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%
- Human research
- 79%
Based on 28 cited sources
Numeric assessment unreviewed
A historical numeric score is recorded but has not passed a current, compound-specific assessment review. No numeric score is displayed.
This is a limitation of the numeric assessment, not a measured absence of benefit. It does not re-review the separately recorded catalogue classification or establish efficacy or safety.
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.
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
Use the source links in the research discussion above to inspect the referenced records.
This dossier synthesizes available evidence from peer-reviewed literature, regulatory documents, and clinical trial registries. Evidence strength labels summarize the cited material for this entry and should be read alongside its population, model, and study limitations.
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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Compared With
1 comparisonConditions Studied
3 entries- Oveporexton for Narcolepsy Type 1 Oveporexton is specifically developed for NT1, caused by autoimmune destruction of orexin-producing neurons. The Phase 2 trial TAK…
- Oveporexton for Narcolepsy Type 2 NT2 patients have excessive sleepiness without cataplexy and usually normal CSF orexin. The Phase 2 trial NCT05687916 evaluated wh…
- Oveporexton for Excessive Daytime Sleepiness In TAK-861-2001 the primary endpoint (MWT sleep latency) improved significantly, and ESS (secondary) was also significantly reduce…