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New phase 2 data from a 24-week assessment suggest the first-in-class drug could benefit exercise and pulmonary-vascular outcomes.
Sotatercept, a novel, first-in-class fusion protein therapy, significantly improved pulmonary-vascular, cardiovascular, and exercise-related outcomes in patients with pulmonary arterial hypertension (PAH) at 24 weeks, according to findings from the PULSAR trial.
In new trial data assessing the Acceleron Pharma investigational drug versus placebo, an international team of investigators reported multifactorial benefits with sotatercept, which is now being assessed in phase 3 trials for the sparsely-resourced field of PAH care.
Sotatercept is comprised of the extracellular domain of human activin receptor type IIA, fused to the Fc domain of human immunoglobulin G1 (IgG1). It provides balance of the growth-promoting activin growth differentiation factor pathway, and the growth-inhibiting BMP pathway by serving as a ligand trap for the TGF-β superfamily.
It has been thus far assessed in healthy volunteers, patients with hematologic disorders, and in patients with TGF-β superfamily signaling-pathway disorders—including bone less, chemotherapy-induced anemia, multiple myeloma, beta-thalassemia, and end-stage kidney disease.
Led by David B. Badesch, MD, of the Divisions of Pulmonary Sciences and Critical Care Medicine and Cardiology at the University of Colorado Anschutz Medical Campus, investigators conducted a 24-week, randomized, placebo-controlled, multicenter assessment of subcutaneous sotatercept versus placebo in adult patients with PAH.
Badesch and colleagues sought a primary endpoint of change from baseline to week 24 in pulmonary vascular resistance. Patients were randomized into 1 of 3 treatment arms:
Investigators noted the patient population was relatively young, with a mean age of 48.3 (±14.3) years old. All patients had moderate to severe PAH.
The team observed a notable reduction in pulmonary vascular resistance among patients treated with either dose of sotatercept at 24 weeks versus placebo. Least-squares mean difference between sotatercept 0.7 mg treatment arm and placebo arm was 21.4 meters (95% CI, -2.8 to 45.7) in six-minute walking test (6MWT). For the 0.3 mg treatment arm, the difference was 29.4 meters (95% CI, 3.8 – 55.0).
Badesch and colleagues additionally observed decreases in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels among treated patients. Common adverse events included increased hemoglobin levels and thrombocytopenia. One patient treated with 0.7 mg sotatercept died from cardia arrest.
In discussing the findings, investigators stressed the overall benefit of sotatercept in pulmonary vascular resistance and 6MWT outcomes—regardless of patient treatment history. As they noted, all trial participants had been receiving background PAH therapy prior to enrollment, and continued such care during PULSAR.
“Sotatercept was shown to reduce pulmonary vascular resistance in patients receiving background monotherapy, double therapy, or triple therapy, including those who were receiving prostacyclin infusion therapy,” they wrote. “Preclinical evidence suggests that sotatercept has a direct effect on pulmonary vascular remodeling, which may explain its clinical effect on pulmonary artery pressure.”
Regarding limitations, investigators noted a small trial sample size and shorter duration of 24 weeks. Future assessment should consider establishing the long-term effects of sotatercept in patients burdened with the chronic effects of PAH.
Lastly, the trial was designed to observe the clinical efficacy of sotatercept on key PAH outcomes, including mortality.
Nonetheless, Badesch and colleagues concluded the phase 2 outcomes for the novel agent give hope to continued success in ongoing phase 3 assessments.
“In this trial, treatment with sotatercept reduced pulmonary vascular resistance among patients with pulmonary arterial hypertension who were receiving stable background therapy, including prostacyclin infusion therapy,” they wrote. “Concordant improvements from baseline in 6-minute walk distance and NT-proBNP levels were also observed.”
The study, “Sotatercept for the Treatment of Pulmonary Arterial Hypertension,” was published online in The New England Journal of Medicine.