Recently, the U.S. FDA approved Merck's "first-in-class" therapy Sotatercept (trade name: Winrevair) for the treatment of pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) in adults, to improve exercise capacity, improve WHO functional classification, and reduce the risk of clinical event deterioration.
About Sotatercept:
Sotatercept is a "first-in-class" activin receptor IIA-Fc type (ActRIIA Fc) fusion protein, which is formed by the fusion of the extracellular domain of human Activin receptor IIA with the Fc domain of IgG1, which can bind and trap TGF-β family ligands (TGF-β ligand traps) and restore proliferation associated with pulmonary artery wall and right ventricular remodeling (ActRIIA/Smad2/ 3-mediated) and antiproliferative (BMPRII/Smad1/5/8-mediated) signaling pathways, thereby regulating basal vascular cell proliferation of PAH.
Dr. Mahesh Patel, Vice President of Global Clinical Development for Cardiovascular and Respiratory Therapies at Merck Research Laboratories, said, "What excites us so much about Sotatercept is that it addresses the fundamental problem of thickening the walls of the pulmonary arteries, allowing for more direct treatment of the disease and a truly far-reaching benefit to patients."
Sotatercept injections can be administered by patients or caregivers with guidance, training, and follow-up by a healthcare provider. The recommended starting dose is 0.3 mg/kg and the recommended target dose is 0.7 mg/kg every 3 weeks. Because Sotatercept may cause an increase in hemoglobin, an increase in red blood cells, it may also lower the platelet count and lead to severe thrombocytopenia. If the patient has a platelet count < 50,000/mm³, it is not recommended to initiate Sotatercept therapy.
About the STELLAR trial
THE FDA'S APPROVAL IS BASED PRIMARILY ON THE PHASE III STELLAR TRIAL. The STELLAR trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group pivotal Phase 3 trial of 324 adults with PAH (WHO Group 1) evaluating the efficacy and safety of Sotatercept versus placebo in addition to standard background therapy.
The results of the study showed that the primary efficacy endpoint of Sotatercept was met, with a statistically and clinically meaningful improvement in 6-minute walk distance (6MWD) at 24 weeks compared to baseline (Figure 1; Table 1).
Fig.1 Primary endpoint
Eight of the nine secondary efficacy measures achieved statistically significant improvements, including 6MWD, NT-proBNP levels, WHO functional classification (WHO FC) or maintenance of WHO FC II, time to death, or first occurrence of clinical deterioration event (TTCW), and the only measure that failed to improve was the score in the cognitive/emotional impact domain of the PAH-SYMPACT questionnaire (Table 1). The overall safety profile of Sotatercept was broadly consistent with the results of the Phase 2 trial.
Table 1 Primary and secondary endpoints
The findings were presented at the 2023 Joint Scientific Meeting of the American College of Cardiology and the World Heart Federation, as well as in the New England Journal of Medicine.
Bibliography:
[1] Megan Brooks. FDA OKs Sotatercept, First-in-Class Agent for Pulmonary Arterial Hypertension. Medscape. March 27, 2024.
[2] Isabella Hornick. FDA approves sotatercept for pulmonary arterial hypertension. Healio. March 27, 2024.
[3] Marius M Hoeper, David B Badesch. et al. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023 Apr 20; 388(16):1478-1490.
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