Sotatercept improves exercise capacity and delays the time to clinical worsening in patients with World Health Organization (WHO) functional class II or III pulmonary arterial hypertension. The effects of add-on sotatercept in patients with advanced pulmonary arterial hypertension and a high risk of death are unclear.

In this phase 3 trial, we randomly assigned patients with pulmonary arterial hypertension (WHO functional class III or IV) and a high 1-year risk of death (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management Lite 2 risk score, ≥9) who were receiving the maximum tolerated dose of background therapy to receive add-on sotatercept (starting dose, 0.3 mg per kilogram of body weight; escalated to target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was a composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening pulmonary arterial hypertension, assessed in a time-to-first-event analysis.

A total of 172 patients were included (86 each in the sotatercept and placebo groups). The trial was stopped early on the basis of the efficacy results of a prespecified interim analysis. At least one primary end-point event occurred in 15 patients (17.4%) in the sotatercept group and in 47 patients (54.7%) in the placebo group (hazard ratio, 0.24; 95% confidence interval, 0.13 to 0.43; P<0.001). Death from any cause occurred in 7 patients (8.1%) in the sotatercept group and in 13 patients (15.1%) in the placebo group; lung transplantation in 1 patient (1.2%) and 6 patients (7.0%), respectively; and hospitalization for worsening pulmonary arterial hypertension in 8 patients (9.3%) and 43 patients (50.0%). The most common adverse events with sotatercept were epistaxis and telangiectasia.

Among high-risk adults with pulmonary arterial hypertension who were receiving the maximum tolerated dose of background therapy, treatment with sotatercept resulted in a lower risk of a composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening pulmonary arterial hypertension than placebo. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; ZENITH ClinicalTrials.gov number, NCT04896008.).