Rationale and design of the CADENCE trial: evaluating sotatercept in Cpc-PH secondary to HFpEF

Abstract Background/Introduction Combined post- and precapillary pulmonary hypertension (Cpc-PH) complicates heart failure with preserved ejection fraction (HFpEF), contributing to an increase in morbidity and mortality. There is no approved therapy for this condition, in addition to recommended treatment for the underlying disorder. Sotatercept, a first-in-class activin signaling inhibitor, may offer a novel therapeutic approach. Purpose The ongoing CADENCE trial evaluates the efficacy and safety of sotatercept in Cpc-PH associated with HFpEF, aiming to improve clinical outcomes. Methods This phase 2, randomized, double-blind, placebo-controlled study enrolled approximately 150 adults (18-85 years) with Cpc-PH associated with HFpEF, who were on stable doses (≥30 days) of guideline-directed medical therapies for HF and other chronic conditions. Inclusion criteria mandated left ventricular ejection fraction (LVEF) ≥50%, mean pulmonary artery pressure (mPAP) >20 mmHg, pulmonary vascular resistance (PVR) ≥4 Wood units, and pulmonary artery wedge pressure (PAWP) >15 mmHg but <30 mmHg. Participants were also required to have New York Heart Association functional class (NYHA-FC) II or III and a 6-minute walk distance (6MWD) ≥100 m. Key exclusion criteria included significant lung disease, severe valvular conditions, uncontrolled hypertension, recent coronary events, and prior use of PAH-related therapies. Participants were stratified by NYHA-FC and randomized 1:1:1 to receive subcutaneous sotatercept (0.3 mg/kg or 0.3 mg/kg escalating to 0.7 mg/kg) or placebo every 3 weeks for 24 weeks. The primary endpoint is the change in PVR at week 24, with 6MWD a key secondary endpoint. Other secondary endpoints include time-to-clinical worsening (TTCW; a composite endpoint of all-cause mortality, heart failure- or PH-related hospitalizations, intravenous diuretic initiation, or ≥15% decrease in 6MWD), echocardiographic and hemodynamic parameters, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and NYHA-FC. Exploratory outcomes include patient-reported outcomes and biomarkers. An interim analysis is planned. Those initially assigned to placebo will be re-randomized to one of the sotatercept dose groups in an open-label extension study. An independent data monitoring committee (DMC) oversees periodic safety reviews. Conclusion The ongoing CADENCE trial aims to demonstrate whether sotatercept improves pulmonary hemodynamics, exercise capacity, and reduces risk of fatal and non-fatal clinical worsening events in patients with Cpc-PH associated with HFpEF, potentially addressing a need for effective treatments in this high-risk population.