What to know about narcolepsy

Narcolepsy is a chronic sleep disorder that causes irregular patterns in rapid eye movement (REM) sleep. It was first described in 1877, but in the last 25 years, the understanding and treatment of this disorder has grown. But the market and treatment landscape are expected to grow tremendously as new developments become available.

Narcolepsy can lead to excessive daytime sleepiness, as well as cataplexy, a sudden loss of muscle tone. Other symptoms can include sleep paralysis and hallucinations that occur both during sleep onset and when awake. Narcolepsy with cataplexy is considered an autoimmune disorder.

Narcolepsy type 1 is caused by low levels of orexin, which is a chemical in the brain that helps control when people are awake and entering REM sleep. A review of research published in January 2024 in Sleep Medicine suggests that genetics and environmental factors are involved, which lead to inflammation and autoimmunity. This review suggests that narcolepsy is linked to specific HLA alleles, which are the variants of human leukocyte antigen (HLA) genes. These genes encode for proteins on white blood cells and are involved in the immune system.

Additionally, the Sleep Medicine review indicated that animal studies and autopsies of patients with narcolepsy type 1 have found T cells in the hypothalamus, the body’s control center. Another review published in November 2024 in the International Journal of Molecular Sciences indicates some studies of CD4+ and CD8+ T cells in patients. But the authors of this review said it’s unclear whether immunotherapies that target these T cells would halt the disease.

Narcolepsy affects 25 to 50 people per 100,000 worldwide, according to a 2023 paper in JAMA. Symptoms typically start at ages 7 to 25 years. It affects both sexes equally. But the disorder is underrecognized and underdiagnosed.

There is no cure for narcolepsy, but treatments are available to help promote wakefulness, improve daytime functioning, improve sleep and manage cataplexy. The most recent narcolepsy treatment guideline from the American Academy of Sleep Medicine (AASM) was issued in 2021.

For adult patients with narcolepsy, the AASM recommends treatment with modafinil (Provigil and its generics), sodium oxybate (Xyrem and Lumryz), or Sunosi (solriamfetol) and Wakix (pitolisant). Additionally, the organization conditionally recommends armodafinil (Nuvigil and its generics); dextroamphetamine (also approved to treat attention deficit hyperactivity disorder) and methylphenidate (also approved for ADHD).

Modafinil, Wakix and Sunosi are used to treat excessive sleepiness caused by narcolepsy. Sodium oxybate is a central nervous system depressant that is used to treat both cataplexy and excessive daytime sleepiness.

For pediatric patients with narcolepsy, the AASM suggests treatment with modafinil or sodium oxybate. The guideline does not include a recommendation for Wakix in this population, because this drug was approved for pediatric patients aged 6 years and older with narcolepsy in 2024.

Another available treatment is Jazz Pharmaceuticals’ Xywav (calcium, magnesium, potassium and sodium oxybates) as an oral solution for cataplexy and daytime sleepiness, as well as IH in adults. Xywav is a central nervous system depressant that is thought to modulate gamma-aminobutyric acid (GABA) neurotransmission at specific neurons, including noradrenergic, dopaminergic, and thalamocortical neurons, during sleep.

Real-world evidence and phase 4 data were presented in September 2025. The DUET phase 4 study was a prospective, single-arm, open-label study to assess the effect of Xywav treatment on excessive daytime sleepiness, polysomnography parameters, and functional outcomes in adults with narcolepsy or IH. Patients with narcolepsy experienced fewer awakenings and decreased wake after sleep onset, suggesting improved sleep measures.

Emerging narcolepsy treatments

Despite current treatments, there is a need for drugs that go beyond addressing symptoms. New therapies in development are targeting the disease. Small molecules that target the orexin receptors are one area that has gained interest from developers. The more advanced research is on orexin receptor 2 (OX2R), which aims to restore the brain’s natural sleep-wake cycle by mimicking the function of orexin neuropeptides.

Oveporexton: Takeda released data in September 2025 from two phase 3 trials of its OX2R selective agonist, oveporexton (TAK-861), to treat patients with narcolepsy type 1. It selectively stimulates the OX2R to restore signaling and address the underlying orexin deficiency. Oveporexton is an oral drug given twice a day.

The FirstLight trial enrolled 168 patients, and those who received oveporexton were split between two groups: 1 mg twice a day (61 patients) and 2 mg twice a day (66 patients) for 12 weeks. RadiantLight enrolled 105 patients, with those who received oveporexton receiving only the 2 mg twice a day for 12 weeks. More than 95% of patients completed the placebo-controlled study and enrolled in the long-term extension trial.

In both studies, oveporexton was shown to result in statistically significant and clinically meaningful improvement in objective wakefulness (the maintenance of wakefulness test) and the 2 mg dose in both trials was able to normalize sleep latency in 64% of patients. Additionally, oveporexton demonstrated a statistically significant and clinically meaningful reduction in cataplexy events compared with placebo, as well as in overall disease severity compared with placebo. About 67% of patients showed meaningful improvement in disturbed nighttime sleep.

Takeda officials indicated they plan to begin U.S. and global regulatory submissions sometime in fiscal year 2025, which for Takeda ends on March 31, 2026. Company officials in a presentation to investors said despite current treatments for narcolepsy, there is a need for new treatments. About 80% of patients have reported residual symptoms despite treatment.

Alixorexton: Another oral, selective OX2R agonist in development is alixorexton. Developed by Alkermes, alixorexton is in development for both narcolepsy type 1 and narcolepsy type 2 (considered a milder form of the condition) and idiopathic hypersomnia (IH). Idiopathic hypersomnia also involves daytime sleepiness and difficulty waking but is not characterized by disruptions in REM sleep.

In the phase 2 trial Vibrance-2 with 93 patients with narcolepsy type 2, alixorexton demonstrated improvements in the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) at week eight. Alixorexton was generally well tolerated at all doses tested. This data was released in November 2025.

Alkermes released data from the phase 2 trial Vibrance-1 in September 2025. This trial enrolled 92 patients with narcolepsy type 1. Alixorexton met the primary endpoint across all doses tested, demonstrating dose-dependent improvements from baseline compared with the mean placebo in mean sleep latency (MSL) on the Maintenance of Wakefulness Test at week six, as well as the secondary endpoint on the Epworth Sleepiness Scale (ESS).

The company intends to study alixorexton in a phase 3 program for both narcolepsy type 1 and 2.

AXS-12 (reboxetine): Axsome Therapeutics will be submitting in January 2026 an NDA for AXS-12 (reboxetine) to treat type 1 narcolepsy. Reboxetine has a different mechanism than the OX2R agonists. Reboxetine is a selective norepinephrine reuptake inhibitor, and it aims to modulate noradrenergic activity to promote wakefulness, maintain muscle tone and enhance cognition. Norepinephrine, also known as noradrenaline, is both a neurotransmitter and a hormone, and it plays a role in regulating stress response, alertness, memory and attention.

The topline results of the phase 3 SYMPHONY trial were published in April 2025 in Neurology. In the trial, 90 patients were enrolled, and the primary endpoint was the ratio of weekly cataplexy attacks and the secondary endpoint was excessive daytime sleepiness, inadvertent naps and cognitive function.

Reboxetine reduced cataplexy attacks by 83% compared with 66% with placebo at week 5; patients received concurrent modafinil/armodafinil treatment. Treatment with reboxetine led to greater improvements in concentration and memory, and it was well-tolerated with no new safety signals or serious adverse events.