Our Pipeline

Restoring Balanced Neurotransmission

Abide’s lead program targets the enzyme monoacylglycerol lipase (MGLL), a key gatekeeper of the endocannabinoid system. MGLL controls neurotransmission, and inhibitors of this enzyme have the potential to restore proper functioning of the central nervous system (CNS) in disease states marked by deregulated neuronal activity. Our MGLL inhibitors represent a compelling and differentiated mechanism to modulate neurotransmission with broad potential to treat a variety of neurological diseases.

Building a Proprietary First-in-Class Pipeline

Abide’s development pipeline includes three first-in-class compounds directed at MGLL for the treatment of neurological diseases, including pain. Our discovery programs include inhibitors directed towards other novel serine hydrolase targets for indications including nonalcoholic steatohepatitis (NASH) and inflammation.

In advancing our portfolio of first-in-class MGLL inhibitors to the clinic, we are committed to addressing major CNS diseases that lack effective therapies. We aspire to bring MGLL inhibitors forward as transformative new medicines to treat these diseases.

Advancing Our Pipeline: MGLL Inhibitors

ABX-1431 is a first-in-class inhibitor of MGLL designed to treat a broad range of CNS diseases by potentiating the endocannabinoid system. ABX-1431 has shown promising clinical data in a Phase 1b placebo-controlled trial in patients with Tourette Syndrome, achieving statistical significance on multiple clinical endpoints. We are developing ABX-1431 and two additional MGLL inhibitors, ABX-1762 and ABX-1626, for Tourette Syndrome and other CNS diseases, such as pain.

MGLL inhibitors tune brain signaling networks by increasing levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) and stimulating the cannabinoid receptor CB1 in active circuits. This regulates neurotransmission in conditions where synaptic equilibrium is disrupted. Because MGLL inhibitors modulate naturally activated neural circuits, they are clearly differentiated from other therapeutic approaches that target the endocannabinoid system, such as medical cannabis, which causes global activation of CB1 and leads to unwanted psychoactive effects.

We have studied ABX-1431 in human clinical trials utilizing translational target engagement biomarkers to establish a generally safe and well-tolerated dose range for inhibition of MGLL and subsequent recovery of MGLL activity following clearance of ABX-1431. We have confirmed occupancy of MGLL in the human brain by orally administered ABX-1431 using PET imaging with our MGLL-specific tracer [18F]ABX-1488.

From Pathway to Patient: Clinical Indications for MGLL Inhibitors

MGLL inhibition provides a novel mechanism to treat neurological diseases by potentiating the body’s natural endocannabinoid signaling system, which, in turn, restores proper levels of neurotransmission in disease states marked by an imbalance of synaptic activity. This mechanism has broad therapeutic potential for a range of neurological diseases. Key indications for our MGLL program are Tourette Syndrome, Levodopa-Induced Dyskinesia, and Neuropathic Pain.

Tourette Syndrome

Tourette Syndrome (TS) is a neuropsychiatric disorder that first appears during childhood. People with TS experience sudden, involuntary, repetitive movements and vocalizations called tics. The tics may be preceded by an uncomfortable feeling or sensation called a premonitory urge. This urge may allow patients to suppress their tics, but suppression may worsen the urge. Current medical treatments for TS include both approved and off-label drugs, including antipsychotic agents. However, many of these therapies are associated with significant side effects such as sedation and undesirable metabolic effects. There is a significant need for therapies with improved side effect profiles.

An exploratory Phase 1b trial with a single dose of ABX-1431 in adult TS patients demonstrated statistically significant effects across multiple endpoints of tic reduction as well as premonitory urge. In addition, encouraging trends were seen in common comorbid conditions like obsessive-compulsive disorder (OCD). According to Dr. Kirsten Müller-Vahl, the Principal Investigator for the study, this suggests that ABX-1431 could be a breakthrough in TS therapeutics with the potential to treat the whole disease, unlike current options which primarily treat tics. Based on these results, we began a Phase 2 trial with ABX-1431 in adult TS in 2018.

Levodopa-Induced Dyskinesia

Dyskinesias are uncontrolled, involuntary movements that can look like fidgeting, writhing, wriggling, head-bobbing, or body-swaying. In patients with Parkinson’s disease, dyskinesia usually develops after long-term use of levodopa (the "gold standard" treatment for Parkinson’s) and is called levodopa-induced dyskinesia, or LID. Patients usually continue levodopa therapy to avoid unacceptable trade-offs with motor instability – i.e., "off" times, when the medication is not working optimally and Parkinson's symptoms return. Not all patients with Parkinson’s disease develop dyskinesia, and in those that do it is expressed variably, affecting different body parts and occurring with different degrees of severity. In many cases, dyskinesia can be disabling and interfere with daily activities like employment, exercise, and social activities. Current treatments for LID include adjusting levodopa dose or formulation. The only specific oral therapy for dyskinesia is amantadine, which does not benefit all patients, and is limited by neuropsychiatric side effects. Selected patients may benefit from neurosurgery (deep brain stimulation) or levodopa gel delivered by tube into the intestine.

LID is associated with dysfunction of the basal ganglia, a part of the brain involved in the regulation of movement. MGLL is highly expressed in the basal ganglia and is a key regulator of neuronal communication. Abide is currently studying the effects of MGLL inhibition for the treatment of LID.

Neuropathic Pain

Chronic neuropathic pain (NP) results from damage to the nervous system in the brain or spinal cord or in the peripheral nerves. NP is a common and debilitating condition that may occur in 10% of Americans. Current approved treatments for NP include gabapentinoids and antidepressants, but many patients find these drugs work poorly. Beyond the lack of effective medications, many patients chronically use opioid drugs, despite the uncertain effects of these drugs in NP. There is a pressing need for efficacious non-opioid therapies for NP.

MGLL inhibitors have been shown to reduce pain in preclinical models of inflammatory, chemical, post-surgical, and neuropathic pain. In addition, significant scientific evidence supports the use of exocannabinoids for the treatment of pain, including controlled clinical studies in patients with NP. MGLL inhibitors may offer significant therapeutic benefits over exocannabinoids, with potential for increased efficacy and a better safety profile. We are advancing ABX-1431 into Phase 2 as a non-opioid treatment for patients with NP.