Download the Full PDF

Natural selection has a conservative bent, favoring variations on well-worn themes. Protein super­families, including enzymes that all share a common catalytic mechanism, are an example of this conser­vation in action, and a boon to drug discovery. Abide Therapeutics is mining one such enzyme superfam­ily, the serine hydrolases (SHs). Comprising over 200 members, the SH enzyme family has considerable untapped potential and has already yielded drug discovery gold in the form of a first-in-class inhibitor of one of these SHs, monoacyl glycerol lipase (MGLL). ABX-1431, an MGLL inhibitor with broad therapeutic potential, has completed initial phase 1 testing, and Abide is moving forward with additional clinical studies in several central nervous system (CNS) dis­orders, including multiple sclerosis (MS) and Tourette syndrome (TS), with an eye to establishing a wider franchise of MGLL-related inhibitors.

SHs play varied roles in CNS signaling, inflamma­tion, digestion, and metabolism, implying equally broad therapeutic and commercial potential for SH inhibitors. The druggability of the SH family is evi­denced by marketed drugs in three classes, notably including Januvia (sitagliptin) for type 2 diabetes. However, the substrates and function of many SHs are poorly understood, and traditional target-directed drug discovery has thus far only scratched the surface of possible SH drug targets.

The Abide discovery platform

Abide’s discovery platform allows rapid identification, characterization, and development of new, highly selective small-molecule inhibitors of individual SHs. It comprises a unique, SH-targeted small-molecule library and chemoproteomics platform based on activity-based protein profiling (ABPP). The Abide library is well characterized and extensive, contain­ing over 17,000 compounds and inhibitors of 80% of human SHs. The ABPP chemoproteomics approach uses chemical probes to selectively and covalently bind SH active sites in whole-cell or tissue lysates. Advantages include the fact that all active SHs are tested in parallel, enzymes are in a native state, and knowledge of the drug target is unnecessary. Target identification is accomplished by combined use of ABPP and mass spectrometry.

The preclinical profile of ABX-1431 demonstrates the power of the Abide platform. ABX-1431 is a potent and selective MGLL inhibitor. Inhibition of MGLL increases levels of its substrate, 2-arachi­donoylglycerol (2-AG), an endocannabinoid. 2-AG binding to cannabinoid receptor 1 (CB1) modulates neurotransmitter release in the CNS, acting as a brake on synaptic activity (Fig. 1). Exocannabinoids are reported to have therapeutic benefits in multiple CNS disorders, including treatment of spasticity in MS, chronic pain, and TS, suggesting that ABX-1431 may have similar positive effects while avoiding the relatively indiscriminate activation of CB1 in the CNS that is seen with exocannabinoids.

Figure 1: Modulating neurotransmission. (a) Classical neurotransmission stimulates 2-AG biosynthesis. (b) 2-AG activates CB1 receptors, reducing neurotransmission. (c) When synaptic equilibrium is disrupted, inhibition of MGLL locally can elevate 2-AG levels to rectifyn neurotransmitter imbalance. AA, arachidonic acid.

A rat acute pain model was used to interrogate the pharmacokinetic/pharmacodynamic (PK/PD) relationship of ABX-1431 preclinically. ABX-1431 showed dose-dependent efficacy, and it reduced MGLL activity and increased levels of 2-AG in the brains of treated animals. Abide developed assays to track these biomarkers clinically, measuring amounts of 2-AG in plasma and assessing MGLL activity and selectivity in peripheral blood mononuclear cell lysates. Kinetics of MGLL inhibition by ABX-1431, including the MGLL recovery (resynthesis) rate, were characterized in multiple cell types and species ahead of clinical trials. Drug-target engagement was also tracked in both brain and periphery in all preclini­cal efficacy models and helped to inform clinical dose selection for the first-in-human study.

Clinical studies of ABX-1431

An ABX-1431 phase 1 safety and tolerability and PK/PD study found no serious adverse events, and psychological profiling results were favorable, with no effect seen on mood or nociception. A separate positron emission tomography (PET) ligand study showed dose-dependent brain penetration by orally administered ABX-1431. A functional magnetic resonance imaging study is in progress to identify the regions of the brain modulated by ABX-1431 in response to pain and to compare these to regions active in subjects receiving placebo or no treatment, as well as to the existing literature on exocannabinoid brain activity patterns. In sum, Abide has developed a highly selective first-in-class inhibitor of MGLL and has correlated dose with drug exposure and target engagement. The stage is set to evaluate whether treatment at steady state modifies disease path­ways, with the knowledge that the target has been engaged, a rare circumstance for a CNS target.

Phase 1b studies with ABX-1431 are now ongoing in patients with TS and neuromyelitis optica, a pain­ful condition with high unmet need. In partnership with Celgene, a phase 2 study of ABX-1431 in MS patients to reduce spasticity is planned for early 2018. Additional studies to explore follow-on MGLL inhibi­tors with different profiles are also planned. Finally, Abide has identified novel targets for nonalcoholic steatohepatits and immuno-oncology, thereby dem­onstrating the diverse opportunities presented by selective targeting of the SHs. Abide is building on its unique chemoproteomics platform to discover and develop a first-in-class pipeline and extract maximum clinical value from the SH family.

Contact:

Alan Ezekowitz, President and CEO
Abide Therapeutics
San Diego, California, USA
Tel: +1-609-924-6452
Email: alan@abidetx.com
Website: www.abidetx.com