Orexin A

Intranasal orexin A significantly increased resting muscle sympathetic nerve activity (MSNA) burst rate versus placebo (+5.8 ± 0.8 vs +2.1 ± 0.6 bursts/min, P = 0.007) in a small double-blind crossover pilot study of 10 healthy men. Blood pressure, heart rate, heart-rate variability, and baroreflex sensitivity were not acutely altered.

Reported changes consistent with REM-sleep stabilization and selected attention effects after intranasal Orexin A.

Intranasal hypocretin-1 produced functional changes in sleep measures in this pilot study.

In a double-blind, randomized, placebo-controlled crossover trial, seven patients with narcolepsy and cataplexy showed improved olfactory threshold scores after intranasal Orexin A (hypocretin-1) compared with placebo. This is a very small study and does not establish general treatment efficacy, improved wakefulness, long-term benefit, or routine use, and the olfactory finding must not be generalized to other symptoms or populations.

Measured CSF hypocretin-1 concentrations and supported the association between low orexin signaling and narcolepsy-cataplexy.

Danavorexton is a synthetic, nonpeptide OX2R agonist studied in humans. It is a distinct molecular class from native Orexin A/Orexin B. Results from danavorexton, oveporexton, or another synthetic receptor agonist cannot establish the identity, stability, brain penetration, dosing, safety, or effectiveness of native orexin peptide products -- used here only as an identity/evidence boundary, not as orexin-peptide evidence.

Orexin A changed several metabolic endpoints, while Orexin B did not show those effects in this model.

Orexin signaling contributed to ventilatory responses to carbon dioxide in wakefulness.

Compared how Orexin A and Orexin B interact with OX1 and OX2 receptor subtypes, supporting distinct pharmacology.

Demonstrated that hypocretin-1 can alter REM sleep through arousal-circuit mechanisms in animals.

Identified orexin A and B as endogenous ligands for two receptors and described hypothalamic expression and feeding-related effects.

Independently described hypocretin-1 and hypocretin-2 as hypothalamic neuroexcitatory peptides.

Orexin A activates both OX1R and OX2R with high functional activity at each. Orexin B activates OX2R efficiently but has substantially weaker functional activity at OX1R than Orexin A, so the two peptides must not be treated as interchangeable or dose-equivalent.

Animal studies report Orexin A effects on wakefulness and cognitive performance during sleep deprivation. This nonhuman-primate finding does not establish human treatment of fatigue, cognitive impairment, obesity, depression, ADHD, dementia, sleep deprivation, or athletic performance.

Structure-activity relationships for Orexin A and Orexin B are concentrated in the C-terminal region. Orexin B is often described as relatively OX2-preferring, but it is not an absolutely selective OX2R ligand, and results from a synthetic selective OX2R agonist cannot be assigned to native Orexin B.

Neither Orexin A nor Orexin B was identified as a current individually evaluated substance in the reviewed FDA 503A bulk-substance category list or FDA significant-safety-risk table as of this update. Absence from those lists is not approval, a safety determination, or authorization to compound.

FDA Office of Orphan Products Development (OOPD) record (grid key 1121625) lists an orphan-drug designation for oveporexton (sponsor: Takeda Pharmaceuticals U.S.A., Inc.), designated March 2, 2026, for the orphan designation "treatment of narcolepsy type 1 (narcolepsy with cataplexy)." Status: Designated. FDA orphan approval status: Not FDA Approved for Orphan Indication. Orphan designation is not marketing approval. This record concerns oveporexton, not native Orexin A.

PubChem records Orexin A as a defined endogenous peptide compound.

On February 10, 2026, the FDA accepted Takeda's New Drug Application and granted Priority Review for oveporexton (TAK-861), an investigational oral OX2R-selective small-molecule orexin receptor agonist, for narcolepsy type 1. The FDA assigned a PDUFA target action date in the third quarter of 2026. Oveporexton is not Orexin A and was not FDA approved as of this review date (July 14, 2026); its NDA is supported by the phase 3 FirstLight and RadiantLight trials, which evaluated oveporexton, not native Orexin A.

General trial-registry search portal used as part of this review's regulatory/trial-landscape check.

No FDA-approved Orexin A or Orexin B peptide drug or indication was identified in the reviewed FDA drug databases.

This systematic review identified three eligible human Orexin A studies. The evidence suggested changes in REM-sleep measures (decreased wake-REM transitions and total REM sleep time) but did not establish increased wake time or support routine replacement therapy. The review's own authors concluded orexin deficiency is not the only factor in narcolepsy type 1 pathophysiology. This review does not override or add evidentiary weight beyond what its three small underlying primary studies individually support, and the underlying human evidence base for Orexin A remains small.

Reviews the role of orexin signaling in wakefulness, narcolepsy, and receptor-targeted drug development.