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

Background: Combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH–HFpEF) 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: 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 [IQR] 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 meters (95% CI, 1.5–39.1) for 0.3 mg/kg and 5.8 meters (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 following activin signalling inhibition with sotatercept in patients with CpcPH–HFpEF.