Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension (PAH). Adding this novel first-in-class agent to background PAH therapy led to significant and clinically relevant improvements in exercise capacity and other endpoints in the placebo-controlled STELLAR trial.
STELLAR (NCT04576988) is the first of three phase 3 trials evaluating sotatercept. Marius Hoeper, MD, presented—at the American College of Cardiology 2023 Annual Scientific Sessions—the results of this multicenter, randomized, double-blind, parallel-group study in adults with PAH (WHO functional class II or III) on stable background therapy.1 The mean age of participants (N=323) was 48; 79% were women. They were randomized 1:1 to subcutaneous sotatercept (starting dose, 0.3 mg/kg; target dose, 0.7 mg/kg) or placebo every 3 weeks. The primary endpoint was median change from baseline at week 24 in 6-minute walk distance (6MWD).
After 24 weeks, the observed change in the placebo group was -1.4 meters (95% CI, -13.2–10.3), compared with 40.1 meters (95% CI, 29.9–50.2) in the sotatercept group. The Hodges–Lehmann estimate of the difference between the groups was 40.8 meters (95% CI, 27.5–54.1; P<0.001). There were nine secondary endpoints, from pulmonary vascular resistance to patient-reported symptoms, eight of which significantly improved with sotatercept versus placebo, including two of three domain scores of the Pulmonary Arterial Hypertension–Symptoms and Impact (PAH-SYMPACT) questionnaire. Dr. Hoeper stressed, “We also saw a decline in the exploratory endpoint of least-squares mean pulmonary artery pressure of 13.9 mmHg, which we have never seen before with any add-on therapy used for PAH.”
After a mean follow-up of 32.7 weeks, the number sof patients who died or experienced at least one clinical worsening event were 42 (32.9%) in the placebo group and nine (5.5%) in the sotatercept group, a relative risk reduction of 84%. Sotatercept was generally well-tolerated. Adverse events, such as bleeding events, telangiectasia, increased hemoglobin levels, and epistaxis, were more common in the sotatercept group.
“These results establish the clinical utility of sotatercept as a new approach to the treatment of PAH in combination with existing approved therapies,” Dr. Hoeper concluded, adding that he expects these results to cause a paradigm shift in the treatment of PAH.
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