Pulmonary arterial hypertension (PAH) is a rare and severe lung disease with a life-threatening prognosis. After several positive trials, a recent study has confirmed the efficacy of a biotherapy, sotatercept. These promising results for patients were presented at the American College of Cardiology 2025 Annual Scientific Session (ACC.25) by Marc Humbert, professor at Université Paris-Saclay, head of the Pneumology Department at Bicêtre Hospital (AP-HP), director of the joint research unit for Pulmonary Hypertension: Pathophysiology and Novel Therapies (UMR 999 – Univ. Paris-Saclay/Inserm) and coordinator of the French Pulmonary Hypertension reference centre.

Pulmonary arterial hypertension (PAH) causes gradual shortness of breath at exercise and then at rest, fainting or even syncope, and can be life-threatening. It is caused by an abnormal increase in blood pressure in the arteries running from the right side of the heart to the lungs. Over time, the small pulmonary arteries thicken and become blocked due to a progressive accumulation of cells in the vascular wall. Sotatercept works as an “activin receptor ligand trap” and aims to restore pulmonary vascular homeostasis by preventing the excessive activation of vascular proliferation pathways.

A previous phase 3 trial (which allowed for a potential market launch to be considered) had already produced positive results, but a new trial, named ZENITH, offers new hope for high-risk patients despite receiving maximal background therapy for PAH. It has just demonstrated the efficacy of sotatercept, a drug marketed by Merck, in significantly reducing the risk of death, lung transplantation or prolonged hospitalization for more than 24 hours compared with placebo. As early as the interim analysis, which was scheduled after 50% of the events planned within the framework of the trial, it was demonstrated that patients receiving sotatercept had a 76% relative risk reduction in morbidity and mortality events compared with patients taking placebo. At a median follow-up of less than one year, 17.4% of patients treated with sotatercept experienced at least one of these events, compared with 54.7% in the placebo group (p

The trial has shown that adding sotatercept to the maximum-tolerated standard treatment for PAH reduces the risk of death or clinical worsening events and improves exercise capacity and functional class compared with standard PAH treatments alone,”

Prof Marc Humbert, Director of the Pulmonary Hypertension Reference Centre, AP-HP, Université Paris-Saclay

Based on these results and for ethical reasons, the study was stopped early by an independent monitoring committee to give patients receiving placebo the opportunity to replace it with sotatercept, to avoid compromising their chances of benefiting from effective treatment. This is the first time in the field of PAH treatment trials that an interim analysis has required a study to be stopped due to efficacy.

The findings were presented at the American College of Cardiology 2025 Annual Scientific Session (ACC.25) and published simultaneously in The New England Journal of Medicine.