TOPLINE:

Treatment with sotatercept — an activin signaling inhibitor — reduced pulmonary vascular resistance (PVR), improved cardiac hemodynamics, and was generally well tolerated in patients with combined postcapillary and precapillary pulmonary hypertension associated with heart failure with preserved ejection fraction (CpcPH-HFpEF).

METHODOLOGY:

• Researchers conducted a phase 2, multicenter, double-blind trial (CADENCE) between January 2022 and September 2025 to test sotatercept for CpcPH-HFpEF — a condition with no recommended pharmacologic treatment.
• They included 164 symptomatic adults with CpcPH-HFpEF (median age, 75 years; 69.5% female). Patients had a mean pulmonary arterial pressure > 20 mm Hg, pulmonary arterial wedge pressure > 15 and < 30 mm Hg, and PVR ≥ 4 Wood units.
• Patients were randomly assigned to subcutaneously receive either sotatercept 0.3 mg/kg, sotatercept started at 0.3 mg/kg and escalated to 0.7 mg/kg after three doses, or a matching placebo every 3 weeks.
• The primary efficacy endpoint was a change from baseline in PVR at week 24, and differences were compared using Hodges-Lehmann location shifts.
• Secondary evaluations included changes from baseline to week 24 in 6-minute walk distance, natriuretic peptide levels, hemodynamic and echocardiographic measures, and time to clinical worsening.

TAKEAWAY:

• Patients who received 0.3 mg/kg sotatercept had a median reduction in PVR of 0.67 Wood units at week 24, whereas those who received placebo had a median increase of 0.26 Wood units (Hodges-Lehmann shift, -1.02 Wood units; P = .004); those who received a dose of 0.7 mg/kg had a median decrease of 0.33 Wood units (Hodges-Lehmann shift, -0.75 Wood units; P = .024).
• Patients who received 0.3 mg/kg sotatercept walked 20.29 m farther in the 6-minute walk test than those who received placebo, and they had lower levels of natriuretic peptides, improved hemodynamics and echocardiographic measures, and a longer time to clinical worsening.
• Both doses of sotatercept produced a reduction of about 9 mm Hg in mean pulmonary arterial pressure compared with placebo. The decline in cardiac output was greater with a dose of 0.7 mg/kg than with a dose of 0.3 mg/kg.
• Both doses were well tolerated over 24 weeks, with increased hemoglobin levels and diarrhea being the most common adverse events. Serious adverse events were higher with a dose of 0.7 mg/kg than with placebo (32.7% vs 21.8%), and three patients discontinued the dose of 0.7 mg/kg for adverse events.

IN PRACTICE:

“As a treatment with a non-vasodilatory mechanism of action, sotatercept differs from vasodilator therapies tried in this setting, for which reductions in PVR are typically accompanied by increases in cardiac output,” the researchers of the study wrote.

“The CADENCE trial emphasizes the importance of targeting underlying biologic mechanisms responsible for disease versus focusing solely on improving hemodynamic parameters. Similar to PAH [pulmonary arterial hypertension] trials, the benefits of sotatercept transcend the relatively modest reductions in resting PVR and highlight the importance of targeting inflammation, cell proliferation, and endothelial function in HFpEF,” Satyam Sarma, MD, and Kelly M. Chin, MD, wrote in an accompanying editorial.

SOURCE:

The study was led by Mardi Gomberg-Maitland, MD, MSc, George Washington University School of Medicine and Health Sciences, Washington, DC. It was published online on March 29 in Circulation. The work was presented as an abstract at the American College of Cardiology (ACC) Scientific Session 2026 in New Orleans.

LIMITATIONS:

The sample size of the trial was relatively small. The 24-week period prevented assessment of long-term benefit and safety. Some PVR values were based on local readings and were not always confirmed centrally.

DISCLOSURES:

The study received funding from Merck Sharp & Dohme LLC. Several authors reported receiving consulting fees, honoraria, speaker fees, advisory board payments, and industry research grants from various companies including Merck. Five authors reported being employees of the sponsor company and may have owned stock and/or hold stock options in the company.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.