FDA Approves First Drug to Treat the Orexin Deficit in Narcolepsy Type 1

Rutgers Researchers Explain How It Works and Its Addictive Potential

Narcolepsy type 1 is a lifelong neurological disorder that affects about 1 in 2,000 people in the United States. People with the disorder have lost most of the brain cells that make orexin (also called hypocretin). Orexin is a neuropeptide that keeps the brain awake; without it, patients with narcolepsy type 1 experience excessive daytime sleepiness, sudden loss of muscle tone while awake (cataplexy), hallucinations at sleep onset or awakening, and poor nighttime sleep [1]. The American Academy of Sleep Medicine currently recommends multiple drugs such as modafinil, pitolisant, solriamfetol, or sodium oxybate to treat symptoms of narcolepsy type 1 [4]. However, these drugs do not directly address the underlying orexin deficit.

Recently, Orzeyful™ (oveporexton) became the first FDA-approved drug available in the US that addresses the orexin deficit underlying the disease rather than the symptoms that the deficit produces [1]. Orexin produced by brain cells binds two different types of endogenous orexin receptors: orexin-1 and -2 receptors. Oveporexton mimics endogenous orexin, but unlike orexin it binds and selectively activates the orexin-2 receptor [2]. While it does not restore the orexin producing neurons that are lost in patients with narcolepsy type 1, oveporexton can partly substitute for the missing endogenous orexin and overcome the deficit in the orexin-2 receptor mediated signaling functions in patients with narcolepsy.

What did the trials show?

Oveporexton approval was based on two 12-week trials across 19 countries. Compared to placebo, study participants administered a twice-daily 2mg dose reached normal daytime alertness on the Maintenance of Wakefulness Test, nearly 85% achieved Epworth Sleepiness score typical of people without a sleep disorder, and median weekly cataplexy rate dropped over 80%. Hallucinations and sleep paralysis also improved for many, and side effects (mainly insomnia, urinary urgency/frequency, and increased saliva) were generally tolerable [1, 2, 5]. The results showed that oveporexton addressed symptoms that previously required treatment with multiple drugs. The FDA approval, however, carries a warning for potential abuse and misuse, and the drug cannot be dispensed until the Drug Enforcement Administration assigns a controlled substance schedule [2].

Why would oveporexton have an addiction potential?

Orexin is not just a wakefulness signal; it is also implicated in addictive behaviors. Extensive research conducted in the laboratories of Gary Aston-Jones, Ph.D., and Morgan James, Ph.D., at the Rutgers Brain Health Institute and other laboratories, has established that orexin signaling in the brain also drives motivated pursuit of rewards, including drugs of abuse [7-11]. These studies raise the possibility that oveporexton might have an addiction potential.

Preclinical work has shown that the activation of orexin-1 receptor is consistently tied to reward and motivated drug seeking while activation of orexin-2 receptor is tied to arousal and sleep–wake control [8]. Aston-Jones and colleagues have found that blocking orexin-1 receptor in rats prevents reinstatement of morphine seeking, reduces alcohol drinking, lowers motivation for opioids, and blunts cue-triggered relapse [7, 9, 10]. Additionally, James and colleagues found that rats showing addiction-like behavior have more orexin neurons, and more active neurons, in the lateral hypothalamus brain region [11]. Similarly in humans, postmortem brains from people who used heroin contained, on average, 54% more detectable orexin-producing neurons than control brains [12].

The newly approved oveporexton is selective for orexin-2 receptor and, theoretically, should not produce the reward-related effects that orexin-1 receptor signaling drives [2]. However, this has not been tested in patients, and the label reflects this.  Data from studies in human have produced mixed results. Some data suggest people with narcolepsy do not appear to escalate doses of addictive drugs they are prescribed [16], yet a study comparing adults with narcolepsy type 1 against matched controls found them no less vulnerable to addictive behaviors [17]. It is possible that orexin loss may cut both ways. Reduced signaling could blunt drug seeking, as the preclinical work predicts, while the sleepiness and emotional symptoms of untreated narcolepsy could independently raise the odds that someone seeks drugs of abuse. Future studies tracking substance use disorders as orexin signaling is therapeutically restored would help, and oveporexton makes that possible for the first time.

Narcolepsy type 1 and sleep disturbances in addiction disorders are pathophysiological manifestation of a dysfunctional orexin neurotransmitter system; the former is caused by too little orexin signaling and the latter by too much [8]. The normal regulation of sleep is disrupted by a dysfunctional orexin system and just as in narcolepsy, sleep disruption is common in substance use disorders and contributes to relapse. This places the orexin system at the intersection of both disorders and has made it a target for treating them together [13].

What is still unknown?

The published trials lasted only 12 weeks; longer-term data are still being collected [1, 5]. Abuse liability, if present, may take longer to appear. No studies have yet examined if restoring signaling at one orexin receptor affects reward processing and addiction risk in people who have lived for decades without orexin. Oveporexton now makes these types of studies possible.

Why does the new drug matter?

This is the first narcolepsy treatment that acts on the orexin deficit rather than on the symptoms it produces [1]. It also demonstrates that a selective orexin-receptor drugs can be developed and approved with clear clinical beneficial outcome. This raises hope for addiction researchers that soon they may be able to develop and get approval for novel drugs that selectively target the orexin-1 receptor and turn down its signaling function to benefit people with substance use disorders. Several selective orexin-1 receptor blockers have entered human trials, but none have been approved [15]. Cutting-edge work by researchers at the Rutgers Brain Health Institute has helped establish why the orexin-1 receptor should be a target for new drugs to treat substance use disorder.

References

1. U.S. Food and Drug Administration. FDA Approves First Drug to Treat the Full Range of Narcolepsy Type 1 Symptoms. August 5, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-full-range-narcolepsy-type-1-symptoms
2. Takeda. U.S. FDA Approves Takeda’s ORZEYFUL (oveporexton), the First and Only Medicine to Treat the Underlying Cause of Narcolepsy Type 1. August 5, 2026. https://www.takeda.com/newsroom/newsreleases/2026/orzeyful-approved-narcolepsy/
3. Takeda. Takeda’s ORZEYFUL (oveporexton) Approved in China for Narcolepsy Type 1. July 23, 2026. https://www.takeda.com/newsroom/newsreleases/2026/orzeyful-approved-china-narcolepsy/
4. Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. Journal of Clinical Sleep Medicine. 2021;17(9):1881-1893. https://doi.org/10.5664/jcsm.9328
5. Takeda. New Pivotal Study Data Show Takeda’s Oveporexton Improved Daily Function, Cognition and Nighttime Sleep for People with Narcolepsy Type 1. June 15, 2026. https://www.takeda.com/newsroom/newsreleases/2026/oveporexton-phase-3-narcolepsy-type-1/
6. Takeda. Takeda Presents Orexin Data from Landmark Oveporexton (TAK-861) Phase 3 Program in Narcolepsy Type 1 at World Sleep 2025. September 8, 2025. https://www.takeda.com/newsroom/newsreleases/2025/takeda-orexin-data-oveporexton-phase-3-narcolepsy-world-sleep-2025/
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