PULSAR open-label extension: Long-term efficacy and safety of sotatercept for the treatment of pulmonary arterial hypertension (PAH)
Pulmonary arterial hypertension (PAH) is a progressive disease driven by pulmonary vascular remodeling. Sotatercept acts as a reverse-remodeling agent proposed to rebalance anti-proliferative (BMPR-II-mediated) and pro-proliferative (ActRIIA-mediated) signaling. In pre-clinical models of PAH, sotatercept reversed pulmonary arterial wall and right ventricular pathologic remodeling.
PULSAR (NCT03496207) is a phase 2, randomized, double-blind, placebo-controlled study followed by an open-label extension (OLE) period evaluating sotatercept on top of background PAH therapy in World Health Organization functional class (WHO FC) II/III PAH participants. Participants originally randomized to placebo were re-randomized 1:1 to sotatercept 0.3 or 0.7 mg/kg (placebo-crossed group). Previously treated sotatercept participants continued the same dose (continued-sotatercept group). Safety was evaluated in all participants who received at least one dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18–24 in pulmonary vascular resistance (PVR). Secondary endpoints included 6-min walk distance (6MWD) and WHO FC. Two pre-specified analyses (placebo-crossed and delayed-start) evaluated efficacy endpoints irrespective of sotatercept dose. Efficacy data at 18–24 months and cumulative safety as of 8 June 2021 are reported.
Of 106 participants initially enrolled in the PULSAR study, 97 (92%) continued into the OLE period. Serious treatment-emergent adverse events (TEAEs) were reported in 32 (31%) participants; 10 (10%) reported TEAEs leading to study discontinuation and 3 (3%) died, none considered related to study drug. The placebo-crossed group demonstrated statistically significant improvements in PVR, 6MWD and WHO FC from baseline to months 18–24 (P < 0.0001), while the continued-sotatercept group at least maintained improvement.
Sotatercept was well tolerated, and safety is consistent with previous reports. Significant clinical improvement across multiple endpoints was achieved following 12–18 months of sotatercept treatment in previous placebo participants; clinical efficacy was maintained or further enhanced in those with longer-term use. These results demonstrate the potential longer-term durability of clinical benefit with sotatercept in participants with this progressive disease.
Marc Humbert, Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique–Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France Vallerie McLaughlin, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA J. Simon R. Gibbs, National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, USA Mardi Gomberg-Maitland, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA Marius M. Hoeper, Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany Ioana R. Preston, Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, Boston, MA, USA Rogerio Souza, Pulmonary Division–Heart Institute, University of São Paulo Medical School, São Paulo, Brazil Aaron Waxman, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA Hossein-Ardeschir Ghofrani, Department of Pneumology, University of Giessen and Marburg, Giessen, Germany Pilar Escribano Subias, Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid, Spain Jeremy Feldman, Arizona Pulmonary Specialists, Phoenix, AZ, USA Gisela Meyer, Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre, Brazil David Montani, Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique–Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France Karen Olsson, Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany Solaiappan Manimaran, Janethe de Oliveira Pena, Acceleron Pharma, a wholly owned subsidiary of Merck & Co., Inc., Cambridge, MA, USA David B. Badesch, Division of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA