Sotatercept, an activin signaling inhibitor, was associated with significant improvements in blood pressure and vascular health in patients with heart failure with preserved ejection fraction (HFpEF) and severe combined post and precapillary pulmonary hypertension (CpcPH), according to results of the CADENCE study presented during a Late-Breaking Clinical Trial session at ACC.26 in New Orleans and simultaneously published in Circulation.

In the phase 2 trial, investigators enrolled 164 patients (mean age, 75 years; 70% women) with both HFpEF and severe CpcPH to sotatercept at 0.3 mg/kg (n=54), sotatercept at 0.7 mg/kg (n=55) or placebo (n=55) every three weeks.

All patients were on guideline-directed medications for HFpEF at baseline. Baseline median pulmonary vascular resistance (PVR) was 5.2 Wood units, mean pulmonary artery pressure (mPAP) was 43 mm Hg and pulmonary arterial wedge pressure (PAWP) was 21 mm Hg.

Results at 24 weeks showed a statistically significant reduction in the primary endpoint of PVR, with a median change from baseline of –0.67 Wood units in the sotatercept 0.3 mg/kg group and –0.33 Wood units in the sotatercept 0.7 mg/kg group, compared with 0.26 Wood units in the placebo group. The Hodges-Lehmann shift estimates of PVR in the two treatment groups, respectively, were –1.02 Wood units (p=0.004) and –0.75 Wood units (p=0.024).

Both the 0.3 mg/kg and 0.7 mg/kg groups saw improvements in mPAP (–9.19 mm Hg and –9.22 mm Hg), PAWP (–3.04 mm Hg and –2.53 mm Hg) and six-minute walking distance (20.3 meters and 5.8 meters, respectively). Time to clinical worsening was 82% lower in the 0.3 mg/kg group but not significantly reduced in the 0.7 mg/kg group.

Three patients (5.5%) in the 0.7 mg/kg discontinued the medication. Serious adverse events were reported in 21%, 33% and 22% of the 0.3 mg/kg, 0.7 mg/kg and placebo groups. Adverse events led to the death of one patient (1.8%) in the 0.7 mg/kg group and two patients (3.6%) in the placebo group. Investigators note that these adverse events are on par with what has been seen in previous clinical trials. The most common adverse events for both treatment groups were increased hemoglobin and diarrhea.

The results provide proof of concept for improved pulmonary vascular and cardiac hemodynamics with activin signaling inhibitor with sotatercept in this patient population, write the authors.

“This is really exciting because we see improvements in heart failure clinical markers as well as biomarkers of heart function in both the right side and the left side,” said Mardi Gomberg-Maitland, MD, FACC, the study’s lead author. “The left atrial volume and left atrial pressure (measured as wedge pressure) improved, features that can put you at risk for a variety of bad outcomes with HFpEF. Seeing these improvements in addition to improvements in the pulmonary vasculature makes this a big deal.”

“Similar to PAH 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. As the biology of ligand traps evolves, sotatercept marks the first step in leveraging the power of signaling networks to reverse fibrosis and cellular hypertrophy,” write Satyam Sarma, MD, and Kelly M. Chin, MD, in an accompanying editorial comment. “Notably, the CADENCE trial emphasizes the importance of targeting underlying biologic mechanisms responsible for disease, versus focusing solely on improving hemodynamic parameters.”

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Acute Heart Failure, Pulmonary Hypertension, Hypertension

Keywords: ACC Annual Scientific Session, ACC26, New Orleans, Heart Failure, Hypertension, Pulmonary, Atrial Pressure, Blood Pressure, Pulmonary Artery, Pulmonary Wedge Pressure, Stroke Volume