What are the highlights for the trial of sotatercept (generic name) and pulmonary arterial hypertension (PAH)?

From the Guidelines

Sotatercept is a promising treatment for pulmonary arterial hypertension (PAH) and should be considered for adults with PAH (WHO Group 1) in combination with background therapy, based on its ability to improve exercise capacity and reduce the risk of death or clinical worsening. The STELLAR trial demonstrated that sotatercept significantly improved exercise capacity with a 40.8-meter improvement in 6-minute walk distance compared to placebo 1. Sotatercept works by restoring balance in the TGF-beta signaling pathway, which is dysregulated in PAH, by acting as a trap for activins and growth differentiation factors. Some key points to consider when using sotatercept for PAH include:

• The typical dose in trials was 0.3 mg/kg administered subcutaneously every 3 weeks, with dose adjustments based on hemoglobin levels 1.
• Common side effects included headache, dizziness, and increased hemoglobin levels requiring monitoring 1.
• Sotatercept received FDA approval in March 2024 for adults with PAH (WHO Group 1) in combination with background therapy, representing the first therapy with a novel mechanism of action for PAH in nearly a decade. It is essential to note that PAH is a complex disease with various underlying causes and risk factors, and the efficacy of available agents may vary depending on the specific form of PAH 1. Therefore, accurate and timely diagnosis, as well as careful consideration of the patient's individual characteristics and preferences, are crucial when selecting a treatment for PAH. The American College of Chest Physicians guideline and expert panel report provide a comprehensive framework for the treatment of PAH, including the use of sotatercept, and emphasize the importance of a multidisciplinary approach to patient care 1.

From the FDA Drug Label

The efficacy of WINREVAIR was evaluated in adult patients with PAH in the STELLAR trial (NCT04576988). STELLAR was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 323 patients with PAH (WHO Group 1 FC II or III) were randomized 1:1 to WINREVAIR (target dose 0. 7 mg/kg) (n=163) or placebo (n=160) administered subcutaneously once every 3 weeks. The primary efficacy endpoint was the change from baseline at Week 24 in 6-Minute Walk Distance (6 MWD) In the WINREVAIR group, the placebo-adjusted median increase in 6 MWD was 41 meters (95% CI: 28,54; p<0. 001). Treatment with WINREVAIR led to an improvement from baseline by at least 1 WHO FC at Week 24 in 29% of patients compared to 14% of patients treated with placebo (p<0. 001). Treatment with WINREVAIR resulted in an 84% reduction in the occurrence of death from any cause or PAH clinical worsening events compared to placebo

The main highlights of the trial with sotatercept and pulmonary hypertension are:

• Efficacy: Sotatercept (WINREVAIR) showed a significant improvement in 6-Minute Walk Distance (6 MWD) and WHO Functional Class (FC) compared to placebo.
• Clinical Worsening Events: Sotatercept treatment resulted in an 84% reduction in the occurrence of death from any cause or PAH clinical worsening events compared to placebo 2.
• Study Design: The STELLAR trial was a double-blind, placebo-controlled, multicenter, parallel-group clinical trial that evaluated the efficacy of sotatercept in adult patients with PAH (WHO Group 1 FC II or III).

From the Research

Trial Overview

• The Phase 3 trial of sotatercept for the treatment of pulmonary arterial hypertension (PAH) showed significant improvements in exercise capacity, as assessed by the 6-minute walk test, compared to placebo 3.
• The trial included adults with PAH who were receiving stable background therapy and were randomly assigned to receive subcutaneous sotatercept or placebo every 3 weeks.

Efficacy and Safety

• The results of the trial showed that sotatercept resulted in a greater improvement in exercise capacity, with a median change from baseline at week 24 in the 6-minute walk distance of 34.4 m, compared to 1.0 m in the placebo group 3.
• Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure 3.
• A meta-analysis of randomized controlled trials found that sotatercept improved the six-minute walk distance, World Health Organization (WHO) functional class, and pulmonary vascular resistance (PVR) in patients with PAH receiving background therapy 4.

Pharmacokinetics and Pharmacodynamics

• Population pharmacokinetic/pharmacodynamic and exposure-response modeling analyses of sotatercept in healthy participants and patients with PAH found that increasing sotatercept average concentration at week 24 is associated with increased predicted 6-minute walk distance, increased probability of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration < 300 pg/mL, decreased predicted PVR, and increased hemoglobin 5.
• The results of the analysis support an appropriate benefit-risk profile for the FDA-approved target dose of sotatercept of 0.7 mg/kg Q3W SC.

Long-Term Follow-Up

• An ongoing open-label study, SOTERIA, is evaluating the long-term safety, tolerability, and efficacy of sotatercept in participants with PAH 6.
• Interim results of SOTERIA show that improvements in 6-minute walk distance, NT-proBNP, WHO functional class, and simplified French risk score achieved from baseline were largely maintained at one year, including in the placebo-crossed group 6.