Eisai (4523) Status Update summary

Overview and Background

• E2086 is a selective orexin receptor 2 agonist developed to address orexin deficiency in narcolepsy type 1 (NT1), aiming to promote wakefulness and reduce cataplexy symptoms.

• Orexin is a neurotransmitter regulating sleep-wake cycles; deficiency causes NT1, while excessive activity is linked to insomnia.

• The compound was discovered through extensive screening and optimization, resulting in a unique chemical structure with strong efficacy and safety in preclinical studies.

• E2086 is positioned as a once-daily therapy, leveraging prior experience with orexin antagonists and agonists.

Clinical Trial Design and Participants

• The phase I-B trial was a multicenter, randomized, double-blind, five-period crossover study comparing three doses of E2086 (5, 10, 25 mg), placebo, and modafinil in adults with NT1.

• 22 patients were randomized and 19 completed the study; safety analysis included 21 participants (mean age 35.6 years, 42.9% female).

Efficacy Results

• All doses of E2086 significantly increased mean sleep latency versus placebo and modafinil in the Maintenance of Wakefulness Test (MWT), with 10 mg and 25 mg sustaining wakefulness for at least 30 minutes per trial.

• Subjective alertness (KSS) was significantly higher for all E2086 doses compared to placebo, and for higher doses compared to modafinil.

• E2086 demonstrated robust, sustained efficacy, with many patients achieving wakefulness comparable to healthy subjects.