danavorexton (TAK-925) / Takeda, Ligand - LARVOL DELTA

Effects of an orexin receptor 2-selective agonist on salivary secretion in rats. (PubMed, Sci Rep) - "In clinical trials, multiple orexin receptor 2 (OX2R)-selective agonists (e.g., danavorexton, TAK-994, and oveporexton) improved wakefulness and decreased cataplexy in individuals with NT1...In this study, we assessed the effect of an OX2R-selective agonist, OX-202, on salivary secretion in anesthetized or freely moving rats using a muscarinic acetylcholine receptor agonist, pilocarpine, as a positive control...Moreover, oral administration of OX-202 (30 and 100 mg/kg) at zeitgeber time 6 (sleep phase) or zeitgeber time 15 (active phase) did not increase salivary secretion in the oral cavity in freely moving rats. In conclusion, OX2R-selective agonists may not directly induce salivary secretion in rats."

Journal • Preclinical • Anesthesia • Cataplexy • Narcolepsy • Sleep Disorder

Pharmacological modulation of wakefulness and extracellular hypothalamic histamine release in adult male mice using TAK-925, modafinil, pitolisant, MK-8133 and Lu AF11167. (PubMed, Neuropharmacology) - "In vehicle-treated male mice, histamine levels were correlated with wakefulness but in pharmacologically treated male mice, this correlation was decoupled. These data demonstrate that wake can be modulated without modulating histamine signaling and vice versa."

Journal • Preclinical

The Role of Danavorexton for Perioperative Opioid-Induced Respiratory Depression and Sedation: A Narrative Review. (PubMed, Clin Pharmacol) - "This narrative review discusses the pathophysiology of OIRD, current reversal strategies, and the emerging evidence supporting the use of Danavorexton in perioperative care. Danavorexton represents a novel and potentially transformative adjunct that could improve postoperative recovery, reduce adverse opioid-related events, and enhance patient safety in the surgical setting."

Journal • Review • Anesthesia • CNS Disorders • Depression • Mood Disorders • Pain • Psychiatry

Basic Science and Pathogenesis. (PubMed, Alzheimers Dement) - "These findings demonstrate that NPTX2 loss of function instigates SCRD by disrupting sleep architecture, orexin signaling, and neuronal synchronicity. This supports the effector role of NPTX2 in sleep regulation and highlights its potential as a therapeutic target for sleep and circadian dysfunction in aging and neurodegenerative conditions."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Narcolepsy • Sleep Disorder

Sleep and Circadian Rhythm Disruption by NPTX2 Loss of Function via Orexin Pathway (Neuroscience 2025) - "NPTX2 KO mice also show hypersensitivity to TAK-925, a clinical OXR2 agonist, implying receptor hypersensitization when NPTX2 scaffolding is lost. While dual orexin receptor antagonists (DORAs) reduce amyloid and tau pathology, targeted modulation of NPTX2-OXR interactions may offer circuit- and cell-type-specific therapies for sleep disturbances in aging, narcolepsy, and early neurodegeneration."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Excessive Daytime Sleepiness • Narcolepsy • Sleep Disorder

Orexin Deficiency in Narcolepsy: Molecular Mechanisms, Clinical Phenotypes, and Emerging Therapeutic Frontiers. (PubMed, Brain Behav) - "Orexin deficiency remains the central mechanism underlying NT1, with far-reaching implications in psychiatric and neurodegenerative disease. While emerging orexin-targeted therapies offer promising disease-modifying potential, critical challenges persist in standardizing biomarkers, resolving NT2 classification ambiguities, and ensuring global access to therapeutics."

Journal • Review • Cataplexy • CNS Disorders • Depression • Excessive Daytime Sleepiness • Immunology • Major Depressive Disorder • Mood Disorders • Narcolepsy • Psychiatry • Sleep Disorder • HLA-DQB1

Differential histamine responses measured with biosensor in wild-type and orexin/ataxin-3 mice: genotype-specific pharmacological sensitivity (WSS 2025) - "The GRAB-HA1h biosensor enables real-time detection of compound-induced changes in extracellular histamine. The effects of pitolisant appear independent of orexin signaling, showing similar profiles across genotypes. In contrast, TAK-925 elicits a genotype-dependent histaminergic response, suggesting heightened sensitivity in the absence of endogenous orexin."

Preclinical • Cataplexy • CNS Disorders • Excessive Daytime Sleepiness • Narcolepsy • Sleep Disorder • ATXN3

Relax and Take a Deep(-er) Breath with Danavorexton. (PubMed, Anesthesiology) - No abstract available

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Relax and Take a Deep(-er) Breath with Danavorexton. (PubMed, Anesthesiology) - No abstract available

Journal

Relax and Take a Deep(-er) Breath with Danavorexton. (PubMed, Anesthesiology) - No abstract available

Journal

Alluring Potential to Accelerate Emergence and Ameliorate Opioid-induced Respiratory Depression without Antagonizing Analgesia: Danavorexton Enters the Anesthetic Landscape. (PubMed, Anesthesiology) - No abstract available

Journal • Anesthesia • CNS Disorders • Depression • Mood Disorders • Psychiatry

TAK-925 (danavorexton), an Orexin Receptor 2 Agonist, Reduces Opioid-Induced Respiratory Depression and Sedation Without Affecting Analgesia in Healthy Adult Males. (PubMed, Anesthesiology) - "Danavorexton has effects on respiration and wakefulness in an opioid-induced respiratory depression setting without reversing opioid analgesia."

Journal • Anesthesia • CNS Disorders • Depression • Insomnia • Mood Disorders • Pain • Psychiatry • Sleep Disorder

A Study of Danavorexton in People With Obstructive Sleep Apnea After General Anesthesia for Abdominal Surgery (clinicaltrials.gov) - P2 | N=41 | Terminated | Sponsor: Takeda | N=180 ➔ 41 | Trial completion date: Mar 2025 ➔ Sep 2024 | Recruiting ➔ Terminated | Trial primary completion date: Jan 2025 ➔ Sep 2024; Business decision unrelated to patient safety.

Enrollment change • Surgery • Trial completion date • Trial primary completion date • Trial termination • Anesthesia • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

TAK-861, a potent, orally available orexin receptor 2-selective agonist, produces wakefulness in monkeys and improves narcolepsy-like phenotypes in mouse models. (PubMed, Sci Rep) - "We discovered a parenteral orexin receptor 2 (OX2R) agonist, danavorexton, and an orally available OX2R agonist, TAK-994; both improving NT1 phenotypes in mouse models and individuals with NT1. Compared with modafinil, TAK-861 induces highly correlated brain-wide neuronal activation in orexin-tTA;TetO DTA mice, suggesting efficient wake-promoting effects. Thus, TAK-861 has potential as an effective treatment for individuals with hypersomnia disorders including narcolepsy, potentially with a favorable safety profile."

Journal • Preclinical • Cataplexy • Excessive Daytime Sleepiness • Hepatology • Narcolepsy • Sleep Disorder • ATXN3

Novel biomarkers derived from the Maintenance of Wakefulness Test as predictors of sleepiness and response to treatment. (PubMed, Sleep) - "Here, we explored microsleeps, sleep probability measures derived from automated sleep scoring, and quantitative electroencephalography (qEEG) features as additional MWT biomarkers of daytime sleepiness, using data from a phase 1B trial of the selective orexin receptor 2 agonist danavorexton (TAK-925) in people with narcolepsy type 1 (NT1) or type 2 (NT2)...The slopes of line-fits to both the log-transformed sleepiness score or log-transformed θ/α ratio correlated well to (inverse) MWT SOL for NT1 (R = 0.93 and R = 0.83, respectively) and NT2 (R = 0.97 and R = 0.84, respectively), suggesting that individuals with narcolepsy have increased sleepiness immediately after lights-off. These analyses demonstrate that novel EEG-based biomarkers can augment SOL as predictors of sleepiness and its response to treatment and provide a novel framework for the analysis of wake EEG in hypersomnia disorders."

Biomarker • Journal • CNS Disorders • Excessive Daytime Sleepiness • Narcolepsy • Sleep Disorder

Orexin receptor 2 agonist activates diaphragm and genioglossus muscle through stimulating inspiratory neurons in the pre-Bötzinger complex, and phrenic and hypoglossal motoneurons in rodents. (PubMed, PLoS One) - "Herein, we assessed the effects of OX2R-selective agonists TAK-925 (danavorexton) and OX-201 on respiratory function...Electromyogram recordings revealed that intravenous administration of OX-201 increased burst frequency of the diaphragm and burst amplitude of the genioglossus muscle in isoflurane- and urethane-anesthetized rats, respectively...Overall, these results suggest that OX2R-selective agonists enhance respiratory function via activation of the diaphragm and genioglossus muscle through stimulation of inspiratory neurons in the pre-Bötzinger complex, and phrenic and hypoglossal motoneurons. OX2R-selective agonists could be promising drugs for various conditions with respiratory dysfunction."

Journal • Preclinical • Anesthesia • Respiratory Diseases

Evaluating pharmacological treatments for excessive daytime sleepiness in obstructive sleep apnea: A comprehensive network meta-analysis and systematic review. (PubMed, Sleep Med Rev) - "Solriamfetol, followed by Pitolisant and modafinil, exhibited the greatest ESS reduction, while Danavorexton, followed by Solriamfetol and MK-7288, had the strongest impact on MWT. MK-7288 had the most total adverse events (AEs), followed by Danavorexton and armodafinil. Pharmacological Interventions significantly alleviate EDS in OSA patients but with heterogeneity across medications. Treatment decisions should involve a personalized assessment of patient factors and desired outcomes."

Journal • Retrospective data • Review • Excessive Daytime Sleepiness • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

A Study of Danavorexton in People With Obstructive Sleep Apnea After General Anesthesia for Abdominal Surgery (clinicaltrials.gov) - P2 | N=180 | Recruiting | Sponsor: Takeda | Trial completion date: Jul 2024 ➔ Mar 2025 | Trial primary completion date: May 2024 ➔ Jan 2025

Surgery • Trial completion date • Trial primary completion date • Anesthesia • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Danavorexton (TAK-925): an orexin receptor 2 agonist as a new 'arousal' agent. (PubMed, Br J Anaesth) - "Although danavorexton reverses opioid sedation, it does not compromise analgesia. This could be a useful addition to the postoperative drug cupboard."

Journal • Anesthesia

Effects of the orexin receptor 2 agonist danavorexton on emergence from general anaesthesia and opioid-induced sedation, respiratory depression, and analgesia in rats and monkeys. (PubMed, Br J Anaesth) - "Danavorexton promoted recovery from anaesthesia and fentanyl-induced sedation, and antagonised fentanyl-induced respiratory depression without compromising fentanyl analgesia."

Journal • Preclinical • Anesthesia • CNS Disorders • Depression • Mood Disorders • Pain • Psychiatry

Danavorexton Inhibits Opioid-induced Sedation/respiratory Depression Without Compromising Analgesic Effects (ASA 2023) - P1 | "Here we assessed if danavorexton can promote recovery from fentanyl-induced sedation and inhibit OIRD, without compromising the analgesic effects of fentanyl. These findings suggest that danavorexton has potential to accelerate recovery from opioid-induced sedation and improve OIRD without affecting opioid-induced analgesia. Danavorexton may be a promising treatment for postanesthesia recovery. Clinical characterization of danavorexton when administered with anesthetics is underway (ClinicalTrial.gov Identifier: NCT05025397)."

Anesthesia • CNS Disorders • Depression • Mood Disorders • Narcolepsy • Pain • Psychiatry • Sleep Disorder

Danavorexton Accelerated Recovery From Isoflurane/propofol-induced Anesthesia And Motor Dysfunction (ASA 2023) - P1 | "These findings suggest that danavorexton can help facilitate recovery from anesthesia and could be a promising treatment for postanesthesia recovery. Clinical characterization of danavorexton when administered with anesthetics is underway (ClinicalTrial.gov Identifier: NCT05025397)."

Anesthesia • Cardiovascular • CNS Disorders • Cognitive Disorders • Narcolepsy • Sleep Disorder • Solid Tumor

Pharmacology of viable mechanism agnostic respiratory stimulants for the reversal of drug-induced respiratory depression in humans. (PubMed, Expert Opin Drug Metab Toxicol) - "In this review, we discuss agnostic respiratory stimulants, tested in humans with promising results, i.e. ampakines, drugs that act at the carotid bodies, N-methyl-D-aspartate receptor antagonist ketamine, and orexin receptor-2-agonist danavorexton, and others that demonstrated positive effects in animals but not yet in humans. While several agnostic respiratory stimulants showed promise in humans, further research is needed to optimize dosing, evaluate safety and efficacy in deeper respiratory depression (apnea). Additionally, future studies should combine agnostic stimulants with naloxone, to improve rapid, effective rescue from drug overdoses."

Journal • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Mood Disorders • Psychiatry

A single overnight infusion of TAK-925, a selective orexin 2 receptor agonist, reduces obstructive sleep apnea severity (WSS 2023) - P1b | "Overnight danavorexton infusion significantly decreased OSA severity in participants with OSA, with no serious adverse events. AHI reductions were driven by decreased airway collapsibility and respiratory control instability (loop gain). However, OX2R stimulation was associated with reduced REM sleep and wake-promoting effects, including increased WASO and reduced arousal threshold.Acknowledgements: This study was funded by Takeda Pharmaceuticals USA, Inc."

Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Discovery of a highly potent and orally available orexin 2 receptor-selective agonist, TAK-861, as a novel therapeutic agent for narcolepsy and other hypersomnia disorders (WSS 2023) - "We have previously discovered a parenteral OX2R agonist, danavorexton, and an orally available OX2R agonist, TAK-994, which improved NT1-like phenotypes in mouse models and showed promising therapeutic effects in NT1 patients. Compared with TAK-994, the novel orally available OX2R-selective agonist TAK-861 showed approximately 10-fold higher potency in OX2R activation, better selectivity over OX1R, and 10-fold lower effective dosage for arousal in both mice and monkeys.Acknowledgements: This work was conducted by Takeda Pharmaceutical Company Limited."

Cataplexy • CNS Disorders • Excessive Daytime Sleepiness • Hepatology • Narcolepsy • Sleep Disorder