Narcolepsy & excessive sleepiness

Source date: 2026-11-09. Recorded in this review: November 10, 2026. Evidence: DEA interim final rule on public inspection; publication and effective date pending.

What changed: DEA's interim final rule (FR Doc. 2026-23075; docket DEA-1775) was signed November 6 and filed November 9 at 4:15 p.m. for public inspection. It places oveporexton in Schedule IV and is scheduled for publication November 12, with effectiveness on publication. This replaces the previously unknown scheduling window; as of this review the publication has not occurred.

Limitations and safety: Scheduling and existing FDA approval do not establish commercial launch, pharmacy fulfillment, insurer coverage or another indication. The rule's abuse-potential assessment includes supratherapeutic studies; it is not a new clinical efficacy result or real-world incidence estimate.

U.S. status: August 5 FDA approval is for Orzeyful in adults with narcolepsy type 1. Type 2 narcolepsy and idiopathic hypersomnia remain distinct. October Japan/China launch and U.S. access remain separate.

Next milestones: Verify November 12 Federal Register publication and effectiveness, then Takeda's actual U.S. launch and distribution separately.

Sources: DEA oveporexton Schedule IV interim final rule, filed November 9, 2026; scheduled publication November 12; takeda.com · source page.

Source date: 2026-10-19. Recorded in this review: October 30, 2026.

Original abstract recovered; the extension's broad findings were already announced in July. The Sleep Europe abstract first published October 19 reports alixorexton extension NCT06767683, through 24 extension weeks (up to nine months total exposure), using a May 12, 2026 cutoff.

Seventy-eight participants with NT1 and 63 with NT2 entered the extension; 70 (90%) and 51 (81%) were continuing at cutoff. Doses could be adjusted early in the extension. The original presentation describes week-37 dose groups rather than the parent randomized groups, and dashed figure connectors are not observed visit measurements. This prevents treating the extension as a new randomized comparison or drawing new curves from endpoint connectors.

No serious treatment-emergent adverse event was reported in the abstract. Common events included urinary frequency and headache; insomnia was among common NT2 events. The accessible abstract does not provide complete arm/visit denominators, uncertainty intervals or a complete safety table. Controlled confirmation, durability and night/day function remain separate questions. Do not repeat July's extension announcement as new October efficacy news.

U.S. status: Alixorexton remains investigational in the U.S.

Sources: onlinelibrary.wiley.com · article; alkermesmedicalaffairs.com · source page; ClinicalTrials.gov · NCT06767683.

Coverage and remaining gaps: Focused partial appraisal through October 30, 2026. Complete retrieval of the specified query and saved named records; incomplete worldwide review. No full successful-check or baseline-completion claim.. Focused appraisal only. All pages of the specified ClinicalTrials.gov query were retrieved, but not every returned record underwent full results/harms appraisal. This is not complete worldwide coverage.; Independent non-U.S. registry searches, a comprehensive publication/hold/discontinuation census, and complete original conference/podcast audio and transcripts remain incomplete. Full successful-check timestamps and incomplete sleep baseline flags must remain unchanged.; Actual DEA scheduling/commercial availability was not verified for oveporexton; no launch date inferred from approval or an old proposed schedule.; Original alixorexton abstract was recovered, but complete extension visit/arm uncertainty and harms tables remain unavailable; extension groups do not preserve randomized allocation.

Informal-source coverage: Re-read the original TAK-360 Reddit discussion, including u/statistics_squirrel’s nighttime-fragmentation account. Exact dose, assignment, causality and source date remain unknown. New orexin-community searches were selective and did not provide a meaningful status change.

Full coverage record.

Takeda announced October 15 that ORZEYFUL (oveporexton), an oral orexin receptor 2 agonist, launched in Japan and China for narcolepsy type 1: adults in Japan and patients aged 16 and older in China. This is a commercial-availability change in those countries, not new trial evidence or an indication for narcolepsy type 2/idiopathic hypersomnia.

The August 5 U.S. FDA approval letter requires DEA interim-final scheduling and a labeling supplement before marketing. The sponsor's November 2026 U.S. launch expectation remains conditional. A bounded October 23 search did not verify completion of those steps or an actual U.S. launch. The drug restores orexin signaling pharmacologically; it does not demonstrate replacement of lost neurons or a cure. Existing safety findings remain separate from the launch announcement.

Sources: takeda.com · source page; FDA · regulatory document; takeda.com · source page.

Coverage and remaining gaps: Focused incomplete coverage. All pages of the specified ClinicalTrials.gov discovery query and saved named records were retrieved on 2026-10-20; retrieval is not exhaustive appraisal of every record or worldwide evidence. Do not advance full successful-check timestamps. Original source dates remain unchanged. Independent non-US registries, complete conference tables/audio, and a comprehensive harms/discontinuation census remain incomplete.; ClinicalTrials.gov discovery: 27 records across 1 retrieved pages; final retrieval errors: []. Named records also retrieved successfully.; Sleep incomplete baselines used 90-day context through October 20; other topics used the last full successful check minus seven days. Earlier October 16 focused checks did not reset that window.; An October 23 TGA listing describes a lapsed priority-review determination (review April 2; lapse October 2). This is not proof of Australian approval, rejection, trial hold or a new October 23 clinical event. No claim promoted.; October 23 was a bounded source follow-up only; broad registry discovery remains the October 20 snapshot. No full successful check is claimed.

Informal-source coverage: Original informal sources were sampled on October 20; not a comprehensive podcast, social-media, or anonymous-source search. Reposts were not treated as independent confirmation. No resolved claim was inferred from source silence. Re-read TAK-360/Kyra participant thread; prior wakefulness/night-awakening anecdote unchanged, dose/assignment/causality unverified. No repeat alert.

Full coverage record.

Newly public protocol — NCT07871006, first posted October 13. Xijing Hospital, Xi’an plans 20 people aged 10–60 with treatment-refractory narcolepsy type 1 in an open-label single-group Phase 1/2 study of one 20 mg subcutaneous ofatumumab dose. Primary measures are Epworth Sleepiness Scale and cataplexy frequency at one month; adverse events are listed over one week.

Ofatumumab is a CD20-directed B-cell-depleting antibody, a different approach from restoring orexin signaling with an agonist. With no concurrent comparator, the protocol cannot establish superiority, remission/cure, restoration of orexin neurons or durable safety. Particularly brief registered safety endpoints do not exclude later infection/immune harms; the established MS label warns about infections, injection/hypersensitivity reactions, reduced immunoglobulins and liver injury.

The registry says recruiting, actual start October 1, 2025, estimated primary completion June 30, 2027, final December 31, 2027. Thus October 13 is registration disclosure, not verified first dosing. No results. Existing U.S. Kesimpta approval is for adult relapsing MS, not narcolepsy or this pediatric exposure.

Sources: ClinicalTrials.gov · NCT07871006; novartis.com · PDF document.

Remaining gaps: Read current canonical scope, shared summaries/state and assigned topic notes. September 5–October 13 overlap preserves the September 12 full-review dates; October 6/9 entries were deduplicated. All pages of each bounded ClinicalTrials.gov query were downloaded, and named records plus selected relevant new/changed protocols were appraised. This is focused partial review, not a worldwide full literature/regulator/safety census; successful full-topic dates must remain unchanged.; Bounded query retrieved 15 records across 1 pages; incidental studies excluded. Named topic records refreshed: 7. Full older evidence, international registries, comprehensive harms and all original conference/podcast recordings remain gaps.; New condition-specific baseline remains incomplete. Selected inherited older pivotal sources and newly recovered formal programs were reviewed, without declaring the preceding 90-day/older trial corpus complete.

Informal-source coverage: Revisited original narcolepsy threads on expected Orzeyful availability and trial experiences; November forecast remains conditional and no official DEA action found. The older August 24 alixorexton paper is not new October news. No new verified availability or attributable development rumor selected; full talk/audio incomplete.

Full coverage record.

Baseline context, XYRISE / NCT07625280, JZP258-304. Jazz plans 120 adults with narcolepsy or idiopathic hypersomnia in a masked placebo-controlled randomized-withdrawal study of expanded Xywav regimens. Narcolepsy and IH cohorts each include once- and twice-nightly regimens.

Participants receive open-label medication for up to 14 weeks to reach a stable dose, then continue that dose or switch to placebo for two weeks. Primary is Epworth Sleepiness Scale change between stabilization and the withdrawal period, not a polysomnographic sleep-architecture endpoint. This enrichment/design limits generalization to unselected patients and comparison with orexin agonists. Exact expanded dose ceilings are not supplied in the public arm descriptions; do not invent them.

The October 8 record says recruiting, actual start July 9, 2026; no results. Existing approved Xywav uses do not establish approval for each expanded regimen. Estimated primary completion December 23, 2027 and final January 6, 2028 are not public-result promises.

Sources: Primary source 1.

Remaining gaps: New condition baseline remains incomplete. Reviewed inherited hub, preceding 90-day development leads and selected older pivotal/contextual sources; October 6 findings deduplicated.; 93 named NCT records across the ten topics and ten discovery queries downloaded successfully through the ClinicalTrials.gov public API. Download is not a claim that all fields/safety/results were exhaustively appraised.; Focused review only. Do not advance full successful-check timestamps or label incomplete remaining searches as no news.; All 13 matches in the bounded hypersomnolence discovery downloaded; selected relevant records screened. Saved orexin protocols refreshed. Established oxybate/stimulant/pitolisant/solriamfetol full labeling/safety and whole-world baseline remain incomplete.; Official Orzeyful page retains expected-by-November availability conditional on DEA scheduling. No completed official DEA scheduling action established; do not imply launch.

Informal-source coverage: Original Oct7 r/Narcolepsy thread contains anonymous patient participation in an orexin trial, not a new official recruitment/readout milestone. Sponsor conditional Orzeyful forecast checked; full talk/audio not reviewed.

Full coverage record.

Historical baseline addition reviewed October 6, 2026. Cleminorexton / ORX750 adds another orexin-2 agonist program. SAPPHIRE (NCT07598708) is a recruiting randomized quadruple-masked phase 2/3 trial, 222 planned adults with narcolepsy types 1/2, comparing two doses with placebo. Primary: Maintenance of Wakefulness Test change at week 12. Actual start May 29, 2026; September 30, 2027 primary and December 31 final completion are estimates. The protocol may later add idiopathic hypersomnia by amendment; it is not currently an established included cohort.

CRYSTAL-1 (NCT06752668), 248 planned participants, also includes idiopathic hypersomnia, has primary safety measures through day35 and secondary MWT/ESS through day28. Its April record remains recruiting with December2026 estimated completion. No registry results are posted. These older programs are new-to-watch baseline, not October starts or approvals. Current trial eligibility does not establish long-term efficacy/safety; urinary and insomnia effects require full published/sponsor appraisal.

ClinicalTrials.gov · NCT07598708 · ClinicalTrials.gov · NCT07598708 · ClinicalTrials.gov · NCT06752668 · ClinicalTrials.gov · NCT06752668

Historical baseline addition reviewed October 6, 2026. TAK-360 is separate from approved oveporexton/TAK-861. Recruiting randomized placebo-controlled phase 2 trials enroll 88 planned narcolepsy-type-2 adults (NCT06952699) and 96 with idiopathic hypersomnia (NCT06812078). Both use four weeks of treatment; safety is primary and diagnosis-specific sleepiness/wakefulness or IH severity is secondary. November 30, 2026 primary/final completion is estimated, not an announced public result. The recruiting open-label extension NCT07646678 plans 500 prior-study participants and safety monitoring through up to five years; estimated completion June 15, 2031.

No results are posted and no U.S. marketing approval is established. Extension enrollment is selected and lacks a blinded comparator. Preserve separate NT2/IH populations, TAK aliases and the difference between measured wakefulness, symptom/function and long-term safety.

ClinicalTrials.gov · NCT06952699 · ClinicalTrials.gov · NCT06952699 · ClinicalTrials.gov · NCT06812078 · ClinicalTrials.gov · NCT06812078 · ClinicalTrials.gov · NCT07646678 · ClinicalTrials.gov · NCT07646678