Sotatercept May Promote Broad Cardiac Remodeling in Addition to Pulmonary Vascular Benefit

Sotatercept may provide broad and favorable cardiac remodeling on top of pulmonary vascular effects in patients with combined post- and pre-capillary pulmonary hypertension with heart failure with preserved ejection fraction (CpcPH-HFpEF), according to an analysis of CADENCE.1

These data were presented at the American Heart Association (AHA) Scientific Sessions 2026 in Chicago, Illinois, by Ryan Tedford, MD, the Dr. Peter C. Gazes Endowed Chair in Heart Failure and professor of medicine/cardiology at the Medical University of South Carolina, as well as the deputy editor of Circulation.1

“The take-home message is that we really like what we’re seeing,” Tedford told HCPLive in an exclusive interview. “This is a huge population with a huge unmet need – we know that it’s associated with high morbidity and mortality, and so the ability to not only potentially target the pulmonary circulation, but also to have favorable benefits on the left side of the heart as well as the right, I think is very fascinating.”

CADENCE was a multicenter, randomized, placebo-controlled phase 2 trial comparing sotatercept 0.3 or 0.7 mg/kg to placebo in patients with CpcPH-HFpEF. Patients were required to have a clinical diagnosis of HFpEF and demonstrate Cpc-PH, as well as having a New York Heart Association (NYHA) functional class of 2 or 3 and a 6-minute walk distance ≥100 m repeated twice during screening, among other criteria. Those with a diagnosis of pulmonary hypertension (PH), clinically significant and active lung disease, or a known history of chronic liver disease, among other criteria, were excluded.2

Eligible patients were randomly assigned in a 1:1:1 ratio to receive either sotatercept 0.3 mg/kg or placebo subcutaneously every 3 weeks for 24 weeks, with a third group receiving sotatercept 0.3 mg/kg and escalating to 0.7 on the fourth dosing visit. The primary endpoint was change from baseline in pulmonary vascular resistance at week 24. Secondary endpoints included change from baseline in 6-minute walk distance, time to first clinical worsening event, and change from baseline in right ventricular fractional area change, among others.2

CADENCE ultimately enrolled 164 patients, of whom 54 received sotatercept 0.3 mg/kg, 55 received 0.7 mg/kg, and 55 received placebo. By week 24, investigators recorded a mean change in pulmonary vascular resistance of -0.67 Wood units in the 0.3 mg/kg group, -0.33 Wood units in the 0.7 mg/kg group, and 0.26 Wood units in the placebo group. Additionally, the Hodges-Lehmann shift estimates in pulmonary vascular resistance were -1.02 Wood units (95% CI, -1.81 to -0.23; P = .004) for 0.3 mg/kg and -0.75 Wood units (95% CI, -1.52 to 0.03; P = .024) for 0.7 mg/kg.3

In the present analysis, Tedford and colleagues collected the echocardiographic data from patients enrolled in the CADENCE trial – changes from baseline in continuous parameters were recorded from those patients with non-missing baseline values. Changes from baseline in tricuspid regurgitation were also recorded from patients with paired baseline and week 24 measurements.1

Compared with placebo, Tedford and colleagues noted that sotatercept improved right ventricular function and structure – specifically, it targeted tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (sPAP) ratio, right ventricular fractional area change (RVFAC)/sPAP ratio, right ventricular free wall strain (RVFWS)/sPAP ratio, tissue-Doppler peak systolic velocity/right atrial area index (RAAi), and right ventricle cavity area from end-diastole. Additionally, it reduced RAAi and pressure estimates and improved left atrial and ventricular structure, as well as ventricular interaction, at week 24. It was also associated with greater improvements in the severity of tricuspid regurgitation from baseline.1

Ultimately, Tedford and colleagues noted that these findings could suggest a broader role for sotatercept, highlighting its potential promotion of broad, favorable cardiac remodeling on top of its pulmonary vascular effects. The team encourages further investigation of this mechanism of action, particularly given its potential in a population with such a substantial unmet need.1

“Keep in mind that this was a phase 2 study,” Tedford said. “We’re now studying this drug in the phase 3 study course, which will hopefully give us a definitive answer if this can help our patients.”

Editors’ Note: Tedford reports disclosures with Abbott, Acceleron, Cytokinetics, Medtronic, Merck, United Therapeutics, and others.

References

1. Tedford R, Badagliacca R, Asleh R, et al. Effects of Sotatercept on Cardiac Structure and Function: Analysis of the CADENCE Study. Presented at the American Heart Association (AHA) Scientific Sessions 2026, Chicago, IL. November 6-9, 2026.

2. Acceleron Pharma. A Study of Sotatercept for the Treatment of Cpc-PH Due to HFpEF (MK-7962-007/​A011-16) (CADENCE). ClinicalTrials.gov Identifier: NCT04945460. Updated September 23, 2026. Accessed November 8, 2026. https://www.clinicaltrials.gov/study/NCT04945460?term=NCT04945460&rank=1

3. Gomberg-Maitland M, Tedford RJ, Langleben D, et al. Sotatercept for combined post- and precapillary pulmonary hypertension associated with heart failure: Results from the Phase 2, randomized, placebo-controlled cadence study. Circulation. 2026;153(19):1446-1459. doi:10.1161/circulationaha.126.079918