TAK-925 (Danavorexton), an Orexin Receptor 2 Agonist, Reduces Opioid-induced Respiratory Depression and Sedation without Affecting Analgesia in Healthy Men.

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 (11 mg [low-dose], then 19 mg [high-dose]) or placebo, under remifentanil infusion, on two occasions separated by a 36-h or longer washout period. Remifentanil infusion was titrated under isohypercapnic conditions to achieve an approximately 30 to 40% decrease in minute ventilation (from approximately 20 to approximately 14 l/min) before danavorexton/placebo administration. Assessments included safety, ventilation measurements, sedation, and pain tolerance.

RESULTS

A total of four (30.8%) danavorexton-treated participants and one (8.3%) placebo-treated participant experienced treatment-emergent adverse events (all mild in severity). Insomnia, lasting 1 day, occurred in one participant, and was considered related to danavorexton. Compared with placebo, low- and high-dose danavorexton significantly increased ventilation variables (observed mean [95% CI] change, sensitivity analysis model-based P values) including minute volume (8.2 [95% CI, 5.0 to 11.4] and 13.0 [95% CI, 9.4 to 16.5] l/min), tidal volume (312 [95% CI, 180 to 443] and 483 [95% CI, 309 to 657] ml), and respiratory rate (3.8 [95% CI, 1.9 to 5.7] and 5.2 [95% CI, 2.7 to 7.7] breaths/min; all P < 0.001). High-dose danavorexton significantly decreased sedation on a visual analog scale (-29.7 [95% CI, -54.1 to -5.3] mm; P < 0.001) and the Richmond Agitation Sedation Scale (0.4 [95% CI, 0.0 to 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 (approximately 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.