Sotatercept Reduces Risk of Death, Transplant, or Hospitalization in Advanced PAH

Among high-risk adults with pulmonary arterial hypertension (PAH), treatment with sotatercept (Winrevair; Merck) significantly reduced the risk of death, lung transplantation, or prolonged hospitalization due to worsening PAH compared with placebo, according to results from the phase 3 ZENITH trial.¹

The new findings were presented today at the American College of Cardiology 2025 Annual Scientific Session (ACC.25) and published simultaneously in The New England Journal of Medicine.² The study was funded by Merck.

Despite the use of maximal background therapy, patients receiving sotatercept had a 76% relative risk reduction in a composite of major morbidity and mortality events compared with patients taking placebo (HR, 0.24; 95% CI, 0.13-0.43; P < .0001) despite maximal background therapy.¹ At a median follow-up of 10.6 months, 17.4% of patients treated with sotatercept experienced at least 1 of these events, compared with 54.7% in the placebo group.

Marc Humbert, MD, PhD | Image credit: European Lung Foundation

“On the basis of this result, the data monitoring committee recommended stopping the trial early for efficacy, a highly unusual occurrence for a randomized, placebo-controlled trial involving patients with pulmonary arterial hypertension,” the researchers said.²

According to a Merck press release, ZENITH is the first PAH trial to use a composite primary end point comprised solely of these 3 major outcomes rather than softer clinical worsening measures such as functional class deterioration or decreased exercise capacity.³

Sotatercept is a first-in-class activin signaling inhibitor that targets the underlying vascular remodeling in PAH. In the ZENITH trial, 172 patients with World Health Organization functional class 3 or 4 PAH at high risk of mortality—defined by a REVEAL Lite 2.0 score of 9 or higher—were randomized 1:1 to receive sotatercept or placebo in addition to their maximum tolerated background therapy, which included double or triple combination therapy in all participants.¹

Each individual component of the composite endpoint favored sotatercept. Death occurred in 8.1% of patients in the sotatercept group vs 15.1% in the placebo group. Lung transplantation occurred in 1.2% vs 7.0% of patients, and PAH-related hospitalizations occurred in 9.3% vs 50.0%, respectively.

The study population had a mean age of 54.4 years and was predominantly female (77%). Baseline characteristics, including 6-minute walk distance, pulmonary vascular, and NT-proBNP levels, indicated advanced disease despite background therapy.

While the trial met its primary end point, the key secondary end point of overall survival did not meet the prespecified statistical threshold for significance (HR, 0.42; 95% CI, 0.17-1.07; P = .0313). As a result, subsequent secondary end points were not formally tested, although descriptive results generally favored sotatercept.

Safety findings were consistent with prior studies. With 86 patients in each treatment arm, adverse events (AEs) occurred in nearly all participants, with a higher incidence of treatment-related events in the sotatercept arm than placebo (65.1% vs 32.6%). Common AEs that impacted the treatment group more included:

• Epistaxis (44.2% vs 9.3%)
• Telangiectasia (25.6% vs 3.5%)
• Gingival bleeding (10.5% vs 2.3%)
• Vomiting (12.8% vs 5.8%)
• Back pain (10.5% vs 4.7%)

Serious AEs were reported in 53.5% of the sotatercept group compared with 64.0% in the placebo group, but only 5 of these cases total were connected to treatment, and no patients discontinued sotatercept due to AEs.

Marc Humbert, MD, PhD, dean of the medical school and professor of respiratory medicine at the University Paris-Saclay and Inserm in France, presented these findings at ACC.25 with 2 other updates: the continuation of the SOTERIA study in assessing long-term safety, and the discontinuation of the HYPERION study due to the “loss of clinical equipoise” for additional placebo-controlled research of sotatercept in PAH. All participants who completed the ZENITH trial were offered access to the open-label SOTERIA extension study, according to Merck.

References

1. Humbert M, McLaughlin VV, Badesch DB, et al. Efficacy and safety of sotatercept in high-risk patients with pulmonary arterial hypertension: results from ZENITH phase 3 trial. Abstract presented at: ACC.25; March 31, 2025; Chicago, IL.
2. Humbert M, McLaughlin VV, Badesch DB, et al. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med. Published online March 31, 2025. doi:10.1056/NEJMoa2415160
3. 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 in the phase 3 ZENITH trial. News release. Merck. March 31, 2025. Accessed March 31, 2025.