TAK-994 / Takeda - LARVOL DELTA

Functional Regression Methods for Estimating 24-Hour Ambulatory Blood Pressure and Heart Rate Parameters in Narcolepsy Type 1. (PubMed, Digit Biomark) - P2 | "Baseline ABPM data were from participants with NT1 in the randomized TAK-994 phase 2 clinical trial (NCT04096560)...The 24-h pattern approach offers a robust alternative to the fixed-window method for assessing dipping, especially in populations with sleep timing variations and disturbances, like NT1, and does not require simultaneous actigraphy measurement. The classification of a "non-dipper" varies depending on both the dip type (SBP vs. DBP) and the dip estimation method."

Journal • Cardiovascular • Narcolepsy • Sleep Disorder

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

Orexin receptor 2 agonists: a pathophysiologic approach to narcolepsy type 1. (PubMed, Ann Med Surg (Lond)) - "TAK-994, the first oral OX2R agonist, demonstrated remarkable efficacy in reducing cataplexy and improving wakefulness but was discontinued due to dose-dependent hepatotoxicity. If validated in large-scale Phase 3 studies, TAK-861 could become the first disease-modifying therapy for NT1, representing a paradigm shift from symptomatic management to mechanism-based treatment. The ongoing development of OX2R agonists highlights a promising frontier in precision sleep medicine, offering renewed hope for patients by targeting orexin restoration."

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

TAK-994 Mechanistic Investigation into Drug-Induced Liver Injury. (PubMed, Toxicol Sci) - "A potential covalent binding liability was uncovered with TAK-994 following hepatic metabolism consistent with idiosyncratic DILI and the delayed-onset clinical toxicity. Although idiosyncratic DILI is challenging to detect preclinically, reductions in total daily dose and covalent binding can reduce the covalent body binding burden and, subsequently, the clinical incidence of idiosyncratic DILI."

Journal • Hepatology • Liver Failure

A Study of TAK-994 in Adults With Type 1 and Type 2 Narcolepsy (clinicaltrials.gov) - P2 | N=97 | Terminated | Sponsor: Takeda | N=257 ➔ 97

Enrollment change • Cataplexy • Narcolepsy • 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

Impact of the Oral Orexin Receptor 2 Agonist TAK-994 on Sustained Attention in Patients with Narcolepsy Type 1: Exploratory Results from a Phase 2 Study (AAN 2024) - P2 | "Significant improvements on the PVT and SART were achieved with TAK-994 versus placebo, suggesting potential use for OX2R agonists to address attention deficits in patients with narcolepsy."

Clinical • P2 data • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Developmental Disorders • Hepatology • Narcolepsy • Psychiatry • Sleep Disorder

The orexin receptor 2 (OX2R)-selective agonist TAK-994 increases wakefulness without affecting cerebrospinal fluid orexin levels in cynomolgus monkeys. (PubMed, Pharmacol Biochem Behav) - "Moreover, oral administration of TAK-994 (10 mg/kg) during the active phase (ZT1) did not increase OX-A levels in monkey CSF. These findings indicate that the OX2R agonist TAK-994 selectively activates OX2R in vivo and would not robustly induce spontaneous orexin release during the daytime or nighttime in monkeys."

Journal • 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

"The more accessible version was TAK-994 which was withdrawn due to adverse liver side effects." (,@MattwithIH)

Adverse events

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1. (PubMed, N Engl J Med) - P2 | "In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.)."

Journal • Cataplexy • Hepatology • Liver Failure • Narcolepsy • 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

A Study of TAK-994 in Adults With Type 1 and Type 2 Narcolepsy (clinicaltrials.gov) - P2; N=257; Terminated; Sponsor: Takeda; Trial completion date: Apr 2022 ➔ Nov 2021; Active, not recruiting ➔ Terminated; Trial primary completion date: Apr 2022 ➔ Nov 2021; A safety signal has emerged in Phase 2 studies of TAK-994. As an immediate precautionary measure, Takeda has suspended dosing of patients and has decided to stop Phase 2 studies early.

Clinical • Trial completion date • Trial primary completion date • Trial termination • Cataplexy • Narcolepsy • Sleep Disorder

A Study of TAK-994 in Adults With Narcolepsy (clinicaltrials.gov) - P2; N=26; Terminated; Sponsor: Takeda; N=112 ➔ 26; Active, not recruiting ➔ Terminated; A safety signal has emerged in Phase 2 studies of TAK-994. As an immediate precautionary measure, Takeda has suspended dosing of patients and has decided to stop Phase 2 studies early.

Clinical • Enrollment change • Trial termination • Cataplexy • Narcolepsy • Sleep Disorder

A Study of TAK-994 in Adults With Narcolepsy (clinicaltrials.gov) - P2; N=112; Active, not recruiting; Sponsor: Takeda; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Cataplexy • Narcolepsy • Sleep Disorder

A Study of TAK-994 in Adults With Type 1 and Type 2 Narcolepsy (clinicaltrials.gov) - P2; N=202; Active, not recruiting; Sponsor: Takeda; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Cataplexy • Narcolepsy • Sleep Disorder

Takeda Provides Update on TAK-994 Clinical Program (Businesswire) - "Takeda Pharmaceutical Company Limited...today announced that a safety signal has emerged in the Phase 2 studies of TAK-994 , an investigational oral orexin agonist. As an immediate precaution, the company stopped dosing patients and decided to stop the two Phase 2 studies sooner. This allows for timely interpretation of the TAK-994 risk/benefit profile and determining next steps for the program."

Trial suspension • CNS Disorders • Narcolepsy • Sleep Disorder

"Safety signal scuppers two phase 2 trials of @Takedapharma's orexin agonist TAK-994 for #narcolepsy, handing a possible advantage to @NLSPharma rival Quilience #pharma https://t.co/oIxEM2kwZu" (,@pharmaphorum)

Clinical • Narcolepsy • Sleep Disorder

A Study of TAK-994 in Participants With Narcolepsy Type 1 TAK 994 vizsgálat 1-es típusú narkolepsziában szenvedő betegek esetében (clinicaltrialsregister.eu) - P2; N=112; Ongoing; Sponsor: Takeda Development Center Americas, Inc.`TAKEDA DEVELOPMENT CENTER AMERICAS INC.

New P2 trial • Cataplexy • Narcolepsy • Sleep Disorder

U.S. Food and Drug Administration Grants Breakthrough Therapy Designation to Takeda’s Investigational Compound, TAK-994, an Oral Orexin Agonist in Clinical Development for Narcolepsy Type 1 (NT1) (Businesswire) - "Takeda Pharmaceutical Company Limited...announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) to TAK-994, its Phase 2 investigational oral orexin agonist...The TAK-994 BTD was based, in part, on early phase and preliminary clinical data that indicates Takeda’s investigational oral orexin agonist may demonstrate substantially improved objective and subjective measurements of daytime wakefulness in NT1 patients. TAK-994 is being studied in an ongoing Phase 2 (TAK-994-1501) study. Data from the completed Phase 2 study will be presented at a future scientific conference after the study’s conclusion."

Breakthrough therapy designation • Trial status • CNS Disorders • Excessive Daytime Sleepiness in Narcolepsy • Narcolepsy • Sleep Disorder

Study to Evaluate Absorption, Metabolism, and Excretion, of TAK-994 in 6 Healthy Male Adults (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: Takeda; Recruiting ➔ Completed

Clinical • Trial completion

A Study of TAK-994 in Adults With Narcolepsy (clinicaltrials.gov) - P2; N=112; Recruiting; Sponsor: Takeda; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Cataplexy • Narcolepsy • Sleep Disorder

"@TakedaPharma Hi, any updates on the Tak-994 trials for Type 1 Narcolepsy? Interested to find out when it will be available." (,@BeatriceFl0wers)

Narcolepsy • Sleep Disorder

A Study of TAK-994 in Adults With Type 1 and Type 2 Narcolepsy (clinicaltrials.gov) - P2; N=202; Recruiting; Sponsor: Takeda; Trial completion date: May 2021 ➔ Apr 2022; Trial primary completion date: May 2021 ➔ Apr 2022

Clinical • Trial completion date • Trial primary completion date • Cataplexy • Narcolepsy • Sleep Disorder

A Study of Different Forms of TAK-994 in Healthy Adults (clinicaltrials.gov) - P1; N=54; Completed; Sponsor: Takeda; Active, not recruiting ➔ Completed

Trial completion