Consistent Safety and Efficacy of Sotatercept for Pulmonary Arterial Hypertension in BMPR2 Mutation Carriers and Noncarriers: A Planned Analysis of Phase 2, Double-Blind, Placebo-controlled Clinical Trial (PULSAR)

To evaluate the effect of genetic variant status on sotatercept efficacy and effect of sotatercept treatment on biomarkers in pulmonary arterial hypertension Methods: PULSAR (NCT03496207) was a phase 2, randomized, controlled study of sotatercept vs placebo added to background therapy for pulmonary arterial hypertension. Participants had DNA sequencing done at baseline to detect genetic variants in disease-associated genes (ACVRL1, BMPR2, CAV1, EIF2AK4, ENG, KCNA3, KCNK3, and SMAD9). Safety (adverse events) and efficacy (pulmonary vascular resistance, 6-minute walk distance) were assessed by variant status and treatment at 24 weeks. Serum levels of BMPR2 mRNA and N-terminal pro-hormone B-type natriuretic peptide were assessed at baseline and 24 weeks by treatment and variant status. Analysis of covariance was used to compare the change from baseline by treatment and variant status. Of 76 participants included, 25 had pathogenic variants detected (23 BMPR2; 2 other) and 51 had no variants or variants of uncertain significance. BMPR2 mutation carriers were younger and more frequently on triple therapy but had less severe clinical characteristics at baseline. Changes at 24 weeks in pulmonary vascular resistance and 6-minute walk distance did not differ by variant status. BMPR2 gene expression varied less than twofold from baseline over time, irrespective of treatment or variant status. The adverse events profile was generally consistent with that seen in the parent PULSAR study. These results suggest consistent safety and clinical efficacy of sotatercept for treatment of pulmonary arterial hypertension, irrespective of BMPR2 variant status. Clinical trial registration available at www. gov, ID: NCT03496207.