If you’ve been following the development of orexin agonists for narcolepsy, 2025 has been an exciting year. Most recently at the World Sleep Congress in Singapore, I had a front row seat on history as  researchers shared the latest clinical trial results from Takeda, Alkermes, and Eisai. These orexin-targeted therapies are showing great promise for reducing daytime sleepiness and cataplexy in people with type 1 narcolepsy with cataplexy, and is one of the most exciting developments in neurology and sleep medicine right now.

The History of Orexin

Since 1999, we’ve known that type 1 narcolepsy with cataplexy (the condition I live with and wrote a memoir about) is caused by a loss of neurons producing the neuropeptide orexin (or hypocretin), which plays a central role in maintaining wakefulness. However, finding treatments able to cross the blood-brain barrier and mimic the function of orexin has been scientifically challenging.

Twenty years after the discovery of orexin, at World Sleep 2019 in Vancouver, Canada, Takeda presented their first-in-human clinical trial findings (in people with narcolepsy, healthy adults, and elderly people) for the orexin 2 receptor selective agonist, TAK-925. Sitting in that room in Vancouver on that day, the excitement was undeniable. I felt honored to be there as these early outcomes were shared publicly for the first time. Read my post about this experience, Orexin/Hypocretin Agonists are Coming! Part I: Reporting Back from World Sleep 2019.

Since 2019, Takeda has made great progress and other companies have joined the space to develop orexin agonists. At World Sleep 2023 in Rio de Janeiro, Brazil, Alkermes presented early outcomes from their first-in-human study of ALKS-2680 in people with type 1 narcolepsy and healthy adults. Takeda also presented on TAK-861 in a small study of healthy adults.  Also in 2023, I participated in an orexin agonist trial (see glamorous “Clinical Trial Barbie” photo above), it wasn’t easy, but it was important to me that I personally take part in this historic development. 

Front Row Seat at World Sleep 2025

The pharmaceutical interest in this space has continued to grow, with Takeda’s and Alkermes’ trials advancing, and Centessa sharing early phase 1 results in healthy adults for their novel orexin agonist (ORX-750) at APSS SLEEP 2025 in Seattle. (Centessa expects to have data from their phase 2a study of ORX-750 for treatment of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) by the end of 2025.)

At World Sleep 2025 in Singapore, I knew to arrive early to the narcolepsy drug development to get a seat. Given that I may be one of the only people living with narcolepsy at this session, I didn’t feel shy about sitting in the front row. By the time the session began, the (really small) room was overflowing with people standing along the walls and sitting on the floor, and more people trying to sneak a peek from outside the doorways. Everyone had their phones out to take pictures of every single slide, in unison. It was comical but also a reminder how important this moment was.

Note to conference organizers: please put historic sessions in big conference rooms.

Takeda’s Oveporexton (TAK-861): Phase 3 Outcomes

Following strong phase 2b results for Takeda’s TAK-861, an oral, selective orexin receptor 2 agonist (OX2R agonist) now called “oveporexton” (still working on saying that word), Takeda announced positive Phase 3 data from two international trials in people with type 1 narcolepsy at World Sleep 2025 — the first large-scale, late-stage studies of an orexin-directed therapy.

Lead investigators and research superstars (Drs. Emmanuel Mignot, Yves Dauvilliers, and Lucie Barateau) reported the results from two phase 3 clinical trials. Participants (in both trials around the world) receiving oveporexton showed:

• Significant improvements in daytime wakefulness as measured by the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS).
• Reduced frequency of cataplexy, with many people experiencing few or no episodes of cataplexy by the end of the study. 
• Favorable tolerability and gains in functional outcomes (like mood, cognitive clarity, and quality of life).

From here, we expect Takeda will file a new drug application (NDA) for oveporexton in people with NT1 with the FDA in the next 6 months. Importantly, Takeda is also advancing phase 2 trials of oveporexton in people with narcolepsy type 2 (NT2, or narcolepsy without cataplexy) and idiopathic hypersomnia (IH).

Alkermes’ Alixorexton (ALKS-2680): Phase 2 Results

During the same session, lead researchers (Drs. Giuseppe Plazzi and Yves Dauvilliers) presented phase 2 data from Alkermes’ Vibrance-1 trial of ALKS-2680, now called “alixorexton” (working on saying this word too), an oral selective orexin-2 receptor agonist for people with type 1 narcolepsy.

The clinical trial participants receiving alixorexton showed:

• Dose-dependent improvements in daytime wakefulness on the Maintenance of Wakefulness Test (MWT) and reduced sleepiness on the Epworth Sleepiness Scale (ESS) compared to placebo.
• The data also showed fewer cataplexy episodes, improvements in cognitive clarity and fatigue, with favorable safety and tolerability across all dose groups.

Alkermes’ findings further strengthen the evidence and promise of orexin-targeted treatments for people with type 1 narcolepsy with cataplexy, with phase 3 trials planned to begin by the first quarter of 2026. Alkermes is also currently advancing phase 2 clinical trials for people living with type 2 narcolepsy (without cataplexy) and idiopathic hypersomnia (IH).

Eisai’s E2086: First NT1 Results

On the same day at World Sleep 2025 in Singapore, Eisai presented the first clinical study of E2086, a selective orexin-2 receptor agonist, in people with NT1. The study aimed to evaluate the efficacy, safety, and tolerability of three dose strengths of E2086 compared to placebo and modafinil in people with NT1. This was a small study, with 19 participants completing the study, and the results are promising, indicating that:

• All three doses improved EDS compared to placebo and modafinil on the objective Maintenance of Wakefulness Test (MWT). In my opinion, this data was particularly striking, with the two higher doses showing average sustained wakefulness for over 30 minutes on the MWTs.
• All doses reduced sleepiness as measured by subjective measurers (using the Karolinska Sleepiness Scale, KSS). 
• E2086 was generally well tolerated.

With these promising results, E2086 will move into phase 2 clinical trials in people with NT1 (narcolepsy type 1, with cataplexy) and NT2 (narcolepsy type 2, without cataplexy).

The Future is Bright

It’s hard to believe that orexin agonists are getting closer to FDA approval, especially for people with type 1 narcolepsy. I find myself daydreaming about the years ahead, wondering if this time next year, I may be taking an FDA-approved orexin agonist as part of my treatment regimen. I’m cautiously optimistic that this will be an exciting turning point for many people with narcolepsy to improve their symptoms and quality of life.

Personally, I wonder if I’ll have less cataplexy while playing tennis (the moment right before I’m about to hit a great shot is a huge trigger currently, especially when I play tennis in the evening or without a nap). I wonder if I’ll regain minutes or hours of wakefulness, I wonder what I might accomplish with any extra time reclaimed. But I also want to be cautious, as I don’t believe this will be a cure, but a positive step toward a brighter future.

Our International Community 

As we get closer to orexin agonists becoming a reality, I wonder about the international access to the orexin agonists, as my friends and co-advocates around the world are so close to my heart. We do not have to share a language to feel a deep sense of camaraderie with each other, as narcolepsy knows no boundaries and doesn’t discriminate on how it can uproot a person’s life, regardless if they live in Los Angeles, Singapore, Kenya, Brazil, Italy, Iran, or Israel. International drug access is a complicated topic, but I am hoping that as many people with narcolepsy around the world may benefit from this historic development in the near future. 

NT1 v. NT2 v. IH Diagnoses

One additional curiosity is that I believe this will be the first treatment approved specifically for narcolepsy type 1 before it’s approved for narcolepsy type 2. Previous treatments received approval for the indications like “excessive daytime sleepiness (EDS) of narcolepsy” or “cataplexy in people with narcolepsy.” As long as the treatment was approved for EDS of narcolepsy, people diagnosed with type 1 or type 2 could access as on-label treatment. This will be the first time that the narcolepsy community will be a bit more divided in this way, with trials for type 2 narcolepsy coming along, but a bit behind those for type 1. In part, I find this interesting because I do fear that some people get confused about whether they are diagnosed with type 1 or 2. I’ve heard people say, “I have type 1 narcolepsy without cataplexy.” There are also people who believe they are diagnosed with both NT2 and IH.

While Project Sleep aims to educate the patient community via the Types of Narcolepsy toolkit and What is Idiopathic Hypersomnia resources, this confusion is still understandable. As the field works to evolve our understanding of the “borderlands of narcolepsy,” and develop better diagnostic tools for those living with central disorders of hypersomnolence, I do think it will be strange at first for NT1 and NT2 to be divided in access to an orexin agonist at least initially. Importantly, clinical trials are advancing for both NT2 and IH as well. To learn more and get involved in clinical trials, visit Project Sleep’s Participate in Research page. 

Huge Thanks to Participants & Researchers!

Thank you to each and every person who has participated in a research study. I know it’s not easy and can take a lot of personal sacrifice to participate in clinical trials. Your contributions have helped orexin agonists advance as quickly as possible. Thank you also to the researchers and drug developers who are working tirelessly. When I was on a clinical trial in 2023, the team at the trial site was so supportive and patient, we navigated some vulnerable moments together and for those intense few months, they felt like family. I know these are just a few of the countless dedicated individuals who are working behind the scenes daily to advance these novel therapies. Your work matters. You give us so much hope!

What are your thoughts or questions about the orexin agonists in development? Let me know in the comments!