding events (62.8%), cutaneous telangiectasia (25.6%), and thrombocytopenia (14%). No patients discontinued treatment due to adverse events.

Why was Merck's (MRK) ZENITH trial stopped early?

The trial was stopped early due to overwhelming efficacy demonstrated in the primary endpoint, allowing participants to receive WINREVAIR through the SOTERIA open-label extension study.

What is the current approval status of Merck's WINREVAIR for PAH treatment?

WINREVAIR is currently approved in more than 40 countries based on results from the previous Phase 3 STELLAR trial.