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), with the most recent and highest quality study demonstrating its efficacy in improving exercise capacity and reducing the risk of death or clinical worsening 1.

Key Findings

• Sotatercept works by restoring balance in the TGF-beta signaling pathway, which is dysregulated in PAH, by acting as a ligand trap for activins and growth differentiation factors.
• The drug is administered subcutaneously at doses of 0.3 mg/kg to 0.7 mg/kg every 3 weeks.
• Beyond improving exercise capacity, sotatercept reduced the risk of death or clinical worsening by 84% and improved multiple secondary endpoints including NT-proBNP levels, WHO functional class, and quality of life measures.
• Common side effects include headache, dizziness, and changes in hemoglobin levels requiring monitoring.

Clinical Guidelines

The American College of Chest Physicians Guideline and Expert Panel Report on Pharmacotherapy for PAH provides evidence-based guidelines for the treatment of PAH, including the use of sotatercept 1.

• The guideline emphasizes the importance of accurate and timely diagnosis, and the need for clinicians to consider multiple factors, including exercise capacity, right ventricular function, hemodynamics, and patient preferences, when choosing pharmacologic therapy.
• The guideline also highlights the limitations of current therapies, including the lack of effective means of predicting which patients with PAH may benefit from individual agents, and the need for further research to address the gaps in the evidence base.

Recommendation

Based on the most recent and highest quality study, sotatercept is recommended as a treatment option for adults with PAH, particularly those with WHO functional class II or III symptoms 1.

• Clinicians should carefully review prescribing information and consult reliable resources to check for drug-drug interactions, and monitor patients for common side effects.
• Further research is needed to fully understand the benefits and risks of sotatercept and to address the gaps in the evidence base for PAH treatment.

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:

• Improvement in 6-Minute Walk Distance: The placebo-adjusted median increase in 6 MWD was 41 meters.
• Improvement in WHO Functional Class: 29% of patients had an improvement from baseline by at least 1 WHO FC at Week 24.
• Reduction in Clinical Worsening Events: 84% reduction in the occurrence of death from any cause or PAH clinical worsening events compared to placebo. These results are based on the STELLAR trial 2, 2, 2.

From the Research

Trial Overview

• The Phase 3 trial of sotatercept for the treatment of pulmonary arterial hypertension 3 demonstrated a significant improvement in exercise capacity, as assessed by the 6-minute walk test, compared to placebo.
• The trial included 163 patients assigned to receive sotatercept and 160 to receive placebo, with a median change from baseline at week 24 in the 6-minute walk distance of 34.4 m in the sotatercept group and 1.0 m in the placebo group.

Efficacy and Safety

• Sotatercept was associated with a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension 4.
• The treatment was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels and an improvement in 6-minute walk distance 4.
• Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure 3, 4.

Comparative Effectiveness

• A systematic review and network meta-analysis found that sotatercept is an effective add-on therapy for pulmonary arterial hypertension, likely superior to many approved add-on PAH therapies in reducing clinical worsening 5.
• Sotatercept probably improves 6-minute-walk distance compared to placebo and add-on endothelin receptor antagonists, and prostanoid taken orally 5.

Long-Term Follow-Up

• An ongoing open-label study, SOTERIA, is evaluating the long-term safety, tolerability, and efficacy of sotatercept in participants with pulmonary arterial hypertension 6.
• Interim results of SOTERIA support the favorable benefit-risk of add-on sotatercept treatment in adults with PAH, with improvements in 6MWD, NT-proBNP, WHO FC, and SFRS achieved from baseline largely maintained at one year 6.

Additional Studies

• A review of the characteristics, efficacy, safety, and clinical relevance of sotatercept in pulmonary arterial hypertension found that adding sotatercept to background therapy increased 6-minute walk distance in phase II-III trials 7.
• Pooled analysis from PULSAR and STELLAR showed improvements in pulmonary vascular resistance and NT-proBNP, and exploratory data from PULSAR revealed that BMPR2 genetic variant status was not associated with significant differences in treatment effects 7.