The endocannabinoid system includes the cannabinoid receptors (CB1 and CB2), which are responsible for the effects of both marijuana and natural ligands (like 2-AG and anandamide) that are produced by the body to activate cannabinoid receptors thereby modulating physiological processes such as pain, mood, and inflammation. Monoacylglycerol lipase (MGLL) breaks down 2-AG and thus serves as a key control-point for endocannabinoid signaling.
Abide has developed a novel first-in-class small-molecule inhibitor of MGLL, ABX-1431, that controls the magnitude of endogenous cannabinoid signaling by augmenting the levels of the endocannabinoid 2-AG. Abide has shown in preclinical animal studies that ABX-1431, by elevating the levels of 2-AG in the brain, mimics the beneficial analgesic effects of marijuana without negatively affecting cognition or behavior. Additionally, MGLL inhibition by ABX-1431 depletes the supply of arachidonic acid necessary for production of pro-inflammatory lipid mediators, thereby providing another mechanism through which ABX-1431 reduces pain and inflammation.
ABX-1431 has successfully completed dosing in a first-in-human, placebo-controlled, Phase 1a study. The drug was well tolerated and there were no serious adverse events. Preliminary data from an ongoing PET occupancy study indicate dose-related brain penetrance of orally-administered ABX-1431 using [18F]ABX-1488, an Abide proprietary, MGLL-specific PET ligand. Furthermore, an fMRI study aimed at assessing the patterns of neural activity in brain associated with ABX-1431 administration is scheduled to start early in the fourth quarter of 2016.
ABX-1431 provides a novel mechanism to treat both pain and neuroinflammation by enhancing the activity of the body’s natural cannabinoid signaling system. This mechanism has broad therapeutic potential for a range of neurological diseases, including multiple sclerosis [link to ABX-1431 Celgene option press release], movement disorders, and Alzheimer’s disease.
Abide is systematically interrogating the serine hydrolase family to identify and validate new targets, understand their basic biological functions, uncover their clinical relevance in disease areas with unmet need, and develop drugs to treat those disease states. While the therapeutic potential of serine hydrolases is broad and diverse, areas of particular interest to Abide scientists include central and peripheral inflammation, chronic and neuropathic pain, and metabolic disease. Other areas of relevant biology are partnering opportunities.