A1185 - PULSAR Study Open-Label Extension: Interim Results from a Phase 2 Study of the Efficacy and Safety of Sotatercept When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)
Author Block: D. B. Badesch¹, S. Gibbs², M. Gomberg-Maitland³, M. M. Hoeper⁴, V. V. McLaughlin⁵, I. Preston⁶, R. Souza⁷, A. B. Waxman⁸, S. Manimaran⁹, J. Barnes⁹, J. de Oliveira Pena⁹, M. Humbert¹⁰; ¹University of Colorado, Aurora, CO, United States, ²National Heart & Lung Institute, Imperial College, London, United Kingdom, ³GWMFA- Heart and Vascular Institute, George Washington University, Washington DC, DC, United States, ⁴Department of Respiratory Medicine, Hannover Medical School and German Center of Lung Research, Hannover, Germany, ⁵University of Michigan, Ann Arbor, MI, United States, ⁶Tufts Medical Center, Boston, MA, United States, ⁷InCor, University of Sao Paulo, Sao Paulo, Brazil, ⁸Pulm Crit Care Med, Brigham and Woman's Hosp, Boston, MA, United States, ⁹Acceleron Pharma, Cambridge, MA, United States, ¹⁰Assistance Publique Hopitaux de Paris, University of Paris-Saclay, Le Kremlin-Bicêtre, France.
Background: PAH is characterized by pulmonary vascular remodeling, resulting in increased pulmonary artery pressure (PAP) and progressive right ventricular dysfunction. Disruptions in transforming growth factor-β and bone morphogenetic protein signaling are associated with PAH. Novel therapies are needed that target these underlying mechanisms of vascular remodeling to attenuate disease development and progression. Sotatercept is a novel first-in-class fusion protein that is proposed to act by rebalancing signaling between these pro-and anti-proliferative pathways. Preclinically, sotatercept has been shown to reverse vascular muscularization, normalize PAP, and improve right ventricular function. The PULSAR study (NCT03496207) released positive topline 24-week results. Here we report interim safety and efficacy of sotatercept for the treatment of PAH up to 48 weeks, including patients who were re-randomized to sotatercept after the primary placebo-controlled treatment period. Methods: 106 WHO Group 1 PAH patients were enrolled with: WHO functional class (FC)II-III; age ≥18; baseline pulmonary vascular resistance of ≥5 Wood units by right heart catheterization; 6MWD of 150-550meters; stable PAH standard of care (SOC) therapy. Sotatercept was administered by subcutaneous injection every 21 days for a 24-week double-blind, placebo-controlled treatment period in 3 treatment arms: placebo+SOC, 0.3mg/kg sotatercept+SOC, 0.7mg/kg sotatercept+SOC. The extension period is ongoing in which sotatercept-treated patients maintain their current dose level, and placebo-treated patients were re-randomized 1:1 to 0.3mg/kg sotatercept+SOC or 0.7mg/kg sotatercept+SOC. Results: Continuation of sotatercept treatment for up to 48 weeks maintained or further enhanced the improvements observed in 6MWD, NT-proBNP levels, and change in WHO FC at 24 weeks versus baseline (Table 1). Patients re-randomized from placebo+SOC to sotatercept+SOC showed improvements in 6MWD, NT-proBNP levels, and change in WHO FC at 48 weeks compared to 24 weeks and baseline. Cumulatively during the trial, 30/106(28.3%) patients reported serious treatment-emergent adverse events (TEAEs); 9(8.5%) TEAEs led to study discontinuation; 2(1.9%) TEAEs led to death. Conclusions: In this first report of the open-label extension period of PULSAR, continued sotatercept treatment in patients with PAH suggests that clinical efficacy is maintained across multiple study endpoints for up to 48 weeks. Improvements observed in patients re-randomized from the placebo group to sotatercept treatment aligns with the initial results from the placebo-controlled treatment period. Importantly, placebo assignment did not affect the ability to respond after 24 weeks. Safety was consistent with previous reports in PAH and other patient populations. These longer-term results highlight the versatility of sotatercept as a new treatment for PAH.