New STELLAR, SOTERIA Data Provide Insight into Effects of Sotatercept in Pulmonary Arterial Hypertension

Article Highlights

New data from the European Respiratory Society (ERS) International Congress 2023 are providing clinicians with further insight into the potential of sotatercept as a treatment for pulmonary arterial hypertension (PAH).

Among the 9 total PAH-related, Merck-sponsored abstracts from ERS Congress 2023 were an exploratory posthoc analysis of the STELLAR trial examining impact of sotatercept on cardiovascular function and an interim analysis of data from the SOTERIA open-label extension study, which is billed as the longest safety and efficacy analysis of sotatercept to date.

“Despite available therapies, PAH remains incurable, with high morbidity and mortality, highlighting the urgent need for novel treatments that target new pathways,” said Vallerie McLaughlin, MD professor of medicine and director of the Pulmonary Hypertension Program in the Division of Cardiovascular Medicine at the University of Michigan, who presented the STELLAR hemodynamics and echocardiography analysis. “Sotatercept is the first activin signaling inhibitor therapy and is proposed to modulate the vascular proliferation underlying PAH. Acknowledging the exploratory nature of these findings, this is the first clinical evidence suggesting that sotatercept may positively impact certain measures of right heart function and dimensions. This is encouraging and further supports the primary results from the STELLAR analysis, underscoring the potential of sotatercept to play a critical role in the treatment of PAH.”

Sotatercept captured the medical community’s attention in late 2022 with the release of topline data from their phase 3 STELLAR trial. Published in the New England journal of Medicine and presented at the American College of Cardiology 2023 annual scientific sessions, results of the study support use of sotatercept as an adjunct to background medical therapy in treatment of PAH, with the trial meeting its primary endpoint of change from baseline to week 24 in 6-minute walking distance as well as achieving statistical significance for 7 of its 8 key secondary endpoints.^2,3

STELLAR Posthoc Analysis

The STELLAR analysis, which was featured in an oral presentation and simultaneously published in the European Respiratory Journal, examined the effects of sotatercept on select hemodynamic parameters and right-ventricle (RV) function among 298 participants with hemodynamic data and 275 patients with echocardiogram data. Of note, this represented 92% and 85%, respectively. of the entire STELLAR cohort.¹

Improvements from baseline relative to the placebo cohort were observed for the following hemodynamic outcomes of interest:¹

Analysis of echocardiography data suggested the sotatercept group experienced improvements from baseline in ratio of tricuspid annular plane systolic excursion to systolic pulmonary artery pressure (TAPSE/sPAP; 0.12 mm mmHg−1), end-systolic and end-diastolic RV areas (−4.39 cm2 and −5.31 cm2, respectively), tricuspid regurgitation, and RV fractional area change (2.04%; P <.050) relative to placebo therapy. The release from Merck noted there were no significant between-group changes observed from baseline for TAPSE, heart rate, cardiac output/index or stroke volume/stroke volume index.¹

SOTERIA Interim Analysis

An open-label follow-up of patients with PAH who have successfully completed 1 of 4 previous sotatercept trials, SOTERIA was launched to evaluate the long-term safety, tolerability, and efficacy of sotatercept as an adjunct to background therapy for the treatment of PAH. The primary objective of the study was to evaluate long-term safety and tolerability, with efficacy serving as a secondary objective. To estimate the efficacy of the agent, investigators measured 6-minute walking distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP), World Health Organization (WHO) functional class, pulmonary vascular resistance, overall survival, and simplified French risk score.¹

As of the April 20, 2023, cutoff date, a total of 409 patients were enrolled in the study. Of these, 143 were rolled over from the placebo portion of their respective trial. The median duration of exposure to sotatercept was 462 (range, 21-1762) days, with the median duration of exposure to sotatercept in SOTERIA being 189 days.¹

Results of the interim analysis suggested sotatercept was well-tolerated and had a safety profile similar to previous studies, with 98.5% of participants on treatment at the time of the interim analysis. Investigators reported treatment-emergent adverse events occurred in 81.7% of participants and serious treatment-emergent adverse events occurred in 19.3% of participants. Additionally, 1.5% of patients discontinued treatment, 1.0% died during the study, and 1.7% experienced clinical worsening events.¹

When examining efficacy outcomes, results suggested the clinical improvements observed in a previous 24-week analysis were maintained through the first year of the open-label period. Investigators highlighted the mean change (SD) from baseline at week 24 in 6-minute walking distance (20.2 [SD, 66.5] meters) and NT-proBNP (−374.9 [SD, 1479.4] pg/mL) were largely maintained at 1 year (10.9 [SD, 73.6] meters and −227.2 [SD, 1580.1]pg/mL, respectively). Further analysis suggested the proportion of participants who improved or maintained WHO functional class II from baseline at week 24 (77.2%) was similar to the proportion achieving the same metric at 1 year (76.3%). Investigators also pointed out 30.1% and 37.4% of patients achieved a low French risk score at week 24 and 1 year, respectively.¹

“These latest data build on the clinically meaningful efficacy results from the STELLAR trial and support our belief that sotatercept has the potential to transform the treatment of PAH," Eliav Barr, MD, senior vice president and head of global clinical development as well as chief medical officer with Merck Research Laboratories.¹ "PAH can strain the heart and lead to eventual right heart failure, so we are particularly encouraged by the exploratory analysis from STELLAR suggesting that treatment with sotatercept improved right heart size and function.”