Article Impact Level: HIGH Data Quality: STRONG Summary of New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2508170 Dr. Vallerie V. McLaughlin et al.
Points
- Sotatercept, an activin-signaling inhibitor, was studied in newly diagnosed adult patients with pulmonary arterial hypertension.
- Patients with WHO functional class II or III PAH and intermediate or high risk of death received sotatercept or placebo.
- The trial was stopped early due to clear positive results from previous sotatercept studies.
- Sotatercept significantly reduced primary end-point events, occurring in 10.6% vs. 36.9% for placebo (HR 0.24).
- Common adverse events with sotatercept included epistaxis (31.9%) and telangiectasia (26.2%).
Summary
This Phase 3 trial, known as HYPERION, investigated the efficacy of sotatercept, an activin-signaling inhibitor, in adult patients newly diagnosed with World Health Organization (WHO) functional class II or III pulmonary arterial hypertension (PAH) within one year of diagnosis. Patients also had an intermediate or high risk of death and were already receiving double or triple background therapy. The study aimed to determine if add-on subcutaneous sotatercept (starting at 0.3 mg/kg, escalated to 0.7 mg/kg every 21 days) could reduce clinical worsening compared to placebo.
The trial was prematurely halted due to loss of clinical equipoise, following positive outcomes from previous sotatercept trials. A total of 320 patients were enrolled, with 160 allocated to the sotatercept group and 160 to the placebo group. The median follow-up duration was 13.2 months. A primary end-point event, defined as a composite of death, unplanned hospitalization for worsening PAH, atrial septostomy, lung transplantation, or deterioration in exercise performance due to PAH, occurred in 17 patients (10.6%) in the sotatercept group, significantly fewer than the 59 patients (36.9%) in the placebo group. This yielded a hazard ratio of 0.24 (95% confidence interval, 0.14 to 0.41; P<0.001), indicating a substantial reduction in risk.
Further detailed results showed that deterioration in exercise performance occurred in 8 patients (5.0%) with sotatercept versus 46 patients (28.8%) with placebo. Unplanned hospitalization for worsening PAH was observed in 3 patients (1.9%) in the sotatercept group compared to 14 patients (8.8%) in the placebo group. Death from any cause occurred in 7 patients (4.4%) in the sotatercept group and 6 patients (3.8%) in the placebo group, with no cases of atrial septostomy or lung transplantation in either group. The most frequent adverse events in the sotatercept group were epistaxis (31.9%) and telangiectasia (26.2%). These findings robustly support sotatercept’s benefit in reducing clinical worsening in newly diagnosed PAH patients.
Link to the article: https://www.nejm.org/doi/10.1056/NEJMoa2508170
References
McLaughlin, V. V., Hoeper, M. M., Badesch, D. B., Ghofrani, H. A., Gibbs, J. S. R., Gomberg-Maitland, M., Preston, I. R., Souza, R., Waxman, A. B., Kopeć, G., Meyer, G., Olsson, K. M., Fu, W., Shi, Y., Miller, B., Kim, S. S., Mackenzie, H. S., Brambatti, M., Patel, M. J., … Humbert, M. (2025). Sotatercept for pulmonary arterial hypertension within the first year after diagnosis. New England Journal of Medicine, NEJMoa2508170. https://doi.org/10.1056/NEJMoa2508170
