Oveporexton
InvestigationalA first-in-class oral orexin receptor 2 (OX2R) selective agonist developed by Takeda for narcolepsy type 1. Though not a peptide itself, oveporexton restores orexin peptide signaling lost due to autoimmune destruction of orexin-producing neurons. A Phase 2 trial (NEJM 2025) demonstrated significant reductions in excessive daytime sleepiness and cataplexy; Phase 3 trials are ongoing. Granted FDA Breakthrough Therapy designation.
TAK-861
22 human studies
- Preclinical
- 21%
- Clinical
- 79%
Based on 28 cited sources
clinically demonstrated · moderate confidence
Demonstrated effect magnitude — not a recommendation or safety claim.
Research Depth 70: best verified human evidence is a single adequately-powered, double-blind, placebo-controlled multicenter Phase 2 RCT (Dauvilliers et al., NEJM 2025, PMID 40367374, NCT05687903, n=112) — 1A=28 (single RCT n>=50; the real Phase 3 trials NCT06470828/NCT06505031 are completed but not yet published, so Phase 3 efficacy is not credited), 1B=15 (low-RoB RCT, no systematic review yet), 1C=6 (total human N ~112, 50-300 band), 1D=13 (direct: NT1 population, oral route, MWT/ESS/cataplexy outcomes), 1E=8 (substantial multi-model preclinical foundation: orexin and OX2R knockouts PMID 10481909 / 12797957, discovery work PMID 9491897). Mechanism 91: OX2R is a named target with binding + functional confirmation and OX2R-knockout dissection of the wake effect (2A=40), full Gq/11 -> arousal-center pathway mapped (2B=26), dose-response across human dose groups and in-vivo models (2C=15), confirmed in vivo (2D=10). Plausibility 91: full mechanism -> surrogate (MWT/ESS) -> clinical outcome (cataplexy) chain (3A=34), restoring the exact deficient orexin signal is textbook NT1 pathophysiology (3B=25), same-class OX2R agonists danavorexton/TAK-994 show the analogous effect (3C=18), tightly scoped single-indication claim (3D=14). Global Coverage 55: pivotal data from one sponsor program (Takeda) replicated for the class across groups (4A=18), Phase 2 multinational across ~7 countries (4B=20), modest compound-specific literature ~28 sources (4C=12), FDA Breakthrough Therapy + registered ongoing Phase 3 but no approval yet (4D=5). Community Experience 12: investigational, not marketed, no meaningful documented real-world use or longevity (5A=3,5B=3,5C=2,5D=4). Effectiveness 74 (clinical, moderate confidence): Phase 2 RCT showed large, MCID-exceeding effects — MWT average sleep latency +25.4 min vs -1.2 placebo and ESS -13.8 vs -2.5 (E1=27, E2=22), validated patient-relevant wakefulness/cataplexy endpoints (E3=12), superior to placebo on clinical outcomes with no head-to-head vs sodium oxybate (E4=13); confidence moderate as evidence rests on one Phase 2 trial with Phase 3 pending.
Oveporexton is a first-in-class selective orexin receptor 2 (OX2R) agonist that restores the missing orexin signal in narcolepsy type 1 patients.
How It Works (Simplified)
Oveporexton replaces the missing orexin signal through targeted receptor activation:
Selectively binds and activates orexin receptor 2 in key arousal centers, mimicking the effect of endogenous orexin peptides.
Activates wake-promoting neurons in TMN, locus coeruleus, and VTA, releasing histamine, norepinephrine, and dopamine.
Restores clear boundaries between sleep and wakefulness, reducing inappropriate sleep intrusions during the day.
Suppresses REM sleep intrusions that cause cataplexy, the sudden muscle weakness triggered by emotions in NT1.
Key Research: Sakurai et al. (Cell 1998) discovered orexins and their receptors. PMID:9491897
Important Limitations
- Oveporexton is NOT a peptide; it is a small molecule that modulates the orexin peptide system
- Currently investigational - not yet approved by FDA or other regulatory agencies
- Efficacy in narcolepsy type 2 (normal CSF orexin) is still being evaluated
- Long-term safety data beyond clinical trial duration is pending
- Head-to-head comparative trials vs sodium oxybate not yet completed
Based on Phase 2 data: Rapid onset of wake-promoting effects. Patients may notice reduced daytime sleepiness within first weeks. Cataplexy frequency begins to decrease.
NCT05687903Continued improvement in wakefulness measures. Phase 2 endpoints assessed at multiple timepoints showed progressive benefit. Optimal steady-state drug levels achieved.
NCT05687903Full therapeutic effects observed in the Phase 2 trial. ESS improvements stabilize and weekly cataplexy rate is significantly reduced vs placebo through week 8.
NCT05687903Long-term extension study (NCT05816382) ongoing to assess durability. Safety monitoring continues. Phase 3 trials completed in 2025 with results pending publication.
NCT05816382Research-based observations
This timeline reflects observations from published clinical and preclinical studies. Individual responses may vary significantly. This is not a guarantee of effects or a dosing schedule. Consult qualified healthcare providers for personalized guidance.
Good Signs (5 indicators)
Warning Signs (4 indicators)
Bad Signs (5 indicators)
For Research Evaluation Only
These quality indicators are general guidelines based on typical peptide characteristics. Professional laboratory testing (HPLC, mass spectrometry) provides definitive quality verification. This checklist is for initial visual evaluation only.
Orexin-A
SynergisticOveporexton mimics the endogenous orexin peptide signal at OX2R. In narcolepsy type 1, where orexin-A is deficient, oveporexton provides replacement receptor activation.
Orexin-B
SynergisticOrexin-B preferentially activates OX2R, the same target as oveporexton. The drug compensates for lost orexin-B signaling in NT1 patients.
Modafinil
CompatibleDifferent wake-promoting mechanisms (dopamine/NE modulation vs OX2R agonism). May be used in combination, though oveporexton alone may be sufficient.
Pitolisant
CompatibleH3 receptor antagonist with different mechanism. Potential for complementary wake promotion, though clinical combination data is limited.
Suvorexant
AvoidSuvorexant is a dual orexin receptor antagonist (DORA) used for insomnia. Concurrent use would cause direct pharmacological antagonism, negating therapeutic effects.
Lemborexant
AvoidLemborexant is a DORA for insomnia. Combining with oveporexton would result in opposing receptor effects and is contraindicated.
Research Note: Interaction data is based on published literature, mechanistic understanding, and theoretical considerations. Most peptide combinations lack direct clinical study. This information is for educational purposes only and does not constitute medical advice. Always consult qualified healthcare providers.
Key Studies Cited
Full reference list available on request. All citations link to PubMed for verification.
This dossier synthesizes available evidence from peer-reviewed literature, regulatory documents, and clinical trial registries. Evidence strength ratings follow a modified GRADE approach.
For complete methodology details, see our Methodology page.
Important Disclaimer
This dossier is for educational purposes only and does not constitute medical advice. Always consult a qualified healthcare provider before making health decisions.
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