Investigational Orexin Agonist Improved Narcolepsy Type 1 Symptoms

In data presented at the World Sleep 2025 Congress, TAK-861 (oveporexton; Takeda, Cambridge, MA), an investigational oral orexin receptor 2-selective agonist, was shown to significantly improve key symptoms in individuals diagnosed with narcolepsy type 1 (NT1). Treatment with TAK-861, designed to address the underlying orexin deficiency driving NT1, was associated with improvements in cataplexy, symptom severity, wakefulness, and quality of life.

Results were reported from 2 phase 3, global, randomized, double-blind, placebo-controlled trials—FirstLight (NCT06470828) and RadiantLight (NCT05687916)—which together included a total of 273 individuals with NT1 across 19 countries. In the trials, participants received twice-daily treatment with either 1 mg or 2 mg of TAK-861 or placebo for 12 weeks. According to a statement published by Takeda, >95% of participants continued into an ongoing long-term extension study. Both studies, FirstLight and RadiantLight, met all primary and secondary end points: treatment with TAK-861 at both dose levels was associated with statistically significant improvements in symptoms of NT1 compared with placebo (P<.001).

Key results from the 14 end points studied in both trials include the following:

• Wakefulness: Participants treated with TAK-861 showed significant improvements in scores on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS).
• Most participants receiving the TAK-861 2 mg dose achieved normative wakefulness levels (≥20 minutes on the MWT).
• Approximately 85% of participants showed similar levels of wakefulness to healthy individuals (ESS scores of ≤10).
• Cataplexy: Participants receiving TAK-861 showed a median >80% decrease in weekly cataplexy rates from baseline.
• There was a median of 4 to 5 cataplexy-free days compared with placebo at week 12 vs 0 days at baseline.
• Symptom severity: Over 70% of participants reported mild disease severity at week 12, which is the lowest symptom severity level.
• 97% of TAK-861–treated participants reported improvements according to the Patient Global Impression of Change (PGI-C) scale.
• Quality of life: Significant improvements were observed in results obtained from the Short Form-36-item (SF-36) and EuroQol 5-Dimension 5-Level (EQ-5D-5L) surveys.
• Safety: No serious treatment-related events were reported; the most common adverse events noted were mild insomnia and urgency and frequency of urination.