Sotatercept Lowers Risk of Major PAH Outcomes in Phase 3 ZENITH Trial

Late-breaking results from the Phase 3 ZENITH trial, presented at American College of Cardiology (ACC) 2025 Annual Scientific Sessions, showed sotatercept (WINREVAIR) significantly reduced the risk of major morbidity and mortality events among patients with pulmonary arterial hypertension (PAH).1

Announced by Merck, and published simultaneously in the New England Journal of Medicine, on March 31, 2025, sotatercept lowered the risk of a composite endpoint of all-cause mortality, lung transplantation, and hospitalization by approximately 76%, compared with placebo.

“The ZENITH study represents the first PAH clinical trial with a primary endpoint comprised entirely of major outcome measures – all-cause death, lung transplantation and hospitalization for PAH,” said Marc Humbert, MD, PhD, department of respiratory and intensive care medicine, Hospital Bicêtre (AP-HP), University Paris-Saclay.2 “[Sotatercept] had a significant and clinically meaningful impact on the composite of these outcomes, and together with the growing body of evidence from the clinical development program, these data support the practice-changing potential of [sotatercept] for a broad range of patients with PAH.”

The US Food and Drug Administration (FDA) approved sotatercept subcutaneous injection 45 or 60 mg for the treatment of PAH in March 2024, becoming the first active signaling inhibitor therapy approved to treat PAH.3 Based on results from the STELLAR trial, sotatercept was targeted to boost exercise capacity, improve World Health Organization (WHO) functional class (FC), and lower the risk of clinical worsening events.

In ZENITH, sotatercept was compared with placebo among patients with PAH FC III or IV at a raised mortality risk on maximally tolerated background therapy.1 In November 2024, Merck previously announced the trial was halted early given overwhelming efficacy cited by an independent data monitoring board.

The pivotal Phase 3 multicenter, double-blind, placebo-controlled ZENITH trial randomized 172 participants on maximally tolerated background PAH therapy in a 1:1 ratio to sotatercept (n = 86) once every 6 weeks at 0.3 mg/kg at Visit 1 and 0.7 mg/kg at all subsequent visits, or placebo (n = 86). Patients were 87% White, 77% female, and had a mean age of 54.4 years.

With a median follow-up of 10.6 months, sotatercept lowered the relative risk of major morbidity and mortality, or the composite endpoint of all-cause mortality, lung transplantation, and PAH-worsening hospitalization, by 76% (hazard ratio [HR], 0.24 [95% CI, 0.13-0.43]; P <.0001), compared with placebo. Examined as standalone outcomes, the components of the primary composite endpoint was directionally consistent with the overall treatment effect.

Approximately 17.4% (n = 15 of 86) of the patient cohort experienced ≥1 major morbidity or mortality events, compared with 54.7% (n = 47 of 86) of patients in the placebo arm (HR, 0.24; 95% CI, 0.13 to 0.43; P <0.001 The overall safety profile of sotatercept remained consistent with previous study data and no patients on sotatercept discontinued treatment due to an adverse event.

Adverse events occurring more frequently with sotatercept versus placebo were cutaneous telangiectasia (25.6% vs 3.5%), increased hemoglobin (12.8% vs 1.2%), and thrombocytopenia (14% vs 8.1%). All-cause death occurred in 7 patients (8.1%) in the sotatercept group and in 13 patients (15.1%) in the placebo group; lung transplantation in 1 (1.2%) and 6 patients (7.0%), and hospitalization for worsening pulmonary arterial hypertension in 8 (9.3%) and 43 patients (50.0%), respectively.

“These results led to the ZENITH study being the first PAH clinical trial stopped early due to overwhelming efficacy, representing an important milestone in clinical research with promise for the PAH community,” said Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories.2

As the trial was halted early, key second endpoints of overall survival did not attain the threshold (P <.0021) required to establish statistical significance at the interim analysis (HR, 0.42 [95% CI, 0.17-1.07]; P =.0313).1 Other secondary endpoints, including transplant-free survival, showed numerical improvement for those on sotatercept, but were not tested due to the hierarchical strategy.

In January 2025, Merck announced the Phase 3 HYPERION study assessing sotatercept added to background therapy among individuals with PAH FC II or III at intermediate or high risk of disease progression was halted early for final analysis.4 Participants could continue on open-label sotatercept in the SOTERIA extension study.

References

1. Humbert M, McLaughlin VV, Badesch DB. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. The New England Journal of Medicine. March 31, 2025. Accessed April 1, 2025. https://www.nejm.org/doi/full/10.1056/NEJMoa2415160.

2. WINREVAIRTM (sotatercept-csrk) reduced the risk of a composite of all-cause death, lung transplantation and hospitalization for pulmonary arterial hypertension (PAH) by 76% compared to placebo in the phase 3 zenith trial. Merck.com. April 1, 2025. Accessed April 1, 2025. https://www.merck.com/news/winrevair-sotatercept-csrk-reduced-the-risk-of-a-composite-of-all-cause-death-lung-transplantation-and-hospitalization-for-pulmonary-arterial-hypertension-pah-by-76-compared-to-placebo-i/.

3. Campbell P. FDA approves Sotatercept (Winrevair) for Pulmonary arterial hypertension. HCP Live. June 30, 2024. Accessed April 1, 2025. https://www.hcplive.com/view/fda-approves-sotatercept-winrevair-for-pulmonary-arterial-hypertension.

4. Iapoce C. Merck halts phase 3 hyperion trial of sotatercept for final analysis. HCP Live. January 30, 2025. Accessed April 1, 2025. https://www.hcplive.com/view/merck-halts-phase-3-hyperion-trial-of-sotatercept-for-final-analysis.