Therapeutics

T-817MA

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Overview

Name: T-817MA
Synonyms: T 817MA, T817MA
Chemical Name: 1-{3-[2-(1-benzothiophen-5-yl)ethoxy] propyl}-3-azetidinol maleate
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline), Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Toyama Chemical Co., Ltd.

Background

T-817MA is an orally available neurotrophic agent being developed for the treatment of Alzheimer's disease. T-817MA's molecular target has not been disclosed, but the compound has been reported in various cell-based and preclinical models to protect neurons against Aβ-induced neurotoxicity and memory deficits (e.g. Hirata et al., 2005Nguyen et al., 2007; Kimura et al., 2009). T-817MA appears to act by promoting neurite outgrowth and preserving synaptic plasticity in the cortex and hippocampus (Takamura et al., 2014). 

A treatment benefit has also been reported in sensorimotor gating, which is a biomarker for cognitive deficits in schizophrenia, as well as in models of hearing loss; however, no clinical development is ongoing in these indications (Seo et al., 2008; Uehara et al., 2012; Yamashita et al., 2008).

Findings

Phase 1 clinical development for T-817MA began in 2005. From 2008 to 2011, a multicenter Phase 2a trial in the United States and Canada compared a once-daily dose of 224 mg of T-817MA to placebo in 373 patients with mild to moderate Alzheimer's disease who are stable on donepezil therapy. The primary outcome was cognitive function as measured by the ADAS-cog; secondary outcomes were safety and overall impression using the ADCS Global Clinical Impression of Change (CGIC) and ADCS Activities of Daily Living (ADL). In this trial, only 72.1 percent of patients on placebo, versus 61.6 percent on T-817MA, completed the trial, limiting the conclusions that can be drawn from its results. Within these limitations, T-817MA appeared to show potential to slow cognitive and functional decline. The numerical differences on the cognitive, clinical, and functional readouts favored treatment but did not reach statistical significance. Results of a neuropsychiatric measure favored placebo, also without reaching statistical significance. A small imaging sub-study indicated trends favoring T-817MA, again not statistically significant. Side effects included diarrhea, nausea, dizziness, and headache; two serious adverse events were considered possibly related to the study drug (Schneider et al., 2013).

In March 2014, the North American consortium Alzheimer's Disease Cooperative Study (ADCS) started another one-year, Phase 2 study of T-817MA called Noble. It will compare 224 mg to 448 mg of T-817MA once daily and to placebo in 450 patients with mild to moderate Alzheimer's disease who are already taking donepezil or donepezil with memantine. This study will use similar primary and secondary outcomes, and is set to run until March 2016. Unlike most ADCS trials, this study receives no federal funding but is fully sponsored by Toyama.

For clinical trials on T-817MA, see clinicaltrials.gov.

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References

Therapeutics Citations

  1. Donepezil
  2. Memantine

Paper Citations

  1. . A novel neurotrophic agent, T-817MA [1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl}-3-azetidinol maleate], attenuates amyloid-beta-induced neurotoxicity and promotes neurite outgrowth in rat cultured central nervous system neurons. J Pharmacol Exp Ther. 2005 Jul;314(1):252-9. PubMed.
  2. . Ameliorative effects of a neuroprotective agent, T-817MA, on place learning deficits induced by continuous infusion of amyloid-beta peptide (1-40) in rats. Hippocampus. 2007;17(6):443-55. PubMed.
  3. . T-817MA, a neurotrophic agent, ameliorates the deficits in adult neurogenesis and spatial memory in rats infused i.c.v. with amyloid-beta peptide. Br J Pharmacol. 2009 Jun;157(3):451-63. PubMed.
  4. . Effects of the neurotrophic agent T-817MA on oligomeric amyloid-β-induced deficits in long-term potentiation in the hippocampal CA1 subfield. Neurobiol Aging. 2013 Oct 7; PubMed.
  5. . T-817MA, a novel neurotrophic compound, ameliorates phencyclidine-induced disruption of sensorimotor gating. Psychopharmacology (Berl). 2008 Apr;197(3):457-64. PubMed.
  6. . T-817MA, a novel neurotrophic agent, ameliorates loss of GABAergic parvalbumin-positive neurons and sensorimotor gating deficits in rats transiently exposed to MK-801 in the neonatal period. J Psychiatr Res. 2012 May;46(5):622-9. Epub 2012 Feb 18 PubMed.
  7. . Neuroprotective effects of T-817MA against noise-induced hearing loss. Neurosci Res. 2008 May;61(1):38-42. PubMed.

External Citations

  1. Schneider et al., 2013
  2. Noble
  3. clinicaltrials.gov

Further Reading

Papers

  1. . T-817MA, a novel neurotrophic agent, improves sodium nitroprusside-induced mitochondrial dysfunction in cortical neurons. Neurochem Int. 2006 Jan;48(2):124-30. PubMed.
  2. . A neuroprotective agent, T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate), prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice. Neuropharmacology. 2008 Oct;55(5):654-60. PubMed.
  3. . Blocking Effects of Human Tau on Squid Giant Synapse Transmission and Its Prevention by T-817 MA. Front Synaptic Neurosci. 2011;3:3. PubMed.
  4. . Protective effect of neurotrophic agent T-817MA against inner ear barotrauma in the guinea pig. J Pharmacol Sci. 2011;117(1):67-70. Epub 2011 Aug 25 PubMed.
  5. . T-817MA, but Not Haloperidol and Risperidone, Restores Parvalbumin-Positive γ -Aminobutyric Acid Neurons in the Prefrontal Cortex and Hippocampus of Rats Transiently Exposed to MK-801 at the Neonatal Period. ISRN Psychiatry. 2012;2012:947149. Print 2012 PubMed.