Efficacy and safety of the activin signalling inhibitor, sotatercept, in a pooled analysis of PULSAR and STELLAR studies.

Introduction: Pulmonary arterial hypertension is a progressive disease associated with significant morbidity and mortality. Sotatercept is a first-in-class activin signalling inhibitor that acts to restore the balance between the growth-promoting and growth-inhibiting signalling pathways.

Methods: This post hoc, exploratory, pooled analysis combines data from the double-blind placebo periods of the phase 2 PULSAR (NCT03496207) and phase 3 STELLAR (NCT04576988) studies. Both studies were international, multicentre, randomised, double-blind, placebo-controlled trials in patients with pulmonary arterial hypertension. Efficacy and safety parameters common to both studies were analysed.

Results: A total of 429 patients were randomised and treated; 237 received sotatercept and 192 received placebo. Adding sotatercept to background pulmonary arterial hypertension therapy for 24 weeks improved exercise capacity (as assessed by 6-min walk distance), pulmonary vascular resistance and World Health Organization functional class, and delayed time to first occurrence of death or clinical worsening event. There were clinically important reductions in both pulmonary and right heart pressures; improvements in right ventricle size during both systole and diastole; and enhancements in right ventricle contractility and right ventricular-pulmonary artery coupling. The number of patients who experienced at least one adverse event of interest or special interest (increased haemoglobin, thrombocytopenia, bleeding events (mostly epistaxis), increased blood pressure and telangiectasia) was higher in the sotatercept group than the placebo group.

Conclusion: This pooled analysis confirms that sotatercept delivers therapeutic benefit across a range of efficacy end-points and has favourable safety in patients with pulmonary arterial hypertension. Increased duration of follow-up will provide further insight into long-term outcomes of sotatercept in patients with pulmonary arterial hypertension.