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

Abstract

Event Abstract Back to Event Preclinical characterization and first-in-human administration of a selective monoacylglycerol lipase inhibitor, ABX-1431 Iain Fraser1*, Jacqueline Blankman1, Jason Clapper1, Cheryl Grice1, Gary O'Neill1, Alan Ezekowitz1, Archie Thurston2, Els Geenens3, Corinne Vandermeulen3 and Jan De Hoon3 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 (2019). 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 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Aug 2017; Published Online: 25 Jan 2019. * Correspondence: Dr. Iain Fraser, Abide Therapeutics, N/A, San Diego, CA, United States, iain@abidetx.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Iain Fraser Jacqueline Blankman Jason Clapper Cheryl Grice Gary O'Neill Alan Ezekowitz Archie Thurston Els Geenens Corinne Vandermeulen Jan De Hoon Google Iain Fraser Jacqueline Blankman Jason Clapper Cheryl Grice Gary O'Neill Alan Ezekowitz Archie Thurston Els Geenens Corinne Vandermeulen Jan De Hoon Google Scholar Iain Fraser Jacqueline Blankman Jason Clapper Cheryl Grice Gary O'Neill Alan Ezekowitz Archie Thurston Els Geenens Corinne Vandermeulen Jan De Hoon PubMed Iain Fraser Jacqueline Blankman Jason Clapper Cheryl Grice Gary O'Neill Alan Ezekowitz Archie Thurston Els Geenens Corinne Vandermeulen Jan De Hoon Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.