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

Summary

In a controlled remifentanil-induced respiratory depression model, danavorexton significantly increased minute ventilation, tidal volume, and respiratory rate, while reducing sedation, without diminishing pain tolerance. Adverse events were mild, suggesting a favorable safety profile in healthy men.

Key Findings

• Minute ventilation increased by 8.2 and 13.0 L/min (low- and high-dose) vs placebo; all P<0.001.
• Tidal volume (+312 and +483 mL) and respiratory rate (+3.8 and +5.2 breaths/min) both significantly increased; all P<0.001.
• Sedation decreased (VAS −29.7 mm; RASS improvement) without change in pain tolerance; adverse events were mild.

Clinical Implications

If efficacy and safety are confirmed in patients, danavorexton could be used perioperatively or in overdose settings to restore ventilation without antagonizing analgesia, reducing intubations and rescue opioid reversal.

Limitations

• Small sample size (n=13) of healthy men limits generalizability to clinical populations.
• Short-term physiological endpoints; no patient-centered outcomes or long-term safety.

Future Directions

Phase 2/3 trials in perioperative and overdose populations, interaction studies with varied opioids, and evaluation of cardiovascular safety and sleep/wake impacts.