Oral Orexin Agonist Oveporexton Shows Promise for Narcolepsy Without Liver Toxicity
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Reviewed by Dat Tien Nguyen, B.A, ScM.
Translated by Nhi Phuong Quynh Le, B.A |
Posted on June 11th, 2025
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The loss of orexin-producing neurons in the hypothalamus is the primary driver of narcolepsy, particularly type 1. While existing treatments focus on alleviating symptoms—such as promoting daytime wakefulness and reducing cataplexy—they do not target the underlying orexin deficiency. Previous attempts to develop orexin receptor agonists have been hampered by the need for intravenous delivery and concerns over liver toxicity. With funding from Takeda, a new study explored the use of oveporexton, a blood-brain barrier–permeable, orally administered orexin agonist, for the treatment of narcolepsy.
This phase 2 clinical trial enrolled 90 participants diagnosed with type 1 narcolepsy, as defined by the third edition of the International Classification of Sleep Disorders. Diagnoses were confirmed with nocturnal polysomnography. At baseline, participants demonstrated a profound inability to stay awake, with an average Maintenance of Wakefulness Test (MWT) result of about 5 minutes—far below the normal threshold of 20 minutes or more. Their average Epworth Sleepiness Scale (ESS) score was 18.5, indicating significant daytime sleepiness (normal: <10).
Participants were randomly assigned to receive either a placebo or oveporexton, delivered orally at various dosages: 0.5 mg twice daily, 2 mg twice daily, 2 mg followed by 5 mg daily, and 7 mg once daily. After 8 weeks, the treatment groups—particularly those on the 2 mg twice-daily and 2 mg followed by 5 mg regimens—demonstrated marked improvements in wakefulness, as measured by MWT. ESS scores also declined significantly in the oveporexton groups, with most patients achieving scores within the normal range. Additionally, cataplexy frequency was reduced. Adverse effects associated with oveporexton included insomnia, headaches, and increased urinary frequency and urgency, but most were mild in severity. Notably, no signs of hepatotoxicity were observed, marking an important advance over earlier orexin-targeted therapies.
This phase 2 clinical trial enrolled 90 participants diagnosed with type 1 narcolepsy, as defined by the third edition of the International Classification of Sleep Disorders. Diagnoses were confirmed with nocturnal polysomnography. At baseline, participants demonstrated a profound inability to stay awake, with an average Maintenance of Wakefulness Test (MWT) result of about 5 minutes—far below the normal threshold of 20 minutes or more. Their average Epworth Sleepiness Scale (ESS) score was 18.5, indicating significant daytime sleepiness (normal: <10).
Participants were randomly assigned to receive either a placebo or oveporexton, delivered orally at various dosages: 0.5 mg twice daily, 2 mg twice daily, 2 mg followed by 5 mg daily, and 7 mg once daily. After 8 weeks, the treatment groups—particularly those on the 2 mg twice-daily and 2 mg followed by 5 mg regimens—demonstrated marked improvements in wakefulness, as measured by MWT. ESS scores also declined significantly in the oveporexton groups, with most patients achieving scores within the normal range. Additionally, cataplexy frequency was reduced. Adverse effects associated with oveporexton included insomnia, headaches, and increased urinary frequency and urgency, but most were mild in severity. Notably, no signs of hepatotoxicity were observed, marking an important advance over earlier orexin-targeted therapies.