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

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

Orexin 2 receptor agonist activates pre-Bötzinger complex neurons, phrenic motoneurons and the diaphragm in rodents (SLEEP 2023) - "Methods OX2R-selective agonists danavorexton (TAK-925) and OX-201 (a tool compound with longer plasma half-life than danavorexton in rodents) were used...OX2R agonists may have therapeutic potential in patients with CSA if enhancement of respiratory function by OX2R agonists can be observed at non-arousal concentrations. Further preclinical and clinical studies are worth conducting in patients with CSA."

Preclinical • CNS Disorders • Obstructive Sleep Apnea • Sleep Apnea • Sleep Disorder

Orexin 2 receptor agonist activates pre-Bötzinger complex neurons, hypoglossal motoneurons and the genioglossus muscle in rodents (SLEEP 2023) - "Methods OX2R-selective agonists danavorexton (TAK-925) and OX-201 (a tool compound with longer plasma half-life than danavorexton in rodents) were used...OX2R agonists may have therapeutic potential in patients with OSA if enhancement of respiratory function by OX2R agonists can be observed at non-arousal concentrations. Further preclinical and clinical studies are worth conducting in patients with OSA."

Preclinical • CNS Disorders • Obstructive Sleep Apnea • Sleep Disorder

Safety and pharmacodynamics of a single infusion of danavorexton in adults with obstructive sleep apnea experiencing excessive daytime sleepiness despite adequate use of CPAP. (PubMed, Sleep Med) - "Among 25 randomized patients, 16 (64.0%) had treatment-emergent adverse events (TEAEs) and 12 (48.0%) had TEAEs considered related to treatment, all mild or moderate. Seven patients (28.0%) had urinary TEAEs: three, seven, and none while taking danavorexton 44 mg, danavorexton 112 mg, and placebo, respectively. There were no deaths or TEAEs leading to discontinuation. Improvements in mean MWT, KSS, and PVT scores were observed with danavorexton 44 mg and 112 mg vs placebo. These findings show that danavorexton can improve subjective and objective measures of EDS in patients with OSA and residual EDS despite adequate CPAP use."

Journal • PK/PD data • CNS Disorders • 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 | Not yet recruiting ➔ Recruiting

Enrollment open • Anesthesia • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

A Study of Danavorexton in People With Obstructive Sleep Apnea After General Anesthesia for Abdominal Surgery (clinicaltrials.gov) - P2 | N=180 | Not yet recruiting | Sponsor: Takeda

New P2 trial • Surgery • Anesthesia • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

TAK-994, a novel orally available brain-penetrant orexin 2 receptor-selective agonist, suppresses fragmentation of wakefulness and cataplexy-like episodes in mouse models of narcolepsy. (PubMed, J Pharmacol Exp Ther) - "In fact, in early proof-of-concept studies, intravenous infusion of danavorexton, an OX2R-selective agonist, significantly increased wakefulness in individuals with NT1. Oral administration of TAK-994, a novel OX2R agonist, promoted wakefulness in normal mice, but not in OX2R knockout mice, and ameliorated fragmentation of wakefulness and cataplexy-like episodes in mouse models of narcolepsy. These findings indicate that TAK-994 is an orally available brain-penetrant OX2R-selective agonist with potential to improve narcolepsy-like symptoms."

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

Orexin 2 receptor-selective agonist danavorexton (TAK-925) promotes wakefulness in non-human primates and healthy individuals. (PubMed, J Sleep Res) - P1b | "In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n = 18). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p = 0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase."

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

Safety and pharmacodynamics of a single infusion of danavorexton in adults with idiopathic hypersomnia. (PubMed, Sleep) - "A single infusion of danavorexton improves subjective and objective excessive daytime sleepiness in people with IH with no serious TEAEs, indicating orexin-2 receptor agonists are promising treatments for IH."

Journal • PK/PD data • Excessive Daytime Sleepiness • Sleep Disorder

Evaluation of the efficacy of the hypocretin/orexin receptor agonists TAK-925 and ARN-776 in narcoleptic orexin/tTA; TetO-DTA mice. (PubMed, J Sleep Res) - "TAK-925 and ARN-776 also increased gross motor activity, running wheel activity, and T , suggesting that the wake-promoting and sleep-suppressing activities of these compounds could be a consequence of hyperactivity. Nonetheless, the anti-cataplectic activity of TAK-925 and ARN-776 is encouraging for the development of HCRTR2 agonists."

Journal • Preclinical • Cataplexy • CNS Disorders • Narcolepsy • Sleep Disorder