The New England Journal of MedicineOral Orexin Receptor 2 Agonist in Narcolepsy Type 1

Could TAK-994 open new avenues in narcolepsy treatment despite its hepatotoxic effects?

In the search for treatment solutions for narcolepsy type 1, a phase 2 trial was conducted to test the effects of TAK-994, an oral orexin receptor 2-selective agonist. The study aimed to measure the impact of this treatment on patients’ sleep latency and associated symptoms over an 8-week period. However, the trial was terminated early due to hepatic adverse events.

Study Design:

• Trial Type: Phase 2, randomized, placebo-controlled
• Participants: 73 patients with confirmed narcolepsy type 1
• Treatment: Twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo
• Duration: 8 weeks
• Primary End Point: Mean change from baseline in average sleep latency on the Maintenance of Wakefulness Test (MWT)
• Secondary End Points: Change in Epworth Sleepiness Scale (ESS) score and weekly cataplexy rate

Key Findings:

• Sleep Latency: Significant improvements in the MWT in all TAK-994 groups compared to placebo (P<0.001)
• ESS Score: Reductions in all TAK-994 groups versus placebo
• Cataplexy Rate: Reduced weekly incidences in all TAK-994 groups versus placebo
• Adverse Events: 44 of 56 patients (79%) experienced adverse events, including urinary urgency/frequency and liver-enzyme elevations; 3 patients met Hy’s law criteria for drug-induced liver injury

Conclusion:

• TAK-994 demonstrated greater improvements in sleepiness and cataplexy over an 8-week period compared to placebo but was associated with hepatotoxic effects.

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Did You Know?
Narcolepsy type 1 is caused by a severe loss or lack of brain orexin neuropeptides, a condition that affects approximately 1 in 2,000 people.