ZENITH Trial Breakthrough: Winrevair Shows Significant Impact on Outcomes of Pulmonary Arterial Hypertension
USA: In patients with advanced pulmonary arterial hypertension (PAH), adding the biologic sotatercept-csrk (Winrevair; Merck) to the maximum tolerated background therapy significantly lowers the risk of death compared to background therapy alone, as shown by the top-line results of the ZENITH trial.
Merck announced yesterday that an interim analysis of the ZENITH trial confirmed it had achieved its primary endpoint, which measured the time to the first morbidity or mortality event. Following this finding, the trial's independent data monitoring committee recommended ending the phase III trial early to enable all participants to transition into an open-label extension study and access the drug.
The ZENITH trial enrolled 172 patients with PAH classified as WHO Functional Class III or IV. Participants were randomized to receive either WINREVAIR or a placebo alongside their maximum tolerated PAH therapy. The study's primary endpoint was the time to the first morbidity or mortality event, defined as all-cause death, lung transplantation, or PAH-related hospitalization lasting 24 hours or more. Secondary measures included overall survival and transplant-free survival.
An interim analysis revealed statistically significant and clinically meaningful results. Compared to placebo, sotatercept reduced the risk of morbidity and mortality events, prompting an independent data monitoring committee to recommend early trial termination. This decision allows all participants to transition to an open-label extension study, SOTERIA, ensuring continued access to the drug.
WINREVAIR’s mechanism of action as an activin signaling inhibitor is groundbreaking. Modulating vascular proliferation restores the balance between pro- and antiproliferative signals, addressing a key aspect of PAH pathophysiology. Based on data from the STELLAR trial, this innovative approach has already led to regulatory approval in the U.S. and 36 other countries.
The STELLAR study had previously demonstrated sotatercept’s effectiveness in improving exercise capacity, as measured by a 6-minute walk test while reducing mortality and clinical worsening rates. Building on this foundation, the ZENITH trial has provided robust evidence of the drug’s impact on survival outcomes.
Adverse events in ZENITH were balanced between the treatment and placebo groups, reinforcing the safety profile of sotatercept. According to Merck, the results set a new standard for PAH treatment, offering hope to patients who face limited therapeutic options.
Dr. Vallerie McLaughlin, an investigator in the ZENITH trial, noted that the findings represent a significant milestone. "This is the first study in PAH where overwhelming efficacy led to early trial termination, bringing optimism to the field,” she remarked.
Full results from ZENITH will be presented at an upcoming medical conference and are expected to inform further regulatory submissions. With its potential to transform PAH management, WINREVAIR continues to garner attention as a pivotal development in cardiopulmonary medicine.
