Sotatercept decreases pulmonary vascular resistance in PAH: PULSAR
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In the phase 2 PULSAR trial, treatment with sotatercept for 24 weeks resulted in greater reduction in pulmonary vascular resistance than placebo in patients with pulmonary arterial hypertension on stable background therapies.
The PULSAR researchers randomly assigned 106 patients with PAH to receive placebo or sotatercept (Acceleron Pharma) at 0.3 mg/kg or 0.7 mg/kg, administered subcutaneously every 21 days in combination with stable background PAH-specific therapies, including mono, double and triple therapy over a 24-week period.
At 24 weeks, the primary endpoint of percent reduction in pulmonary vascular resistance was 2.1% with placebo vs. 33.9% with sotatercept 0.7 mg/kg (P < .0001 for comparison) and 20.5% with 0.3 mg/kg (P = .0027 for comparison), according to results presented at the American Thoracic Society’s Breaking News: Clinical Trial Results in Pulmonary Medicine virtual session.
Treatment with sotatercept also yielded improvement in the trial’s key secondary endpoint of 6-minute walk distance. At 24 weeks, both sotatercept dose groups achieved at least a 50-m increase in 6-minute walk distance from baseline; the mean change was 50 m with the 0.7 mg/kg dose and 58 m with 0.3 mg/kg dose. In a prespecified pooled analysis of both doses, treatment with sotatercept resulted in a 54-m change in 6-minute walk distance from baseline and a placebo-corrected difference of 25 m (nominal P = .03), according to a press release by Acceleron Pharma. In an exploratory analysis of 6-minute walk distance in patients on triple background therapy, the placebo-corrected difference in 6-minute walk distance was 40 m in the lower-dose group and 35 m in the higher-dose group; in a pooled analysis of both doses, the placebo-corrected difference was 37 m, according to data presented during the virtual session.
“The PULSAR study achieved the objectives of demonstrating improvement in pulmonary vascular resistance and in 6-minute walk distance at 24 weeks vs. placebo,” David B. Badesch, MD, professor of medicine and clinical director of the Pulmonary Hypertension Center at the University of Colorado, said during the ATS virtual session.
Subgroup analyses favored sotatercept at both dose levels and in patients receiving mono, double or triple therapy, Badesch said during the presentation.
In other results, treatment with sotatercept showed improvement across multiple exploratory endpoints at 24 weeks, including a 51% reduction in NT-proBNP and a 20% reduction in mean pulmonary arterial pressure. Twenty-three percent of patients improved their WHO functional class.
Sotatercept was generally well tolerated in patients with PAH, with a safety profile consistent with that observed in other patient populations, Badesch said. Serious treatment-emergent adverse events occurred in 9% of patients assigned placebo, 6% assigned sotatercept 0.3 mg/kg and 24% assigned sotatercept 0.7 mg/kg. Treatment-emergent adverse events occurring in 10% or more of all patients in any treatment group included headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia and nausea. There was one death in the higher-dose sotatercept group that the researchers deemed unrelated to treatment.
Hemoglobin increase was reported in one patient (3%) in the 0.3 mg/kg sotatercept group and six patients (14%) in the 0.7 mg/kg group; there was no increase in hemoglobin in the placebo group. Thrombocytopenia was reported in two patients (6%) in the 0.3 mg/kg group and five (21%) in the 0.7 mg/kg group.
Sotatercept is an investigational agent designed to be a selective ligand trap for members of the transforming growth factor-beta superfamily to rebalance bone morphogenetic protein receptor type II (BMPR-II). In clinical trials sotatercept reversed pulmonary vessel muscularization and improved indicators of right heart failure. In April, the FDA granted breakthrough therapy designation to sotatercept for treatment of PAH.
The PULSAR trial was conducted at 43 sites in eight countries. Patients enrolled had WHO group 1 PAH, were evenly distributed between WHO functional class II and III and had baseline right heart catheterization with pulmonary vascular resistance 5 Wood units. Those enrolled were predominantly , mean age was 48 years, had a diagnosis of PAH for approximately 7 years and PAH classification was idiopathic in the majority. All patients were receiving stable treatment with standard of care therapies for PAH, including an endothelin-receptor antagonist, a phosphodiesterase 5 inhibitor, a soluble guanylate cyclase inhibitor and/or a prostacyclin. At the start of the study, 35% of patients were receiving double background PAH-specific therapies and 56% were receiving triple therapies.
Following the 6-month, double-blind treatment period, PULSAR participants were eligible to continue in an 18-month extension period. As of June 22, 94 of 97 patients who opted to participate in the extension period were still enrolled, and 64 patients have been treated with sotatercept for at least 12 months, according to the company release.
“Proof of concept has been demonstrated and a phase 3 program is planned,” Badesch said during the presentation.