Merck Announces Pivotal Phase 3 ZENITH Trial Evaluating WINREVAIR™ (sotatercept-csrk) Met Primary Endpoint at Interim Analysis

Rhea-AI Summary

Merck (NYSE: MRK) announced positive topline results from the Phase 3 ZENITH study of WINREVAIR in adults with pulmonary arterial hypertension (PAH) functional class III or IV at high risk of mortality. The study met its primary endpoint, demonstrating a statistically significant reduction in the risk of morbidity or mortality events compared to placebo. Due to overwhelming efficacy, the independent monitoring committee recommended early study termination, with all participants being offered WINREVAIR through the SOTERIA open-label extension study. WINREVAIR is currently approved in the U.S. and 36 countries based on Phase 3 STELLAR trial results.

Positive

• Early trial termination due to overwhelming efficacy
• Met primary endpoint with statistically significant results
• Already approved in U.S. and 36 other countries
• Balanced safety profile between treatment groups

Negative

• None.

Insights

Medical Research Analyst

The ZENITH trial results mark a significant breakthrough for Merck's WINREVAIR in treating severe PAH. The study's early termination due to overwhelming efficacy is unprecedented in PAH clinical trials. The drug demonstrated a statistically significant reduction in critical endpoints including mortality, lung transplantation and PAH-related hospitalizations.

The positive results from both STELLAR and ZENITH trials, particularly in high-risk patients with functional class III or IV PAH, strengthen WINREVAIR's position as a potential game-changer in PAH treatment. The drug's mechanism as an activin signaling inhibitor addresses the underlying disease pathology, rather than just managing symptoms. With approval already secured in 37 countries and pending in Japan, these results will likely accelerate broader global adoption and potentially establish WINREVAIR as a new standard of care for severe PAH patients.

Financial Analyst

This clinical success significantly enhances Merck's market position in the PAH therapeutics space, estimated at $6.8 billion globally. WINREVAIR's demonstrated efficacy in high-risk patients, combined with its novel mechanism of action, positions it for potential market leadership. The early trial termination due to overwhelming efficacy will likely accelerate market penetration and adoption.

The expansion into Japan, the world's second-largest pharmaceutical market, coupled with these strong Phase 3 results, suggests substantial revenue potential. Given PAH's chronic nature and the drug's efficacy profile, WINREVAIR could achieve blockbuster status, potentially generating annual peak sales exceeding $2 billion. This strengthens Merck's cardiovascular portfolio and provides a new growth driver beyond its oncology franchise.

WINREVAIR met primary endpoint of time to first morbidity or mortality event for the treatment of patients with pulmonary arterial hypertension (PAH) functional class III or IV at high risk of mortality

Study to be stopped early and participants will be offered the opportunity to receive WINREVAIR

Second positive phase 3 trial adds to growing body of evidence for WINREVAIR, an activin signaling inhibitor therapy that targets an underlying cause of PAH

RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced today positive topline results from the Phase 3 ZENITH study evaluating WINREVAIR (sotatercept-csrk) in adults with pulmonary arterial hypertension (PAH, WHO* Group 1) functional class (FC) III or IV at high risk of mortality. ZENITH met its primary endpoint of time to first morbidity or mortality event (all-cause death, lung transplantation, or PAH worsening related hospitalization of ≥ 24 hours). In the study, WINREVAIR demonstrated a statistically significant and clinically meaningful reduction in the risk of morbidity or mortality events compared to placebo, both on top of background PAH therapy. Based on the strength of these results, an independent data monitoring committee has recommended ZENITH be stopped early and all participants be offered the opportunity to receive WINREVAIR through the SOTERIA open-label extension study. In preliminary assessment, adverse events and serious adverse events were balanced between the treatment groups.

“PAH is a serious, progressive disease with a high incidence of morbidity and mortality,” said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Based on the primary endpoint demonstrating overwhelming efficacy, all ZENITH study participants will be offered the opportunity to receive WINREVAIR. These findings are impressive, set a high evidentiary bar for studies of future candidates developed for the treatment of PAH and support the potential of WINREVAIR to be practice-changing in the management of PAH.”

“The ZENITH trial was designed to evaluate whether the addition of WINREVAIR, an activin signaling inhibitor, could reduce the risk of death, lung transplantation, or PAH hospitalizations for patients living with advanced PAH,” said Dr. Vallerie McLaughlin**, Kim A Eagle MD Endowed Professor of Cardiovascular Medicine and Director, Pulmonary Hypertension Program, University of Michigan in Ann Arbor. “This is the first study in PAH in which the interim analysis led to an early conclusion of the study due to overwhelming efficacy. WINREVAIR has brought significant optimism to the field, and we thank the investigators and patients for being part of this important study.”

WINREVAIR is currently approved in the U.S. and 36 countries based on the results from the Phase 3 STELLAR trial. Most recently, in November of this year, WINREVAIR was submitted for approval in Japan based on the STELLAR trial and results from an open-label Phase 3 study in Japanese patients.

Results from ZENITH will be presented at an upcoming medical meeting and will be submitted to regulatory authorities.

*World Health Organization
** Dr. McLaughlin is an investigator in the ZENITH trial and a paid consultant to Merck.

About ZENITH

The ZENITH study (NCT04896008) is a global, double-blind, placebo-controlled clinical trial to evaluate WINREVAIR when added to maximum tolerated background PAH therapy on time to first event of all-cause death, lung transplantation, or PAH worsening related hospitalization of ≥ 24 hours, in participants with WHO FC III or IV PAH at high risk of mortality. ZENITH study inclusion criteria required Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 risk score of ≥9.

The study enrolled 172 participants, who were randomized in a 1:1 ratio to either WINREVAIR plus background PAH therapy or placebo plus background PAH therapy. The primary composite outcome measure is time to first confirmed morbidity or mortality event. Events are 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. Participants who have completed the ZENITH trial have the opportunity to receive sotatercept as part of the open-label, long-term extension study, SOTERIA (NCT04796337), consistent with that study’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, 2023 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.

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Source: Merck & Co., Inc.

FAQ

What were the results of Merck's (MRK) Phase 3 ZENITH trial for WINREVAIR?

The Phase 3 ZENITH trial met its primary endpoint, showing statistically significant reduction in morbidity and mortality events compared to placebo in PAH patients. The trial was stopped early due to overwhelming efficacy.

Where is Merck's (MRK) WINREVAIR currently approved?

WINREVAIR is currently approved in the United States and 36 other countries, based on results from the Phase 3 STELLAR trial.

What is the primary endpoint of Merck's (MRK) ZENITH trial for WINREVAIR?

The primary endpoint was time to first morbidity or mortality event, including all-cause death, lung transplantation, or PAH worsening related hospitalization of ≥ 24 hours.

What are the next steps for Merck's (MRK) WINREVAIR after the ZENITH trial?

Results from ZENITH will be presented at an upcoming medical meeting and submitted to regulatory authorities. Participants will be offered WINREVAIR through the SOTERIA open-label extension study.