OREXIN 2 RECEPTOR AGONISTS AS A POTENTIAL THERAPEUTIC APPROACH TO THE TREATMENT OF SLEEP-WAKE DISTURBANCE, FATIGUE, AND COGNITIVE DEFICIT IN NEUROPSYCHIATRIC DISEASE

Sleep disorders are among the most prevalent and impairing health conditions globally. These conditions frequently co-occur with psychiatric disorders, especially among individuals with mood, anxiety, psychotic, and neurodevelopmental disorders, leading to some of the most common comorbidities in clinical practice. Orexin neuropeptides, which signal through orexin receptor 1 (OX1R) and 2 (OX2R), are regulators of sleep-wake behavior and stabilize wakefulness through activation of downstream arousal neurocircuitry, including histamine, serotonin, dopamine, acetylcholine, and norepinephrine circuits. OX2R agonists have recently emerged as potentially transformative treatment options for patients with central disorders of hypersomnolence, including narcolepsy. Alixorexton, a highly potent, selective OX2R agonist, has been shown to normalize daytime sleepiness (i.e., achievement of mean sleep latency on the Maintenance of Wakefulness Test > 20 minutes) in a phase 2 study (Vibrance-1; NCT06358950) of patients with narcolepsy type 1 (NT1), where the pathophysiology involves loss of orexin-producing neurons. Furthermore, the study showed clinically meaningful improvements across a multitude of NT1 symptoms that are often inadequately treated with current therapies, including cataplexy and more recently recognized symptoms related to cognitive impairment and fatigue. Alixorexton also demonstrated clinically meaningful improvements in measures of wakefulness, cognitive impairment, and fatigue in a phase 2 study (Vibrance-2; NCT06555783) of patients with narcolepsy type 2 (NT2), a population that typically has preserved cerebrospinal orexin levels and a less well defined disease pathophysiology. Achieving clinical effects with an OX2R agonist across multiple symptoms, including cognitive impairment and fatigue, in a population with central disorders of hypersomnolence indicates that it is plausible to target improvement in the lives of patients in areas other than sleepiness by targeting the orexin pathway. Two other OX2R agonist molecules are currently being evaluated in healthy volunteers, with plans for clinical testing in patients with attention deficit and hyperactivity disorder (ADHD) and patients with fatigue associated with multiple sclerosis or Parkinson’s disease, respectively, later this year. This presentation will highlight the key data supporting the utility of alixorexton across sleep-wake disturbance, fatigue, and cognition, and discuss ongoing product development plans.