Clinical Pearls & Morning Reports
Published April 19, 2023
Hoeper et al. conducted a phase 3, placebo-controlled trial that investigated the efficacy, safety, and adverse-event profile of sotatercept in combination with stable background therapy in adult patients with symptomatic pulmonary arterial hypertension. Read the NEJM Original Article here.
Q: What is the median survival after a diagnosis of pulmonary arterial hypertension with currently available therapies?
A: Pulmonary arterial hypertension is a disease characterized by proliferative remodeling of the small pulmonary arteries and progressive luminal narrowing. The resulting elevations in pulmonary artery pressure strain the heart, eventually culminating in right ventricular failure and death. When administered alone or in combination, available treatments improve pulmonary hemodynamics, exercise capacity, and progression-free survival in patients with pulmonary arterial hypertension. Median survival ranges from 5 to 7 years after diagnosis, but no substantial improvements in survival have been realized during the past decade. The continued high morbidity and mortality underscore the need for additional treatment options that target new pathways involved in pulmonary vascular remodeling.
Q: What is the mechanism of action of sotatercept?
A: Pulmonary vascular remodeling affects all layers of the vessel wall and is driven predominantly by enhanced proliferation and diminished apoptosis of endothelial and smooth-muscle cells. Recent research has highlighted the role of altered signal transduction by members of the transforming growth factor Β (TGF-Β) superfamily, including bone morphogenetic protein receptor type II, activin receptor type IIA (ActRIIA), and the ActRIIA ligands activin A, activin B, growth differentiation factor 8 (GDF8), and GDF11. A shift toward proliferative and antiapoptotic signaling by these TGF-Β superfamily members is thought to be a prominent mechanism driving pulmonary vascular remodeling in patients with pulmonary arterial hypertension. Sotatercept is a first-in-class fusion protein consisting of the Fc domain of human IgG linked to the extracellular domain of human ActRIIA, which acts as a ligand trap for selected TGF-Β superfamily members.
A: 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—the primary end point—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). Of the trial’s nine secondary end points, the first eight were significantly improved with sotatercept as compared with placebo
A: The adverse-event profile that was observed with sotatercept treatment was generally consistent with that reported in previous studies of sotatercept. Increases in hemoglobin levels, a known effect of sotatercept, were reported as adverse events in 5.5% and 6.1% of the patients who received the trial drug through week 24 and trial completion, respectively. The 24-week incidence of telangiectasia was 10.4% among patients who received sotatercept and 3.1% among those who received placebo. Epistaxis and gingival bleeding were also more common among patients who received sotatercept. These adverse events were mostly considered to be mild by the investigators. Ongoing and future studies will continue to evaluate the incidence and clinical relevance of telangiectasia with longer-term treatment.