Originally published by 2 Minute Medicine^® (view original article). Reused on AccessMedicine with permission.

1. Among patients on stable therapy for pulmonary arterial hypertension (PAH), sotatercept resulted in a significant improvement in six-minute walk distance compared to placebo.

2. Sotatercept was associated with more frequent adverse events, but the benefit-risk ratio was considered favorable and consistent with previous evidence.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

PAH is a chronic lung disease that occurs due to proliferative remodeling and progressive narrowing of pulmonary arteries, leading to right heart strain, failure, and death. Current therapies, namely phosphodiesterase-5 inhibitors and endothelin-receptor antagonists, can improve symptoms and progression-free survival. However, morbidity and mortality continue to be high. Sotatercept is a fusion protein that traps activins and growth differentiation factors that drive pathologic pulmonary arterial remodeling. The current study was a phase three trial to assess the efficacy and safety of sotatercept in adults with PAH on stable background therapy. At 24 weeks, the triweekly administration of sotatercept resulted in a significant improvement from baseline in the six-minute walk distance compared to a placebo. Additionally, sotatercept also improved cardiopulmonary hemodynamics and functional outcomes. Adverse events, including epistaxis, dizziness, thrombocytopenia, and telangiectasia, were more common with sotatercept. Limitations included limited duration, underrepresentation of specific causes of PAH and minority groups, and potential for unintended unblinding due to adverse events. Nevertheless, these results showed clinical efficacy and a favorable risk profile of sotatercept consistent with existing evidence in treating PAH.

Click here to read the study in NEJM

Relevant Reading: Sotatercept for the treatment of pulmonary arterial hypertension

In-Depth [randomized controlled trial]:

The current study was a multicenter, double-blinded, placebo-controlled assessing sotatercept in treating PAH. Adult patients with PAH (idiopathic, heritable, drug-induced, connective-tissue disease-associated, or after shunt correction) belonging to Word Health Organization functional class II or III, who were stable on background therapy, were eligible for inclusion. Exclusion criteria included chronic liver disease, intravenous inotrope use, human immunodeficiency virus infection-associated PAH, and baseline abnormal hematologic findings. In total, 323 patients were randomized 1:1 to receive subcutaneous sotatercept at 0.3mg/kg starting dose with escalation to target 0.7mg/kg dose or placebo. The primary efficacy outcome was the change from baseline at week 24 in the six-minute walk distance. At 24 weeks, the median change from baseline in the six-minute walk distance was 34.4m (95% Confidence Interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0m (95% CI, 0.3 to 3.5) in the placebo group. The estimate of the difference between the sotatercept and placebo groups in change from baseline at 24 weeks was 40.8 (95% CI, 27.5 to 54.1; p<0.001). Although the rates of adverse events overall were comparable between the two groups, sotatercept was associated with a higher incidence of epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. The study only included the prespecified causes of PAH, WHO functional classes II or III, and underrepresented certain minority groups and PAH causes. Notwithstanding, these results demonstrated a sotatercept’s efficacy and acceptable risk profiles in the management of PAH in adults, in addition to stable therapy.

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