Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension

N Engl J Med. 2023 Apr 20;388(16):1478-1490. doi: 10.1056/NEJMoa2213558. Epub 2023 Mar 6.


Background: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension.

Methods: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit.

Results: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.

Conclusions: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR number, NCT04576988.).

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase III
  • Multicenter Study

MeSH terms

  • Adult
  • Cardiovascular Agents / administration & dosage
  • Cardiovascular Agents / adverse effects
  • Cardiovascular Agents / pharmacology
  • Cardiovascular Agents / therapeutic use
  • Double-Blind Method
  • Exercise Tolerance / drug effects
  • Humans
  • Hypertension, Pulmonary / drug therapy
  • Injections, Subcutaneous
  • Pulmonary Arterial Hypertension* / diagnosis
  • Pulmonary Arterial Hypertension* / drug therapy
  • Recombinant Fusion Proteins* / administration & dosage
  • Recombinant Fusion Proteins* / adverse effects
  • Recombinant Fusion Proteins* / pharmacology
  • Recombinant Fusion Proteins* / therapeutic use
  • Respiratory System Agents / administration & dosage
  • Respiratory System Agents / adverse effects
  • Respiratory System Agents / pharmacology
  • Respiratory System Agents / therapeutic use
  • Treatment Outcome
  • Vascular Resistance / drug effects
  • Walk Test


  • ACE-011
  • Recombinant Fusion Proteins
  • Cardiovascular Agents
  • Respiratory System Agents

Associated data