Development of a Novel, Oral Orexin Receptor 2 Agonist, ORX750 for Treatment of Patients with Narcolepsy (type 1 and 2) and Idiopathic Hypersomnia
Recommended Citation
Plazzi G, Dauvilliers Y, Plante D, Mignot E, Roth T, Sterkel M, Leary EB, Hartman D, Accardi MA, Saha S, Kanes S. Development of a Novel, Oral Orexin Receptor 2 Agonist, ORX750 for Treatment of Patients with Narcolepsy (type 1 and 2) and Idiopathic Hypersomnia. Sleep Med 2026; 138.
Document Type
Conference Proceeding
Publication Date
2-1-2026
Publication Title
Sleep Med
Abstract
Introduction: Narcolepsy types 1 (NT1), 2 (NT2), and idiopathic hypersomnia (IH) are rare, life-long, disabling central disorders of hypersomnolence characterized by excessive daytime sleepiness (EDS). None of the currently available treatments target the orexin system, which is a core element of wake-promoting circuitries and specifically, of NT1 pathology. ORX750 is a novel, investigational, highly potent, 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 of ORX750, supporting clinical investigation. The development program is ongoing and includes a first-in-human phase 1 study to evaluate the safety and wake-promoting effects of single and multiple oral doses of ORX750, a phase 2a study (ORX750-0201 [CRYSTAL-1]) in NT1, NT2 and IH patients, and a long-term extension (LTE) study (ORX750-202) for participants who complete ORX750-0201. Materials and methods: In the phase 1 study, safety, tolerability, and pharmacokinetics (PK) of ORX750 are evaluated at single-ascending doses (SAD) and multiple-ascending doses (MAD) in a randomized, placebo-controlled design in healthy participants. In parallel, wake-promoting effects are 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). ORX750-0201 (CRYSTAL-1) is evaluating the safety, tolerability, efficacy, and PK of ORX750 in NT1, NT2, and IH patients. Initial dosing is 1 mg (NT1) and 2 mg (NT2 and IH) with adaptive, sequential dose selection between cohorts. Efficacy endpoints include the MWT, Epworth Sleepiness Scale (ESS), and weekly cataplexy rate (WCR, NT1 only). Other exploratory assessments include measures of overall symptom improvement, sleep, cognition, attention, memory, and general health. Participants who complete ORX750-0201 can enroll in the LTE study (ORX750-202). In ORX750-202, the primary endpoint is safety, with efficacy assessments including MWT, ESS, and WCR (NT1 only), alongside other exploratory endpoints. Results: In the phase 1 study, 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=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. Conclusions: ORX750 showed a favorable safety profile and clinically meaningful and statistically significant improvements on wakefulness in the phase 1 study 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. The phase 1 study, ORX750-0201 and ORX750-202 are open, and results will inform future clinical development.
Volume
138
