data + articles · 3 listed
newest 2026spec sheet7 rows
TAK-994; the first oral OX2R orexin agonist to show major narcolepsy efficacy in phase 2, halted for dose-dependent liver toxicity, and the direct predecessor to oveporexton (TAK-861).
- proved an oral OX2R agonist can produce large gains in wakefulness and cataplexy control in narcolepsy type 1
- set the efficacy benchmark that justified advancing the safer successor TAK-861
Overview
oral OX2R agonist with excellent narcolepsy efficacy in phase 2 that was killed by dose-dependent liver toxicity; the failure that directly produced the safer TAK-861 (oveporexton).
- it clearly worked; big improvements in staying awake and in cataplexy, before liver toxicity ended it.
- its failure was the reason Takeda built TAK-861, which kept the benefit without the liver signal.
- the hepatotoxicity turned out to be specific to this molecule, not a curse on all orexin agonists.
Mechanism
TAK-994 is an orally bioavailable, receptor 2 (OX2R)-selective , the pill-form successor to injectable TAK-925/danavorexton. it works by the same logic: narcolepsy type 1 is caused by loss of hypothalamic orexin neurons and the resulting orexin deficiency, and TAK-994 directly re-activates OX2R downstream to reinstate wakefulness and suppress cataplexy. according to PubMed, its phase 2 randomized, placebo-controlled trial in narcolepsy type 1 delivered clear, large benefits: twice-daily oral TAK-994 improved the Maintenance of Wakefulness Test sleep latency, lowered Epworth Sleepiness Scale scores, and reduced the weekly cataplexy rate relative to placebo (Dauvilliers et al., 2023, N Engl J Med, https://doi.org/10.1056/NEJMoa2301940). the story turned on safety, not efficacy: the trials were halted early because of dose-dependent hepatotoxicity (drug-induced liver injury), and Takeda terminated the TAK-994 program. importantly, this liability appears to have been molecule-specific rather than a class effect; the reworked successor TAK-861 (oveporexton) reproduced the efficacy in phase 2 without the same hepatic signal (Dauvilliers et al., 2025, N Engl J Med, https://doi.org/10.1056/NEJMoa2405847).
TAK-994 therefore stands as the compound that proved oral -replacement can work in humans while also demonstrating why medicinal-chemistry safety optimization mattered so much for the class.
receptor fingerprint
receptor 2 (OX2R / HCRTR2)orally bioavailable selective agonist; restores OX2R signaling lost in narcolepsy type 1
hepatocytes (off-target liability)dose-dependent hepatotoxicity emerged in the phase 2 trial and led to program termination
receptor 1 (OX1R / HCRTR1)selective for OX2R; minimal OX1R engagement
Safetyrisks and cautions, not medical advice
TAK-994's defining safety event is dose-dependent hepatotoxicity (drug-induced liver injury), which was serious enough that trials were stopped early and the program was discontinued. it is not approved, not available, and should not be sought; its main legacy is as a cautionary example of a mechanistically successful drug halted for liver toxicity.
History
TAK-994 was Takeda's oral follow-up to danavorexton (TAK-925), designed to bring OX2R agonism to a convenient pill for narcolepsy type 1. phase 2 efficacy in 2021-2022 was compelling, but emergent dose-dependent liver injury forced early trial termination and the end of the program. the disappointment was formative: Takeda applied the lesson to TAK-861 (oveporexton), which was engineered to keep the efficacy while shedding the hepatotoxic liability.
Reputation
in the narcolepsy field TAK-994 is remembered as 'the one that worked but wrecked the liver'; a jolt of excitement followed by an abrupt halt. its cancellation is precisely what set up oveporexton as the redemption compound, and comparisons between the two are a standard way to explain that the liver signal was chemistry-specific, not inherent to orexin agonism.
Subjective profileweighing the evidence above
It proved the mechanism works, producing large gains in wakefulness and cataplexy control, then was halted for dose-dependent liver injury serious enough to end the program. Not available and not worth seeking; its successor TAK-861 is the reason it mattered.
Resources
This entry is here for reference.
Research
- 2023first citedOral Orexin Receptor 2 Agonist in Narcolepsy Type 1.
- 2026most recentOrexin receptor 2 agonists: a pathophysiologic approach to narcolepsy type 1.
- 1.Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1.
- 2.Orexin receptor 2 agonists: a pathophysiologic approach to narcolepsy type 1.
- 3.Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1.
3 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
what was TAK-994?
it was Takeda's first oral orexin receptor 2 (OX2R) agonist for narcolepsy type 1; the pill version of the concept proven by injectable TAK-925. it aimed to restore the wake-promoting orexin signal that narcolepsy type 1 patients lose.
did it work?
strikingly well, on efficacy. in a phase 2 randomized trial in narcolepsy type 1, oral TAK-994 produced large improvements in objective wakefulness (Maintenance of Wakefulness Test), daytime sleepiness (Epworth score) and weekly cataplexy rate versus placebo (Dauvilliers et al., 2023, N Engl J Med, https://doi.org/10.1056/NEJMoa2301940).
so why isn't it a drug?
because it hurt the liver. the trials were stopped early after dose-dependent hepatotoxicity (drug-induced liver injury) showed up. the efficacy was real, but the safety signal was unacceptable, so the whole TAK-994 program was discontinued (Dauvilliers et al., 2023, N Engl J Med, https://doi.org/10.1056/NEJMoa2301940).
was the liver problem a class effect for all orexin agonists?
that was the key question, and the current answer appears to be no. the next compound, TAK-861 (oveporexton), was structurally reworked and in its phase 2 trials did not reproduce the hepatotoxicity that ended TAK-994, which suggests the liver injury was specific to TAK-994's chemistry rather than intrinsic to OX2R agonism (Dauvilliers et al., 2025, N Engl J Med, https://doi.org/10.1056/NEJMoa2405847).
why does it still matter if it was cancelled?
because it was the proof that an oral orexin agonist can deliver disease-modifying-level benefit in narcolepsy; the efficacy bar it set is what justified pushing straight into TAK-861. it is a textbook case of a drug that failed on safety, not on whether the mechanism works.
can i get it?
no. it was never approved, its development was terminated, and it caused liver injury. there is no legitimate source and no reason to seek it out.