Orexin Agonist Shows Promise for Treating Narcolepsy, Hypersomnia: Richard Bogan, MD

A dose-finding, placebo-controlled study of an orexin agonist has demonstrated early but encouraging signals of efficacy in patients with narcolepsy type 2 and idiopathic hypersomnia, according to data presented at the American Academy of Sleep Medicine and Sleep Research Society Annual Meeting.

Richard Bogan, MD, FCCP, FAASM, sleep specialist at Bogan Sleep Consultants, shared some of the findings from the VIBRANCE-2 (NCT06555783) study.

The investigational agent, referred to as alixorexton, targets orexin, a neuropeptide described by Bogan as the “command and control center for wakefulness.”

Orexin-producing neurons help maintain stable wakefulness by activating downstream monoaminergic systems in the brain. In narcolepsy type 1, patients lack orexin, whereas individuals with narcolepsy type 2 and idiopathic hypersomnia generally retain orexin production but still experience profound daytime sleepiness. The central question for this study was whether pharmacologic activation of the orexin system could meaningfully improve alertness in these patients.

Participants entered the study with marked objective and subjective sleepiness. On the Multiple Wakefulness Test (MWT), patients fell asleep within approximately 5 to 6 minutes on average—far below the more than 20 minutes typically seen in healthy individuals. Subjectively, their Epworth Sleepiness Scale scores averaged 17 to 18, well above the conventional threshold of 10 that distinguishes normal from pathologic sleepiness.

In this placebo-controlled, parallel-group trial, patients were randomized to receive alixorexton at doses of 10, 14, or 18 mg. The primary aim was to detect a biological signal of efficacy, assessed by changes in MWT latency and Epworth scores. According to Bogan, both measures improved with active treatment compared with placebo, suggesting that orexin agonism may enhance daytime wakefulness even in patients who already produce orexin.

The investigators also evaluated fatigue and executive function—domains frequently impaired in hypersomnolence disorders and only partially explained by sleepiness alone. Early results indicated beneficial signals in both areas, with improvements in thinking, memory, focus, and the ability to manage divided tasks.

Although these findings are preliminary, they support further development of orexin agonists as a novel therapeutic class for central disorders of hypersomnolence. Ongoing and future studies will be needed to define the optimal dosing, durability of response, safety profile, and broader functional outcomes in real-world populations.