O013 Preliminary Results from a Phase 1 Study of ALKS 2680, an Orexin-2 receptor Agonist, in Healthy Participants and Patients with Narcolepsy or Idiopathic Hypersomnia

INTRODUCTION: ALKS 2680, a potent, brain-penetrant, highly selective orexin-2 receptor (OX2R) agonist, is being developed for treatment of narcolepsy and other hypersomnias. We report preliminary results from the ALKS 2680 first-in-human study. METHODS: This randomized, double-blind, phase 1 study of ALKS 2680 is being conducted at two Australia sites. Healthy participants received single- (n=48, 6 dosages) or multiple- (n=32, 4 dosages once-daily for 10 days) oral doses of ALKS 2680 or placebo. Patients with narcolepsy type 1 (NT1) or type 2 (NT2) or idiopathic hypersomnia (IH; up to 8 patients for each indication) will also be studied, receiving single doses ALKS 2680 or placebo in a 4-way crossover design with 3 active dose levels. Pharmacodynamic assessments will include the Maintenance of Wakefulness Test, Karolinska Sleepiness Scale, and tracking of sleep and cataplexy episodes. RESULTS: In healthy participants, ALKS 2680 was orally absorbed and showed biphasic distribution/elimination, with a terminal half-life suitable for maintaining daytime wakefulness with once-daily administration. There were no systematic changes in vital signs, safety laboratory tests, or ECG at any dose level, and no serious or severe adverse events (AEs). Most drug-related events were mild and resolved without medical intervention. There was a single discontinuation due to a nonserious AEs that resolved without treatment. CONCLUSIONS: Preliminary results suggest that the OX2R agonist ALKS 2680 is generally well-tolerated with a pharmacokinetic profile potentially suitable for once-daily oral administration to promote daytime wakefulness. Effects of ALKS 2680 in patients with NT1, NT2, and IH are being evaluated.