Narcolepsy Update

And The New Horizon of Orexin Agonists

Sleep medicine is a quickly expanding field, with new therapies developing what feels like monthly in every space. On this substack, Chris and Robson have spoken extensively about the cutting edge of obstructive sleep apnea (OSA), whether that is diagnosis, treatment, or outcomes. For this post, we will take a brief detour. However, I hope you will see the relevance to anyone treating sleep disorders.

Disorders of Hypersomnolence

Central disorders of hypersomnolence are not common. Estimates of these diseases are on the order of 0.02-0.05% of the population and include type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia. All three are defined by excessive daytime sleepiness, often confirmed with a rigorous study called a multiple sleep latency test (MSLT). This test involves 4-5 opportunities to nap within 20 minutes, and an average sleep latency of 8 minutes or fewer is pathologic. In addition, each disorder has a unique spin.

The hallmark of type 1 narcolepsy is the presence of cataplexy, which is defined by sudden loss of muscle tone with strong emotion. This is not a sudden onset of sleep, but rather the normal hypotonia of REM sleep suddenly entering wakefulness. In addition, type 1 narcolepsy is well understood to be caused by a loss of the wake promoting neurotransmitter orexin. Type 2 narcolepsy is like type 1 but without cataplexy- orexin loss is not present in these patients. Both types of narcolepsies require the presence of at least 2 sleep onset REM periods (scored during any of the naps or within the first 20 minutes of the previous night in-lab polysomnography). Finally, idiopathic hypersomnia (IH) has no cataplexy and no sleep onset REM periods, but is often characterized by long sleep time (sometimes > 10 hours) and significant difficulty with rising from sleep, called sleep inertia.

Current Treatment Landscape

Treatments for these disorders cover a few domains. The simplest way to separate these are wake promoting drugs and sleep consolidation drugs.

Wake promoting drugs are extremely common and include both old and new pharmaceuticals. Most people will have heard of the amphetamines (Adderall, Vyvanse), and modafinil/armodafinil (Provigil/Nuvigil). These are very effective drugs that have a variety of dosing regimens, allowing excellent customization options for patients. However, they often can have side effects such as jitteriness and headaches. Many patients also describe continuing to feel the general sleepiness that encompasses their life, but without the irresistible need to sleep. Newer (and more expensive) drugs include pitolisant (Wakix) and solriamfetol (Sunosi). These 2 drugs work through a different pathway and can often be more effective, while having fewer side effects for many patients. Wakix has the additional benefit of treating cataplexy as well.

The sleep consolidation drugs include different formulations of an old drug, sodium oxybate. These newer formulations have taken off more recently, as they have shown high levels of effectiveness in the hard-to-treat IH population. IH patients typically have responded poorly to wake promoting drugs, making these drugs extremely valuable. In addition, they are excellent for the treatment of cataplexy as well. Xyrem is the oldest version of this drug and is dosed as a twice nightly formulation. Xywave removes the sodium from the original formulation and is therefore seen as more favorable for patients with hypertension or cardiovascular risk, both extremely common comorbidities in narcolepsy/IH patients. Finally, Lumryz keeps the salt but removed the twice nightly dosing, one of the biggest barriers to use because of the need to set an alarm to wake up and take it. Lumryz, whose original company Avadel was acquired by Alkermes, is particularly interesting considering it being in the portfolio of one of the companies attempting to bring a new class of narcolepsy drugs to market.

New Kids on the Block

As you can see, the narcolepsy/IH market has not been dormant. However, a new class of drugs, the orexin receptor 2 agonists (OX2R), are on the horizon and represent a possible colossal shift in the treatment landscape. Three companies are positioning themselves to try to establish dominance in this space: Takeda, Alkermes (recently acquired Avadel and its flagship drug Lumryz), and Eli Lilly (Yes, the conglomerate, declaring their interest with the purchase Centessa pharmaceuticals and their pipeline OX2R candidate).

Takeda is the company closest to market and possibly best poised to establish early dominance. Takeda is a large, Japanese biopharmaceutical company with a portfolio spanning vaccines, oncologic drugs, orphan drugs, and more. Their drug oveporexton (TAK-861) has been accepted by the FDA for a priority review, and was approved for use in China as of this month (July 2026). Their phase 3 clinical trials, FirstLight (NCT06470828) and RadiantLight (NCT06505031) showed significant improvements in the maintenance of wakefulness test (MWT) in type 1 narcolepsy patients. This test requires patients to try to stay awake as long as possible sitting in a dark room with nothing to do. For comparison, the placebo groups lasted 4.5 and 3.3 minutes in each trial, while the treatment groups with 2mg BID dosing lasted 21.8 and 24.6 minutes. For comparison, the MWT improvement with modafinil in a recent meta-analysis was 3.56 minutes. Epworth sleepiness scale scores also improved significantly compared to placebo, with a drop of 8-9 points. Importantly, side effects of this drug were mild and included insomnia and urinary urgency.

Alkermes is also coming to market with their on OX2R alixorexton, with their recent phase 2 clinical trial showing similar outcomes to Takeda’s. Their trials include Vibrance-1, Vibrance-2, and Vibrance-3 for narcolepsy type 1, type 2, and IH, respectively. This inclusion of trials for type 2 narcolepsy and IH distinguish it from Takeda, which has only performed trials in type 1 narcolepsy. Logically it would make sense that the medication would work best in patients with known orexin deficiency, which is the unique pathology of type 1 narcolepsy. However, positive outcomes trials in type 2 narcolepsy and IH patients could push Alkermes into the more dominant company in this space (given the insurance landscape in the U.S., it could be approved more easily with any of the central disorders of hypersomnolence).

Finally, Centessa/Eli Lilly, is in the beginning of their phase 2 trial of a novel OX2R. They, like Alkermes, are also poised to treat all 3 central disorders of hypersomnolence in their trials. With their blockbuster drug tirzepatide (zepbound, monjauro) already taking the world by storm in the obesity and OSA space, the play here appears to be comprehensive pharmaceutical sleep management.

What Does this Mean?

This new class of drugs, based on current data, may completely change the way we treat narcolepsy and IH. The impressive results speak for themselves. However, the recent acquisitions by large companies may tell a different story.

The incredible success of tirzapetide (with even more shown thus far by retatrutide) has put sleep at the center of the pharma world. This drug sells itself because it works. Demand is off the charts. Beyond the weight-loss, these patients have huge improvement in OSA metrics.

There is a push in sleep medicine to move away from treating the apnea hypopnea index (AHI) for patients with OSA. With that, there is renewed focus on the symptoms of the disease, especially sleepiness. This is because multiple post hoc analyses of big cohort studies and randomized controlled trials have shown that OSA patients with high levels of sleepiness are at much higher risk for poor cardiovascular outcomes.

Could a drug with such a huge improvement in sleepiness be marketed as a more “natural” path than the typical wake promoting agents? Could these drugs improve health in sleepy patients, even those without the 3 central disorders of hypersomnolence? We don’t know the long-term risks of these drugs yet, but there could be multiple research opportunities to expand the utility of these drugs into OSA. For example, could a trial of tirzepatide combined with an OX2R in patients with OSA and excessive daytime sleepiness supercharge a patient’s improved metabolic profile?

These 3 companies are investing heavily on that potential. Sleep has higher visibility than ever, and our treatment options are growing in number and effectiveness. We look forward to seeing how this plays out.

-Abhay (Chris provided minimal editorial feedback).