Abide Therapeutics announced initiation of dosing in a Phase 1b study to evaluate the effects of ABX-1431, a first-in-class investigational monoacylglycerol lipase (MGLL) inhibitor in patients with neuromyelitis optica (NMO) and related neuroinflammatory disorders associated with central pain. NMO is a rare, serious autoimmune disorder of the central nervous system that selectively attacks the optic nerves and spinal cord.
The Phase 1b study, which is ongoing at two clinical centers in the UK, is a placebo-controlled crossover design using ABX-1431, an orally available small molecule that modulates the activity of the endocannabinoid neurotransmitter system. The study will assess the effect of an ABX-1431 on chronic central pain in patients with NMO and related disorders.
Pain is a common and disabling consequence of disorders such as NMO, and has been linked to dysregulation of the endocannabinoid system. Treatment of central pain in these patients is challenging; pain relief is frequently inadequate. New therapeutic options for central pain, particularly the pain experienced by NMO patients, are needed urgently. The ABX-1431 study will provide the opportunity to assess the potential therapeutic impact of modulating the dysregulated neurotransmission in these patients, with the goal of providing them relief from their severe, chronic pain.
"Restoring neurotransmitter balance represents a common thread of the mode of action of ABX-1431, and this study in NMO patients provides an opportunity to test the ability of the drug to provide relief to patients with a painful central demyelinating condition," said Alan Ezekowitz, MBChB, DPhil, CEO and President of Abide Therapeutics.
ABX-1431 has successfully completed dosing in a first-in-human, placebo-controlled, Phase 1 dosing study. The drug was generally well tolerated, and there were no serious adverse events. Data from a PET occupancy study indicate dose-dependent brain penetrance of orally-administered ABX-1431 using ABX-1488, an Abide proprietary, MGLL-specific PET ligand. A study of ABX-1431 in patients with Tourette Syndrome was initiated in early 2017 and is nearing completion.
Cannabinoid receptor 1 (CB1) is critical to regulating neurotransmission. It is the most highly expressed G-protein coupled receptor in the brain, and its main endogenous ligand is 2-arachidonoylglycerol (2-AG). Monoacylglycerol lipase (MGLL) is an enzyme that catalyzes the breakdown of 2-AG, and as a result regulates the activation of CB1. A second cannabinoid receptor, CB2, which is found primarily on immune cells and is thought to mediate certain immune functions, also has 2-AG as an endogenous ligand. Preclinical studies with MGLL inhibitors demonstrate that raising the level of 2-AG has multiple therapeutic effects, including reduction of pain responses, control of spasticity, anxiolytic effects, and reduction of neurodegenerative pathology.
Abide Therapeutics is developing ABX-1431, a first-in-class, small-molecule inhibitor of monoacylglycerol lipase (MGLL) to treat neurological disorders, pain, and neuroinflammation. ABX-1431, a potent and selective inhibitor of MGLL, has been shown to modulate 2-arachidonoylglycerol (2-AG) levels in preclinical species and is expected to produce beneficial effects in humans through selective elevation of 2-AG. MGLL inhibition causes an elevation of 2-AG in the brain and propagates signaling through the CB1 endocannabinoid receptor pathway. Additionally, MGLL inhibition by ABX-1431 depletes the supply of the inflammatory signaling molecule arachidonic acid, thereby providing another potential mechanism for alleviating pain and inflammation.