Abide Therapeutics Announces Dosing of First Subject in Phase 1b Study of ABX-1431 in Patients with Neuromyelitis Optica (NMO)
- Category: Small Molecules
- Published on Tuesday, 10 October 2017 20:35
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Potential Therapy for Chronic Central Pain
SAN DIEGO, CA, USA I October 10, 2017 I Abide Therapeutics, a developer of innovative pharmaceuticals, announced today 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 a 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 [18F]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.
About the Endocannabinoid System
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.
Direct activation of cannabinoid receptors by medicinal cannabis demonstrates therapeutic benefits on pain, spasticity, sleep, appetite, and nausea; however, the numerous psychoactive side effects limit clinical use. Cannabis indiscriminately activates cannabinoid receptors throughout the body; this global activation is likely responsible for the side effects of medical cannabis. In contrast, inhibiting MGLL boosts the body's natural 2-AG concentrations in discrete areas of the brain only when and where 2-AG is being released. By amplifying this natural physiological response, MGLL inhibition is expected to rectify neurotransmitter imbalance through activation of CB1 receptors.
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.
In September 2016, Celgene Corporation exercised its option to obtain ex-US rights to ABX-1431. Celgene will be responsible for development costs for all indications from Phase 2 clinical trials and beyond, while Abide retains US rights and is conducting a number of Phase 1b studies to explore indications where endocannabinoid modulation may affect disease progression.
About Abide Therapeutics
Abide Therapeutics combines an innovative discovery platform and a library of proprietary small molecules to address biological pathways with therapeutics that enhance the body's normal physiological response to disease. The platform enables Abide to quickly and efficiently identify, modify and validate small molecule inhibitors that target serine hydrolases, a highly relevant but under-explored class of enzymes. Abide's initial area of focus is on addressing neurological disorders with limited treatment options through the endocannabinoid pathway.
SOURCE: Abide Therapeutics