Oveporexton

updated

Oveporexton (ORZEYFUL) is an orexin receptor 2 agonist for narcolepsy type 1 in adults, and FDA issued an approval letter dated 5 August 2026, but the formal approval date and marketing wait on a DEA scheduling notice that a Federal Register search on 10 October 2026 did not find. In two 12-week phase 3 trials (273 participants), mean Maintenance of Wakefulness Test sleep latency rose 14.3 to 19.8 minutes versus a fall of 0.4 to 0.8 on placebo, and the label's pooled data show insomnia and urinary frequency in more than half of treated patients. No human trial tests it as a wakefulness or cognition agent in healthy or sleep-deprived people, and the narcolepsy type 2 phase 2 trial showed no significant effect.

Orexin receptor 2 agonist

  • FDA issued an approval letter for NDA 220860 (ORZEYFUL, Takeda) dated 5 August 2026 for adults with narcolepsy type 1; under 21 U.S.C. 355(x) the approval date will be the date DEA publishes an interim final scheduling notice.
  • Federal Register searches on 10 October 2026 for oveporexton and Orzeyful returned 0 documents, and a DailyMed search returned no label.
  • In the two phase 3 trials (273 participants, 12 weeks), mean MWT sleep latency changed by 14.3 to 19.8 minutes with oveporexton versus -0.4 to -0.8 with placebo.
  • In the label's pooled phase 3 data, insomnia occurred in 55% and 60% versus 1% on placebo, and urinary frequency in 53% and 58% versus 5%.
  • The phase 2 trial in narcolepsy type 2 (71 participants) showed no significant MWT effect in the results posted on ClinicalTrials.gov.
  • The earlier compound TAK-994 was stopped early for hepatic adverse events, with drug-induced liver injury meeting Hy's law in 3 patients.

What is oveporexton, and has FDA approved it?

FDA issued an approval letter for ORZEYFUL (oveporexton) dated 5 August 2026 for adults with narcolepsy type 1. The formal approval date and marketing wait on a DEA scheduling notice that a Federal Register search on 10 October 2026 did not find.

FDA issued an approval letter for NDA 220860 (ORZEYFUL, oveporexton tablets, Takeda) dated 5 August 2026, for narcolepsy type 1 in adult patients. The application was received on 10 December 2025, and openFDA lists it as a priority-review new molecular entity with orphan status.

The letter states the approval is effective on the date of the letter, but that DEA scheduling under the Controlled Substances Act is not yet complete. Under 21 U.S.C. 355(x), the date of approval will therefore be the date DEA publishes a Federal Register notice of interim final scheduling, and ORZEYFUL may be marketed only after that notice and a labeling supplement. Federal Register searches on 10 October 2026 for oveporexton and for Orzeyful returned 0 documents, and a DailyMed search returned no label, so a formal approval date and marketing are not established here.

The ORZEYFUL label (revised 8/2026) states it is an orexin receptor 2 agonist indicated for narcolepsy type 1 (narcolepsy with cataplexy) in adults. Safety and effectiveness in pediatric patients have not been established.

Oveporexton (TAK-861, ORZEYFUL) is C23H25F5N2O4S (520.5 g/mol, CAS 2460722-04-5, PubChem CID 154617563); the label gives molecular weight 520.51. It is a different molecule from danavorexton (TAK-925, an injected orexin 2 agonist) and from TAK-994, an earlier oral orexin 2 agonist from the same program.

FDA approval letter dated 5 August 2026: effective approval date deferred until DEA scheduling

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record and approval letter for NDA 220860 (ORZEYFUL, oveporexton tablets, Takeda), letter dated 5 August 2026.

FDA issued an approval letter for NDA 220860 (ORZEYFUL, oveporexton tablets, Takeda) dated 5 August 2026, for narcolepsy type 1 in adult patients. The application was received on 10 December 2025, and openFDA lists it as a priority-review new molecular entity with orphan status. The letter states the approval is effective on the date of the letter but that DEA scheduling under the Controlled Substances Act is not yet complete, so under 21 U.S.C. 355(x) the date of approval will be the date DEA publishes a Federal Register notice of interim final scheduling, and ORZEYFUL may be marketed only after that notice and a labeling supplement. Federal Register searches run on 10 October 2026 for oveporexton and for Orzeyful returned 0 documents, and a DailyMed search for oveporexton and Orzeyful returned no label.

Participants / model
Not a clinical population
Treatment
Drug application
Follow-up
Approval letter dated 5 August 2026
Study design
FDA application record and approval letter
Funding
not stated in the source

The approval is an FDA letter whose formal date and marketing depend on a DEA scheduling notice that was not found. Its status may have changed since 10 October 2026.

Read the original source
ORZEYFUL label, revised 8/2026: indication, contraindication, adverse reactions in 196 treated patients

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf.

The label states ORZEYFUL is an orexin receptor 2 agonist indicated for narcolepsy type 1 (narcolepsy with cataplexy) in adults. It is contraindicated with strong CYP3A inhibitors. In the two pooled 12-week phase 3 studies (196 treated, 76 on placebo), insomnia occurred in 55% and 60% on the two studied dose levels versus 1%, urinary frequency in 53% and 58% versus 5%, urinary urgency in 15% and 16% versus 1%, and salivary hypersecretion in 8% and 7% versus 0%. Creatine phosphokinase above 5 times the upper limit occurred in 11% (21 of 196) versus 5% (4 of 76), with two cases that also had markedly elevated transaminases and led to discontinuation; LDL above 160 mg/dL occurred in 32% (62 of 196) versus 20% (15 of 76). Discontinuation for an adverse reaction was 2.6% versus 1.3%. Safety and effectiveness in pediatric patients have not been established, and only 1 treated patient was aged 65 or older.

Participants / model
Adults with narcolepsy type 1 in the pivotal trials
Treatment
ORZEYFUL oral tablets
Follow-up
Label revised 8/2026; pooled 12-week phase 3 studies
Study design
FDA prescribing information
Funding
not stated in the source

The label shows Initial U.S. Approval as pending and no label was found on DailyMed on 10 October 2026. Long-term safety is open because the safety pool is 12 weeks long.

Read the original source
PubChem: oveporexton identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 154617563 (oveporexton).

Oveporexton: PubChem CID 154617563, C23H25F5N2O4S, 520.5 g/mol, CAS 2460722-04-5; the label gives molecular weight 520.51. TAK-861 and Orzeyful are synonyms on the PubChem record. It is a different molecule from danavorexton (TAK-925, an injected orexin 2 agonist) and from TAK-994.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source

What did the narcolepsy type 1 trials find?

In two phase 3 trials (273 participants with narcolepsy type 1, 12 weeks), mean MWT sleep latency changed by 14.3 to 19.8 minutes with oveporexton versus -0.4 to -0.8 with placebo, and median weekly cataplexy fell by 79.0 to 88.8% versus 27.7 to 39.1%. A phase 2 trial in 112 participants also favored oveporexton.

The label reports two randomized double-blind placebo-controlled 12-week studies (Study 1, NCT06470828, 168 patients; Study 2, NCT06505031, 105 patients) in patients with narcolepsy type 1 (ICSD-3 criteria, mean age 31, ages 16 to 65 in Study 1 and 18 to 62 in Study 2). The primary endpoint was change in mean sleep latency on the Maintenance of Wakefulness Test (MWT). Placebo-adjusted differences were 13.8 minutes (95% CI 10.2 to 17.4) on the lower dose and 17.2 (13.7 to 20.7) on the higher dose in Study 1, and 20.1 (16.6 to 23.6) on the higher dose in Study 2. Epworth Sleepiness Scale differences were -8.0, -9.8 and -9.5 points, and weekly cataplexy incidence rate ratios were 0.34, 0.38 and 0.25 against placebo. Baseline mean MWT sleep latency was 4.1 to 5.5 minutes across arms.

The published report of the same two phase 3 trials (First Light, 168 participants; Radiant Light, 105) randomized people aged 16 to 70 with narcolepsy type 1 to oveporexton or placebo for 12 weeks. Mean change in MWT sleep latency ranged from 14.3 to 19.8 minutes with oveporexton versus -0.4 to -0.8 with placebo, ESS changed by -9.7 to -11.8 versus -1.5 to -1.7, and median weekly cataplexy reduction was 79.0 to 88.8% versus 27.7 to 39.1% (adjusted P under 0.001 for all). Adverse events occurred in 86 to 89% versus 43 to 54%, mostly increased urinary frequency and transient insomnia. Takeda funded the trials.

The phase 2 trial (NCT05687903) randomized 112 participants with narcolepsy type 1 (90 on oveporexton, 22 on placebo) for 8 weeks. MWT sleep latency changed by 12.5, 23.5, 25.4 and 15.0 minutes across the four oveporexton regimens versus -1.2 with placebo, and the ESS fell by 8.9 to 13.8 points versus 2.5. Insomnia occurred in 48%, urinary urgency in 33% and urinary frequency in 32%, with no hepatotoxic effects reported. Takeda funded the trial.

All of these results are in patients with narcolepsy type 1.

ORZEYFUL label section 14: two phase 3 studies, 168 and 105 patients, 12 weeks

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf. Section 14, clinical studies.

Section 14 reports two randomized double-blind placebo-controlled 12-week studies (Study 1, NCT06470828, 168 patients; Study 2, NCT06505031, 105 patients). The primary endpoint was change in mean sleep latency on the Maintenance of Wakefulness Test (MWT). Placebo-adjusted differences were 13.8 minutes (95% CI 10.2 to 17.4) on the lower dose and 17.2 (13.7 to 20.7) on the higher dose in Study 1, and 20.1 (16.6 to 23.6) on the higher dose in Study 2. Epworth Sleepiness Scale differences were -8.0, -9.8 and -9.5 points, and weekly cataplexy incidence rate ratios were 0.34, 0.38 and 0.25 against placebo. Baseline mean MWT sleep latency was 4.1 to 5.5 minutes across arms.

Participants / model
Patients with narcolepsy type 1 (ICSD-3 criteria), mean age 31, ages 16 to 65 in Study 1 and 18 to 62 in Study 2
Treatment
Oral oveporexton at two dose levels, or placebo
Follow-up
12 weeks
Study design
Two randomized double-blind placebo-controlled phase 3 studies, results read from label section 14
Funding
not stated in the source

Patients with narcolepsy type 1 only. Endpoints were MWT sleep latency, ESS and weekly cataplexy rate.

Read the original source
First Light and Radiant Light: 273 participants, 12 weeks, MWT sleep latency up 14.3 to 19.8 minutes

Randomized controlled trial

Dauvilliers Y et al. N Engl J Med. 2026;395(12):1166-1179. PMID 42714024.

Mean change in MWT sleep latency ranged from 14.3 to 19.8 minutes with oveporexton versus -0.4 to -0.8 with placebo, ESS changed by -9.7 to -11.8 versus -1.5 to -1.7, and median weekly cataplexy reduction was 79.0 to 88.8% versus 27.7 to 39.1% (adjusted P under 0.001 for all). Adverse events occurred in 86 to 89% versus 43 to 54%, mostly increased urinary frequency and transient insomnia. Funded by Takeda.

Participants / model
273 participants with narcolepsy type 1, aged 16 to 70 (First Light 168, Radiant Light 105)
Treatment
Oral oveporexton at two dose levels, or placebo
Follow-up
12 weeks
Study design
Two randomized placebo-controlled phase 3 trials (NCT06470828, NCT06505031)
Funding
not stated in the source

Patients with narcolepsy type 1 only. Endpoints were MWT sleep latency, ESS, weekly cataplexy rate and adverse events.

Read the original source
Phase 2: 112 participants, 8 weeks, MWT sleep latency up 12.5 to 25.4 minutes

Randomized controlled trial

Dauvilliers Y et al. N Engl J Med. 2025;392(19):1905-1916. PMID 40367374.

MWT sleep latency changed by 12.5, 23.5, 25.4 and 15.0 minutes across the four oveporexton regimens versus -1.2 with placebo, and the ESS fell by 8.9 to 13.8 points versus 2.5. Insomnia occurred in 48%, urinary urgency in 33% and urinary frequency in 32%, with no hepatotoxic effects reported. Funded by Takeda.

Participants / model
112 participants with narcolepsy type 1 (90 on oveporexton, 22 on placebo)
Treatment
Oral oveporexton in four regimens, or placebo
Follow-up
8 weeks
Study design
Randomized phase 2 trial (NCT05687903)
Funding
not stated in the source

Patients with narcolepsy type 1 only. Endpoints were MWT sleep latency, ESS, weekly cataplexy rate and adverse events.

Read the original source

Did oveporexton work in narcolepsy type 2?

Not significantly. In the phase 2 trial in 71 participants with narcolepsy type 2, the results posted on ClinicalTrials.gov show the MWT change from baseline was 2.14 minutes on placebo, 1.90 on one TAK-861 arm and 4.54 on the other.

In the phase 2 trial in narcolepsy type 2 (NCT05687916, 71 participants, 8 weeks), the results posted on ClinicalTrials.gov show no significant MWT effect: the change from baseline was 2.14 minutes on placebo, 1.90 on one TAK-861 arm and 4.54 on the other, with differences from placebo of -0.24 (95% CI -6.67 to 6.18, P = 0.989) and 2.4 (95% CI -3.93 to 8.72, P = 0.916).

This result comes from the registry record, not a journal publication. The approval is limited to narcolepsy type 1.

Narcolepsy type 2 phase 2, 71 participants: no significant MWT effect in posted results

Trial registry record

ClinicalTrials.gov. NCT05687916, phase 2 trial of TAK-861 in narcolepsy type 2, with posted results.

The results posted on ClinicalTrials.gov show no significant MWT effect: the change from baseline was 2.14 minutes on placebo, 1.90 on one TAK-861 arm and 4.54 on the other, with differences from placebo of -0.24 (95% CI -6.67 to 6.18, P = 0.989) and 2.4 (95% CI -3.93 to 8.72, P = 0.916).

Participants / model
71 participants with narcolepsy type 2
Treatment
Oral TAK-861 in two regimens, or placebo
Follow-up
8 weeks
Study design
Phase 2 randomized trial; results posted on the registry
Funding
not stated in the source

The result comes from the registry record, not a journal publication. Endpoints were MWT sleep latency and ESS.

Read the original source

Did oveporexton improve attention and memory?

In a secondary analysis of the phase 2 trial in 112 adults with narcolepsy type 1, attention, memory and executive function improved over 8 weeks. It is a post hoc analysis in patients whose cognition was impaired by narcolepsy, not evidence of a cognitive boost in healthy people.

A secondary analysis of the phase 2 trial (112 adults with narcolepsy type 1) found oveporexton improved attention, memory and executive function over 8 weeks; for example, placebo-adjusted psychomotor vigilance lapses fell by 8.60 to 10.77 across the four regimens. The tests were the Psychomotor Vigilance Task, paired-associate learning, One Back and digit symbol substitution. Several authors are Takeda employees.

This is a post hoc analysis in patients whose cognition was impaired by narcolepsy. It is not evidence of a cognitive boost in healthy people.

Phase 2 secondary analysis: attention, memory and executive function improved in 112 patients

Randomized controlled trial

Lammers GJ et al. JAMA Neurol. 2026;83(2):145-152. PMID 41359331.

Oveporexton improved attention, memory and executive function over 8 weeks; for example, placebo-adjusted psychomotor vigilance lapses fell by 8.60 to 10.77 across the four regimens. Several authors are Takeda employees.

Participants / model
112 adults with narcolepsy type 1
Treatment
Oral oveporexton, 8 weeks
Follow-up
8 weeks
Study design
Secondary analysis of a randomized trial; post hoc
Funding
not stated in the source

A post hoc analysis in patients whose cognition was impaired by narcolepsy. It is not evidence of a cognitive boost in healthy people. Tests were the Psychomotor Vigilance Task, paired-associate learning, One Back and digit symbol substitution.

Read the original source

Is oveporexton a wakefulness or cognition aid for people without narcolepsy?

No human trial found tests it. Searches on 10 October 2026 found no trial of oveporexton as a wakefulness or cognition agent in healthy or sleep-deprived people, and the interventional records with posted eligibility criteria all list healthy volunteers as not accepted.

Interest in oveporexton beyond narcolepsy treats it as a wakefulness or cognition agent. The approval letter covers adults with narcolepsy type 1 only.

A PubMed search on 10 October 2026 for oveporexton or TAK-861 with healthy, volunteers, narcolepsy type 2 or hypersomnia returned 4 records: the monkey and mouse paper described below, a rat salivary-secretion study, a review of hypersomnolence treatments and an actigraphy algorithm paper in narcolepsy type 1. A ClinicalTrials.gov search for oveporexton or TAK-861 returned 7 records: two phase 3 trials and one phase 2 trial in narcolepsy type 1, one phase 2 trial in narcolepsy type 2, a long-term extension, a randomized-withdrawal trial and a Spanish epidemiology study.

The six interventional records with posted eligibility criteria (NCT05687903, NCT06470828, NCT06505031, NCT05687916, NCT05816382, NCT07363720) all list healthy volunteers as not accepted. No human trial of oveporexton in healthy or sleep-deprived people was found, so that interest has no human trial behind it.

Searches, 10 October 2026: 4 PubMed records and 7 registry records, none in healthy or sleep-deprived people

PubMed search record

Searches run on 10 October 2026: PubMed, (oveporexton[tiab] OR TAK-861[tiab]) AND (healthy[tiab] OR volunteers[tiab] OR "narcolepsy type 2"[tiab] OR hypersomnia[tiab]), 4 records; ClinicalTrials.gov, oveporexton OR TAK-861, 7 records.

The PubMed search returned 4 records: the monkey and mouse paper described on this page, a rat salivary-secretion study, a review of hypersomnolence treatments and an actigraphy algorithm paper in narcolepsy type 1. The ClinicalTrials.gov search returned 7 records: two phase 3 trials and one phase 2 trial in narcolepsy type 1, one phase 2 trial in narcolepsy type 2, a long-term extension (NCT05816382, recruiting, estimated completion 28 February 2028), a randomized-withdrawal trial and a Spanish epidemiology study. The six interventional records with posted eligibility criteria (NCT05687903, NCT06470828, NCT06505031, NCT05687916, NCT05816382, NCT07363720) all list healthy volunteers as not accepted. No human trial of oveporexton as a wakefulness or cognition agent in healthy or sleep-deprived people was found.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source

How does oveporexton work, and what does the body do with it?

Oveporexton is an orexin receptor 2 agonist. In Takeda preclinical work it activated the receptor with an EC50 of 2.5 nM and promoted wakefulness in mice and monkeys, and the label gives a terminal half-life of about 23.2 hours with metabolism mainly by CYP3A4.

The label describes oveporexton as an orexin receptor 2 agonist. In preclinical work from Takeda, TAK-861 activated the orexin receptor 2 with a half-maximal effective concentration of 2.5 nM and promoted wakefulness at 1 mg/kg in mice and monkeys. In two narcolepsy mouse models it reduced wake fragmentation and cataplexy-like episodes. The authors compared it with modafinil by brain-wide neuronal activation in mice, which is not a head-to-head efficacy trial, and all authors were Takeda employees.

In the label, median time to peak at steady state is 1.5 hours (range 1 to 4), the terminal half-life is about 23.2 hours, steady state is reached within 5 days (accumulation about 1.6), protein binding is above 96%, and metabolism is mainly by CYP3A4. Itraconazole raised oveporexton AUC 7.4-fold and fluconazole 2.9-fold, and phenytoin lowered AUC by 81%. No clinically relevant QTc effect was seen up to 11 times the mean steady-state Cmax.

ORZEYFUL label, revised 8/2026: indication, contraindication, adverse reactions in 196 treated patients

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf.

The label states ORZEYFUL is an orexin receptor 2 agonist indicated for narcolepsy type 1 (narcolepsy with cataplexy) in adults. It is contraindicated with strong CYP3A inhibitors. In the two pooled 12-week phase 3 studies (196 treated, 76 on placebo), insomnia occurred in 55% and 60% on the two studied dose levels versus 1%, urinary frequency in 53% and 58% versus 5%, urinary urgency in 15% and 16% versus 1%, and salivary hypersecretion in 8% and 7% versus 0%. Creatine phosphokinase above 5 times the upper limit occurred in 11% (21 of 196) versus 5% (4 of 76), with two cases that also had markedly elevated transaminases and led to discontinuation; LDL above 160 mg/dL occurred in 32% (62 of 196) versus 20% (15 of 76). Discontinuation for an adverse reaction was 2.6% versus 1.3%. Safety and effectiveness in pediatric patients have not been established, and only 1 treated patient was aged 65 or older.

Participants / model
Adults with narcolepsy type 1 in the pivotal trials
Treatment
ORZEYFUL oral tablets
Follow-up
Label revised 8/2026; pooled 12-week phase 3 studies
Study design
FDA prescribing information
Funding
not stated in the source

The label shows Initial U.S. Approval as pending and no label was found on DailyMed on 10 October 2026. Long-term safety is open because the safety pool is 12 weeks long.

Read the original source
ORZEYFUL label: half-life about 23.2 hours, CYP3A4 interactions, abuse potential study

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf.

Median time to peak is 1.5 hours (range 1 to 4) at steady state, the terminal half-life is about 23.2 hours, steady state is reached within 5 days (accumulation about 1.6), protein binding is above 96%, and metabolism is mainly by CYP3A4. Itraconazole raised oveporexton AUC 7.4-fold and fluconazole 2.9-fold, and phenytoin lowered AUC by 81%. No clinically relevant QTc effect was seen up to 11 times the mean steady-state Cmax. A human abuse potential study at doses up to 7.5 times the maximum daily dose, in people experienced with recreational stimulant use, found drug-liking scores above placebo and similar to or lower than phentermine 75 mg (a schedule IV drug); euphoria was reported by 0 to 4.2% on oveporexton and 4.1% on phentermine. The label says the controlled-substance schedule is to be determined after DEA review, and that 277 patients in repeat-dose studies showed limited evidence of withdrawal events.

Participants / model
Label PK and abuse-potential study participants (population sizes for PK are not stated in the text read)
Treatment
ORZEYFUL oral tablets
Follow-up
Label revised 8/2026
Study design
FDA prescribing information
Funding
not stated in the source

Abuse potential is label-level, from a human abuse potential study against phentermine, with no incidence data outside it.

Read the original source
Takeda preclinical work: OX2R EC50 2.5 nM, wakefulness in mice and monkeys

Animal study

Mitsukawa K et al. Sci Rep. 2024;14(1):20838. PMID 39242684.

TAK-861 activated the orexin receptor 2 with a half-maximal effective concentration of 2.5 nM and promoted wakefulness at 1 mg/kg in mice and monkeys. In two narcolepsy mouse models it reduced wake fragmentation and cataplexy-like episodes. The authors compared it with modafinil by brain-wide neuronal activation in mice. All authors were Takeda employees.

Participants / model
Mice and monkeys
Treatment
Oral dosing in animals
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

The modafinil comparison is brain-wide neuronal activation in mice, not a head-to-head efficacy trial. Animal findings cannot be read as human effects.

Read the original source

What risks do the label and the trials report?

In the label's pooled phase 3 data, insomnia occurred in 55% and 60% versus 1% on placebo and urinary frequency in 53% and 58% versus 5%, and creatine phosphokinase above 5 times the upper limit in 11% versus 5%. The label contraindicates strong CYP3A inhibitors, the earlier compound TAK-994 was stopped early for hepatic adverse events including drug-induced liver injury, and abuse potential and scheduling are still pending.

In the two pooled 12-week phase 3 studies in the label (196 treated, 76 on placebo), insomnia occurred in 55% and 60% on the two studied dose levels versus 1% on placebo, urinary frequency in 53% and 58% versus 5%, urinary urgency in 15% and 16% versus 1%, and salivary hypersecretion in 8% and 7% versus 0%. Creatine phosphokinase above 5 times the upper limit occurred in 11% (21 of 196) versus 5% (4 of 76), with two cases that also had markedly elevated transaminases and led to discontinuation. LDL above 160 mg/dL occurred in 32% (62 of 196) versus 20% (15 of 76). Discontinuation for an adverse reaction was 2.6% versus 1.3%.

The label contraindicates oveporexton with strong CYP3A inhibitors. Safety and effectiveness in pediatric patients have not been established, and only 1 treated patient was aged 65 or older. No data on pregnancy or severe hepatic impairment were found beyond what the label states.

The earlier oral orexin 2 agonist TAK-994, a different molecule from the same program, worked on MWT sleep latency in 73 patients with narcolepsy type 1 (least-squares changes of 23.9 to 32.6 minutes versus -2.5 with placebo), but its phase 2 trial and extension were terminated early for hepatic adverse events: clinically important liver-enzyme elevations in 5 patients and drug-induced liver injury meeting Hy's law in 3. This is class context, not oveporexton data, and the oveporexton phase 2 trial reported no hepatotoxic effects.

A human abuse potential study at doses up to 7.5 times the maximum daily dose, in people experienced with recreational stimulant use, found drug-liking scores above placebo and similar to or lower than phentermine 75 mg (a schedule IV drug). Euphoria was reported by 0 to 4.2% on oveporexton and 4.1% on phentermine. The label says the controlled-substance schedule is to be determined after DEA review, and that 277 patients in repeat-dose studies showed limited evidence of withdrawal events. No abuse incidence data exist outside the label.

Phase 3 data are 12 weeks long with 196 treated patients in the safety pool, so long-term safety is open. A long-term extension (NCT05816382) is recruiting, with estimated completion on 28 February 2028.

ORZEYFUL label, revised 8/2026: indication, contraindication, adverse reactions in 196 treated patients

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf.

The label states ORZEYFUL is an orexin receptor 2 agonist indicated for narcolepsy type 1 (narcolepsy with cataplexy) in adults. It is contraindicated with strong CYP3A inhibitors. In the two pooled 12-week phase 3 studies (196 treated, 76 on placebo), insomnia occurred in 55% and 60% on the two studied dose levels versus 1%, urinary frequency in 53% and 58% versus 5%, urinary urgency in 15% and 16% versus 1%, and salivary hypersecretion in 8% and 7% versus 0%. Creatine phosphokinase above 5 times the upper limit occurred in 11% (21 of 196) versus 5% (4 of 76), with two cases that also had markedly elevated transaminases and led to discontinuation; LDL above 160 mg/dL occurred in 32% (62 of 196) versus 20% (15 of 76). Discontinuation for an adverse reaction was 2.6% versus 1.3%. Safety and effectiveness in pediatric patients have not been established, and only 1 treated patient was aged 65 or older.

Participants / model
Adults with narcolepsy type 1 in the pivotal trials
Treatment
ORZEYFUL oral tablets
Follow-up
Label revised 8/2026; pooled 12-week phase 3 studies
Study design
FDA prescribing information
Funding
not stated in the source

The label shows Initial U.S. Approval as pending and no label was found on DailyMed on 10 October 2026. Long-term safety is open because the safety pool is 12 weeks long.

Read the original source
ORZEYFUL label: half-life about 23.2 hours, CYP3A4 interactions, abuse potential study

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf.

Median time to peak is 1.5 hours (range 1 to 4) at steady state, the terminal half-life is about 23.2 hours, steady state is reached within 5 days (accumulation about 1.6), protein binding is above 96%, and metabolism is mainly by CYP3A4. Itraconazole raised oveporexton AUC 7.4-fold and fluconazole 2.9-fold, and phenytoin lowered AUC by 81%. No clinically relevant QTc effect was seen up to 11 times the mean steady-state Cmax. A human abuse potential study at doses up to 7.5 times the maximum daily dose, in people experienced with recreational stimulant use, found drug-liking scores above placebo and similar to or lower than phentermine 75 mg (a schedule IV drug); euphoria was reported by 0 to 4.2% on oveporexton and 4.1% on phentermine. The label says the controlled-substance schedule is to be determined after DEA review, and that 277 patients in repeat-dose studies showed limited evidence of withdrawal events.

Participants / model
Label PK and abuse-potential study participants (population sizes for PK are not stated in the text read)
Treatment
ORZEYFUL oral tablets
Follow-up
Label revised 8/2026
Study design
FDA prescribing information
Funding
not stated in the source

Abuse potential is label-level, from a human abuse potential study against phentermine, with no incidence data outside it.

Read the original source
TAK-994 (different compound): 73 patients, stopped early for liver injury

Randomized controlled trial

Dauvilliers Y et al. N Engl J Med. 2023;389(4):309-321. PMID 37494485.

TAK-994 worked on MWT sleep latency (least-squares changes of 23.9 to 32.6 minutes versus -2.5 with placebo), but the phase 2 trial and its extension were terminated early for hepatic adverse events: clinically important liver-enzyme elevations in 5 patients and drug-induced liver injury meeting Hy's law in 3.

Participants / model
73 patients with narcolepsy type 1
Treatment
Oral TAK-994 at three dose levels, or placebo
Follow-up
not stated in the source
Study design
Randomized phase 2 trial, a different compound from the same program
Funding
not stated in the source

A class-context finding, not oveporexton data. Endpoints were MWT sleep latency, ESS, cataplexy and liver enzymes.

Read the original source
Phase 2: 112 participants, 8 weeks, MWT sleep latency up 12.5 to 25.4 minutes

Randomized controlled trial

Dauvilliers Y et al. N Engl J Med. 2025;392(19):1905-1916. PMID 40367374.

MWT sleep latency changed by 12.5, 23.5, 25.4 and 15.0 minutes across the four oveporexton regimens versus -1.2 with placebo, and the ESS fell by 8.9 to 13.8 points versus 2.5. Insomnia occurred in 48%, urinary urgency in 33% and urinary frequency in 32%, with no hepatotoxic effects reported. Funded by Takeda.

Participants / model
112 participants with narcolepsy type 1 (90 on oveporexton, 22 on placebo)
Treatment
Oral oveporexton in four regimens, or placebo
Follow-up
8 weeks
Study design
Randomized phase 2 trial (NCT05687903)
Funding
not stated in the source

Patients with narcolepsy type 1 only. Endpoints were MWT sleep latency, ESS, weekly cataplexy rate and adverse events.

Read the original source
Searches, 10 October 2026: 4 PubMed records and 7 registry records, none in healthy or sleep-deprived people

PubMed search record

Searches run on 10 October 2026: PubMed, (oveporexton[tiab] OR TAK-861[tiab]) AND (healthy[tiab] OR volunteers[tiab] OR "narcolepsy type 2"[tiab] OR hypersomnia[tiab]), 4 records; ClinicalTrials.gov, oveporexton OR TAK-861, 7 records.

The PubMed search returned 4 records: the monkey and mouse paper described on this page, a rat salivary-secretion study, a review of hypersomnolence treatments and an actigraphy algorithm paper in narcolepsy type 1. The ClinicalTrials.gov search returned 7 records: two phase 3 trials and one phase 2 trial in narcolepsy type 1, one phase 2 trial in narcolepsy type 2, a long-term extension (NCT05816382, recruiting, estimated completion 28 February 2028), a randomized-withdrawal trial and a Spanish epidemiology study. The six interventional records with posted eligibility criteria (NCT05687903, NCT06470828, NCT06505031, NCT05687916, NCT05816382, NCT07363720) all list healthy volunteers as not accepted. No human trial of oveporexton as a wakefulness or cognition agent in healthy or sleep-deprived people was found.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source

Why does oveporexton sit in A tier?

The A rests on an FDA approval letter and two positive randomized phase 3 trials in narcolepsy type 1. The label is narrow, narcolepsy type 2 showed no significant effect, no human trial tests it in healthy or sleep-deprived people, and marketing waits on DEA scheduling.

For narcolepsy type 1 the efficacy data are strong: two randomized phase 3 trials (273 patients) and a phase 2 trial, with MWT sleep latency, sleepiness and cataplexy all favoring oveporexton. The grade is held at A because the label covers only adults with narcolepsy type 1, the narcolepsy type 2 phase 2 trial showed no significant effect, and the cognition data come from patients with a disorder that impairs cognition.

No human trial tests oveporexton in healthy or sleep-deprived people, long-term safety is open, and marketing is not permitted until DEA schedules it. The safety signals are specific: insomnia in 55 to 60% and urinary frequency in 53 to 58% in the label's pooled data, creatine phosphokinase elevations in 11%, and a program history of drug-induced liver injury with TAK-994.

FDA approval letter dated 5 August 2026: effective approval date deferred until DEA scheduling

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record and approval letter for NDA 220860 (ORZEYFUL, oveporexton tablets, Takeda), letter dated 5 August 2026.

FDA issued an approval letter for NDA 220860 (ORZEYFUL, oveporexton tablets, Takeda) dated 5 August 2026, for narcolepsy type 1 in adult patients. The application was received on 10 December 2025, and openFDA lists it as a priority-review new molecular entity with orphan status. The letter states the approval is effective on the date of the letter but that DEA scheduling under the Controlled Substances Act is not yet complete, so under 21 U.S.C. 355(x) the date of approval will be the date DEA publishes a Federal Register notice of interim final scheduling, and ORZEYFUL may be marketed only after that notice and a labeling supplement. Federal Register searches run on 10 October 2026 for oveporexton and for Orzeyful returned 0 documents, and a DailyMed search for oveporexton and Orzeyful returned no label.

Participants / model
Not a clinical population
Treatment
Drug application
Follow-up
Approval letter dated 5 August 2026
Study design
FDA application record and approval letter
Funding
not stated in the source

The approval is an FDA letter whose formal date and marketing depend on a DEA scheduling notice that was not found. Its status may have changed since 10 October 2026.

Read the original source
ORZEYFUL label, revised 8/2026: indication, contraindication, adverse reactions in 196 treated patients

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf.

The label states ORZEYFUL is an orexin receptor 2 agonist indicated for narcolepsy type 1 (narcolepsy with cataplexy) in adults. It is contraindicated with strong CYP3A inhibitors. In the two pooled 12-week phase 3 studies (196 treated, 76 on placebo), insomnia occurred in 55% and 60% on the two studied dose levels versus 1%, urinary frequency in 53% and 58% versus 5%, urinary urgency in 15% and 16% versus 1%, and salivary hypersecretion in 8% and 7% versus 0%. Creatine phosphokinase above 5 times the upper limit occurred in 11% (21 of 196) versus 5% (4 of 76), with two cases that also had markedly elevated transaminases and led to discontinuation; LDL above 160 mg/dL occurred in 32% (62 of 196) versus 20% (15 of 76). Discontinuation for an adverse reaction was 2.6% versus 1.3%. Safety and effectiveness in pediatric patients have not been established, and only 1 treated patient was aged 65 or older.

Participants / model
Adults with narcolepsy type 1 in the pivotal trials
Treatment
ORZEYFUL oral tablets
Follow-up
Label revised 8/2026; pooled 12-week phase 3 studies
Study design
FDA prescribing information
Funding
not stated in the source

The label shows Initial U.S. Approval as pending and no label was found on DailyMed on 10 October 2026. Long-term safety is open because the safety pool is 12 weeks long.

Read the original source
First Light and Radiant Light: 273 participants, 12 weeks, MWT sleep latency up 14.3 to 19.8 minutes

Randomized controlled trial

Dauvilliers Y et al. N Engl J Med. 2026;395(12):1166-1179. PMID 42714024.

Mean change in MWT sleep latency ranged from 14.3 to 19.8 minutes with oveporexton versus -0.4 to -0.8 with placebo, ESS changed by -9.7 to -11.8 versus -1.5 to -1.7, and median weekly cataplexy reduction was 79.0 to 88.8% versus 27.7 to 39.1% (adjusted P under 0.001 for all). Adverse events occurred in 86 to 89% versus 43 to 54%, mostly increased urinary frequency and transient insomnia. Funded by Takeda.

Participants / model
273 participants with narcolepsy type 1, aged 16 to 70 (First Light 168, Radiant Light 105)
Treatment
Oral oveporexton at two dose levels, or placebo
Follow-up
12 weeks
Study design
Two randomized placebo-controlled phase 3 trials (NCT06470828, NCT06505031)
Funding
not stated in the source

Patients with narcolepsy type 1 only. Endpoints were MWT sleep latency, ESS, weekly cataplexy rate and adverse events.

Read the original source
Phase 2: 112 participants, 8 weeks, MWT sleep latency up 12.5 to 25.4 minutes

Randomized controlled trial

Dauvilliers Y et al. N Engl J Med. 2025;392(19):1905-1916. PMID 40367374.

MWT sleep latency changed by 12.5, 23.5, 25.4 and 15.0 minutes across the four oveporexton regimens versus -1.2 with placebo, and the ESS fell by 8.9 to 13.8 points versus 2.5. Insomnia occurred in 48%, urinary urgency in 33% and urinary frequency in 32%, with no hepatotoxic effects reported. Funded by Takeda.

Participants / model
112 participants with narcolepsy type 1 (90 on oveporexton, 22 on placebo)
Treatment
Oral oveporexton in four regimens, or placebo
Follow-up
8 weeks
Study design
Randomized phase 2 trial (NCT05687903)
Funding
not stated in the source

Patients with narcolepsy type 1 only. Endpoints were MWT sleep latency, ESS, weekly cataplexy rate and adverse events.

Read the original source
Narcolepsy type 2 phase 2, 71 participants: no significant MWT effect in posted results

Trial registry record

ClinicalTrials.gov. NCT05687916, phase 2 trial of TAK-861 in narcolepsy type 2, with posted results.

The results posted on ClinicalTrials.gov show no significant MWT effect: the change from baseline was 2.14 minutes on placebo, 1.90 on one TAK-861 arm and 4.54 on the other, with differences from placebo of -0.24 (95% CI -6.67 to 6.18, P = 0.989) and 2.4 (95% CI -3.93 to 8.72, P = 0.916).

Participants / model
71 participants with narcolepsy type 2
Treatment
Oral TAK-861 in two regimens, or placebo
Follow-up
8 weeks
Study design
Phase 2 randomized trial; results posted on the registry
Funding
not stated in the source

The result comes from the registry record, not a journal publication. Endpoints were MWT sleep latency and ESS.

Read the original source
Searches, 10 October 2026: 4 PubMed records and 7 registry records, none in healthy or sleep-deprived people

PubMed search record

Searches run on 10 October 2026: PubMed, (oveporexton[tiab] OR TAK-861[tiab]) AND (healthy[tiab] OR volunteers[tiab] OR "narcolepsy type 2"[tiab] OR hypersomnia[tiab]), 4 records; ClinicalTrials.gov, oveporexton OR TAK-861, 7 records.

The PubMed search returned 4 records: the monkey and mouse paper described on this page, a rat salivary-secretion study, a review of hypersomnolence treatments and an actigraphy algorithm paper in narcolepsy type 1. The ClinicalTrials.gov search returned 7 records: two phase 3 trials and one phase 2 trial in narcolepsy type 1, one phase 2 trial in narcolepsy type 2, a long-term extension (NCT05816382, recruiting, estimated completion 28 February 2028), a randomized-withdrawal trial and a Spanish epidemiology study. The six interventional records with posted eligibility criteria (NCT05687903, NCT06470828, NCT06505031, NCT05687916, NCT05816382, NCT07363720) all list healthy volunteers as not accepted. No human trial of oveporexton as a wakefulness or cognition agent in healthy or sleep-deprived people was found.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source

Studies and sources

FDA approval letter dated 5 August 2026: effective approval date deferred until DEA scheduling

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record and approval letter for NDA 220860 (ORZEYFUL, oveporexton tablets, Takeda), letter dated 5 August 2026.

FDA issued an approval letter for NDA 220860 (ORZEYFUL, oveporexton tablets, Takeda) dated 5 August 2026, for narcolepsy type 1 in adult patients. The application was received on 10 December 2025, and openFDA lists it as a priority-review new molecular entity with orphan status. The letter states the approval is effective on the date of the letter but that DEA scheduling under the Controlled Substances Act is not yet complete, so under 21 U.S.C. 355(x) the date of approval will be the date DEA publishes a Federal Register notice of interim final scheduling, and ORZEYFUL may be marketed only after that notice and a labeling supplement. Federal Register searches run on 10 October 2026 for oveporexton and for Orzeyful returned 0 documents, and a DailyMed search for oveporexton and Orzeyful returned no label.

Participants / model
Not a clinical population
Treatment
Drug application
Follow-up
Approval letter dated 5 August 2026
Study design
FDA application record and approval letter
Funding
not stated in the source

The approval is an FDA letter whose formal date and marketing depend on a DEA scheduling notice that was not found. Its status may have changed since 10 October 2026.

Read the original source
ORZEYFUL label, revised 8/2026: indication, contraindication, adverse reactions in 196 treated patients

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf.

The label states ORZEYFUL is an orexin receptor 2 agonist indicated for narcolepsy type 1 (narcolepsy with cataplexy) in adults. It is contraindicated with strong CYP3A inhibitors. In the two pooled 12-week phase 3 studies (196 treated, 76 on placebo), insomnia occurred in 55% and 60% on the two studied dose levels versus 1%, urinary frequency in 53% and 58% versus 5%, urinary urgency in 15% and 16% versus 1%, and salivary hypersecretion in 8% and 7% versus 0%. Creatine phosphokinase above 5 times the upper limit occurred in 11% (21 of 196) versus 5% (4 of 76), with two cases that also had markedly elevated transaminases and led to discontinuation; LDL above 160 mg/dL occurred in 32% (62 of 196) versus 20% (15 of 76). Discontinuation for an adverse reaction was 2.6% versus 1.3%. Safety and effectiveness in pediatric patients have not been established, and only 1 treated patient was aged 65 or older.

Participants / model
Adults with narcolepsy type 1 in the pivotal trials
Treatment
ORZEYFUL oral tablets
Follow-up
Label revised 8/2026; pooled 12-week phase 3 studies
Study design
FDA prescribing information
Funding
not stated in the source

The label shows Initial U.S. Approval as pending and no label was found on DailyMed on 10 October 2026. Long-term safety is open because the safety pool is 12 weeks long.

Read the original source
ORZEYFUL label: half-life about 23.2 hours, CYP3A4 interactions, abuse potential study

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf.

Median time to peak is 1.5 hours (range 1 to 4) at steady state, the terminal half-life is about 23.2 hours, steady state is reached within 5 days (accumulation about 1.6), protein binding is above 96%, and metabolism is mainly by CYP3A4. Itraconazole raised oveporexton AUC 7.4-fold and fluconazole 2.9-fold, and phenytoin lowered AUC by 81%. No clinically relevant QTc effect was seen up to 11 times the mean steady-state Cmax. A human abuse potential study at doses up to 7.5 times the maximum daily dose, in people experienced with recreational stimulant use, found drug-liking scores above placebo and similar to or lower than phentermine 75 mg (a schedule IV drug); euphoria was reported by 0 to 4.2% on oveporexton and 4.1% on phentermine. The label says the controlled-substance schedule is to be determined after DEA review, and that 277 patients in repeat-dose studies showed limited evidence of withdrawal events.

Participants / model
Label PK and abuse-potential study participants (population sizes for PK are not stated in the text read)
Treatment
ORZEYFUL oral tablets
Follow-up
Label revised 8/2026
Study design
FDA prescribing information
Funding
not stated in the source

Abuse potential is label-level, from a human abuse potential study against phentermine, with no incidence data outside it.

Read the original source
ORZEYFUL label section 14: two phase 3 studies, 168 and 105 patients, 12 weeks

FDA prescribing information

U.S. Food and Drug Administration. ORZEYFUL (oveporexton) tablets, prescribing information, revised 8/2026, NDA 220860. Drugs@FDA label file 220860Orig1s000lbl.pdf. Section 14, clinical studies.

Section 14 reports two randomized double-blind placebo-controlled 12-week studies (Study 1, NCT06470828, 168 patients; Study 2, NCT06505031, 105 patients). The primary endpoint was change in mean sleep latency on the Maintenance of Wakefulness Test (MWT). Placebo-adjusted differences were 13.8 minutes (95% CI 10.2 to 17.4) on the lower dose and 17.2 (13.7 to 20.7) on the higher dose in Study 1, and 20.1 (16.6 to 23.6) on the higher dose in Study 2. Epworth Sleepiness Scale differences were -8.0, -9.8 and -9.5 points, and weekly cataplexy incidence rate ratios were 0.34, 0.38 and 0.25 against placebo. Baseline mean MWT sleep latency was 4.1 to 5.5 minutes across arms.

Participants / model
Patients with narcolepsy type 1 (ICSD-3 criteria), mean age 31, ages 16 to 65 in Study 1 and 18 to 62 in Study 2
Treatment
Oral oveporexton at two dose levels, or placebo
Follow-up
12 weeks
Study design
Two randomized double-blind placebo-controlled phase 3 studies, results read from label section 14
Funding
not stated in the source

Patients with narcolepsy type 1 only. Endpoints were MWT sleep latency, ESS and weekly cataplexy rate.

Read the original source
First Light and Radiant Light: 273 participants, 12 weeks, MWT sleep latency up 14.3 to 19.8 minutes

Randomized controlled trial

Dauvilliers Y et al. N Engl J Med. 2026;395(12):1166-1179. PMID 42714024.

Mean change in MWT sleep latency ranged from 14.3 to 19.8 minutes with oveporexton versus -0.4 to -0.8 with placebo, ESS changed by -9.7 to -11.8 versus -1.5 to -1.7, and median weekly cataplexy reduction was 79.0 to 88.8% versus 27.7 to 39.1% (adjusted P under 0.001 for all). Adverse events occurred in 86 to 89% versus 43 to 54%, mostly increased urinary frequency and transient insomnia. Funded by Takeda.

Participants / model
273 participants with narcolepsy type 1, aged 16 to 70 (First Light 168, Radiant Light 105)
Treatment
Oral oveporexton at two dose levels, or placebo
Follow-up
12 weeks
Study design
Two randomized placebo-controlled phase 3 trials (NCT06470828, NCT06505031)
Funding
not stated in the source

Patients with narcolepsy type 1 only. Endpoints were MWT sleep latency, ESS, weekly cataplexy rate and adverse events.

Read the original source
Phase 2: 112 participants, 8 weeks, MWT sleep latency up 12.5 to 25.4 minutes

Randomized controlled trial

Dauvilliers Y et al. N Engl J Med. 2025;392(19):1905-1916. PMID 40367374.

MWT sleep latency changed by 12.5, 23.5, 25.4 and 15.0 minutes across the four oveporexton regimens versus -1.2 with placebo, and the ESS fell by 8.9 to 13.8 points versus 2.5. Insomnia occurred in 48%, urinary urgency in 33% and urinary frequency in 32%, with no hepatotoxic effects reported. Funded by Takeda.

Participants / model
112 participants with narcolepsy type 1 (90 on oveporexton, 22 on placebo)
Treatment
Oral oveporexton in four regimens, or placebo
Follow-up
8 weeks
Study design
Randomized phase 2 trial (NCT05687903)
Funding
not stated in the source

Patients with narcolepsy type 1 only. Endpoints were MWT sleep latency, ESS, weekly cataplexy rate and adverse events.

Read the original source
Phase 2 secondary analysis: attention, memory and executive function improved in 112 patients

Randomized controlled trial

Lammers GJ et al. JAMA Neurol. 2026;83(2):145-152. PMID 41359331.

Oveporexton improved attention, memory and executive function over 8 weeks; for example, placebo-adjusted psychomotor vigilance lapses fell by 8.60 to 10.77 across the four regimens. Several authors are Takeda employees.

Participants / model
112 adults with narcolepsy type 1
Treatment
Oral oveporexton, 8 weeks
Follow-up
8 weeks
Study design
Secondary analysis of a randomized trial; post hoc
Funding
not stated in the source

A post hoc analysis in patients whose cognition was impaired by narcolepsy. It is not evidence of a cognitive boost in healthy people. Tests were the Psychomotor Vigilance Task, paired-associate learning, One Back and digit symbol substitution.

Read the original source
Narcolepsy type 2 phase 2, 71 participants: no significant MWT effect in posted results

Trial registry record

ClinicalTrials.gov. NCT05687916, phase 2 trial of TAK-861 in narcolepsy type 2, with posted results.

The results posted on ClinicalTrials.gov show no significant MWT effect: the change from baseline was 2.14 minutes on placebo, 1.90 on one TAK-861 arm and 4.54 on the other, with differences from placebo of -0.24 (95% CI -6.67 to 6.18, P = 0.989) and 2.4 (95% CI -3.93 to 8.72, P = 0.916).

Participants / model
71 participants with narcolepsy type 2
Treatment
Oral TAK-861 in two regimens, or placebo
Follow-up
8 weeks
Study design
Phase 2 randomized trial; results posted on the registry
Funding
not stated in the source

The result comes from the registry record, not a journal publication. Endpoints were MWT sleep latency and ESS.

Read the original source
TAK-994 (different compound): 73 patients, stopped early for liver injury

Randomized controlled trial

Dauvilliers Y et al. N Engl J Med. 2023;389(4):309-321. PMID 37494485.

TAK-994 worked on MWT sleep latency (least-squares changes of 23.9 to 32.6 minutes versus -2.5 with placebo), but the phase 2 trial and its extension were terminated early for hepatic adverse events: clinically important liver-enzyme elevations in 5 patients and drug-induced liver injury meeting Hy's law in 3.

Participants / model
73 patients with narcolepsy type 1
Treatment
Oral TAK-994 at three dose levels, or placebo
Follow-up
not stated in the source
Study design
Randomized phase 2 trial, a different compound from the same program
Funding
not stated in the source

A class-context finding, not oveporexton data. Endpoints were MWT sleep latency, ESS, cataplexy and liver enzymes.

Read the original source
Takeda preclinical work: OX2R EC50 2.5 nM, wakefulness in mice and monkeys

Animal study

Mitsukawa K et al. Sci Rep. 2024;14(1):20838. PMID 39242684.

TAK-861 activated the orexin receptor 2 with a half-maximal effective concentration of 2.5 nM and promoted wakefulness at 1 mg/kg in mice and monkeys. In two narcolepsy mouse models it reduced wake fragmentation and cataplexy-like episodes. The authors compared it with modafinil by brain-wide neuronal activation in mice. All authors were Takeda employees.

Participants / model
Mice and monkeys
Treatment
Oral dosing in animals
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

The modafinil comparison is brain-wide neuronal activation in mice, not a head-to-head efficacy trial. Animal findings cannot be read as human effects.

Read the original source
PubChem: oveporexton identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 154617563 (oveporexton).

Oveporexton: PubChem CID 154617563, C23H25F5N2O4S, 520.5 g/mol, CAS 2460722-04-5; the label gives molecular weight 520.51. TAK-861 and Orzeyful are synonyms on the PubChem record. It is a different molecule from danavorexton (TAK-925, an injected orexin 2 agonist) and from TAK-994.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source

Why is Oveporexton in A tier?

A fits a drug with an FDA approval letter and two positive randomized phase 3 trials in narcolepsy type 1, but a narrow label. The narcolepsy type 2 trial showed no significant effect, no human trial tests oveporexton in healthy or sleep-deprived people, long-term safety is open, and marketing waits on DEA scheduling.