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

Abstract 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.