TS-134 / Taisho - LARVOL DELTA

Glutamatergic Mechanisms: Aim2 (clinicaltrials.gov) - P1 | N=120 | Suspended | Sponsor: New York State Psychiatric Institute | Trial completion date: Aug 2027 ➔ Aug 2029 | Trial primary completion date: Aug 2025 ➔ Aug 2028

Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry

Glutamatergic Mechanisms: Aim2 (clinicaltrials.gov) - P1 | N=120 | Suspended | Sponsor: New York State Psychiatric Institute | Trial completion date: Aug 2026 ➔ Aug 2027

Trial completion date • CNS Disorders • Psychiatry

Chemical composition, sources, and health risks of PM in small cities with different urbanization during 2020 Chinese Spring Festival. (PubMed, Environ Sci Pollut Res Int) - "The study found high levels of PM pollution with the average concentration of 168.05 µg/m in TS, 134.59 µg/m in SY, and 125.71 µg/m in GG...As and Cr(VI), as the major pollutants, their associated sources, industry sources, and fireworks sources, posed the greatest risk to people at the sampling sites after exposure to PM. This work supports the improvement of PM control strategies in small Chinese cities during the CSF."

Journal • Infectious Disease • Novel Coronavirus Disease

Glutamatergic Mechanisms: Aim2 (clinicaltrials.gov) - P1 | N=120 | Suspended | Sponsor: New York State Psychiatric Institute | Recruiting ➔ Suspended

Trial suspension • CNS Disorders • Psychiatry

Ketamine Induced Pharmacobold as a Target Engagement Biomarker in Schizophrenia: Dose Response Of Pharmacobold And Cardiovascular Effects (CINP 2023) - P1, P1/2 | "This data supports an “optimal” dose of 0.086 mg/kg to generate an effect size of 1.5, supporting follow-up studies with TS-134 (NCT05401227) and in patients. Current ketamine safety guidelines require termination of a scan if blood pressure exceeds specified thresholds (e.g., systolic blood pressure >180 or diastolic blood pressure >120 for more than two minutes). Increases in vitals were modest, unrelated to age or gender, supporting safety of this pharmacodynamic target-engagement biomarker."

Biomarker • Cardiovascular • CNS Disorders • Psychiatry • Schizophrenia

Glutamatergic Mechanisms: Aim2 (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: New York State Psychiatric Institute | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Psychiatry

Glutamatergic Mechanisms: Aim2 (clinicaltrials.gov) - P1 | N=120 | Not yet recruiting | Sponsor: New York State Psychiatric Institute | Initiation date: Aug 2022 ➔ Dec 2022

Trial initiation date • CNS Disorders • Psychiatry

Glutamatergic Mechanisms: Aim2 (clinicaltrials.gov) - P1 | N=120 | Not yet recruiting | Sponsor: New York State Psychiatric Institute

New P1 trial • CNS Disorders • Psychiatry

Bottom-up physiologically based pharmacokinetic modeling for predicting the human pharmacokinetic profiles of the ester prodrug MGS0274 and its active metabolite MGS0008, a metabotropic glutamate 2/3 receptor agonist. (PubMed, Xenobiotica) - "This research was aimed at constructing a PBPK model for predicting the human PK of the ester prodrug MGS0274 and its parent compound MGS0008 after a single oral administration of MGS0274 besylate.3...We confirmed that our method reliably predicted the human PK and that the estimated CL was comparable to that calculated retrospectively using the PBPK model, suggesting that the methodology for estimating the CL was valid.5. Our proposed methodology is expected to be helpful for human PK prediction of ester prodrugs hydrolyzed by CES1 and their hydrophilic parent compounds even during the preclinical phase."

Journal • PK/PD data • Gastrointestinal Disorder • CES1

Drugs Targeting the Glutamate System Warrant Continued Development for Schizophrenia, Study Finds - "In the continuing effort to develop new medicines to treat schizophrenia... Jeffrey Lieberman, M.D., and including nine other Council Members, BBRF grantees and prize winners, has reported encouraging results from a test of two drugs that target a novel mechanism in the brain....Dr. Lieberman and colleagues postulated that POMA failed to generate therapeutic effects because the doses tested were too low, and perhaps too low to engage the drug’s receptor-target. A parallel study of TS-134 using doses of presumably equal potency was performed in tandem. Such comparisons of novel drugs in early development are highly informative but rarely done."

Clinical • Schizophrenia

Discovery of MGS0274, an ester prodrug of a metabotropic glutamate receptor 2/3 agonist with improved oral bioavailability. (PubMed, Eur J Med Chem) - "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)."

Journal • CNS Disorders • Schizophrenia

Safety and Pharmacokinetic Profiles of MGS0274 Besylate (TS-134), a Novel Metabotropic Glutamate 2/3 Receptor Agonist Prodrug, in Healthy Subjects (ACNP 2018) - "After single and multiple dose administrations of TS134, the molar ratio of MGS0008 AUCs were approximately twenty-fold higher than those of MGS0274. TS-134 (active ingredient: MGS0274 besylate) is orally bioavailable in humans, converts rapidly and extensively to MGS0008 and exhibits a good brain penetration profile. Orally administered TS-134 in HVs was generally safe and well-tolerated up to 10 mg as a single dose, and up to 80 mg when administered daily using the multiple dose titration schemes for 14 days. TS-134 is a promising candidate for further clinical development for the treatment of schizophrenia."

Clinical • PK/PD data • CNS Disorders • Schizophrenia

Safety, Tolerability and Pharmacokinetics of 14-day Multiple Dose Titrations of TS-134 in Healthy Volunteers (clinicaltrials.gov) - P1; N=59; Completed; Sponsor: Taisho Pharmaceutical R&D Inc.

New P1 trial • Biosimilar

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. (PubMed, Neuropsychopharmacology) - "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."

Clinical • Journal • CNS Disorders • Schizophrenia

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia. (PubMed, Pharmacol Res Perspect) - "Furthermore, the hydrolytic activity against MGS0274 in the human liver S9 fraction was comparable to that in monkeys, suggesting the possibility of the rapid presystemic hydrolysis of MGS0274 to MGS0008 in humans, as it is in monkeys. Consequently, MGS0274 besylate is expected to function as a preferable prodrug in humans."

Journal • Preclinical

Safety and Pharmacokinetic Profiles of MGS0274 Besylate (TS-134), a Novel Metabotropic Glutamate 2/3 Receptor Agonist Prodrug, in Healthy Subjects. (PubMed, Br J Clin Pharmacol) - "TS-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."

Clinical • Journal • PK/PD data • CNS Disorders • Schizophrenia

Are mobile device applications effective at supporting COPD self-management compared to usual care? (ERS 2019) - "Results 1341 citations were retrieved and 12 RCTs were eligible for review...Conclusions Use of mobile device applications by people with COPD may offer benefits in quality of life, physical function and activity levels; however, there was significant heterogeneity in the outcomes reported by the studies. Future trials should collect data on a standardised set of outcomes to allow comparison of findings."

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 (SOBP 2019) - "Results of this TS-134 target engagement study showed a greater target engagement (suppression against ketamine-evoked pharmacoBOLD) at 20 mg than that of 60 mg. Unexpectedly, large placebo effects were seen in the TS-134 study, reducing power to detect between group differences. Results comparing to a parallel study of another mGlu2/3 agonist, pomaglumetad, will be 1 presented"

Clinical