Sotatercept for Pulmonary Arterial Hypertension within the First Year after Diagnosis

Vallerie V. McLaughlin, University of Michigan Medical School, Ann Arbor.
Marius M. Hoeper, Hannover Medical School and the German Center for Lung Research, Hannover, Germany.
David B. Badesch, University of Colorado, Anschutz Medical Campus, Aurora.
H Ardeschir Ghofrani, Department of Internal Medicine, Justus-Liebig University Giessen, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany.
J Simon Gibbs, National Heart and Lung Institute, Imperial College London, London.
Mardi Gomberg-Maitland, George Washington University School of Medicine and Health Sciences, Washington, DC.
Ioana R. Preston, Lahey Hospital and Medical Center, Burlington, MA.
Rogerio Souza, Instituto do Coração, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo.
Aaron B. Waxman, Brigham and Woman's Hospital, Harvard Medical School, Boston.
Grzegorz Kopeć, Department of Cardiac and Vascular Diseases, St. John Paul II Hospital in Krakow, Krakow, Poland.
Gisela Meyer, Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil.
Karen M. Olsson, Hannover Medical School and the German Center for Lung Research, Hannover, Germany.
Wei Fu, Merck, Rahway, NJ.
Yaru Shi, Merck, Rahway, NJ.
Barry Miller, Merck, Rahway, NJ.
Samuel S. Kim, Merck, Rahway, NJ.
Harald S. Mackenzie, Merck, Rahway, NJ.
Michela Brambatti, Merck, Rahway, NJ.
Mahesh J. Patel, Merck, Rahway, NJ.
Joerg Koglin, Merck, Rahway, NJ.
Alexandra G. Cornell, Merck, Rahway, NJ.
Marc Humbert, Université Paris-Saclay, INSERM Unité Mixte de Recherche en Santé 999, Hypertension Pulmonaire, Physiopathologie et Innovation Thérapeutique, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre (Assistance Publique-Hôpitaux de Paris), European Reference Network for Rare Respiratory Diseases, Le Kremlin-Bicêtre, France.

Document Type

Journal Article

Publication Date

9-30-2025

Journal

The New England journal of medicine

DOI

10.1056/NEJMoa2508170

Abstract

BACKGROUND: Sotatercept, an activin-signaling inhibitor, reduces morbidity and mortality among patients with long-standing pulmonary arterial hypertension. Its effects in patients with pulmonary arterial hypertension within the first year after diagnosis are unclear. METHODS: In this phase 3 trial, we enrolled adult patients with World Health Organization functional class II or III pulmonary arterial hypertension who had received the diagnosis less than 1 year earlier, had an intermediate or high risk of death, and were receiving double or triple background therapy. Patients were randomly assigned to receive add-on therapy with subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; escalated to target dose, 0.7 mg per kilogram) or placebo every 21 days. The primary end point was clinical worsening, a composite of death from any cause, unplanned hospitalization lasting at least 24 hours for worsening of pulmonary arterial hypertension, atrial septostomy, lung transplantation, or deterioration in performance in exercise testing due to pulmonary arterial hypertension, assessed in a time-to-first-event analysis. RESULTS: The trial was stopped early owing to loss of clinical equipoise after the reporting of positive results from previous sotatercept trials. A total of 320 patients were included (160 each in the sotatercept and placebo groups). The median duration of follow-up was 13.2 months. At least one primary end-point event occurred in 17 patients (10.6%) in the sotatercept group and in 59 patients (36.9%) in the placebo group (hazard ratio, 0.24; 95% confidence interval, 0.14 to 0.41; P<0.001). Deterioration in performance in exercise testing due to pulmonary arterial hypertension occurred in 8 patients (5.0%) in the sotatercept group and in 46 patients (28.8%) in the placebo group; unplanned hospitalization for worsening of pulmonary arterial hypertension occurred in 3 patients (1.9%) and 14 patients (8.8%), respectively; and death from any cause occurred in 7 patients (4.4%) and 6 patients (3.8%). No cases of atrial septostomy or lung transplantation occurred. The most common adverse events with sotatercept were epistaxis (31.9%) and telangiectasia (26.2%). CONCLUSIONS: Among adults with pulmonary arterial hypertension who had received the diagnosis less than 1 year earlier, the addition of sotatercept to background therapy resulted in a lower risk of clinical worsening than placebo. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; HYPERION ClinicalTrials.gov number, NCT04811092.).

Department

Medicine

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