As mechanism-based orexin agonists get close to market, sleep physicians may feel compelled to reduce ambiguity between narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia diagnoses.
By Sree Roy
The landscape of central disorders of hypersomnolence is approaching a pivot point. In February, Takeda announced that the US Food and Drug Administration (FDA) accepted its New Drug Application for oveporexton (TAK-861) for the treatment of narcolepsy type 1 (NT1). This investigational oral orexin receptor 2 (OX2R)-selective agonist is designed to address the underlying orexin deficiency that characterizes NT1, marking a shift from symptom-based management to mechanism-based therapy.
For years, any clinical distinctions between narcolepsy type 1, narcolepsy type 2 (NT2), and, to a lesser extent, idiopathic hypersomnia (IH) have been more academic than practical. Because existing treatments for excessive daytime sleepiness (EDS) were often approved for narcolepsy broadly, the sub-classification had little bearing on a patient’s medication access. However, the impending arrival of orexin agonists—which will almost certainly be split by indication based on the specific sleep disorder’s presumed presence or absence of orexin deficiency—could fundamentally raise the diagnostic stakes.
“Until now, it has been largely a moot point because drugs have always been approved for narcolepsy, including type 1 and type 2,” says psychiatrist-sleep physician David T. Plante, MD, PhD, medical director at Wisconsin Sleep and program director of the sleep medicine fellowship at the University of Wisconsin School of Medicine and Public Health. “In this space we are moving into, it is going to be much more important for providers to do a better job of clearly identifying if people have type 1 narcolepsy or not.”
Caution: Do Not ‘Invalidate’ Patients in Categorization Quest
However, experts also caution against becoming too rigid in a classification quest. The understanding of the underlying science of sleep-wake control is evolving, and patients shouldn’t be denied potentially life-changing medications based on academic distinctions, says neurologist-sleep physician Anne Marie Morse, DO, director of pediatric neurology at Geisinger Medical Center.
“My fear is that we may shortchange either who we offer the medication to, or how we judge the responder profile,” Morse says.
Rushing to perfectly nuance narcolepsy type 1 versus type 2 might lead clinicians astray, as there is rarely a singular endotype for the disease, she argues, emphasizing that sleep physicians must ensure they “don’t start invalidating or dismissing people, because [a person with hypersomnolence] doesn’t fit the script that we’re expecting based on a partially-baked story on what the pathophysiology may be.”
Instead of restricting prescriptions based on drug designations, Morse advocates for prioritizing a patient’s lived experience and clinical response. “It is more important for clinicians to learn how to be resilient in this time and really learn how to flex in a way that the patients need us to,” she says, rather than holding back therapies because of “an insecurity of mislabeling.”
Biomarkers Options for Differential Diagnosis
Still, since the hurdles payors may enact to limit access to orexin agonists remain unknown, as do the real-world responders to this drug class, some sleep physicians have begun reevaluating the tools used to confirm NT1. While the multiple sleep latency test (MSLT or “nap test”) is effective for identifying sleep-onset REM periods (SOREMPs), it can be influenced by factors such as shift work, sleep deprivation, and the use of psychotropic medications, particularly antidepressants.
To improve differential diagnosis, some thought leaders predict that biomarker testing, specifically HLA typing and cerebrospinal fluid (CSF) orexin measurements, will become more popular.
HLA-DQB1*06:02 Testing
The HLA-DQB1*06:02 allele is highly associated with NT1, though its presence is not diagnostic on its own, as roughly 12% to 40% of the general population carries the gene. However, its absence can be a powerful signal. “The data suggests that it’s extraordinarily rare for someone who does not have cataplexy but has sleep study findings consistent with narcolepsy to be HLA negative and have an orexin deficiency,” Plante says. “The probability approaches zero.”
Julie Flygare, JD, president and CEO of patient advocacy organization Project Sleep and a person with type 1 narcolepsy, suggests that HLA testing is an underrated and less invasive step that can be used before moving to more intensive procedures. It provides a “pre-test probability” that can guide the clinician toward or away from an NT1 diagnosis, especially when MSLT results are borderline or confounded by medication, she says.
CSF Orexin Measurement
Orexin levels in the cerebrospinal fluid (CSF) can be measured via lumbar puncture. Thus far, the procedure has seen limited uptake in the United States due to its invasiveness and the historical lack of a targeted therapy that would justify it.
“The problem with that is there’s a lumbar puncture, right? So patients aren’t necessarily lining up to do this,” says Plante, who is also an associate professor in the department of psychiatry at the University of Wisconsin School of Medicine and Public Health. “But, certainly, I use CSF orexin as a measure in appropriate patients to confirm a diagnosis of type 1 narcolepsy, when patients are amenable to that.” Use cases may include people with symptoms of narcolepsy type 1 (such as EDS and cataplexy) but who are unable to follow MSLT prep protocols (such as shift workers and people who cannot stop taking antidepressants).
Cataplexy Identification Challenges
A central pillar of NT1 diagnosis is the presence of cataplexy, yet this symptom is often misunderstood or misreported. Flygare says many people with narcolepsy do not realize they experience cataplexy because they expect it to involve a total physical collapse. “They think you completely fall over,” she says. “They don’t realize that slurring words when laughing is cataplexy.”
Plante emphasizes the need for careful clinical descriptions to differentiate between typical and atypical cataplexy. He notes that some patients with NT2 may actually have low orexin levels but have not yet developed—or have not yet recognized—cataplexy symptoms.
“Sometimes cataplexy is a lagging symptom,” Plante explains. “If you follow some of those people over time, they may develop it, and then their diagnosis changes. Ideally, we want our categorization to be pointed toward pathophysiology—what’s causing it—rather than just symptoms.”
The Real-World Is Different from Clinical Trials
While clinical trials for oveporexton have demonstrated “near normal” improvements in wakefulness and cataplexy, the transition from controlled studies to real-world effectiveness introduces new variables. Morse warns that the average patient in a clinic often has medical complexities and polypharmacy that were excluded from pivotal trials.
She raises the concern that a less-than-optimal response to an orexin agonist might be used by clinicians or payers to “de facto” invalidate an NT1 diagnosis. “Does that mean a person doesn’t have an orexin deficiency? That would be my biggest fear.”
Furthermore, the dosing requirements appear to differ across the hypersomnolence spectrum. While oveporexton is being moved forward for NT1, Takeda’s TAK-360 is in development for NT2 and IH (as are other orexin agonists by other drug developers), with indications that these populations may require higher doses to achieve a therapeutic effect. This suggests that mismatching a patient—giving an NT2 patient a dose intended for an NT1 patient—could lead to perceived treatment failure.
The Future of Polytherapy
Despite the potential for orexin agonists to transform the treatment paradigm, experts agree that they are unlikely to be a “silver bullet” that eliminates the need for other medications. Morse points out that orexin signaling is only one part of the sleep-wake regulatory system, which also involves glutamate, melanin-concentrating hormone, and dopamine.
“Narcolepsy is a condition that is burdened by a full 24 hours of disability,” Morse says. “Even when looking at the use of selective orexin-2 agonists, it is only addressing one of the pathways. There still may be nocturnal fragmentation of sleep.”
She anticipates that polytherapy—combining orexin agonists with oxybates, stimulants, or other drugs—will remain the standard for optimizing patient outcomes.
Additionally, off-label use could become common once safety profiles are established. Morse, coming from a pediatric neurology background where off-label use is common, suggests that clinicians will lead with evidence of safety and physiologic logic, regardless of the narrowness of initial FDA indications.
Preparing Sleep Clinics for a New Era
As the Prescription Drug User Fee Act date for oveporexton approaches in late 2026, sleep clinics must decide if, and how, to evolve their diagnostic workflows.
Practical steps for sleep physicians could include:
- Refining Cataplexy Screening: Moving beyond “do you fall down?” to specific questions about facial sagging, speech changes, or weakness during positive emotions.
- Utilizing HLA Testing: Using the blood test as a “probabilistic” tool to clarify the likelihood of orexin deficiency in complex cases.
- Considering CSF Testing: Developing a referral pathway or in-house capability for lumbar punctures for patients who fail to respond to standard therapies or who cannot undergo an MSLT due to medication constraints.
- Educating Patients on Diagnostic Evolution: Helping patients understand that a shift from NT2 to NT1 is often a reflection of improved diagnostic clarity rather than a change in their underlying condition.
The arrival of orexin agonists represents more than just a new drug class; it is a catalyst for a more precise, pathophysiology-driven approach to sleep medicine.
“It is a very exciting time to be in medicine,” Morse says. “The existence of these medications is introducing a trans-disciplinary conversation as to why sleep-wake and circadian variables are relevant in every other system in our body. This is just the beginning.”
