Article Impact Level: HIGH Data Quality: STRONG Summary of Circulation https://doi.org/10.1161/CIRCULATIONAHA.126.079918 Dr. Mardi Gomberg-Maitland et al.
Points
- Researchers conducted a Phase 2 randomized trial to evaluate if sotatercept could improve pulmonary vascular resistance and heart function in patients with heart failure and severe combined pulmonary hypertension.
- The study found that patients treated with sotatercept experienced a statistically significant reduction in lung blood pressure and improved walking distances compared to those who received a placebo treatment.
- Data revealed that participants saw measurable improvements in both right and left heart function, including a reduction in left atrial volume and pressure which are critical risk factors.
- Clinical results indicated that the lower dosage of zero point three milligrams per kilogram provided an optimal balance of therapeutic benefit and safety for this elderly patient population.
- These findings provide the first proof of concept for using activin signaling inhibitors to treat Group 2 pulmonary hypertension and support the launch of a larger Phase 3 trial.
Summary
This study evaluated the efficacy and safety of sotatercept, a first-in-class activin signaling inhibitor, in patients with heart failure with preserved ejection fraction (HFpEF) and severe combined post- and pre-capillary pulmonary hypertension (CpcPH). Given that Group 2 pulmonary hypertension currently lacks approved targeted therapies, the Phase 2 CADENCE trial sought to determine if inhibiting abnormal cell proliferation in the pulmonary vasculature could improve hemodynamic profiles and clinical outcomes in this high-risk subset.
The randomized, placebo-controlled trial enrolled 164 participants (average age 75 years; 70% female) across three cohorts receiving either 0.3 mg/kg of sotatercept, 0.7 mg/kg of sotatercept, or a placebo. After 24 weeks, the primary endpoint demonstrated a statistically significant reduction in pulmonary vascular resistance (PVR) compared to the placebo group. Furthermore, treatment with sotatercept yielded significant improvements in secondary clinical markers, including increased six-minute walking distance, enhanced right heart function, and a reduced rate of clinical worsening events.
Hemodynamic assessments also revealed favorable changes in left-sided cardiac parameters, specifically reductions in left atrial volume and wedge pressure. These improvements suggest that sotatercept effectively unloads the pulmonary vasculature while simultaneously alleviating stress on both cardiac chambers. The safety profile remained consistent with previous Group 1 pulmonary hypertension trials, with the 0.3 mg/kg dose appearing to optimize the benefit-risk ratio. While limited by a 24-week duration, these findings provide a critical proof of concept for activin signaling inhibition as a therapeutic strategy for CpcPH-HFpEF, supporting the advancement to Phase 3 clinical testing.
Link to the article: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.126.079918
References
Gomberg-Maitland, M., Tedford, R. J., Langleben, D., Rosenkranz, S., Miller, B., Jones, A. D., Urbinati, A., McMullan, C. J., Cornell, A. G., & Vachiery, J.-L. (2026). Sotatercept for combined post- and pre-capillary pulmonary hypertension associated with heart failure: Results from the phase 2, randomized, placebo-controlled cadence study. Circulation, CIRCULATIONAHA.126.079918. https://doi.org/10.1161/CIRCULATIONAHA.126.079918
