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.
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
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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