Oveporexton
Oveporexton (TAK-861), oral orexin receptor 2 selective agonist
Written by Aaron CuhaReviewed Sep 2026
Also known as: TAK-861, Orzeyful
An oral orexin receptor 2 agonist, not a peptide, approved by the FDA on 5 August 2026 for narcolepsy type 1 in adults. In two 12 week phase 3 trials totalling 273 people it lengthened time awake on the Maintenance of Wakefulness Test by 14 to 20 minutes against roughly no change on placebo; a majority of treated participants developed insomnia and urinary frequency.
Overview
Oveporexton is a small molecule, molecular weight 520.51 daltons, not a peptide. It is on this site because it is the first approved drug that acts at the receptor for orexin-A, the wake-promoting peptide whose neurons are lost in narcolepsy type 1. Where the endogenous peptide cannot be given by mouth, this molecule can. It is taken as two tablets in the morning, three to five hours apart, and was developed by Takeda under the code TAK-861.
The human record is two randomised, double-blind, placebo-controlled phase 3 trials of 12 weeks, published together in the New England Journal of Medicine on 9 September 2026 and funded by Takeda. First Light randomised 168 people aged 16 to 70 with narcolepsy type 1 to 1 mg twice daily, 2 mg twice daily or placebo; Radiant Light randomised 105 to 2 mg twice daily or placebo. The primary endpoint was the change in mean sleep latency on the Maintenance of Wakefulness Test, a 40 minute test of the ability to stay awake in a darkened room, on which 20 minutes or more counts as normal. Oveporexton arms gained 14.3 to 19.8 minutes; placebo arms changed by minus 0.4 to minus 0.8 minutes (adjusted P below 0.001 for every comparison). Epworth Sleepiness Scale scores fell 9.7 to 11.8 points against 1.5 to 1.7 on placebo, and the median weekly cataplexy rate fell 79.0 to 88.8 percent against 27.7 to 39.1 percent on placebo. An earlier 8 week phase 2 trial in 112 people had shown the same pattern at doses from 0.5 mg twice daily to 7 mg once daily, and a secondary analysis of that trial reported improvements in attention, memory and executive function tests.
The adverse event burden is high and the FDA label states it plainly. Adverse events occurred in 86 to 89 percent of treated participants against 43 to 54 percent on placebo. Insomnia affected 60 percent on 2 mg twice daily, 55 percent on 1 mg twice daily and 1 percent on placebo; urinary frequency 58, 53 and 5 percent; urinary urgency 16, 15 and 1 percent; salivary hypersecretion 7 to 8 percent against none. About 90 percent of insomnia began in the first two days and about 63 percent resolved within a week, but 17 percent was still present at the end of the 12 weeks. Asymptomatic creatine phosphokinase elevations above five times the upper limit of normal occurred in 11 percent (21 of 196) of treated participants against 5 percent (4 of 76) on placebo; two cases had markedly raised transaminases as well and both people stopped treatment. Discontinuation for an adverse reaction was 2.6 percent against 1.3 percent. The predecessor compound in the same programme, TAK-994, was stopped for dose-dependent liver toxicity; the oveporexton phase 2 reported no hepatotoxic effects and the label carries no liver warning.
Regulatory position: FDA approved on 5 August 2026 as Orzeyful, NDA 220860, a new molecular entity with orphan designation and priority review, for narcolepsy type 1 in adults. The trials enrolled from age 16 but the label says safety and effectiveness in paediatric patients have not been established. The label lists the controlled substance schedule as pending review by the Drug Enforcement Administration and states that the drug has potential for abuse. No MHRA, TGA or Health Canada record was located on 11 September 2026.
Mechanism of action
In people with narcolepsy type 1 the hypothalamic neurons that make orexin-A and orexin-B are lost, so both orexin peptides are deficient while their receptors remain. Oveporexton is a selective agonist at orexin receptor 2 (OX2R), the receptor most tied to maintaining wakefulness, and it restores signalling at that receptor without replacing the peptide. The FDA label describes the mechanism in narcolepsy as presumed to be OX2R agonism rather than proven, which is the usual wording for a receptor agonist. Human pharmacokinetics, from the label: peak plasma concentration at a median 1.5 hours, terminal half-life about 23.2 hours, protein binding above 96 percent, elimination mainly by CYP3A4 metabolism with 80.5 percent of a radiolabelled dose recovered in faeces. Strong CYP3A inhibitors raise exposure about 7 fold and are contraindicated; moderate inhibitors require a dose reduction to 0.5 mg twice daily. The urinary adverse effects are described on the label as consistent with OX2R agonism, since orexin signalling also acts on bladder control.
Human evidence
Two randomised placebo-controlled phase 3 trials totalling 273 people over 12 weeks, one randomised phase 2 of 112 people over 8 weeks, and an FDA label built on them. All sponsor funded. No trial has run longer than 12 weeks of blinded treatment and none has compared it with an existing narcolepsy drug.
- First Light: 168 people aged 16 to 70, randomised 3:3:2 to 1 mg twice daily, 2 mg twice daily or placebo for 12 weeks. Primary endpoint met with sleep latency gains of 14.3 to 19.8 minutes across both trials against roughly no change on placebo.
- Radiant Light: 105 people randomised 2:1 to 2 mg twice daily or placebo, same design and endpoints.
- Epworth Sleepiness Scale fell 9.7 to 11.8 points on oveporexton against 1.5 to 1.7 on placebo; a 2 point fall is the conventional threshold for a meaningful change.
- Weekly cataplexy rate, self-reported in a diary, fell by a median 79.0 to 88.8 percent against 27.7 to 39.1 percent on placebo.
- Phase 2 (TAK-861-2001): 112 people, 8 weeks, four active regimens; sleep latency rose 12.5 to 25.4 minutes against a 1.2 minute fall on placebo. Secondary analysis reported gains in attention, memory and executive function.
- Safety, pooled phase 3, 196 treated: insomnia 58 percent, any urinary adverse reaction 63 percent, creatine phosphokinase above 5 times normal 11 percent against 5 percent placebo, systolic blood pressure rises above 20 mmHg on day 1 in 22 percent against 13 percent. Discontinuation for adverse reactions 2.6 percent against 1.3 percent.
- Only 1 participant aged 65 or older was treated across both phase 3 trials.
What this does not tell you: Twelve weeks of controlled data for a lifelong condition, so nothing is known from trials about durability, tolerance, long-term insomnia or the meaning of the creatine phosphokinase signal over years. No head to head comparison against modafinil, sodium oxybate, pitolisant or solriamfetol exists, so the trials cannot say whether it is better than what patients already take. The adverse event rate of 86 to 89 percent means the blind was probably imperfect for many participants, which matters most for the self-reported endpoints (Epworth and cataplexy diary) and less for the laboratory-measured Maintenance of Wakefulness Test. Adults only in the indication despite enrolment from 16; almost no data over 65.
Reading the research record
The record is compact because the development path was fast: an orphan disease, a mechanism that directly addresses the known cause, and a sponsor that had already run one OX2R agonist (TAK-994) far enough to find liver toxicity and stop it. Everything published on oveporexton is Takeda funded, from the phase 2 to the phase 3 to the regulatory science paper that derived the attention threshold, which is normal for a new drug and worth saying. The approval arrived less than a month before the phase 3 paper, so for several weeks the only approval record was the sponsor's announcement; Drugs@FDA now carries the application (NDA 220860, approved 5 August 2026) and the label, and this profile is built from those.
The honest tension in this compound is efficacy against tolerability. The wakefulness effect is large by the standards of the field. So is the side effect burden: most treated people get insomnia at the start and most get urinary frequency, and the label's own statement that 17 percent of insomnia was still present at week 12 is the number to watch. Whether people stay on it for years, and what a small creatine phosphokinase signal means over that time, are open questions that no current trial answers. The label also lists the controlled substance schedule as pending, a reminder that a drug which produces wakefulness on demand will be assessed for abuse potential.
The evidence, charted
Fig. 1 · evidence composition
6of 9 citations (67%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Citations here span just two years, 2025 and 2026.
Too few distinct publication years on this page to plot as a timeline.
Fig. 3 · legal status at a glance
US
Approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 3 of 4, prescription route in 0, not approved in 1. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Human2026
Oveporexton for Narcolepsy Type 1 - Results from Two Phase 3 Trials
First Light (168 participants, 1 mg or 2 mg twice daily or placebo, 3:3:2) and Radiant Light (105 participants, 2 mg twice daily or placebo, 2:1), both 12 weeks, ages 16 to 70. Maintenance of Wakefulness Test sleep latency rose 14.3 to 19.8 minutes with oveporexton against minus 0.4 to minus 0.8 minutes on placebo; Epworth Sleepiness Scale fell 9.7 to 11.8 against 1.5 to 1.7 points; weekly cataplexy fell 79.0 to 88.8 percent against 27.7 to 39.1 percent (all adjusted P below 0.001). Adverse events in 86 to 89 percent against 43 to 54 percent. Funded by Takeda Development Center Americas.
New England Journal of Medicine - Human2025
Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1
Phase 2, 8 weeks, 112 randomised: 90 to four oveporexton regimens (0.5 mg twice daily, 2 mg twice daily, 2 mg then 5 mg, 7 mg once daily) and 22 to placebo. Sleep latency changes of 12.5, 23.5, 25.4 and 15.0 minutes against minus 1.2 on placebo. Insomnia in 48 percent, urinary urgency 33 percent, urinary frequency 32 percent, with no hepatotoxic effects reported. Funded by Takeda.
New England Journal of Medicine - Human2026
Effects of Oveporexton, an Orexin Receptor 2-Selective Agonist, on Cognition in Narcolepsy Type 1: A Secondary Analysis of a Randomized Clinical Trial
Secondary analysis of the 112 person phase 2 trial. Placebo-adjusted reductions of 8.6 to 10.8 lapses on the Psychomotor Vigilance Task and 15.5 to 22.5 errors on a paired associate learning test across dose groups, with improvements on executive function tests. Adults 18 to 70 only; 8 weeks.
JAMA Neurology - Human2026
Defining a Clinically Meaningful Within-Person Change Threshold for the Psychomotor Vigilance Test in Narcolepsy Type 1
Using phase 3 data, a reduction of 2 or more attention lapses was derived as a meaningful within-person change. On that threshold, 66.9 percent of oveporexton participants against 25.7 percent on placebo improved in First Light, and 57.6 against 17.6 percent in Radiant Light (both P at or below 0.0001). Sponsor-derived threshold applied to sponsor trials.
Therapeutic Innovation and Regulatory Science - Review2026
ORZEYFUL (oveporexton) tablets, prescribing information
Indication: narcolepsy type 1 in adults. Pooled 12 week safety in 196 treated patients: insomnia 55 to 60 percent against 1 percent placebo, urinary frequency 53 to 58 against 5 percent, urinary urgency 15 to 16 against 1 percent, creatine phosphokinase above 5 times upper limit of normal in 11 percent against 5 percent. Half-life about 23.2 hours, CYP3A4 metabolised, strong CYP3A inhibitors contraindicated. Controlled substance schedule pending.
U.S. Food and Drug Administration, Drugs@FDA label, NDA 220860 - Human2026
A Study of TAK-861 for the Treatment of Narcolepsy Type 1 (First Light)
Phase 3, 168 participants, completed June 2025, results posted 31 August 2026. Sponsor Takeda.
ClinicalTrials.gov - Human2026
A Study of TAK-861 in People With Narcolepsy Type 1 (Radiant Light)
Phase 3, 105 participants, completed June 2025, results posted 16 July 2026. Sponsor Takeda.
ClinicalTrials.gov - Review2026
Orexin receptor 2 agonists: a pathophysiologic approach to narcolepsy type 1
Editorial recording that TAK-994, the first oral OX2R agonist in the programme, was discontinued for dose-dependent hepatotoxicity, and that oveporexton was designed as its successor. Written before the phase 3 publication.
Annals of Medicine and Surgery - Review2026
Oveporexton: The first-in-class orexin receptor 2 (OX2R) agonist approved for treatment of narcolepsy type 1 (NT1)
Short review describing the approval and the two phase 3 trials; it does not name the approving agency or date, which are taken here from Drugs@FDA. Notes that long-term safety and real-world efficacy remain to be evaluated.
Drug Discoveries and Therapeutics
Frequently asked questions
Is oveporexton a peptide?
No. It is a small molecule of 520.51 daltons taken as a tablet. It is on this site because it acts at the receptor for orexin-A, the wake-promoting peptide that is lost in narcolepsy type 1, and it is the first approved drug to do so. The peptide itself cannot be taken by mouth.
How much does it help people stay awake?
In two 12 week trials of 273 people with narcolepsy type 1, time awake on the Maintenance of Wakefulness Test rose by 14.3 to 19.8 minutes on oveporexton against roughly no change on placebo. Self-rated sleepiness fell about 10 to 12 points on the Epworth scale and weekly cataplexy attacks fell by about 80 to 89 percent. Both trials were funded by the manufacturer.
What are the side effects?
Insomnia in 55 to 60 percent of treated people against 1 percent on placebo, urinary frequency in 53 to 58 percent against 5 percent, urinary urgency in 15 to 16 percent, and excess saliva in 7 to 8 percent. Most insomnia started in the first two days and about two thirds resolved within a week, but 17 percent was still present at 12 weeks. Creatine phosphokinase, a muscle enzyme, rose above five times normal in 11 percent against 5 percent on placebo.
Is it approved, and where?
The FDA approved it on 5 August 2026 as Orzeyful for adults with narcolepsy type 1. No UK, Australian or Canadian approval record could be located in September 2026. The trials enrolled people from age 16 but the US indication is adults only.
How does it compare with modafinil or sodium oxybate?
Nobody knows from a trial. Both phase 3 trials compared oveporexton with placebo. No randomised comparison against any existing narcolepsy treatment has been published.