This is a randomized, double-blind, and placebo controlled. 120 HV will be randomized to one of three ketamine arms, delivered in a bolus dose over one minute: low (0.086 mg/kg), medium (0.125 mg/kg), and high (0.23 mg/kg).
Within each ketamine arm, subjects will be randomized to 4 days of TS-134 20 mg or placebo in a 5:3 ratio (25 TS-134:15 placebo). Following an outpatient Screening Period (up to 31 days), eligible subjects will undergo an up to 5-day inpatient Treatment Period. During the study, each subject will undergo a total of two ketamine sessions: a first session during the Screening Period and a second session on Day 4 of the Treatment Period, conducted at least 7 days apart. All randomized subjects will be dosed with TS-134 or placebo daily in a fed state for 4 days during the study, titrated to 20 mg over the first 2 days.

开始日期2022-10-15

申办/合作机构

The New York State Psychiatric Institute

[+1]

NCT03141658 / Completed临床1期

A Randomized, Single-blind, Parallel-group Study to Evaluate the Effects of TS-134 on Ketamine-induced BOLD Signals in Resting fMRI in Healthy Adult Subjects

The purpose of this study is to evaluate the effects of TS-134 on ketamine-induced BOLD signals in ROIs in resting fMRI in healthy adult subjects.

开始日期2017-06-28

申办/合作机构

Taisho Pharmaceutical R&D, Inc.

NCT03742791 / Completed临床1期

A Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Titration Study to Evaluate the Safety, Tolerability and Pharmacokinetics of TS-134 Administered Orally to Healthy Male and Female Subjects

This is a Phase 1 study involving multiple dose titrations of TS-134 in healthy male and female subjects. The safety, tolerability and pharmacokinetics of multiple dose titrations of TS-134 will be evaluated.

开始日期2016-06-28

申办/合作机构

Taisho Pharmaceutical R&D, Inc.

100 项与 TS-134 相关的临床结果

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100 项与 TS-134 相关的转化医学

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100 项与 TS-134 相关的专利（医药）

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项与 TS-134 相关的文献（医药）

2020-11-01·British Journal of Clinical Pharmacology2区 · 医学

Safety and pharmacokinetic profiles of MGS0274 besylate (TS‐134), a novel metabotropic glutamate 2/3 receptor agonist prodrug, in healthy subjects

2区 · 医学

Article

作者: Hikichi, Hirohiko ; Watanabe, Mai ; Marcy, Brian ; Fukasawa, Misako ; Okuyama, Shigeru ; Chaki, Shigeyuki ; Kinoshita, Kohnosuke ; Yoshida, Shigeru ; Gevorkyan, Hakop

AimsThe safety and pharmacokinetics of single and multiple doses of a novel mGlu2/3 receptor agonist prodrug, MGS0274 besylate (TS‐134), were investigated in healthy subjects.MethodsPhase 1 single‐ascending dose (5–20 mg) and multiple‐ascending dose titration (5–80 mg) studies were conducted in healthy male and female subjects. Both studies were randomized, double‐blinded and placebo‐controlled. In one cohort of single‐ascending dose study (10 mg), concentrations of MGS0008, the active compound, in the cerebrospinal fluid (CSF) were measured for up to 24 hours postdose.ResultsFollowing single and multiple oral administrations, MGS0274 was rapidly absorbed and extensively converted into MGS0008, which reached a maximum concentration (Cmax) in plasma within 4 hours postdose and declined with a terminal half‐life (t1/2) of around 10 hours. Plasma exposure to MGS0274 was minimal, accounting for approximately 3% of the area under the concentration–time curve (AUC) of MGS0008. Plasma Cmax and AUC of MGS0008 at steady state increased dose proportionally (5–80 mg). MGS0008 penetrated into CSF, with a CSF‐to‐plasma Cmax ratio of 3.66%, and was eliminated with a t1/2 of approximately 16 hours. The most frequent treatment‐emergent adverse events observed following single and multiple oral administration included headache, nausea, somnolence, dizziness and vomiting.ConclusionTS‐134 is orally bioavailable in humans and converts rapidly and extensively to MGS0008, which exhibits good CSF penetration. Orally administered TS‐134 was safe and generally well‐tolerated; hence, TS‐134 is a promising candidate for further clinical development for the treatment of disorders in which glutamatergic abnormalities are involved, such as schizophrenia.

2020-10-01·European Journal of Medicinal Chemistry1区 · 医学

Discovery of MGS0274, an ester prodrug of a metabotropic glutamate receptor 2/3 agonist with improved oral bioavailability

1区 · 医学

Article

作者: Kinoshita, Kohnosuke ; Yamaguchi, Jun-Ichi ; Nozoe, Akiko ; Urabe, Hiroki ; Chaki, Shigeyuki ; Fukasawa, Misako ; Ohtake, Norikazu ; Ochi, Motoki ; Hikichi, Hirohiko ; Miyakoshi, Naoki ; Hashihayata, Takashi ; Marumo, Toshiyuki

We previously reported that MGS0008 is a selective group II metabotropic glutamate receptor (mGlu2/3 receptor) agonist that is effective in animal models of schizophrenia. MGS0008 is a highly hydrophilic glutamate analog and is therefore expected to show low oral bioavailability in humans. To improve the oral bioavailability of MGS0008, ester prodrugs of MGS0008 were synthesized and their usefulness was evaluated. Among the prodrugs, the l-menthol-ester prodrug 4h demonstrated preferable lipophilicity, good chemical stability, and a high conversion rate to MGS0008 in human and monkey liver microsomes. A pharmacokinetic study in monkeys revealed that the oral bioavailability of MGS0008 after oral dosing of compound 4h was approximately 15-fold higher than that after oral dosing of MGS0008. Based on these findings, a diastereomer of compound 4h (compound 4j, or MGS0274), was selected as a candidate for clinical drug development, and its besylate is currently under development for the treatment of schizophrenia (Development code: TS-134).

2020-10-01·Neuropsychopharmacology1区 · 医学

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers

1区 · 医学

Article

作者: Kantrowitz, Joshua T ; Lahti, Adrienne C ; Potter, William Z ; Kegeles, Lawrence S ; Sobeih, Tarek ; Yang, Yvonne S ; Javitt, Daniel C ; Horga, Guillermo ; Grinband, Jack ; Krystal, John H ; Girgis, Ragy R ; Lee, Junghee ; Goff, Donald C ; Lieberman, Jeffrey A ; Wall, Melanie M ; Green, Michael F ; Choo, Tse-Hwei ; Marder, Stephen R

AbstractGlutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = −0.41; p = 0.04, d = −0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = −0.36; p = 0.008, d = −0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = −0.56; p = 0.079, d = −0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

100 项与 TS-134 相关的药物交易

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