Merck's WINREVAIR™ (sotatercept-csrk) has achieved a significant milestone in the treatment of advanced pulmonary arterial hypertension (PAH). The Phase 3 ZENITH trial, designed to evaluate WINREVAIR's ability to reduce the risk of death, lung transplantation, or PAH-related hospitalizations, was stopped early due to overwhelming efficacy. This outcome marks a potentially practice-changing advancement for patients with this serious and progressive disease.
The global, double-blind, placebo-controlled ZENITH trial enrolled 172 participants with WHO FC III or IV PAH at high risk of mortality, indicated by a REVEAL Lite 2.0 risk score of ≥9. Participants were randomized 1:1 to receive either WINREVAIR plus background PAH therapy or placebo plus background PAH therapy. The primary composite outcome measured was time to first confirmed morbidity or mortality event, defined as all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥ 24 hours.
"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."
Current Treatment Landscape and WINREVAIR's Novel Approach
Pulmonary arterial hypertension (PAH) is characterized by the constriction of small pulmonary arteries, leading to 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%.
WINREVAIR is the first activin signaling inhibitor therapy approved for PAH. It works by improving the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation. Preclinical models have shown that WINREVAIR induces cellular changes associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.
Regulatory Status and Future Plans
WINREVAIR is currently approved in the U.S. and 36 countries based on results from the Phase 3 STELLAR trial. A submission for approval in Japan has also been made based on the STELLAR trial and an open-label Phase 3 study in Japanese patients. Data from the ZENITH trial will be presented at an upcoming medical meeting and submitted to regulatory authorities.
Safety Considerations
WINREVAIR carries warnings and precautions regarding potential increases in hemoglobin, decreases in platelet count, bleeding risk, fetal harm, and potential effects on fertility. Common adverse reactions observed in the Phase 3 clinical trial included headache, epistaxis, rash, telangiectasia, diarrhea, dizziness, and erythema. Monitoring of hemoglobin and platelet counts is recommended during treatment.
