By Alyx Arnett

For the first time, investigational treatments for narcolepsy type 1 (NT1) are targeting the disorder’s root cause: the loss of orexin-producing neurons. Unlike the symptom-based therapies on the market today, these candidates aim to mimic orexin signaling, offering a potentially disease-modifying approach. 

Some are also being evaluated for narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH). Although these conditions are not defined by orexin deficiency, investigators hypothesize that enhancing orexin signaling may alleviate excessive daytime sleepiness by modulating wake-promoting pathways.

Several companies have entered the race to bring orexin-based hypersomnia therapies to market, with development spanning from preclinical to phase 3 studies. Takeda Pharmaceuticals’ oral orexin-2 receptor agonist, TAK-861, is the furthest along, currently in phase 3 development. Alkermes and Centessa Pharmaceuticals have phase 2 candidates—ALKS 2680 and ORX750, respectively. Eisai Inc’s E2086 is in phase 1, while Jazz Pharmaceuticals’ phase 1 trial of JZP441 was halted due to safety concerns. Harmony Biosciences’ BP1.15205 and NLS Pharmaceutics’ AEX-2 are in preclinical development.

“Across the orexin class, the data have been incredibly promising. The orexin agonists have the ability to really transform the way that we treat patients with narcolepsy and idiopathic hypersomnia moving forward,” says Craig Hopkinson, MD, chief medical officer and executive vice president of research and development at Alkermes. 

Understanding the Orexin Link

The discovery of orexin—also known as hypocretin—began in the late 1990s, when Luis de Lecea, PhD, Thomas Kilduff, PhD, and colleagues set out to identify genes with region-specific expression in the hypothalamus. De Lecea, then a molecular biologist at Scripps Research Institute, described the effort as purely exploratory. “We had no bias towards the function. We had no idea what we were looking for. We were just looking for interesting patterns of gene expression,” says de Lecea, a professor of psychiatry and behavioral sciences at Stanford University School of Medicine.

One of the genes they identified encoded two peptides with similarities to the secretin family of hormones. De Lecea and Kilduff named the peptides “hypocretins” in their 1998 PNAS paper, while a research team in Japan independently published a paper just over a month later, identifying the same molecules and naming them “orexins.”^1,2 The peptides were found to be highly localized in the hypothalamus, a brain region known to regulate sleep and wakefulness. Studies had already shown that if the hypothalamus is lesioned, it can impact sleep, “so that was really one of our hypotheses,” says de Lecea.

Animal models soon strengthened the link between orexin/hypocretin and sleep regulation. Knockout mice lacking the orexin gene exhibited excessive sleepiness and sudden episodes of muscle weakness, while narcoleptic dogs were found to have mutations affecting the orexin receptor.^3,4 These findings pointed to orexin’s critical role in maintaining wakefulness and paved the way for human studies. 

In the early 2000s, a group at Stanford examined cerebrospinal fluid from patients with narcolepsy and found orexin levels to be undetectable levels in seven of the nine cases,⁵ an absence later confirmed to result from the degeneration of orexin-producing neurons in the hypothalamus, definitively tying the loss of this signaling system to NT1.⁶

De Lecea described the discovery of the orexin system as a “Rosetta Stone” for sleep science. “It has allowed us to decipher many of the secrets that were underlying how we regulate sleep,” he says. 

But First, Insomnia

The discovery of orexin’s role in wakefulness didn’t immediately lead to exploring treatments for narcolepsy. Instead, pharmaceutical companies pursued the opposite approach: developing orexin receptor antagonists to treat insomnia. 

As Kilduff explains, the logic was straightforward. If the absence of orexin causes excessive sleepiness in narcolepsy, blocking its action might help people who can’t fall asleep. “It immediately became clear that if these patients have a problem staying awake because the receptor is not getting stimulated, then if you could block that receptor, you might have a new treatment for insomnia,” says Kilduff, director of the Center for Neuroscience at SRI International. 

Antagonists are also considered easier to develop at the molecular level. “There are lots of ways to screw up the lock,” Kilduff says. “But there’s really only one way to make a key.” In other words, blocking a receptor is simpler than designing a molecule that fits it perfectly for activation.

With insomnia affecting a far larger population than narcolepsy, it also made commercial sense to develop drugs that blocked orexin signaling, the first of which received US Food and Drug Administration approval in 2014. 

Still, de Lecea doesn’t view the shift toward agonist development as slow. “The opposite is true,” he says. “It’s gone extremely, extremely fast.”

Inside the Orexin Agonist Pipeline

Orexin Drug Candidates in Development for NT1, NT2, or IH

Several companies are advancing orexin-2 receptor agonists through clinical development, with some programs now in later-stage trials.

Takeda

Takeda began exploring orexin agonists for narcolepsy in 2013. Its initial compound, TAK-925, confirmed the therapeutic potential of replacing orexin, but its intravenous formulation made long-term use impractical. A follow-up oral version, TAK-994, showed strong efficacy but was discontinued after signs of liver toxicity emerged after around 16 weeks of use.

Now on its third compound, TAK-861, the company is in phase 3 trials in patients with NT1 and expects to report top-line results by mid-year. The study aims to evaluate the effectiveness of TAK-861 in reducing excessive daytime sleepiness after three months of treatment. It will also assess its impact on cataplexy frequency, attention, quality of life, and daily functioning.

Phase 2 data presented at SLEEP 2024 showed that TAK-861 improved measures of wakefulness and sleepiness and reduced cataplexy frequency versus placebo in 112 participants with NT1 over eight weeks. The team also explored cognition, documenting meaningful gains in attention, executive function, and memory. 

“We have really been working on this, learning and iterating, going from one compound to the next. And so when we saw the phase 2 data back almost a year ago…we were really thrilled to see the biology being confirmed in various ways,” says Elena Koundourakis, PhD, vice president and head of franchise orexin development and portfolio strategy at Takeda.

TAK-861 was generally well-tolerated in phase 2 trials, with no treatment-related serious adverse events reported. More than 95% of participants completed the eight-week study and enrolled in the long-term extension, with many now on treatment for over a year. “Importantly, we haven’t seen the hepatoxicity, which we have observed with the previous molecule, and no visual disturbances, which have been around some of the competitors,” Koundourakis says. (Jazz Pharmaceuticals, for example, halted its phase 1 trial of JZP441 in November 2023 due to visual disturbances and cardiovascular effects, and Alkermes reported transient visual disturbances with ALKS 2680 at higher doses.)

Takeda also conducted a separate phase 2 trial of TAK-861 in patients with NT2, though it does not plan to advance the compound in NT2 at this time. The company is exploring a different compound, TAK-360, for NT2 and IH. 

Alkermes and Centessa

Alkermes and Centessa Pharmaceuticals’ drug candidates are in phase 2 studies for NT1, NT2, and IH. In a 1b study completed last year, Alkermes’ ALKS 2680 showed improvements in wakefulness across all three populations and was generally well-tolerated. “It’s very clear that an orexin agonist makes perfect sense” in patients with NT1, says Hopkinson. In NT2 and IH, “we did see an improvement in wakefulness…which has led us to initiate phase 2 studies in those populations as well.” 

Separate phase 2 trials in patients with NT1 and NT2 are underway to evaluate ALKS 2680 over six and eight weeks of dosing, respectively, to further assess safety and efficacy, with top-line results expected this year. Results from a phase 2 study in IH patients are expected next year.

In Centessa’s phase 1 study, healthy volunteers with normal orexin levels were dosed with ORX750 at 11 pm. At four different doses, at all time points assessed—1 am, 3 am, 5 am, and 7 am—the volunteers achieved over 30 minutes on the Maintenance of Wakefulness Test, with the largest dose (5 mg) reaching a mean of 38 minutes. Wakefulness was corroborated on the Karolinska Sleepiness Scale.

“These healthy volunteers managed to stay awake throughout the entire duration of the night with what looks to be completely normal levels of wakefulness,” says Mario Alberto Accardi, PhD, president of the orexin program at Centessa. “That is extremely impressive because you’re going up against immense sleep pressure from the healthy volunteers. At the same time, you’re going up against the natural clearance of the drug. So that is a testament that this is a highly efficacious drug, but at the same time, we’re not causing insomnia.”

Centessa’s ongoing phase 2 study is evaluating ORX750 in patients with NT1, NT2, and IH to determine sustained efficacy and safety. It includes a randomized withdrawal component to assess the drug’s effects after discontinuation and re-initiation. Data from the phase 2 trial are expected this year.

What Still Needs to Be Understood

De Lecea says the potential of these candidates “is fantastic” for NT1 as “you’re replacing a molecule that is effectively missing in the narcoleptic patients.” On the other hand, he notes, “Challenges are many, of course.” 

One is the risk of receptor desensitization. Orexin receptors are G-protein-coupled receptors, and prolonged activation can cause them to internalize and become less responsive. “If you don’t regulate the doses very well, it may happen that patients are no longer responsive to the drug after a long period of treatment,” de Lecea says.

De Lecea adds that he is less concerned about major side effects from small-molecule agonists that selectively target the orexin-2 receptor, since these compounds are expected to primarily influence sleep-wake regulation. He says the main safety concern in activating the orexin system—sympathetic nervous system activation—is largely associated with orexin-1 receptor activity. However, because the orexin system is highly flexible and still not fully understood, he cautions that unexpected effects could still emerge.

Finding the right dosing strategies is also a challenge—and it is critical to not only maintaining therapeutic effects but also to avoiding interfering with patients’ sleep at night. “These are very potent wake-promoting molecules, but every molecule has a half-life,” says Kilduff. “The question is, how do you get the beneficial effect of keeping the person awake without interfering with their sleep at night?”

Low concentrations of hypocretin are detectable at night in healthy individuals, but it remains unclear whether that means orexin signaling is needed during sleep. “The unanswered basic science question is whether a low level of hypocretins is actually beneficial to having a good night’s sleep or whether it’s the decline from a high level to a low level,” Kilduff says. This could have implications for how orexin agonists are dosed.

Clinical questions extend beyond NT1. For NT2 and IH, where orexin deficiency has not been definitively established, the mechanism of action remains theoretical. Trials underway aim to determine how consistently orexin agonists benefit different patient populations. Clarifying these differences will be key to guiding future treatment strategies.

The biggest unanswered question, according to Kilduff, is why orexin-producing neurons degenerate in the first place. While evidence strongly suggests an autoimmune origin, such as links to infections like streptococcus, “we’re really still missing the smoking gun for that,” he says.^7,8

Changing the Treatment Landscape

As the first orexin agonists move closer to clinical use, the drugs’ developers see their potential for improving care for patients with NT1. Alkermes’ Hopkinson says standard therapies today typically yield sub-10-minute gains on the Maintenance of Wakefulness Test. Meanwhile, Centessa’s candidate, for example, is showing well beyond that in clinical trials, nearing the 40-minute ceiling of the test. 

Additionally, these drugs could shift the treatment landscape from polypharmacy to “a functional cure,” says Centessa’s Accardi.

Orexin agonists could offer new treatment options for NT2 and IH as well. “I think everybody’s waiting for these drugs to progress through clinical development and be almost a revolution in the treatment for these indications,” says Accardi.

Beyond sleep-wake disorders, developers are also exploring the broader potential of orexin modulation. Takeda, Alkermes, and Centessa are each building pipelines aimed at expanding into other conditions where excessive daytime sleepiness—as well as fatigue, cognitive dysfunction, or mood symptoms—is common, such as neurologic, neurodegenerative, and psychiatric disorders. Koundourakis notes that orexin also influences respiration and metabolism, opening up biological possibilities for orexin in areas like obstructive sleep apnea and metabolism as well. 

“The landscape is incredibly promising because there are many actors involved; many companies have jumped on this. And that is necessary because not one compound is going to hit all of the sweet spots,” says de Lecea. “The more tools we have, the better.” 

Looking ahead, de Lecea suggests that combination therapies—featuring agonists and antagonists with varying half-lives—may one day allow patients to precisely control their sleep and wakefulness.

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References

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7. Valizadeh P, Momtazmanesh S, Plazzi G, et al. Connecting the dots: An updated review of the role of autoimmunity in narcolepsy and emerging immunotherapeutic approaches. Sleep Med. 2024;113:378-96. 
8. Wenz ES, Schinkelshoek MS, Kallweit U, et al. Narcolepsy type 1 and Sydenham chorea – Report of 3 cases and review of the literature. Sleep Med. 2023;112:234-8.