Lu AG06466

Lu AG06466 (elcubragistat; formerly ABX-1431) is a highly potent, selective, orally bioavailable, and central nervous system-penetrant irreversible inhibitor of monoacylglycerol lipase (MAGL, also designated MGLL), the principal serine hydrolase responsible for the hydrolysis of the endocannabinoid signaling lipid 2-arachidonoylglycerol (2-AG) in the mammalian brain. The compound was identified through an activity-based protein profiling-guided medicinal chemistry campaign at Abide Therapeutics in La Jolla, California, and was disclosed as compound 28 in the Cisar et al. (2018) report in the Journal of Medicinal Chemistry. It inhibits human MAGL with an IC50 of 14 nanomolar and mouse MAGL with an IC50 of 27 nanomolar through covalent carbamoylation of the catalytic serine residue (Ser122), and it demonstrates exquisite selectivity within the serine hydrolase superfamily, with greater than 100-fold selectivity over ABHD6 and greater than 200-fold selectivity over PLA2G7 as demonstrated in competitive activity-based protein profiling experiments.

The pharmacological consequence of MAGL inhibition is elevation of brain 2-AG concentrations, which enhances retrograde endocannabinoid signaling at presynaptic CB1 and CB2 cannabinoid receptors, reducing excessive excitatory and inhibitory neurotransmission in a synapse-selective, activity-dependent manner. A concurrent pharmacological effect is the reduction of the free arachidonic acid pool in the central nervous system, since MAGL-catalyzed hydrolysis of 2-AG is the dominant source of arachidonic acid in brain tissue; this reduction attenuates cyclooxygenase-mediated prostaglandin biosynthesis and downstream neuroinflammation. The dual mechanism of enhanced endocannabinoid tone and attenuated neuroinflammatory prostanoid production underwrites the antinociceptive, anxiolytic, anticonvulsant, and anti-inflammatory preclinical pharmacology of the compound.

Preclinically, Lu AG06466 inhibits brain MAGL activity in rodents with an oral ED50 of 0.5 to 1.4 mg/kg, produces dose-dependent elevation of brain 2-AG concentrations, suppresses pain behavior in the rat formalin inflammatory pain model, and exhibits anticonvulsant activity in a mouse model of Dravet syndrome. Oral bioavailability is approximately 64 percent in rats and 57 percent in dogs. The compound generates a pharmacologically active metabolite, Lu AG06988, which is itself a potent and selective MAGL inhibitor with comparable in vitro and in vivo pharmacodynamic properties.

Lundbeck acquired Abide Therapeutics in May 2019 for 250 million US dollars upfront with up to 150 million in development milestones, redesignating the compound from ABX-1431 to Lu AG06466 and advancing it into a broad Phase 2 clinical program spanning Tourette syndrome, focal epilepsy, post-traumatic stress disorder, fibromyalgia, and spasticity in multiple sclerosis. In a Phase 1b single-dose crossover study in 20 adults with Tourette syndrome, a single 40 mg fasted dose produced statistically significant reduction in tic severity on the Yale Global Tic Severity Scale Total Tic Score at 8 hours, significant motor tic intensity reduction on the Adult Tic Questionnaire at 4, 8, and 12 hours, and significant reduction in premonitory urges. However, the subsequent Phase IIa 12-week randomized, placebo-controlled trial in 49 adults with Tourette syndrome failed to demonstrate efficacy, with the treatment difference at week 8 favoring placebo. The Tourette syndrome indication was discontinued. Other indications remain under investigation; published efficacy data from the epilepsy, PTSD, fibromyalgia, and spasticity programs have not yet appeared in peer-reviewed literature as of the most recent monograph revision. Brain MAGL occupancy has been characterized by positron emission tomography using [18F]MNI-1188 in healthy volunteers, and drug-drug interaction studies have characterized the compound as a CYP3A4 substrate with interaction potential at CYP3A4, CYP2D6, and CYP2B6 pathways. The compound is well tolerated at single and repeated doses studied, with headache, somnolence, and fatigue as the most frequently reported adverse events. This monograph reviews the chemistry, synthesis, and structural class; the molecular pharmacology of MAGL inhibition and endocannabinoid system modulation; the preclinical and clinical pharmacology across all studied indications; pharmacokinetics; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event signal; and a comparative assessment of five MAGL inhibitor candidates against Lu AG06466 on five competency standards.