What is the role of sotatercept in treating pulmonary arterial hypertension?

Sotatercept in Pulmonary Arterial Hypertension

Sotatercept is a first-in-class activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that significantly improves exercise capacity, functional status, and reduces clinical worsening events in adults with pulmonary arterial hypertension (PAH) when added to background therapy. This novel medication addresses the underlying pathophysiology of PAH by restoring balance between proliferative and anti-proliferative signaling pathways in pulmonary vasculature 1.

Mechanism of Action and Efficacy

• Sotatercept works as an activin signaling inhibitor that binds to activin A and other TGF-β superfamily ligands, improving the balance between pro-proliferative (ActRIIA/Smad2/3-mediated) and anti-proliferative (BMPRII/Smad1/5/8-mediated) signaling to modulate vascular proliferation 2.
• In rat models of PAH, sotatercept analog reduced inflammation and inhibited proliferation of endothelial and smooth muscle cells in diseased vasculature, resulting in thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics 2.
• The Phase 3 STELLAR trial demonstrated that sotatercept significantly improved 6-minute walk distance (6MWD) with a median treatment difference of 40.8 meters compared to placebo (p<0.001) in patients with WHO functional class II or III PAH on stable background therapy 3.
• Sotatercept also significantly reduced pulmonary vascular resistance (PVR) with a median treatment difference of -235 dynes*sec/cm^5 compared to placebo (p<0.001) 2.

Clinical Applications

• Sotatercept (WINREVAIR) is FDA-approved for treatment of adults with PAH to increase exercise capacity, improve WHO functional class, and reduce the risk of clinical worsening events 2, 4.
• It is administered subcutaneously every 3 weeks at a starting dose of 0.3 mg/kg, with titration to a target dose of 0.7 mg/kg 2, 3.
• The ZENITH trial demonstrated that in high-risk PAH patients (WHO functional class III or IV), sotatercept significantly reduced the composite endpoint of death, lung transplantation, or hospitalization for worsening PAH with a hazard ratio of 0.24 (95% CI: 0.13-0.43, p<0.001) compared to placebo 5.
• A meta-analysis of randomized controlled trials confirmed sotatercept's benefits in improving exercise capacity, WHO functional class, and pulmonary hemodynamics with an acceptable safety profile 6.

Place in Therapy

• Current PAH guidelines recommend a multidisciplinary approach to treatment with combination therapy for patients who remain symptomatic on initial therapy 7.
• While sotatercept is not yet included in published guidelines due to its recent approval, its robust clinical trial data suggests it should be considered as an add-on therapy for patients with PAH who remain symptomatic despite background therapy 3, 5.
• For patients with WHO functional class II or III PAH on stable background therapy, sotatercept can be added to improve exercise capacity and reduce risk of clinical worsening 3.
• For high-risk PAH patients (WHO functional class III or IV) on maximum tolerated background therapy, sotatercept significantly reduces mortality and morbidity events 5.

Safety Considerations and Monitoring

• The most common adverse events associated with sotatercept include epistaxis, telangiectasia, increased hemoglobin/hematocrit levels, dizziness, and thrombocytopenia 2, 3.
• Blood tests should be performed before the first 5 doses of sotatercept, and periodically thereafter, to monitor hemoglobin and platelet levels 2.
• Dose adjustments or delays may be necessary based on hemoglobin levels 2.
• Sotatercept is contraindicated in pregnancy due to potential risk to the fetus, and females of reproductive potential should use effective contraception during treatment and for at least 4 months after the final dose 2.
• Breastfeeding is not recommended during treatment with sotatercept and for 4 months after the final dose 2.

Practical Considerations

• Patients with PAH should be managed at specialized pulmonary hypertension centers with a multidisciplinary approach 7.
• General measures for PAH patients remain important, including avoiding excessive physical activity, pregnancy, high altitude exposure without supplemental oxygen, and non-essential surgery 7.
• Vaccination against influenza and pneumococcal pneumonia is recommended for PAH patients 7.
• When surgery is necessary for PAH patients, care should be coordinated at a pulmonary hypertension center with careful monitoring of clinical status, oxygenation, and hemodynamics 7.

Conclusion

Sotatercept represents a significant advancement in PAH therapy with its novel mechanism of action targeting the underlying pathobiology of the disease. Its demonstrated benefits in improving exercise capacity, functional status, and reducing clinical worsening events make it a valuable addition to the therapeutic armamentarium for PAH, particularly for patients who remain symptomatic despite optimized background therapy.