Therapeutics

NTRX-07

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Overview

Name: NTRX-07
Synonyms: MDA7
Chemical Name: 1-[(3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl]piperidine
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: NeuroTherapia, Inc.

Background

NTRX-07 is a cannabinoid receptor agonist. It enters the central nervous system and activates receptors on microglia, reportedly to reduce neuroinflammation. It is specific for the cannabinoid receptor type 2 (CB2) and does not alter mood or behavior as do CB1 receptor agonists. 

This compound emerged from an academic lab and was subsequently explored by its discoverer. Studies reported activity in animal models of neuropathic pain (Naguib et al., 2008; Diaz et al., 2009). In a model of chemotherapy-induced nerve pain, it altered pathways involved in inflammation and microglia dysregulation (Xu et al., 2014; Wu et al., 2019; see also Naguib et al., 2012). Neuroprotective and anti-inflammatory effects were reported in a model of complex regional pain syndrome (Xu et al., 2016).

Preclinical work related to Alzheimer’s disease was conducted by the same group. In rats injected with Aβ40 fibrils, NTRX-07 was reported to prevent microglial activation, promote Aβ clearance, restore synaptic plasticity, and improve cognition and memory (Wu et al., 2013). In the APP/PS1 mouse, NTRX-07 suppressed neuroinflammation, improved amyloid clearance, synaptic function, and markers of neurogenesis in the hippocampus, and restored behavior in the Morris water maze (Wu et al., 2017).

Findings

From October 2019 to December 2020, NeuroTherapia conducted a Phase 1, single-ascending-dose study in 48 healthy volunteers. Six cohorts received oral doses from 0.3 to 8 mg/kg, with placebo control. Results from the first three cohorts were presented at the July 2020 AAIC (Foss et al., 2020). The drug attained blood levels better than expected from animal studies, and reached concentrations predicted to be efficacious based on preclinical animal models. No adverse effects were reported at the highest dose tested, 2 mg/kg. In December 2020, the company reported results on all cohorts, claiming no dose-limiting side effects (press release). The two highest doses induced lightheadedness and flushing.

At the October 2023 CTAD conference, NeuroTherapia presented data on a Phase 1b study, which involved administration of 10, 30, or 90 mg NTRX-07 daily for seven days to healthy older adults (press release). The drug was reported to induce mild and transient adverse effects, and no safety concerns. A high-fat meal before dosing not change drug exposure. The study went on to evaluate a cohort of eight mild AD patients given 90 mg daily for one week or placebo. The company claimed a trend toward improvement in the ADAS-Cog, with all six treated patients but not the two on placebo scoring better. They also claimed normalization of quantitative electroencephalogram (EEG) outcomes in treated patients. There were no significant changes in biomarkers. This trial does not appear in registries.

For details on NTRX-07 trials, see clinicaltrials.gov.

Last Updated: 10 Nov 2023

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References

Paper Citations

  1. Naguib M, Diaz P, Xu JJ, Astruc-Diaz F, Craig S, Vivas-Mejia P, Brown DL. MDA7: a novel selective agonist for CB2 receptors that prevents allodynia in rat neuropathic pain models. Br J Pharmacol. 2008 Dec;155(7):1104-16. Epub 2008 Sep 1 PubMed.
  2. Diaz P, Phatak SS, Xu J, Fronczek FR, Astruc-Diaz F, Thompson CM, Cavasotto CN, Naguib M. 2,3-Dihydro-1-benzofuran derivatives as a series of potent selective cannabinoid receptor 2 agonists: design, synthesis, and binding mode prediction through ligand-steered modeling. ChemMedChem. 2009 Oct;4(10):1615-29. PubMed.
  3. Xu JJ, Diaz P, Bie B, Astruc-Diaz F, Wu J, Yang H, Brown DL, Naguib M. Spinal gene expression profiling and pathways analysis of a CB2 agonist (MDA7)-targeted prevention of paclitaxel-induced neuropathy. Neuroscience. 2014 Feb 28;260:185-94. Epub 2013 Dec 18 PubMed.
  4. Wu J, Hocevar M, Bie B, Foss JF, Naguib M. Cannabinoid Type 2 Receptor System Modulates Paclitaxel-Induced Microglial Dysregulation and Central Sensitization in Rats. J Pain. 2019 May;20(5):501-514. Epub 2018 Nov 8 PubMed.
  5. Xu J, Tang Y, Xie M, Bie B, Wu J, Yang H, Foss JF, Yang B, Rosenquist RW, Naguib M. Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post-ischemic pain model of complex regional pain syndrome type I in rats. Eur J Neurosci. 2016 Dec;44(12):3046-3055. Epub 2016 Oct 13 PubMed.
  6. Wu J, Bie B, Yang H, Xu JJ, Brown DL, Naguib M. Activation of the CB(2) receptor system reverses amyloid-induced memory deficiency. Neurobiol Aging. 2012 Jul 12; PubMed.
  7. Wu J, Hocevar M, Foss JF, Bie B, Naguib M. Activation of CB2 receptor system restores cognitive capacity and hippocampal Sox2 expression in a transgenic mouse model of Alzheimer's disease. Eur J Pharmacol. 2017 Sep 15;811:12-20. Epub 2017 May 25 PubMed.

External Citations

  1. Foss et al., 2020
  2. press release
  3. press release
  4. clinicaltrials.gov
  5. Naguib et al., 2012

Further Reading

Papers

  1. Astruc-Diaz F, McDaniel SW, Xu JJ, Parola S, Brown DL, Naguib M, Diaz P. In vivo efficacy of enabling formulations based on hydroxypropyl-β-cyclodextrins, micellar preparation, and liposomes for the lipophilic cannabinoid CB2 agonist, MDA7. J Pharm Sci. 2013 Feb;102(2):352-64. Epub 2012 Nov 28 PubMed.
  2. Kiraly M, Foss JF, Giordano T. Neuroinflammation, its Role in Alzheimer's Disease and Therapeutic Strategie. J Prev Alzheimers Dis. 2023;10(4):686-698. PubMed.
  3. Bie B, Wu J, Foss JF, Naguib M. An overview of the cannabinoid type 2 receptor system and its therapeutic potential. Curr Opin Anaesthesiol. 2018 Aug;31(4):407-414. PubMed.