TAK-041 / Takeda, Neurocrine - LARVOL DELTA

Surrogate GPR139 Agonists Reverse Short-Term Startle Habituation Impairment in Larval Zebrafish. (PubMed, FASEB J) - "We examined the effect of GPR139 agonists (JNJ-63533054 and TAK-041) on short-term startle habituation of 6-day post-fertilization (dpf) larval zebrafish (Danio rerio) in an automated solenoid setup and on reversing the pharmacologically impaired startle habituation. Moreover, both GPR139 agonists differently reduced MK-801-induced hyperexcitability of the habenula at both spontaneous and habituated states. Taken together, we showed that GPR139 agonists reverse startle habituation impairment caused by MK-801 via the normalization of hyperexcitability of zebrafish habenula."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia

GPR139, an Ancient Receptor and an Emerging Target for Neuropsychiatric and Behavioral Disorders. (PubMed, Mol Neurobiol) - "Modulation of GPR139 activity by surrogate agonists such as TAK-041 and JNJ-63533054 has shown promising results in experimental models; however, the use of TAK-041 in clinical trials has produced heterogeneous effects and has not met the intended primary endpoint. Here, we highlight current in vitro and in vivo studies of GPR139, its potential physiological roles, and therapeutic potential in the pathophysiology of neuropsychiatric and behavioral disorders. This review aims to focus on the current knowledge gaps to facilitate future studies that will contribute to the understanding of GPR139 as a therapeutic target for neuropsychiatric and behavioral disorders."

Journal • Review • Behavior Disorders • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Substance Abuse

Pharmacological activation of GPR139 by TAK-041 modulates energy balance and hypothalamic inflammation (Neuroscience 2024) - "Combining TAK-041 with semaglutide enhances these effects, showing promise for treating obesity and its complications. However, further research is necessary to understand the mechanisms and safety of this treatment."

CNS Disorders • CX3CR1 • IL6 • NLRP3

A Phase 2 Randomized Proof-Of-Concept Trial of NBI-1065846 (TAK-041) in Adults with Anhedonia Associated with Major Depressive Disorder: Results of the Terpsis Study (ASCP 2024) - P2 | "Of 93 randomized participants, 88 (94.6%) completed the study treatment and 83 (89.2%) 2024 ASCP Annual Meeting completed the study. BL demographics and characteristics were broadly similar between treatment groups. No significant improvement in DARS was observed with NBI-1065846 vs placebo at Day 57 (p = 0.8663, 1-sided), with a least-squares mean (standard error of the mean) [1 sided 90% confidence interval] difference of –3.9 (3.5) [–8.4, infinity]."

Clinical • P2 data • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mental Retardation • Mood Disorders • Pain • Psychiatry • Schizophrenia • Sleep Disorder • Suicidal Ideation

Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment. (PubMed, J Med Chem) - "Guided by the reported structure of GPR139, we conducted medicinal chemistry optimizations of TAK-041, the GPR139 agonist in clinical trials...These findings further demonstrated the potential of GPR139 agonists in alleviating the negative symptoms and cognitive deficits of schizophrenia. Compound 20a is worth further evaluation as an antischizophrenia drug candidate."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • Substance Abuse

TERPSIS: Study to Evaluate the Efficacy and Safety of Once-Weekly Oral NBI-1065846 in the Treatment of Anhedonia in MDD (clinicaltrials.gov) - P2 | N=93 | Completed | Sponsor: Neurocrine Biosciences | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

TERPSIS: Study to Evaluate the Efficacy and Safety of Once-Weekly Oral NBI-1065846 in the Treatment of Anhedonia in MDD (clinicaltrials.gov) - P2 | N=93 | Active, not recruiting | Sponsor: Neurocrine Biosciences | Trial primary completion date: Nov 2023 ➔ Jul 2023

Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

TERPSIS: Study to Evaluate the Efficacy and Safety of Once-Weekly Oral NBI-1065846 in the Treatment of Anhedonia in MDD (clinicaltrials.gov) - P2 | N=93 | Active, not recruiting | Sponsor: Neurocrine Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

TERPSIS: Study to Evaluate the Efficacy and Safety of Once-Weekly Oral NBI-1065846 in the Treatment of Anhedonia in MDD (clinicaltrials.gov) - P2 | N=88 | Recruiting | Sponsor: Neurocrine Biosciences | Trial completion date: May 2023 ➔ Dec 2023 | Trial primary completion date: Apr 2023 ➔ Nov 2023

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

The selective GPR139 agonist TAK-041 reverses anhedonia and social interaction deficits in rodent models related to negative symptoms in schizophrenia (Neuroscience 2022) - "TAK-041 also reversed social interaction (SI) deficits in the maternal immune activation poly-I:C model of SCZ, the subchronic PCP-SI model and in Balb/C and BTBR mice. The GPR139 agonist TAK-041 is proposed as a modulator of habenula circuitry to treat negative symptoms in SCZ based on efficacy in reversing anhedonia and social interaction deficits in multiple rodent models related to negative symptoms in SCZ."

Preclinical • CNS Disorders • Depression • Psychiatry • Schizophrenia

Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions. (PubMed, Neuropharmacology) - "By contrast, TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived; furthermore, this effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress. Overall, this study provides preclinical evidence in support of GPR139 agonism as a molecular target mechanism for treatment of apathy."

Journal • Preclinical • CNS Disorders • Depression • Psychiatry • Schizophrenia

A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia. (PubMed, Br J Clin Pharmacol) - P1 | "TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia. Further investigation of TAK-041 in individuals with schizophrenia is supported."

Journal • P1 data • PK/PD data • CNS Disorders • Depression • Immunology • Mood Disorders • Psychiatry • Schizophrenia

TERPSIS: Study to Evaluate the Efficacy and Safety of Once-Weekly Oral NBI-1065846 in the Treatment of Anhedonia in MDD (clinicaltrials.gov) - P2; N=88; Recruiting; Sponsor: Neurocrine Biosciences

Clinical • New P2 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [C]PHNO PET. (PubMed, Neuropsychopharmacology) - "Ten healthy volunteers underwent [C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development."

Biomarker • Journal • PK/PD data • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia. (PubMed, J Med Chem) - "The pharmacological characterization of these GPR139 agonists in vivo demonstrated GPR139-agonist-dependent modulation of habenula cell activity and revealed consistent in vivo efficacy to rescue social interaction deficits in the BALB/c mouse strain. The clinical GPR139 agonist TAK-041 is being explored as a novel drug to treat negative symptoms in SCZ."

Journal • CNS Disorders • Depression • Psychiatry • Schizophrenia

Neurocrine Biosciences Provides Preliminary Fourth Quarter and Full-Year 2020 Net Product Sales Results and 2021 Program Milestones (PRNewswire) - "Neurocrine Biosciences, Inc....today provided an update on...key commercial and clinical development milestones for 2021. Kevin Gorman, Chief Executive Officer of Neurocrine Biosciences, will discuss these updates as part of a webcast presentation at the 39th Annual J.P. Morgan Healthcare Conference to be held virtually on Monday, January 11 at 2:00 p.m. Eastern Time...2021 Expected Milestones and Key Activities: NBI-1065845: Treatment Resistant Depression: Initiate Phase II; NBI-1065846: Anhedonia in Depression; Initiate Phase II."

New P2 trial • CNS Disorders • Depression

In vitron metabolism of slowly cleared GPR139 agonist TAK-041 using rat, dog, monkey and human hepatocyte models (HepatoPac): correlation with in vivo metabolism. (PubMed, Drug Metab Dispos) - "Significance Statement We investigated the most appropriate in vitro system to assess the biotransformation of the low-turnover and extensively metabolized compound TAK-041; determine any notable species difference in the rate and in the extent of its metabolic pathways and establish correlation with in vivo metabolism. The HepatoPac model was identified and showed its suitability for species comparison and establishing correlation with in vivo metabolism displaying an extensive and unusual downstream sequential β-lyase-derived thiol metabolism in preclinical species and human."

Journal • Preclinical • Metabolic Disorders

Neurocrine Biosciences and Takeda Announce Collaboration to Develop and Commercialize Potential Therapies for Psychiatric Disorders (Businesswire) - "Neurocrine Biosciences, Inc....and Takeda Pharmaceutical Company Limited...today announced a strategic collaboration to develop and commercialize compounds in Takeda’s early-to-mid-stage psychiatry pipeline. Specifically, Takeda granted an exclusive license to Neurocrine Biosciences for seven pipeline programs, including three clinical stage assets for schizophrenia, treatment-resistant depression and anhedonia....Under the terms of the agreement, Neurocrine Biosciences will be responsible for developing and commercializing all pipeline compounds included in the collaboration."

Licensing / partnership • CNS Disorders • Depression • Schizophrenia

Newly added product (clinicaltrials.gov) - P2, Schizophrenia

Pipeline update • CNS Disorders • Schizophrenia

The Selective GPR139 Agonist TAK-041 Reverses Anhedonia and Social Interaction Deficits in Rodent Models Related to Negative Symptoms in Schizophrenia (SIRS 2020) - "Discussion The GPR139 agonist TAK-041 is proposed as a modulator of habenula circuitry to treat negative symptoms in SCZ based on efficacy in reversing anhedonia and social interaction deficits in multiple rodent models related to negative symptoms in SCZ. *Employed by Takeda when the study was done."

A Randomized, Double-Blind, Placebo Controlled, Two-Period Cross-Over, Proof of Activity Study to Evaluate the Effects of TAK-041 on Motivational Anhedonia as Add-On to Antipsychotics in Subjects With Stable Schizophrenia (clinicaltrials.gov) - P2; N=23; Completed; Sponsor: Takeda; Active, not recruiting ➔ Completed

Clinical • Trial completion

Phase 1 TAK-041 First-in-Human Safety, Tolerability, and Pharmacokinetics Study (clinicaltrials.gov) - P1; N=114; Completed; Sponsor: Takeda; Active, not recruiting ➔ Completed

Clinical • Trial completion

Discovery of TAK-041: Potent and Selective GPR139 Agonist for Treatment of Negative Symptoms Associated With Schizophrenia (ACNP 2019) - "These data further support the hypothesis that the habenula plays an important role in schizophrenia, and that selective GPR139 agonists may be a beneficial treatment for the disease."

Phase 1 TAK-041 First-in-Human Safety, Tolerability, and Pharmacokinetics Study (clinicaltrials.gov) - P1; N=114; Active, not recruiting; Sponsor: Takeda; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Discovery of TAK-041: A potent and selective GPR139 agonist for the treatment of negative symptoms associated with schizophrenia (Neuroscience 2019) - "The small molecule GPR139 agonist TAK-041 was observed to reverse deficits in models of schizophrenia, including cognition in a subchronic PCP-impaired attentional set-shifting paradigm (Birrell and Brown, 2000) and impaired social interaction in the Poly(I:C) maternal immune activation model (Bitanihirwe et al., 2010). These data further support the hypothesis that the habenula plays an important role in schizophrenia, and that selective GPR139 agonists may be a beneficial treatment for the disease."