To evaluate safety and wake-promoting effects of single and multiple oral doses of ORX750 in a first-in-human clinical study.

ORX750 is a novel, investigational oral orexin-2 receptor (OX2R) agonist in development for treatment of narcolepsy and idiopathic hypersomnia. Strong wake-promoting effects were observed in preclinical studies, supporting clinical investigation of ORX750.

Safety, tolerability, and pharmacokinetics of ORX750 were evaluated at single-ascending doses (SAD) and multiple-ascending doses (MAD) in a randomized, placebo-controlled study in healthy participants. In parallel to the SAD, wake-promoting effects were evaluated in placebo-controlled Proof of Concept (POC) cohorts with a two-way crossover design in acutely sleep-deprived participants utilizing the Maintenance of Wakefulness Test (MWT).

As of the data cut-off date of December 5, 2024, five SAD (total N=45 active, N=15 placebo), four POC (N=8, N=8, N=10, N=8), and three MAD cohorts (N=24 active, N=6 placebo) have completed the study. Observed least squares (LS) mean (95% confidence interval [CI]) sleep onset latencies (minutes) in the MWT were 17.6 (12.1, 23.2), 32.0 (22.2, 41.8), 33.6 (27.1, 40.1), and 37.9 (31.7, 44.0) at 1.0 mg, 2.5 mg, 3.5 mg, and 5.0 mg once daily (QD), respectively. Average least square (LS) mean (95% CI) difference from placebo for mean sleep latency was 8.1 (0.3,15.9), p=0.04 for 1.0 mg, 15.2 (4.7, 25.8), p=0.01 for 2.5 mg, 20.2 (15.2, 25.2), p<0.0001 for 3.5 mg, and 22.6 (17.0, 28.2), p<0.0001 for 5.0 mg. Treatment emergent adverse events were transient and mild or moderate in severity.

Results support that ORX750 was well tolerated across the evaluated dose range, and clinically meaningful and statistically significant improvements in wakefulness were observed in acutely sleep-deprived healthy participants. Doses ≥2.5 mg produced MWT mean sleep latencies >30 minutes. These results support continued evaluation of ORX750 for the potential treatment of narcolepsy and idiopathic hypersomnia.