Abstract Introduction ORX750 is a novel, investigational oral orexin receptor 2 (OX2R) agonist in development for the treatment of narcolepsy and idiopathic hypersomnia. Strong wake-promoting effects were observed in preclinical studies, supporting clinical investigation of ORX750. A first-in-human phase 1 study is ongoing to evaluate the safety and wake-promoting effects of single and multiple oral doses of ORX750. Methods 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 volunteers. Following the SAD study, wake-promoting effects were evaluated in placebo-controlled Proof of Concept (POC) cohorts with a single dose, two-way crossover design in acutely sleep-deprived subjects utilizing the Maintenance of Wakefulness Test (MWT). Results As of the data cut-off date of October 31, 2024, five SAD (total N=45 active, N=15 placebo), three POC (N=8, N=8, N=10), and 2 MAD cohorts (N=16 active, N=4 placebo) have completed. 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), and 33.6 (27.1, 40.1) at 1.0 mg, 2.5 mg, and 3.5 mg once daily (QD), respectively. Average LS mean (95% CI) difference from placebo for mean sleep latency was 8.1 (0.3,15.9), p=0.04 for 1.0mg, 15.2 (4.7, 25.8), p=0.01 for 2.5 mg, and 20.2 (15.2, 25.2), p< 0.0001 for 3.5 mg. Across SAD and MAD cohorts, treatment emergent adverse events were transient and mild in severity. This abstract will be supplemented with data from additional cohorts at the time of presentation. Conclusion ORX750 showed a favorable safety profile and clinically meaningful and statistically significant improvements on wakefulness in acutely sleep-deprived healthy volunteers. ORX750 was well tolerated, and normative wakefulness (>30 mins on the MWT) was achieved at the doses ≥ 2.5mg. These results support continued evaluation of ORX750 for the potential treatment of narcolepsy (type 1 and type 2) and idiopathic hypersomnia. Support (if any) Centessa Pharmaceuticals