Sotarcept: A Promising Therapy for a High Risk Population

Many of us over the course of our clinical practice have cared for patients with pulmonary arterial hypertension (PAH) and have hoped for better therapies in this challenging patient population. On the last day of ACC 2023 in New Orleans, LA, we had the pleasure of hearing firsthand from Dr. Marius Hoeper, deputy director of the Department of Respiratory Medicine at Hannover Medical School in Hannover, Germany, where heads the pulmonary hypertension program. STELLAR is a multicenter, double-blind, phase 3 trial, which randomized patients with pulmonary arterial hypertension (PAH) (WHO functional Class II or III) on background PAH therapy to sotatercept or placebo. 1

Sotatercept is a fusion protein that inhibits the TGF-β factors involved in the pulmonary vascular remodeling that characterizes PAH. In the phase 2 PULSAR trial, 24 weeks of treatment with sotatercept was associated with improved exercise capacity, lower levels of NT-pro BNP and improved pulmonary hemodynamics.

In STELLAR, a phase 3 trial, 160 patients were randomized to receive placebo and 163 patients were randomized to receive sotatercept. For randomization, patients were stratified by their WHO class (II or III) and degree of background PAH therapy (monotherapy, double therapy, or triple therapy).  Patients had to be on background therapy for at least 90 days before enrollment and had to have a pulmonary vascular resistance of 5 Wood units or more. Notable exclusion criteria included PAH associated with veno-occlusive disease, HIV, portopulmonary disease and schistomosiasis. The primary outcome was change in 6-minute walk distance (6MWD) at 24 weeks compared to baseline. Nine secondary endpoints were also tested hierarchically, including NT-pro BNP, WHO functional class, change in pulmonary vascular resistance, and cognitive-emotional impact domain score, which were also determined after 24 weeks of therapy.  Time to death or clinical worsening was another notable secondary endpoint, which was assessed when the last patient enrolled completed the 24 week visit. Of note, STELLAR was not powered or designed to determine sotatercept’s effects on mortality.

Sotatercept improved 6MWD (+40.8 m, 95% CI, 26.5 to 54.1; p<0.001) and also showed clinical benefit across secondary outcomes including WHO functional class, hemodynamics, NT-pro BNP, and patient-reported outcomes with the exception of the PAH-SYMPACT Cognitive–Emotional Impacts domain score. Furthermore, sotatercept reduced the risk of death and non-fatal clinical deterioration by 84% compared to placebo (HR: 0.16 [95% CI: 0.08 to 0.35]).

In summary, STELLAR showed sotatercept’s significant impact on both mortality and morbidity in patients with PAH. Epistaxis, dizziness, and telangiectasia were more common in patients receiving sotatercept compared to placebo. Long-term durability of response and safety remain to be determined given the median treatment period was only 7.5 months. Dr. Hoeper discussed the need for future investigations to provide further clarity on responders from non-responders, as well as identify those most at risk for adverse outcomes from sotatercept.

Dr. Pooja Prasad is a cardiology Fellow at Oregon Health & Science University in Portland, Oregon, CardioNerds fellow ambassador, and served as a CardioNerds Conference Scholar for the American College of Cardiology 2023 Scientific Sessions.