Seltorexant (DB14961): A Comprehensive Review of its Pharmacology, Clinical Development, and Regulatory Landscape

Abstract

Seltorexant (DrugBank ID: DB14961), an investigational small molecule also known by developmental codes MIN-202 and JNJ-42847922, is a selective orexin-2 receptor (OX2R) antagonist. Its primary mechanism involves the modulation of the orexin system, which is crucial for regulating sleep-wake cycles, arousal, and mood. Seltorexant exhibits high affinity and selectivity for the OX2R over the OX1R. Preclinical studies in animal models demonstrated its efficacy in promoting sleep, particularly by reducing sleep latency and prolonging non-rapid eye movement (NREM) sleep, without significantly impacting REM sleep or showing abuse potential. Human pharmacokinetic studies reveal rapid absorption (Tmax 0.3-1.5 hours) and a short elimination half-life (2-3 hours), primarily metabolized by CYP3A4. Clinical development has focused on Major Depressive Disorder (MDD), especially with comorbid insomnia symptoms, and insomnia disorder. Phase 3 trials, such as MDD3001 (NCT04533529), have shown that adjunctive seltorexant significantly improves depressive symptoms (measured by MADRS) and sleep disturbances in patients with MDD and insomnia. It has been generally well-tolerated, with common adverse events including somnolence, headache, and nausea. A dedicated study (NCT03494907) evaluated its effects on electrocardiogram intervals in healthy adults, though specific QT results are not detailed in the available data. Seltorexant is under active development by Janssen, following an earlier co-development with Minerva Neurosciences. Regulatory activities include an agreed Paediatric Investigation Plan with the European Medicines Agency for MDD in adolescents. This report synthesizes the available pharmacological, preclinical, clinical efficacy, safety, and regulatory information on seltorexant.

1. Introduction to Seltorexant