Merck's First-in-Class Therapy Sotatercept (Winrevair) Receives FDA Approval for Pulmonary Arterial Hypertension
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Sotatercept is a "First-in-class" activin receptor IIA-Fc fusion protein (ActRIIA Fc), composed of the extracellular domain of the human Activin receptor IIA fused with the Fc domain of IgG1. It can bind and capture TGF-β family ligands (TGF-β ligand trap), restoring the balance between pro-proliferative (ActRIIA/Smad2/3-mediated) and anti-proliferative (BMPRII/Smad1/5/8-mediated) signaling pathways associated with pulmonary arterial wall and right ventricular remodeling, thereby regulating the fundamental vascular cell proliferation in PAH.
Mahesh Patel, Ph.D., Vice President of Global Clinical Development in the Cardiovascular and Respiratory Therapeutic Area at Merck Sharp & Dohme Research Laboratories, stated that the reason Sotatercept excites us is that it addresses the root issue of thickened pulmonary arterial walls, allowing for more direct treatment of the disease and bringing truly profound benefits to patients.
Sotatercept injections can be administered by the patient or caregiver under the guidance, training, and follow-up of a healthcare provider. The recommended starting dose is 0.3 mg/kg; the target dose is 0.7 mg/kg every 3 weeks. Since Sotatercept may cause an increase in hemoglobin, polycythemia, and may also reduce platelet count leading to severe thrombocytopenia, it is not recommended to initiate Sotatercept treatment if the patient’s platelet count is <50,000/mm³.
The FDA's approval this time is mainly based on the Phase III STELLAR trial. The STELLAR trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group pivotal Phase 3 trial that enrolled a total of 324 adult patients with PAH (WHO Group 1), evaluating the efficacy and safety of Sotatercept versus placebo when added to standard background therapy.
The study results showed that Sotatercept achieved the primary efficacy endpoint, with a statistically and clinically significant improvement in 6-minute walking distance (6MWD) at week 24 compared to baseline (Figure 1; Table 1).
Figure 1 Primary Endpoint
Among the 9 secondary efficacy endpoints, 8 achieved statistically significant improvements, including 6MWD, NT-proBNP levels, WHO Functional Class (WHO FC) or maintaining WHO FC II, time to death or first clinical worsening event (TTCW), etc.; the only endpoint that did not show improvement was the score in the cognitive/emotional impact domain of the PAH-SYMPACT questionnaire (Table 1). The overall safety profile of Sotatercept was generally consistent with the findings from the Phase 2 trial.
Table 1 Primary and Secondary Endpoints
The study results were presented at the joint scientific meeting of the American College of Cardiology and the World Heart Federation in 2023 and simultaneously published in The New England Journal of Medicine.
