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A Novel Therapeutic (NTRX-07) Targeting Neuroinflammation in Alzheimer's disease is Undergoing Phase I trials
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Mohamed Naguib, MSc, FCARCSI, MD and Tony Giordano, PhD, Cleveland Clinic, Cleveland, OH, USA
Neuroinflammation plays a central role in the pathogenesis of Alzheimer’s disease (AD). More than 25 genetic loci have been associated with the risk of developing late onset AD, and many of the linked genes are expressed in astrocytes, microglia, and oligodendrocytes. Reactive microglia and astrocytes express cannabinoid type 2 (CB2) receptors in post-mortem brains of AD patients and AD rodent models as well as in other neurodegenerative disorders. Activation of the CB2 receptor system results in inhibition of neuroinflammatory signaling pathways and restoration of normal microglial activity in AD and other neurodegenerative disorders.
Method: We have developed a novel, blood brain barrier-permeable, and highly selective CB2 agonist that lacks psychoactivity, NTRX-07 (also known as MDA7), 1-[(3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl] piperidine (Fig. 1), which will undergo Phase I trials in 2019 under an accepted Investigational New Drug Application. We have studied the effect of NTRX-07 on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment in APP/PS1 mice and in rats received bilateral microinjection of amyloid-beta (Ab1–40) fibrils into the hippocampal CA1 area.
Result: NTRX-07 treatment has been shown to i) restore physiological microglial activity (Fig. 2), ii) inhibit the production of inflammatory cytokines by modulating TLR4-NF-kB-MyD88 signal pathways (Fig. 3), iii) promote Aβ clearance (Fig. 4), and iv) restore synaptic plasticity, cognition, and memory in rodent models of AD (Figs. 5 and 6).
Conclusion: Our findings suggest that NTRX-07 has a potential therapeutic effect in the setting of AD. Our clinical development program includes a single ascending dose, randomized, placebo controlled Phase Ia study with normal volunteers scheduled to begin in the Summer of 2019, which will be followed by a randomized, placebo controlled, multiple ascending dose, 28 days treatment Phase Ib study in AD subjects where CSF samples will be collected before and after treatment for biomarker analysis. The analysis of neuroinflammatory, Aß, tau and synaptic biomarkers will provide an indication of whether the effects of NTRX-07 observed in the rodent studies will translate to human AD subjects.

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