Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers

Dijkstra, Francis M; O’Donnell, Patricio; Klaassen, Erica S.; Buhl, Derek L.; Asgharnejad, Mahnaz; Rosen, Laura; Zuiker, Rob; Gerven, Joop van; Jacobs, Gabriël

doi:10.1038/s41398-022-02148-w

Cited by 11 publications

(7 citation statements)

References 81 publications

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“…In line with previous clinical studies of NBI‐1065845 in healthy individuals (NCT02561156) and individuals with MDD (unpublished data), no tremors or seizures nor suicidal ideation or behavior (based on the C‐SSRS and AE reporting) were reported in this DDI study. There were also no new safety signals observed for NBI‐1065845 in the presence of midazolam, ethinyl estradiol, or levonorgestrel 13,14 …”

Section: Discussionmentioning

confidence: 97%

“…There were also no new safety signals observed for NBI-1065845 in the presence of midazolam, ethinyl estradiol, or levonorgestrel. 13,14 T A B L E 2 Summary of TEAEs (safety analysis set).…”

Section: Discussionmentioning

confidence: 99%

“…gov identifier: NCT03792672). 13,14 Based on the preclinical and clinical results, NBI-1065845 may have the potential to overcome the limitations of known AMPA-R potentiators and provide an effective therapeutic approach for MDD.…”

Section: How Might This Change Clinical Pharmacology or Translational...mentioning

confidence: 99%

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Effects of the selective AMPA modulator NBI‐1065845 on the pharmacokinetics of midazolam or ethinyl estradiol–levonorgestrel in healthy adults

Lin,

Ionescu,

Maynard‐Scott

et al. 2024

Clinical Translational Sci

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This parallel‐arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI‐1065845 (TAK‐653), an investigational α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI‐1065845 alone on Days 5–13; on Day 14, NBI‐1065845 was administered with midazolam, then NBI‐1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol–levonorgestrel on Day 1, then NBI‐1065845 alone on Days 5–13; on Day 14, NBI‐1065845 was administered with ethinyl estradiol–levonorgestrel, then NBI‐1065845 alone on Days 15–17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI‐1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79–1.13); ethinyl estradiol, 1.00 (0.87–1.15); and levonorgestrel, 0.99 (0.87–1.13). For area under the plasma concentration–time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78–0.98); and ethinyl estradiol, 1.01 (0.88–1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78–0.96). These findings indicate that NBI‐1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI‐1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Effects of the selective AMPA modulator NBI‐1065845 on the pharmacokinetics of midazolam or ethinyl estradiol–levonorgestrel in healthy adults

Lin,

Ionescu,

Maynard‐Scott

et al. 2024

Clinical Translational Sci

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“…receptor desensitization and internal migration. [30][31][32] In collaboration with Neurocrine Biosciences Inc. and Takeda, TAK-653 is currently undergoing Phase 2 development in both the United States and Japan. 33 This novel compound holds the potential to address MDD and TRD with its unique mechanism of action as a PAM of the AMPA receptor.…”

Section: Major New Antipsychotic Drug Candidates Sep-363856 (Ulotaront)mentioning

confidence: 99%

“…TAK‐653 is a promising oral tablet being developed for the treatment of MDD and treatment‐resistant depression (TRD). As a selective PAM of the AMPA receptor, TAK‐653 acts to potentiate the action of agonist binding at critical sites of the AMPA receptor by slowing receptor desensitization and internal migration 30–32 …”

Section: Major New Antidepressant Candidatesmentioning

confidence: 99%

Emerging trends in antipsychotic and antidepressant drug development: Targeting nonmonoamine receptors and innovative mechanisms

Osaka,

Kanazawa

2023

PCN Reports

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The domain of psychiatric drug development is currently witnessing a notable transformation, with a paramount emphasis on targeting nonmonoamine receptors and exploring inventive mechanisms of action. This paper presents an overview of the ongoing advancements in antipsychotic and antidepressant drug development. Historically, antipsychotics predominantly targeted dopamine receptors, but there is now an escalating interest in drugs that act on alternative receptors, exemplified by the TAAR1 receptor. One noteworthy candidate is Ulotaront (SEP‐363856), an agent acting as a TAAR1 agonist with 5‐HT1A agonist activity, demonstrating promising outcomes in the treatment of schizophrenia, devoid of extrapyramidal symptoms or metabolic side‐effects. Similarly, MIN‐101 (Roluperidone) and KarXT are currently in development, with its focus on addressing the symptoms in schizophrenia. In the domain of antidepressants, novel therapeutic approaches have surfaced, such as Auvelity, a Food and Drug Administration (FDA)‐approved NMDA receptor antagonist synergistically combined with Bupropion to enhance its effects. Another notable candidate is Zuranolone, operating as a GABA A receptor‐positive allosteric modulator, showcasing efficacy in treating major depressive disorder (MDD) and postpartum depression. Additionally, TAK‐653 (NBI‐1065845) and MJI821 (Onfasprodil) have emerged as potential antidepressants targeting AMPA receptors and NMDA receptor 2B (NR2B) negative allosteric modulation, respectively. This paper underscores the transformative potential of these novel drug candidates in psychiatric treatment and their ability to address cases that were previously treatment‐resistant. By focusing on nonmonoamine receptors and introducing innovative mechanisms, these drugs offer a promising prospect of improved outcomes for individuals suffering from schizophrenia and MDD. Thus, sustained attention and dedication to the development of such drugs are essential to augmenting the therapeutic options available for psychiatric patients.

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Safety, Tolerability, and Pharmacokinetic Profile of the Low‐Impact Ampakine CX1739 in Young Healthy Volunteers

Radin,

Cerne,

Witkin

et al. 2024

Clinical Pharm in Drug Dev

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AMPA‐type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the mammalian brain. Ampakines, positive allosteric modulators of AMPAR, hold significant potential for the treatment of a wide range of neurological/neuropsychiatric disorders in which excitatory synaptic transmission is compromised. Low‐impact ampakines are a distinct subset of ampakines that accelerate channel opening yet minimally affect receptor desensitization, which may explain their lack of seizurogenic effects at therapeutic doses in preclinical models. CX1739 is a low‐impact ampakine that has shown efficacy in preclinical studies. The current clinical study examined the tolerability and pharmacokinetics of CX1739 in healthy male volunteers in a 2‐part study. Part A was a single dose escalation study (100‐1200 mg, 48 patients) and Part B was a multiple dose ascending study (300‐600 mg BID for 7‐10 days, 32 patients). CX1739 was well tolerated up to 900 mg once daily (QD) and 450 mg twice a day, with the prominent side effects being headache and nausea. Importantly, the half‐life of CX1739 was 6‐9 hours, and Tmax was 1‐5 hours. CX1739 Cmax and AUC were dose‐proportional. These findings thus set the stage for further explorations of this drug candidate in phase 2 clinical studies.

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Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers

Cited by 11 publications

References 81 publications

Effects of the selective AMPA modulator NBI‐1065845 on the pharmacokinetics of midazolam or ethinyl estradiol–levonorgestrel in healthy adults

Effects of the selective AMPA modulator NBI‐1065845 on the pharmacokinetics of midazolam or ethinyl estradiol–levonorgestrel in healthy adults

Emerging trends in antipsychotic and antidepressant drug development: Targeting nonmonoamine receptors and innovative mechanisms

Safety, Tolerability, and Pharmacokinetic Profile of the Low‐Impact Ampakine CX1739 in Young Healthy Volunteers

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