Adding sotatercept to existing therapy provides a new treatment approach for pulmonary arterial hypertension
Presenter: Marius M. Hoeper, MD, Hannover Medical School, Hannover, Germany
The STELLAR phase III trial: A study of sotatercept in combination with background therapy for the treatment of pulmonary arterial hypertension. Presentation number 410-14. Presented March 6, 2023.
The novel first-in-class medication sotatercept added to existing therapy for pulmonary arterial hypertension (PAH) induces significant improvements in exercise capacity while significantly reducing the risk of death or worsening of clinical events, according to results from the STELLAR trial as presented by Marius M. Hoeper, MD, Hannover Medical School, Hannover, Germany.
These results establish the clinical utility of sotatercept as a new approach to the treatment of PAH in combination with existing approved therapies, Hoeper said.
PAH is a rare progressive disease driven by pulmonary vascular remodeling due in part to an imbalance in anti-proliferative and pro-proliferative signaling pathways. This results in the hyperproliferation of vessel wall cells. Sotatercept, an activin-signaling inhibitor, is proposed to act as a reverse remodeling agent through rebalancing anti-proliferative and pro-proliferative pathways.
The multicenter, double-blind, phase III STELLAR trial enrolled 323 patients (median age 48 years, 79% women) with PAH in 20 countries. The patients received either subcutaneous sotatercept (starting dose 0.3 mg/kg body weight; target dose 0.7 mg/kg) (n = 163 patients) or placebo (n = 160 patients) every 3 weeks, in addition to their other PAH medications. Patients were followed for a median 7.5 months.
At enrollment, 60% of the patients had severe symptoms despite maximal therapy with 3 medications. On average, patients had been living with PAH for almost 9 years before enrolling in the trial.
The primary endpoint was the change from baseline at week 24 in the 6-minute walk distance. The mean improvement among patients receiving sotatercept was 34.4 meters vs 1.0 meter for placebo recipients, a statistically significant difference (P < .001).
“We also saw a marked reduction in mean pulmonary artery pressure (13.9 mmHg) with sotatercept versus placebo, which has never been seen before in a PAH trial,” Hoeper said.
In addition, 8 of 9 secondary endpoints were met, including improvements in functional class; proBNP levels; and several measures of quality of life. In the sotatercept group, 9 patients (5.5%) died or experienced at least 1 clinical worsening event compared with 42 (26.3%) in the placebo group, a risk reduction of 84% (P < .001).
Sotatercerpt was generally well-tolerated, said Hoeper. Adverse events seen more frequently with sotatercept vs placebo included minor bleeding events, teleangiectasia, dizziness, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.
In conclusion, Hoeper said, “Sotatercept improved the 6-minute walk distance and delivered broad clinical benefit across multiple domains, including hemodynamics, WHO functional class, disease biomarkers, risk scores, and patient-reported outcomes.”
The key question that needs answering, he said, is how does sotatercept fit in with other PAH therapies? “In this study, the average time to diagnosis was 9 years, and we saw an impressive response. What would happen if we introduced sotatercept to newly diagnosed patients who have more active disease?”
Most of the STELLAR trial participants are enrolled in a long-term extension study of safety and efficacy, with all patients now receiving sotatercept. Ongoing phase III trials are investigating sotatercept in patients with newly diagnosed PAH and in patients with even more severe PAH than those in the STELLAR trial.
The study results were published simultaneously in the New England Journal of Medicine.
References
Hoeper, MM, Badesch, DB, Ghofrani, HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. New Eng J Med 2023;NEED doi:10.1056/NEJMoa2213558
Hoeper, MM, Badesch, DB, Ghofrani, HA, et al.The STELLAR phase III trial: A study of sotatercept in combination with background therapy for the treatment of pulmonary arterial hypertension. Presented at American College of Cardiology Annual Scientific Session and Expo together with the World Congress of Cardiology, March 6, 2023, New Orleans, LA. Presentation number 410-14.
Disclosures
Marius M. Hoeper. Consultant fees/honoraria: Acceleron Pharma, Actelion, AOP Health, Bayer, Ferrer, Gossamer Bio, Janssen, Merck.