Breakthroughs Ahead

Narcolepsy research is entering an exciting phase, with promising new treatments and discoveries on the horizon. Because narcolepsy symptoms can cause daily disruptions, affecting everything from work to relationships, having effective treatments makes a meaningful difference in improving quality of life. At Wake Up Narcolepsy (WUN), we’re committed to not only funding research that pushes the field forward, but also keeping our community informed about new opportunities and developments.

One way we share important updates with the community is through our Brown Bag Webinars. Earlier this year, WUN Medical Advisory Board Member Thomas E. Scammell, MD, joined us to share some important insights for a Brown Bag Webinar on “Exploring Progress in Narcolepsy Research.”¹ A leading narcolepsy researcher and clinician, Dr. Scammell is a professor of neurology at Harvard Medical School, a neurologist at Beth Israel Deaconess Medical Center, and medical director of the Center for Pediatric Sleep Disorders at Boston Children’s Hospital. 

Building on a basic overview of what narcolepsy entails, Dr. Scammell walked through the latest trial and research developments and highlighted new opportunities in the treatment landscape. In our column this issue, we’ve pulled together some key takeaways from that discussion—though we highly recommend watching the full webinar for a deeper dive.

 Understanding Narcolepsy

Narcolepsy can present in two types: type 1 (NT1) and type 2 (NT2). Both types may include symptoms like excessive daytime sleepiness (EDS), sleep paralysis, hallucinations near sleep onset (hypnagogic) or awakening (hypnopompic), and disrupted nighttime sleep. NT1 also involves cataplexy—sudden muscle weakness triggered by emotions. Scientists have identified that NT1 is caused by low levels of orexin, a chemical that helps to promote and regulate REM sleep. The cause of NT2 is still unknown.

Dr. Scammell emphasized that many symptoms of narcolepsy are often overlooked, despite being common for many patients. These include cognitive and physical effects such as brain fog and memory issues, along with an increased risk of comorbidities such as depression, high blood pressure, and obesity.

Where Current Treatments Fall Short

After reviewing the medications currently available, Dr. Scammell referenced findings from a 2017 study published in the Journal of Clinical Sleep Medicine titled “Listening to the patient voice in narcolepsy: diagnostic delay, disease burden, and treatment efficacy.”²

This U.S.-based cross-sectional survey included 1,699 people with a self-reported diagnosis of narcolepsy. All participants were taking medication—56 percent used modafinil/armodafinil, 32 percent used amphetamines, and 35 percent were on oxybates. Solriamfetol and pitolisant were not yet available treatment options at that time.

Participants were asked to identify the top three most significant symptoms affecting their lives:

These findings underscore the persistent challenges faced even among those on medication. As Dr. Scammell noted, “This sort of sets the stage for [the question]: ‘Why should pharma companies bother developing new medicines?’ Because people need better stuff than what we’ve currently got.”

Emerging Treatments

During the webinar, Dr. Scammell shared a slide listing nine medications currently in development. Noting the length of the list, he remarked that “Prior to the last few years, at any time, there was rarely more than one drug in development for treating narcolepsy.”

This marks a very exciting and hopeful time for the narcolepsy community. The medications being investigated include: Reboxetine (AXS-12, Axsome), Mazindol ER (Quilience, NLS), Serdexmethylphenidate (Zevra), Samelisant (SUVN-G3031, Suven), TAK-861 (Takeda), ALKS-2680 (Alkermes), ORX750 (Centessa), MK-6552 (Merck), and Clarithromycin (Emory University).

One particularly exciting area of development is orexin agonists, a novel class of drugs designed to target the fundamental orexin deficiency in NT1. These compounds bind to orexin receptors, mimicking the body’s natural orexin. Trials suggest they show promise in addressing core symptoms of narcolepsy like EDS and cataplexy.

One such orexin agonist, TAK-994 initially showed promising results: wakefulness improved on the Maintenance of Wakefulness Test (MWT), and weekly cataplexy episodes dropped from 10 to one.³ However, trials were halted due to concerns about liver inflammation, an example of the challenges inherent in drug innovation.

More recently, a phase 2 study of TAK-861 demonstrated that some participants were able to stay awake for a full 30 minutes on the MWT, compared to just four minutes in the placebo group.⁴ Those who continued in the study’s long-term extension also experienced lasting improvements in sleepiness and cataplexy.

Reported side effects were generally mild, including frequent urination, urinary urgency, and insomnia during initial treatment stages. These effects were generally manageable, and the overwhelming majority of participants opted to continue treatment during long-term extensions.

Another promising orexin agonist, ALKS-2680, showed similarly encouraging results in early-phase testing even among individuals with NT2 and idiopathic hypersomnia (IH).⁵ However, higher doses appear necessary for effectiveness in those conditions.

With so many medications showing promise and orexin agonists offering a targeted approach, the future of narcolepsy treatment looks brighter than ever. Innovation and participation in trials remain essential to continued progress.

Why Options Matter

Although unmet treatment needs remain, existing medications already play a crucial role in improving quality of life for many individuals with narcolepsy. As Dr. Scammell noted, “Everybody is unique, and some people are going to do great with one drug and not so great with another.”

The growing number of treatment options enables healthcare professionals to tailor treatment plans to each patient’s unique needs. Oxybates, for example, can be effective in suppressing cataplexy and improving daytime alertness by promoting deeper nighttime sleep. Alternatives like low-sodium and once-nightly versions, as well as newer medications like solriamfetol and pitolisant have further expanded options for personalized care.

With advances in both existing and emerging medications, narcolepsy treatment continues to evolve—offering hope for even more effective and personalized solutions to address the diverse needs of individuals living with narcolepsy.

By Cara Weaver

Source: SleepWorld Magazine May/June 2025

Cara Weaver is the manager of public relations and communications at Wake Up Narcolepsy and is also a person with narcolepsy type 2.

References

1. Scammell TE. Exploring progress in narcolepsy research [webinar]. Wake Up Narcolepsy; February 13, 2025. https://www.youtube.com/watch?v=N6SJO5mcnMU. Accessed March 25, 2025.
2. Maski K, Steinhart E, Williams D, et al. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden, and treatment efficacy. J Clin Sleep Med. 2017;13(3):419-25. doi: 10.5664/jcsm.6494.
3. Dauvilliers Y, Mignot E, del Río Villegas R, et al. Oral orexin receptor 2 agonist in narcolepsy type 1. N Engl J Med. 2023; 389(4):309-21. doi: 10.1056/NEJMoa2301940.
4. Dauvilliers Y, Mignot E, Plazzi G, et al. Efficacy and safety of TAK-861, an oral orexin receptor 2 agonist, in individuals with narcolepsy type 1: results from a phase 2 trial and long-term extension study interim analysis (P12-4.002). Neurology. 2025;104 (7_Suppl_1). doi: 10.1212/WNL.0000000000208433.
5. Grunstein R. Safety and pharmacodynamic effects of the orexin 2 receptor agonist ALKS 2680 in patients with narcolepsy type 1: a first-in-human phase 1 study. Presented at: SLEEP 2024 Annual Meeting; June 4, 2024; Houston, TX. Abstract 1323.