Event Abstract

Preclinical characterization and first-in-human administration of a selective monoacylglycerol lipase inhibitor, ABX-1431

  • 1 Abide Therapeutics, N/A, United States
  • 2 Seventh Wave Laboratories, N/A, United States
  • 3 UZ Leuven, Center for Clinical Pharmacology, Belgium

Background: Monoacylglycerol lipase (MGLL) is a serine hydrolase that breaks down 2-arachidonoylglycerol (2-AG), the major endocannabinoid. Inhibiting MGLL enhances 2-AG concentrations locally, which is expected to rectify neurotransmitter balance through activation of presynaptic CB1 receptors. ABX-1431 is a first-in-class, orally-available, selective, and potent covalent inhibitor of MGLL being developed for the treatment of diseases like multiple sclerosis, movement disorders and pain. Methods: ABX-1431 entered clinical studies supported by a comprehensive preclinical dossier. Selectivity for MGLL amongst other serine hydrolases was profiled using activity-based protein profiling, and MGLL enzyme-recovery kinetics were established. A translatable assay using peripheral blood mononuclear cells (PBMC) was developed to monitor clinical target engagement. ABX-1431 was evaluated in sequential single-, and multiple-ascending dose panels of healthy volunteers. Results: ABX-1431 doses administered orally were 2 to 200 mg as single doses, and 10 to 40 mg daily as multiple doses. Plasma concentrations of ABX-1431 increased in a dose-related fashion, with minimal accumulation. MGLL activity in PBMC was inhibited in a time- and dose-related fashion, with recovery of enzyme activity as drug concentrations declined. Central nervous system manifestations, consistent with activation of the endocannabinoid system were observed at higher doses of ABX-1431. Additional clinical assessments of mood, suicidality, cutaneous nociception and cognition revealed no clinically significant abnormalities. Conclusions: At oral doses that were generally safe and well-tolerated, ABX-1431 plasma concentrations and magnitude of inhibition of PBMC MGLL enzyme activity were similar to those associated with efficacy in preclinical models, supporting the continued clinical evaluation of this first-in-mechanism MGLL inhibitor.

Acknowledgements

None

Keywords: activity-based protein profiling, endocannabinoid modulator, serine hydrolase inhibitor

Conference: EUFEMED 2017, London, United Kingdom, 17 May - 19 May, 2017.

Presentation Type: Poster

Topic: EUFEMED 2017 CONFERENCE

Citation: Fraser I, Blankman J, Clapper J, Grice C, O'Neill G, Ezekowitz A, Thurston A, Geenens E, Vandermeulen C and De Hoon J (2017). Preclinical characterization and first-in-human administration of a selective monoacylglycerol lipase inhibitor, ABX-1431. Front. Pharmacol. Conference Abstract: EUFEMED 2017. doi: 10.3389/conf.fphar.2017.62.00011

Received: 29 Aug 2017; Published Online: 30 Aug 2017.

* Correspondence: Dr. Iain Fraser, Abide Therapeutics, N/A, San Diego, CA, United States, iain@abidetx.com

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