Sotatercept for Combined Post- and Precapillary Pulmonary Hypertension Associated With Heart Failure: Results From the Phase 2, Randomized, Placebo-Controlled CADENCE Study

Abstract

BACKGROUND: Combined post- and precapillary pulmonary hypertension in heart failure with preserved ejection fraction involves remodeling in both the heart and pulmonary vasculature. Despite significant mortality, there are no proven therapies. METHODS: In this multicenter, randomized, placebo-controlled, phase 2 trial, adults received sotatercept (0.3 or 0.7 mg/kg) or placebo every 3 weeks. The primary end point was change in pulmonary vascular resistance at week 24. Hodges-Lehmann shift estimates described placebo-adjusted changes. RESULTS: A total of 164 patients were randomized 54:55:55 to sotatercept 0.3 mg/kg, 0.7 mg/kg, and placebo, and baseline median pulmonary vascular resistance was 5.2 (interquartile range, 4.0–6.9) Wood units. The median change from baseline in pulmonary vascular resistance at week 24 was −0.67 Wood units in the sotatercept 0.3 mg/kg group, −0.33 Wood units in the sotatercept 0.7 mg/kg group, and 0.26 Wood units in the placebo group. The Hodges-Lehmann shift estimates in pulmonary vascular resistance were −1.02 Wood units (95% CI, −1.81 to −0.23; P =0.004) for 0.3 mg/kg and −0.75 Wood units (95% CI, −1.52 to 0.03; P =0.024) for 0.7 mg/kg sotatercept. Reductions were observed in mean pulmonary arterial pressure (0.3 and 0.7 mg/kg: −9.19 mm Hg [95% CI, −13.00 to −5.38] and −9.22 [95% CI, −12.97 to −5.46]) and pulmonary arterial wedge pressure (0.3 and 0.7 mg/kg: −3.04 mm Hg [95% CI, −5.77 to −0.32] and −2.53 [95% CI, −5.33 to 0.28]). Changes in 6-minute walk distance were 20.3 m (95% CI, 1.5–39.1) for 0.3 mg/kg and 5.8 m (95% CI, −17.3 to 28.9) for 0.7 mg/kg sotatercept. The most common adverse events with sotatercept (both groups) were increased hemoglobin and diarrhea. CONCLUSIONS: These findings provide proof of concept for improved pulmonary vascular and cardiac hemodynamics after activin signaling inhibition with sotatercept in patients with combined post- and precapillary pulmonary hypertension in heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04945460.