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Sotatercept in pulmonary hypertension and beyond.

Eur J Clin Invest

January 2025

Department of Surgical, Medical and Molecular Pathology and Critical Area, Laboratory of Biochemistry, University of Pisa, Pisa, Italy.

Sotatercept binds free activins by mimicking the extracellular domain of the activin receptor type IIA (ACTRIIA). Additional ligands are BMP/TGF-beta, GDF8, GDF11 and BMP10. The binding with activins leads to the inhibition of the signalling pathway and the deactivation of the bone morphogenic protein (BMP) receptor type 2.

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Pulmonary arterial hypertension (PAH) is a rare and potentially fatal condition characterized by progressive increases in blood pressure in the arteries of the lungs. Oral selexipag, approved by the Food and Drug Administration (FDA) in 2015 for the treatment of PAH, targets prostacyclin receptors on pulmonary arterial vascular smooth muscle and endothelial cells to improve blood flow through the lungs and reduce pulmonary vascular resistance. Oral selexipag is effective, but may be discontinued due to factors like side effects, emergency conditions, or inability to take oral medication, potentially leading to severe adverse events, such as rebound pulmonary hypertension and right heart failure.

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Challenges in drug development for rare diseases such as pulmonary arterial hypertension can be addressed through the use of mathematical modeling. In this study, a quantitative systems pharmacology model of pulmonary arterial hypertension pathophysiology and pharmacology was used to predict changes in pulmonary vascular resistance and six-minute walk distance in the context of oral treprostinil clinical studies. We generated a virtual population that spanned the range of clinical observations and then calibrated virtual patient-specific weights to match clinical trials.

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Background: Selexipag, an oral prostacyclin (PGI) receptor agonist, is approved for adult patients with pulmonary arterial hypertension (PAH). This study evaluated the efficacy and safety of selexipag for Japanese pediatric patients with PAH.

Methods And Results: The study enrolled 6 patients who received selexipag twice daily at an individualized dose based on body weight; maintenance doses were determined for each patient by 12 weeks after starting administration.

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Prostaglandins are hormones found in almost all mammalian tissues. As signaling molecules, they play a key role in the regulation of many physiological processes, including hair growth cycle. The article describes the history of the discovery of prostaglandins, including the work of Professor Ryszard Gryglewski – the discoverer of prostacyclin.

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