Merck's Phase 3 ZENITH Trial of WINREVAIR™ (sotatercept-csrk) Meets Primary Endpoint at Interim Analysis

3 December 2024
Merck, known as MSD outside the United States and Canada, has announced promising results from its Phase 3 ZENITH study, which evaluated the efficacy of WINREVAIR (sotatercept-csrk) in treating adults with advanced pulmonary arterial hypertension (PAH), classified as WHO Group 1. The study focused on patients with high-risk functional classes III and IV. The ZENITH study successfully met its primary endpoint, demonstrating a notable reduction in the risk of morbidity or mortality events compared to a placebo when used alongside existing PAH therapies. This outcome led an independent data monitoring committee to recommend halting the study early, allowing all participants the option to receive WINREVAIR in the SOTERIA open-label extension study. Preliminary assessments indicated balanced adverse events across treatment groups.

Dr. Eliav Barr, Merck’s senior vice president and head of global clinical development, highlighted the significance of the results, emphasizing the potential of WINREVAIR to transform PAH management practices. Dr. Vallerie McLaughlin, a key investigator in the ZENITH trial and a cardiovascular medicine professor at the University of Michigan, noted the unprecedented decision to conclude the study early due to the drug's overwhelming efficacy. She expressed optimism for the future of PAH treatment based on these findings.

WINREVAIR has already received approval in the United States and 36 other countries, following the successful results from the Phase 3 STELLAR trial. Recently, it was submitted for approval in Japan based on the STELLAR trial and an additional open-label Phase 3 study involving Japanese patients. Detailed results from the ZENITH study are slated for presentation at an upcoming medical conference and will be submitted to relevant regulatory authorities.

The ZENITH study (NCT04896008) was a global, double-blind, placebo-controlled trial designed to assess the impact of adding WINREVAIR to maximum tolerated background PAH therapy. The study measured the time to the first morbidity or mortality event, defined as death from any cause, lung transplantation, or hospitalization due to PAH worsening for 24 hours or more. It enrolled 172 participants who were randomly assigned to receive either WINREVAIR in addition to their background PAH therapy or a placebo. Secondary measures included overall survival, transplant-free survival, and additional PAH-related outcomes. Participants who completed the ZENITH trial were offered the opportunity to continue receiving sotatercept in the SOTERIA long-term extension study (NCT04796337), based on eligibility.

WINREVAIR (sotatercept-csrk) is approved for subcutaneous injection in 45 mg and 60 mg doses to enhance exercise capacity, improve WHO functional class, and reduce clinical worsening events in adults with PAH. It is the first therapy of its kind, targeting activin signaling to modulate vascular proliferation and balance pro- and anti-proliferative signaling. Preclinical models demonstrated that WINREVAIR can induce cellular changes associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.

WINREVAIR comes with specific safety considerations. It can increase hemoglobin levels, potentially leading to thromboembolic events or hyperviscosity syndrome, requiring careful monitoring of hemoglobin and platelet counts. Severe bleeding incidents were reported in some clinical studies, particularly in patients on prostacyclin background therapy or antithrombotic agents. It is advised against use during pregnancy due to potential fetal harm and may impair fertility in both men and women. Common adverse reactions include headache, nosebleeds, rash, telangiectasia, diarrhea, dizziness, and erythema.

Pulmonary arterial hypertension (PAH) is a rare and progressive condition that affects around 40,000 individuals in the U.S. It is characterized by the constriction of small pulmonary arteries, leading to elevated blood pressure and significant strain on the heart. This results in limited physical activity, heart failure, and a reduced life expectancy, with a five-year mortality rate of approximately 43%.

Merck, known as MSD outside the United States and Canada, has been dedicated to advancing health solutions for over 130 years. The company focuses on developing innovative medicines and vaccines, aiming to improve global health outcomes. Through rigorous research and a commitment to diversity and sustainability, Merck continues to address pressing health challenges worldwide.

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