CADENCE (n=164, multicentre, randomized, placebo-controlled phase 2) tested sotatercept (activin signalling inhibitor) in patients with combined post- and pre-capillary pulmonary hypertension (CpcPH) in HFpEF. PVR at week 24 dropped by −1.02 Wood units (95% CI −1.81 to −0.23; p=0.004) at the 0.3 mg/kg dose and −0.75 (p=0.024) at 0.7 mg/kg. Mean PAP fell by ~9 mmHg, wedge pressure by 2.5–3 mmHg, 6-min walk improved 20.3 m at the lower dose. Proof of concept for the first therapy in CpcPH-HFpEF, a high-mortality phenotype without approved treatment. Major extension of the sotatercept (WINREVAIR) platform from PAH into HFpEF-PH. (Originally presented at ACC.26 in March; full Circulation publication during HF26.)
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.
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.
164 patients were randomized 54:55:55 to sotatercept 0.3 mg/kg, 0.7 mg/kg, and placebo (mean age 75, 70% women). Baseline median pulmonary vascular resistance was 5.2 (IQR 4.0–6.9) Wood units. The Hodges-Lehmann shift in pulmonary vascular resistance was −1.02 Wood units (95% CI −1.81 to −0.23; P=0.004) for 0.3 mg/kg and −0.75 (95% CI −1.52 to 0.03; P=0.024) for 0.7 mg/kg sotatercept. Mean pulmonary arterial pressure dropped by ~9 mmHg in both sotatercept groups, with reductions in pulmonary arterial wedge pressure of 3 and 2.5 mmHg. 6-minute walk distance improved 20.3 m at 0.3 mg/kg (95% CI 1.5–39.1) and 5.8 m at 0.7 mg/kg. Most common adverse events were increased haemoglobin and diarrhea.
These findings provide proof of concept for improved pulmonary vascular and cardiac hemodynamics following activin signalling inhibition with sotatercept in patients with CpcPH-HFpEF. The 0.3 mg/kg dose had the most attractive efficacy-safety profile for phase 3 development.
