TAK-925 (danavorexton), an Orexin Receptor 2 Agonist, Reduces Opioid-Induced Respiratory Depression and Sedation Without Affecting Analgesia in Healthy Adult Males

Background: Orexin neuropeptides help regulate sleep/wake states, respiration, and pain. However, their potential role in regulating breathing, particularly in perioperative settings, is not well understood. TAK-925 (danavorexton), a novel, orexin receptor 2-selective agonist, directly activates neurons associated with respiratory control in the brain and improves respiratory parameters in rodents undergoing fentanyl-induced sedation. This study assessed the safety and effect of danavorexton on ventilation in healthy men in an established remifentanil-induced respiratory depression model. Methods: This single-center, double-blind, placebo-controlled, two-way crossover, phase 1 trial randomized (1:1) 13 healthy men to danavorexton (11mg [low-dose] then 19mg [high-dose]) or placebo, under remifentanil infusion, on two occasions separated by a ≥36-hour washout period. Remifentanil infusion was titrated under isohypercapnic conditions to achieve ~30% to 40% decrease in minute ventilation (from ~20 to ~14 L/minute) before danavorexton/placebo administration. Assessments included safety, ventilation measurements, sedation, and pain tolerance. Results: 4 (30.8%) danavorexton-treated participants and 1 (8.3%) placebo-treated participant experienced treatment-emergent adverse events (all mild in severity). Insomnia, lasting 1 day, occurred in 1 participant, and was considered related to danavorexton. Compared with placebo, low- and high-dose danavorexton significantly increased ventilation variables (observed mean [95% confidence interval] change, sensitivity analysis model-based p-values) including minute volume (8.2[5.0, 11.4] and 13.0[9.4, 16.5] L/min), tidal volume (312[180, 443] and 483[309, 657] mL), and respiratory rate (3.8[1.9, 5.7] and 5.2[2.7, 7.7] breaths/min) (all P <0.001). High-dose danavorexton significantly decreased sedation on visual analog scale (–29.7[–54.1, –5.3] mm, P <0.001) and Richmond Agitation Sedation Scale (0.4[0.0, 0.7], P<0.001), compared with placebo. Improvements in respiratory variables continued beyond completion of danavorexton infusion. No significant differences in pain tolerance were observed between danavorexton doses or between danavorexton and placebo (~13% increase from baseline; low-dose: P =0.491; high-dose: P =0.140). Conclusions: Danavorexton has effects on respiration and wakefulness in an opioid-induced respiratory depression setting without reversing opioid analgesia.