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

Abstract

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.

Fig. 1.

Study design. Healthy participants were randomized 1:1 to receive danavorexton (11 mg [low-dose] and 19 mg [high-dose]) followed by placebo, or vice versa. Treatment periods were separated by a 36-h or greater washout period. Danavorexton 11 mg and 19 mg and placebo were administered as sequential 90-min intravenous infusions within each treatment period. Remifentanil was administered greater than 210 min under isohypercapnic conditions throughout danavorexton/placebo infusion and was titrated to achieve 30 to 40% respiratory depression before danavorexton/placebo administration. Minute volume, tidal volume, and respiratory rate were assessed continuously throughout end-tidal forcing, and averages were calculated in the first 10 min of each assessment time window. The RASS, the VAS, and pain assessments were performed two or three times within each time window (−20 to 0 min, 65 to 85 min, 155 to 175 min, and 195 to 215 min from start of infusion), and the average values were used. BL, baseline; RASS, Richmond Agitation Sedation Scale; VAS, visual analog scale.

Fig. 2.

Flow diagram for study participants. The participant who withdrew consent discontinued on the first treatment day after receiving the first sequence of danavorexton and did not return on the second day for placebo.

Fig. 3.

Effect of danavorexton, in the context of remifentanil infusion, on blood pressure over time. (A) Systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) were measured from before the start of remifentanil infusion (room air, no drug) to 9 h after the start of danavorexton/placebo infusions.

Fig. 4.

Effect of danavorexton, in the context of remifentanil infusion, on minute volume, tidal volume, and respiratory rate. Statistically significant increases in (A) minute volume, (B) tidal volume, and (C) respiratory rate were observed with danavorexton versus placebo infusions across treatment periods, and the improvement in minute volume was sustained even after danavorexton infusion was discontinued. Values shown are based on summary statistics and may differ from the least squares means from a model-based analysis (Supplemental Digital Content table 1, https://links.lww.com/ALN/D828). **P ≤ 0.001 from the mixed-effects model with the change from baseline as the outcome, and with baseline, treatment, time window, and treatment-by-time window as fixed effects, and with subject as the only random effect, using maximum likelihood for estimation (i.e., sensitivity analysis). There was no adjustment for multiplicity, and these values are nominal. †Under isohypercapnia with remifentanil infusion, pre-danavorexton/placebo infusion. ‡Under isohypercapnia after discontinuation of remifentanil and danavorexton/placebo infusions.

Fig. 5.

Effect of danavorexton, in the context of remifentanil infusion, on sedation and pain tolerance. Significant differences in (A) sedation VAS and (B) RASS were observed with danavorexton compared with placebo. (C) There was no statistical difference in pain measurements between danavorexton doses and placebo. RASS, Richmond Agitation Sedation Scale: from +4 to –5, where a score of +4 represents a very combative, violent patient; a score of 0 represents an alert and calm patient; and a score of –5 represents an unarousable patient. VAS, visual analog scale: subjective questionnaire about degree of sedation on a visual rating scale from 0 to 100 mm, where 0 indicates no sedation and 100 indicates maximum sedation. For pain tolerance, the room air, no drug time window was used as the baseline. Values shown are based on summary statistics and may differ from the least squares means from a model-based analysis (Supplemental Digital Content table 1, https://links.lww.com/ALN/D828). *P < 0.01, **P ≤ 0.001 from the mixed-effects model with the change from baseline as the outcome, and with baseline, treatment, time window, and treatment-by-time window as fixed effects, and with subject as the only random effect, using maximum likelihood for estimation (i.e., sensitivity analysis). There was no adjustment for multiplicity, and these values are nominal. †Under isohypercapnia with remifentanil infusion, pre-danavorexton/placebo. ‡Under isohypercapnia after remifentanil and danavorexton/placebo discontinuation. mA, milliampere.