Sotatercept reduces pulmonary vascular resistance in patients with PAH

Treatment with sotatercept for 24 weeks resulted in a reduction in pulmonary vascular resistance among patients with pulmonary arterial hypertension therapy, according to results of the PULSAR trial.

Healio previously reported results of the PULSAR trial when presented during the American Thoracic Society’s 2020 virtual session. The trial has now been published in The New England Journal of Medicine.

The PULSAR trial evaluated safety and efficacy of sotatercept (Acceleron Pharma), a first-in-class therapeutic fusion protein targeting an imbalance between growth-promoting and growth-inhibiting signaling pathways.

The multicenter, randomized, double-blind, phase 2 trial followed a 24-week placebo-controlled treatment period and then an 18-month active-drug extension period. Researchers enrolled 106 adults (mean age, 48.3 years; 87% women) who were receiving background PAH therapy. More than half were receiving triple PAH therapy and 37% were receiving prostacyclin infusion therapy. Patients were randomly assigned to receive subcutaneous sotatercept at 0.3 mg/kg of body weight (n = 32) or 0.7 mg/kg of body weight (n = 42) every 3 weeks or placebo (n = 32).

For the primary endpoint, change in pulmonary vascular resistance from baseline to 24 weeks in pulmonary vascular resistance,there was a least-squares mean difference of –145.8 dyn/sec/cm^-5 between participants assigned sotatercept 0.3 mg and participants assigned placebo (P = .003), and a difference of –239.5 dyn/sec/cm^-5 between participants assigned sotatercept 0.7 mg and those assigned placebo (P < .001).

“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. The decrease in pulmonary vascular resistance in the sotatercept groups was achieved by reducing the mean pulmonary artery pressure, without causing a substantial change in cardiac output or pulmonary artery wedge pressure,” Marc Humbert, MD, PhD, professor of respiratory medicine at the South Paris University, Le Kremlin-Bicêtre, France, and colleagues wrote in NEJM. “Preclinical evidence suggests that sotatercept has a direct effect on pulmonary vascular remodeling, which may explain its clinical effect on pulmonary artery pressure.”

At week 24, the mean difference in 6-minute walking distance was 29.4 m (95% CI, 3.8-55) between the sotatercept 0.3 mg group and the placebo group, and 21.4 m (95% CI, –2.8-45.7) between the sotatercept 0.7 mg group and the placebo group.

Researchers also observed an association between N-terminal pro-B-type natriuretic peptide and sotatercept treatment, with a 621.1 pg/mL (95% CI, –1,353.2 to –509.7) decrease in the 0.3 mg group and a 340.6 pg/mL (95% CI, –1,043 to –258.7) decrease in the 0.7 mg group compared with a 310.4 pg/mL increase in the placebo group.

The most commonly adverse events were thrombocytopenia and increased hemoglobin levels in the sotatercept 0.3 mg group (6% and 3%, respectively) and the sotatercept 0.7 group (12% and 17%, respectively). In the sotatercept 0.7 mg group, one patient died from cardiac arrest.

The researchers noted several limitations of the trial, including the small sample size and trial duration of 24 weeks. They also acknowledged that the PULSAR trial was not designed to evaluate the effects of sotatercept on clinical outcomes such as mortality.

“Additional trials, including a phase 3 trial, are ongoing or planned,” the researchers wrote.