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Role of Microglia in Neuroinflammation and Neurodegenerative Diseases

The role of microglia is particularly evident in AD, where M2 microglia help in clearing amyloid β, while M1 microglia contribute to neuroinflammation and synaptic damage. In AD and other neurodegenerative disorders, the M1 phenotype is increased. As microglia transition from the M2 to M1 state, cannabinoid type 2 (CB2) receptor expression is induced.

The activation of immune cells, known as microglia, in the central nervous system (CNS) promotes an inflammatory response that serves as a hallmark for a range of neurologic disorders such as Alzheimer’s Disease (AD), amyotrophic lateral sclerosis, neuropathic pain, multiple sclerosis, and Parkinson’s Disease. Microglia play a critical role in CNS immune responsiveness. There are two states of microglia, an M1 phenotype that is predominantly neurotoxic and a neuroprotective M2 phenotype.

Our lead program, NTRX-07, a novel CB2 agonist, activates this receptor and promotes M1 microglia to transition from the pro-inflammatory phenotype to the neuroprotective, M2 phenotype. This results in reduced neuronal damage, increased clearance of amyloid β and inhibited neuroinflammation.



NTRX-07 as a Treatment for Alzheimer’s Disease (AD)

NTRX-07 is a potent, highly selective, oral, CB2 receptor agonist in development for the treatment of Alzheimer’s Disease (AD).

In a Phase 1b clinical study that included elderly non-AD subjects and patients with early-stage AD, NRTX-07 demonstrated a favorable safety profile at all dose ranges, a pharmacokinetic (PK) profile consistent with preclinical studies expected to drive clinical activity, and a trend toward cognitive improvement in the AD patients that were treated with NTRX-07. This trend included improvements in two key cognitive assessments, the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-Cog) test and quantitative electroencephalogram (qEEG).

Read more here.

summary of phase 1b study results 

  • The safety profile of NTRX-07 supports further clinical development, with no dose-limiting or serious adverse events observed during the trial.

  • PK demonstrated that levels of NTRX-07 in the plasma were within the target ranges expected to drive efficacy based on the preclinical data.

  • Several cognitive function measures were evaluated within the cohort of AD patients. An interesting trend toward improvement was observed in AD participants using the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-Cog) test. Of 6 treated patients tested with ADAS-Cog, all 6 showed a reduction in the number of errors following treatment, with 3 having clinically meaningful improvements (3-4 point score reduction). In contrast, neither of the non-treated AD patients showed an improvement. A post-hoc analysis was carried out on electroencephalogram (EEG) data collected for safety analysis, which showed that following treatment with NTRX-07, patients evaluated with quantitative electroencephalogram (qEEG) demonstrated a partial reversal of the lowering of mean frequency known to exist in AD patients.

potential as a combination therapy

Based on its safety profile, NTRX-07 has strong potential to be used in combination with approved antibody treatments. In preclinical studies we have shown that NTRX-07 reduces microglial activity, leading to reductions in neuroinflammation, while also helping promote clearance of amyloid β. NeuroTherapia plans to test this potential synergy with currently approved antibody treatments.

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