Merck (NYSE: MRK) has announced positive topline results from the Phase 3 ZENITH trial, 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. The study met its primary endpoint, demonstrating 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.
ZENITH Trial Details
The ZENITH study (NCT04896008) is a global, double-blind, placebo-controlled clinical trial designed to evaluate WINREVAIR in addition to maximum tolerated background PAH therapy. The primary composite outcome measure was time to first confirmed morbidity or mortality event, defined as all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥ 24 hours. The study enrolled 172 participants, randomized 1:1 to either WINREVAIR plus background therapy or placebo plus background therapy. Inclusion criteria required a Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 risk score of ≥9.
Clinical Significance
"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."
Mechanism of Action
WINREVAIR is the first activin signaling inhibitor therapy approved for PAH. It improves the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation. Preclinical models showed WINREVAIR induced cellular changes associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.
Current Status and Future Plans
WINREVAIR is currently approved in the U.S. and 36 countries based on the results from the Phase 3 STELLAR trial. Merck recently submitted WINREVAIR 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 submitted to regulatory authorities. Participants who completed the ZENITH trial have the opportunity to receive sotatercept as part of the open-label, long-term extension study, SOTERIA (NCT04796337).
Safety Information
WINREVAIR may increase hemoglobin and decrease platelet count, requiring monitoring and potential dose adjustments. It may also cause fetal harm and affect fertility. Common adverse reactions include headache, epistaxis, rash, telangiectasia, diarrhea, dizziness, and erythema. Breastfeeding is not recommended during treatment and for 4 months after the final dose.
