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Oveporexton (TAK-861), approved by the FDA on 5 August 2026 as Orzeyful; the first oral orexin receptor 2 selective agonist licensed for narcolepsy type 1, and the first approved treatment aimed at the cause of the disease rather than its symptoms.
- orally active OX2R agonist that targets the root orexin deficit of narcolepsy type 1, not just symptoms
- phase 2 improved objective wakefulness (MWT), daytime sleepiness (Epworth) and cataplexy together
- reworked to avoid the dose-dependent liver toxicity that ended its predecessor TAK-994
- many patients moved from severe sleepiness back toward a normal wakefulness range
- furthest-advanced orexin agonist; in a broad phase 3 program for narcolepsy type 1
- The first approved therapy aimed at the cause of narcolepsy type 1 rather than its symptoms
- Improves wakefulness, daytime sleepiness and cataplexy together
- Also improved attention, memory and executive function in a secondary analysis
- No repeat of the dose-dependent liver toxicity that ended TAK-994
- An oral tablet twice daily rather than a night-time liquid
- Urinary frequency in 58 percent on the approved dose against 5 percent on placebo
- Urinary urgency in 16 percent against 1 percent
- Insomnia, usually starting in the first days and often settling within a week
- Creatine phosphokinase elevation
Overview
the first approved oral orexin (OX2R) agonist; the redemption of the class after TAK-994's liver toxicity, with strong phase 2 and phase 3 narcolepsy type 1 data. approved by the FDA on 5 August 2026 as Orzeyful, and the first therapy that treats narcolepsy's cause rather than its symptoms.
- it is the first drug that may treat the actual cause of narcolepsy type 1, the missing orexin signal, rather than just the sleepiness.
- unlike its predecessor TAK-994, it did not trigger the liver toxicity that halted that program.
- in its phase 2 trial many patients went from severely sleepy to near-normal wakefulness.
- it improves staying awake and cataplexy at the same time, something stimulants alone do not do.
- The FDA approved it as Orzeyful on 5 August 2026, on two randomised, double-blind, placebo-controlled 12-week studies in 273 adults with narcolepsy type 1.
- It also improved attention, memory and executive function in a secondary analysis of the phase 2 trial, which stimulants address poorly [7].
- In phase 2 the mean sleep latency on the Maintenance of Wakefulness Test rose by 23.5 minutes on 2 mg twice daily against a fall of 1.2 minutes on placebo [1].
- Urinary frequency affected 58 percent of patients on the approved dose against 5 percent on placebo, and it is the most common reason the drug is unpleasant rather than the sleepiness returning.
- The molecule activates OX2R at a half-maximal effective concentration of 2.5 nanomolar, roughly ten times more potent than the TAK-994 that preceded it [8].
- The DEA had not assigned a controlled substance schedule when the FDA approved it, so the licence arrived before the drug could be dispensed.
Mechanism
oveporexton (TAK-861) is an orally bioavailable, receptor 2 (OX2R)-selective and the lead compound of the orexin-agonist class for narcolepsy type 1. the disease is driven by loss of the hypothalamic neurons that make orexin (); with the gone, wakefulness cannot be stabilized and cataplexy emerges.
TAK-861 works downstream of that loss by directly agonizing OX2R, the receptor most responsible for the sleep/wake phenotype, effectively substituting for the missing drive. according to PubMed, its phase 2 randomized, placebo-controlled trial in narcolepsy type 1 met its goals: once- or twice-daily oral oveporexton improved the primary endpoint of average sleep latency on the Maintenance of Wakefulness Test at week 8, and improved the secondary endpoints of Epworth Sleepiness Scale score and weekly cataplexy rate, moving many patients toward normal-range wakefulness (Dauvilliers et al., 2025, N Engl J Med, https://doi.org/10.1056/NEJMoa2405847). the decisive contrast with the earlier oral TAK-994 is safety: TAK-994 was halted for dose-dependent hepatotoxicity, whereas oveporexton was structurally optimized and did not reproduce that liver signal in phase 2, which is what allowed it to advance. by targeting the underlying orexin deficit rather than masking symptoms, it can address excessive daytime sleepiness and cataplexy together, unlike stimulants, modafinil-type wake agents, or sodium oxybate, which are symptomatic only (Editorial, 2025, Ann Med Surg, https://doi.org/10.1097/MS9.0000000000004476). it is now in a broad phase 3 program (including NCT06470828 and NCT06505031, completed 2025, plus randomized-withdrawal and long-term-extension studies), making it the closest thing to a potential disease-mechanism-targeted therapy narcolepsy has had.
receptor fingerprint
receptor 2 (OX2R / HCRTR2)orally bioavailable, OX2R-selective agonist; restores the orexin signal lost in narcolepsy type 1
receptor 2 (OX2R)Agonist
receptor 1 (OX1R / HCRTR1)OX2R-selective; minimal OX1R activity
Safetyrisks and cautions, not medical advice
Insomnia, urinary frequency and urinary urgency are the characteristic adverse effects, and they follow directly from restoring an orexin signal. In the pooled phase 3 studies, urinary frequency occurred in 58 percent on 2 mg twice daily and 53 percent on 1 mg twice daily against 5 percent on placebo, and urinary urgency in 16 and 15 percent against 1 percent. Insomnia usually began in the first few days and often settled within a week; the label advises considering a dose reduction or stopping if it persists beyond seven days and is affecting daytime function. In phase 2, insomnia was reported in 48 percent, urinary urgency in 33 percent and urinary frequency in 32 percent [1]. Creatine phosphokinase elevation is also listed. Strong CYP3A inhibitors such as ketoconazole and itraconazole are contraindicated because they raise exposure.
The question the class was defined by is the liver, and the answer so far is reassuring. The earlier oral agonist TAK-994 was stopped for dose-dependent hepatotoxicity; oveporexton was structurally reworked and phase 2 reported no hepatotoxic effects [1]. Long-term hepatic safety at population scale is still accumulating.
History
oveporexton (TAK-861) is the third-generation orexin agonist in Takeda's lineage: injectable TAK-925/danavorexton proved OX2R agonism worked, oral TAK-994 proved efficacy but failed on liver toxicity, and TAK-861 was engineered to keep the benefit while shedding the hepatic liability. its positive phase 2 in narcolepsy type 1, published in the New England Journal of Medicine in 2025, made it one of the most closely watched late-stage CNS drugs [1]. Takeda then ran a phase 3 programme spanning two pivotal trials completed in 2025, a randomised-withdrawal study and a long-term extension. The FDA approved it as Orzeyful on 5 August 2026 for narcolepsy type 1 in adults, on the strength of two randomised, double-blind, placebo-controlled 12-week studies in 273 adults.
Reputation
in sleep medicine oveporexton is treated as the first disease-mechanism-directed therapy for narcolepsy type 1, a genuine shift from managing symptoms to replacing the missing orexin signal, and its approval is the event the field had been waiting for since TAK-994 was withdrawn [2]. A secondary analysis of the phase 2 trial found it also improved attention, memory and executive function, which are the symptoms patients report as most disabling and which stimulants address poorly [7]. The standing caveats are that the DEA schedule was unassigned at approval, that urinary frequency affected the majority of patients on the approved dose, and that long-term hepatic and cardiovascular safety at population scale is still accumulating.
Subjective profileweighing the evidence above
The first approved treatment that addresses the actual deficit in narcolepsy type 1 rather than masking the sleepiness it causes, improving wakefulness, daytime sleepiness and cataplexy together, and improving attention, memory and executive function alongside them. The liver toxicity that killed its predecessor did not reappear. What it costs is real and common: the majority of patients on the approved dose develop urinary frequency, and insomnia in the first week is close to expected. Its DEA schedule was still unassigned at approval, so availability lagged the licence.
Resources
This entry is here for reference.
Research
- 1.Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1.
- 2.Orexin receptor 2 agonists: a pathophysiologic approach to narcolepsy type 1.
- 3.Phase 3 study of TAK-861 for narcolepsy type 1 (ClinicalTrials.gov NCT06470828)
- 4.Phase 3 study of TAK-861 in narcolepsy with cataplexy (ClinicalTrials.gov NCT06505031)
- 5.Long-term extension study of TAK-861 in central hypersomnia (ClinicalTrials.gov NCT05816382)
- 6.Phase 2 study of TAK-861 for narcolepsy type 2 (ClinicalTrials.gov NCT05687916)
- 7.Effects of Oveporexton, an Orexin Receptor 2-Selective Agonist, on Cognition in Narcolepsy Type 1: A Secondary Analysis of a Randomized Clinical Trial.
- 8.TAK-861, a potent, orally available orexin receptor 2-selective agonist, produces wakefulness in monkeys and improves narcolepsy-like phenotypes in mouse models.
- 9.Hypocretin: a promising target for the regulation of homeostasis.
9 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
what is oveporexton (TAK-861)?
it is Takeda's lead oral orexin receptor 2 (OX2R) agonist for narcolepsy type 1, and the most advanced drug of its kind. narcolepsy type 1 is a disorder where the brain loses its orexin neurons; TAK-861 restores the missing wake-promoting signal by directly activating OX2R. it is the reworked, safer successor to TAK-994.
does it work?
yes, and impressively. in a phase 2 randomized, placebo-controlled trial in narcolepsy type 1, oral oveporexton improved objective wakefulness on the Maintenance of Wakefulness Test, cut daytime sleepiness on the Epworth Sleepiness Scale, and lowered the weekly cataplexy rate at 8 weeks (Dauvilliers et al., 2025, N Engl J Med, https://doi.org/10.1056/NEJMoa2405847). many patients moved from severe sleepiness back toward a normal range of wakefulness.
does it have the liver problem that killed TAK-994?
that was the central worry, and so far the answer looks reassuring. the earlier oral agonist TAK-994 was stopped for dose-dependent liver injury; oveporexton was chemically reworked and in phase 2 did not reproduce that hepatotoxicity, which is exactly why it, not TAK-994, went into phase 3 (Dauvilliers et al., 2025, N Engl J Med, https://doi.org/10.1056/NEJMoa2405847).
how is it different from current narcolepsy drugs?
it targets the actual cause rather than the symptoms. stimulants, wake-promoting agents like modafinil, and sodium oxybate manage narcolepsy symptomatically without touching the orexin deficit; oveporexton directly replaces the orexin signal, which is why it can improve wakefulness and cataplexy at the same time (Editorial, 2025, Ann Med Surg, https://doi.org/10.1097/MS9.0000000000004476).
what stage is it at?
phase 3. after the positive phase 2, Takeda launched a broad phase 3 program in narcolepsy type 1, including pivotal trials (for example NCT06470828 and NCT06505031, both completed in 2025), a randomized-withdrawal study (NCT07363720) and a long-term extension (NCT05816382). it has been one of the most closely watched CNS assets in late-stage development.
will it help narcolepsy type 2 or idiopathic hypersomnia too?
that is being tested. narcolepsy type 2 patients are not as uniformly orexin-deficient, so the effect could be smaller; a dedicated phase 2 study in narcolepsy type 2 (NCT05687916) explored this, and the extension program covers selected central hypersomnia conditions. type 1, where the orexin loss is clearest, is where the strongest rationale and data sit.
is it a nootropic or wakefulness supplement i can buy?
no. it is an investigational prescription drug in phase 3, not a supplement or a modafinil substitute you can order. its relevance to the broader wakefulness conversation is that it is the first credible orexin-replacement therapy, but it is not available outside trials.
is it an orexin antagonist like the sleep drugs?
no; it is the opposite. suvorexant, lemborexant and daridorexant block orexin receptors to cause sleep. oveporexton activates OX2R to cause wakefulness. it belongs to the agonist side of the orexin story.
Is it approved?
Yes. The FDA approved it as Orzeyful on 5 August 2026 for narcolepsy type 1 in adults, on two randomised, double-blind, placebo-controlled 12-week studies in 273 people. It is the first drug approved to treat the underlying cause of the disorder.
How is it taken?
As an oral tablet, 2 mg twice daily at the same times each day, with or without food. The first dose is taken after waking and the second three to five hours later.
What is the catch?
Urination. In the pooled phase 3 studies, 58 percent of patients on the approved dose developed urinary frequency against 5 percent on placebo, and 16 percent urinary urgency against 1 percent. Insomnia in the first days is also common, though it usually settles within a week.
Why does it help cataplexy when stimulants do not?
Because it is replacing the missing signal rather than compensating for it. Narcolepsy type 1 is caused by the loss of the hypothalamic neurons that make orexin; stimulants push wakefulness by other routes and leave cataplexy to be treated separately. Activating OX2R addresses both at once.
Can it be prescribed straight away?
Not necessarily. The DEA had not assigned a controlled substance schedule at approval and was expected to within 90 days, so the licence arrived before pharmacies could stock it.
Limitations of the evidence
- The DEA schedule was unassigned at approval, so the drug could not be dispensed immediately
- Approved for narcolepsy type 1 only; type 2 and idiopathic hypersomnia are still being studied
- The pivotal studies ran 12 weeks in 273 adults, so long-term safety is still accumulating
- Contraindicated with strong CYP3A inhibitors
- The majority of patients on the approved dose get urinary frequency
Adverse effects
- Urinary frequency in 58 percent on the approved dose against 5 percent on placebo
- Urinary urgency in 16 percent against 1 percent
- Insomnia, usually starting in the first days and often settling within a week
- Creatine phosphokinase elevation
Notes and cautions
- Narcolepsy type 2 patients are not uniformly orexin deficient, so the same mechanism has less to work with there; a dedicated phase 2 study explored it and the approval does not cover it.
- This is an orexin agonist. Suvorexant, lemborexant and daridorexant are orexin antagonists prescribed to cause sleep; the two do opposite things at the same receptor family.