• Marius M Hoeper, David B Badesch, H Ardeschir Ghofrani, GibbsJ Simon RJSRFrom the Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Member of the German Center for Lung Research, Biomedical Research in End-Stage and Obstructive Lung Disease Hannover, Hannover (M.M.H., K.M.O.), Mardi Gomberg-Maitland, Vallerie V McLaughlin, Ioana R Preston, Rogerio Souza, Aaron B Waxman, Ekkehard Grünig, Grzegorz Kopeć, Gisela Meyer, Karen M Olsson, Stephan Rosenkranz, Yayun Xu, Barry Miller, Marcie Fowler, John Butler, Joerg Koglin, Janethe de Oliveira Pena, Marc Humbert, and STELLAR Trial Investigators.
• From the Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Member of the German Center for Lung Research, Biomedical Research in End-Stage and Obstructive Lung Disease Hannover, Hannover (M.M.H., K.M.O.), the Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Institute for Lung Health, Cardio-Pulmonary Institute, Member of the German Center for Lung Research, Giessen (H.A.G.), Thoraxklinik-Heidelberg and the German Center for Lung Research, Heidelberg (E.G.), and the Department of Cardiology, Heart Center, University Hospital Cologne, Cologne (S.R.) - all in Germany; the University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.); the National Heart and Lung Institute, Imperial College London, London (J.S.R.G.); George Washington University, Washington, DC (M.G.-M.); the University of Michigan, Ann Arbor (V.V.M.); Tufts Medical Center (I.R.P.) and Brigham and Women's Hospital (A.B.W.) - both in Boston; Instituto do Coração, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo (R.S.), and Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre (G.M.) - both in Brazil; the Pulmonary Circulation Center, Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital in Krakow, Krakow, Poland (G.K.); Merck (Y.X., J.K.) and Acceleron Pharma (B.M., M.F., J.B., J.O.P.) - both in Rahway, NJ; and Université Paris-Saclay, INSERM Unité Mixte de Recherche en Santé 999, Hôpital Bicêtre (Assistance Publique-Hôpitaux de Paris), Le Kremlin-Bicêtre, France (M.H.).
• N. Engl. J. Med. 2023 Apr 20; 388 (16): 147814901478-1490.

BackgroundPulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension.MethodsWe conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit.ResultsA total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.ConclusionsIn patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).Copyright © 2023 Massachusetts Medical Society.

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