Sotatercept reduces adverse event risk in high-risk pulmonary arterial hypertension

1. In this randomized controlled trial of patients with pulmonary arterial hypertension (PAH) and high risk of mortality, sotatercept reduced the rate of composite all-cause mortality, lung transplantation, or PAH-related hospitalization.

2. Sotatercept was associated with an increased risk of developing epistaxis and telangiectasia.

Evidence Rating Level: 1 (Excellent)

Study Rundown: PAH is a progressive disease characterized by remodeling of the pulmonary vasculature, eventually resulting in right ventricular failure and death. Currently established treatments, such as primarily pulmonary vasodilators, slow clinical progression. Evidence is limited for the treatment impact on major events such as death, lung transplantation, and hospitalization. Sotatercept is a novel activin-signaling inhibitor targeting vascular remodeling with demonstrated clinical benefits in a prior trial. This phase three trial investigated sotatercept in patients with PAH at high risk of death and functional limitation. At the median follow-up of 8.9 months, sotatercept reduced the composite risk of all-cause mortality, lung transplantation, or hospitalization (≥24 hours) for worsening PAH as compared to placebo. The trial was stopped early due to evidence of efficacy at the interim analysis. Sotatercept was associated with a higher risk of epistaxis, telangiectasia, gingival bleeds, increased hemoglobin level, and thrombocytopenia. The study was limited by a short follow-up duration and a small sample size. Overall, it was demonstrated that in patients with advanced PAH, sotatercept reduced the risk of death, lung transplantation, and hospitalization.

Click here to read the study in NEJM

Relevant Reading: Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension

In-Depth [randomized controlled trial]: This study was a randomized controlled trial investigating the efficacy and safety of sotatercept in patients with advanced PAH. Eligible adult patients had symptomatic WHO group 1 PAH, with WHO functional class III or IV, and had a high one-year risk of death (REVEAL Lite 2 risk score of >8). Exclusion criteria included portal hypertension, HIV, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, left ventricular ejection fraction <45%, and/or significant mitral or aortic valve pathology. In total, 172 patients were randomized 1:1 to receive subcutaneous sotatercept every 21 days or a placebo, in addition to maximal background PAH therapy. The primary outcome was a composite of death, lung transplantation, or hospitalization (≥24 hours) for worsening PAH, assessed in a time-to-first-event analysis. The median follow-up was 10.6 months in the sotatercept group and 7.1 months in the placebo group, as the trial was terminated early due to evidence of efficacy. Sotatercept reduced the risk of the primary composite endpoint, 15 patients (17.4%) compared to 47 patients (54.7%) in the placebo group (Hazard Ratio [HR], 0.24; 95% Confidence Interval [CI], 0.13-0.43; p<0.001). The HR for overall survival (sotatercept versus placebo) was 0.42 (95% CI, 0.17-1.07). The HR for transplantation-free survival was 0.34 (95% CI, 0.15-0.78). The median change estimate from baseline at week 24 in mean pulmonary artery pressure was -13.6 mmHg in the sotatercept group and 5.5 mmHg in the placebo group (Hodges-Lehmann location shift from placebo estimate, -21.2; 95% CI, -27.8 to -14.6). The most common adverse events observed with sotatercept were epistaxis (44.2% vs. 9.3% with placebo), telangiectasia (25.6% vs. 3.5%), gingival bleeding (10.5% vs. 2.3%), increased hemoglobin level (12.8% vs. 1.2%), and thrombocytopenia (14.0% vs. 8.1%). There was no discontinuation due to serious adverse events. In summary, sotatercept, when added to maximum tolerated background therapy, significantly reduces the risk of death, lung transplantation, or hospitalization for worsening PAH in high-risk adult patients.

Image: PD

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