Abide Therapeutics has successfully completed an exploratory Phase 1b study in Tourette Syndrome (TS) with ABX-1431, a first-in-class investigational monoacylglycerol lipase (MGLL) inhibitor. ABX-1431 was generally safe and well-tolerated. In this randomized, double-blind, placebocontrolled crossover study in adults, patients receiving a single dose of ABX-1431 consistently showed a positive impact on key measures of TS symptoms, which included the Yale Global Tic Severity Scale (YGTSS). The study was conducted at Hannover Medical School's early-phase proof-of-concept center, CRC Hannover.
"The treatment options for Tourette patients are limited by their efficacy profile and by CNS and metabolic safety concerns. These ABX-1431 data are very encouraging as the drug was well-tolerated, and, remarkably, after only a few hours there was a significant effect compared to placebo. For example, one patient reported a dramatic decrease in his urge to tic, which not only reduced the number and intensity of his tics but also allowed him to focus on his work. This kind of treatment effect was generally observed, suggesting that this drug has the potential to treat all the symptoms of the disorder, unlike current options which primarily treat only tics. ABX-1431 has the potential to be a true breakthrough in the treatment of Tourette Syndrome," said Kirsten Müller-Vahl, MD, Professor of Psychiatry at the Department of Psychiatry, Social Psychiatry and Psychotherapy at the Hannover Medical School, Germany. Dr. Müller-Vahl was the Principal Investigator for the study.
In this placebo-controlled study of 19 adult TS patients receiving a single dose of ABX-1431, change from baseline was measured in the YGTSS, Adult Tic Questionnaire (ATQ), Premonitory Urge for Tics Scale (PUTS), and Modified Rush Video Scale (MRVS). A statistically significant reduction of 10% (placebo-adjusted, p= 0.0384) in the Total Tic Score of the YGTSS was observed at eight hours. Furthermore, statistically significant effects were seen in the PUTS, a scale measuring the intensity of the premonitory urge to tic, which is an uncomfortable sensation experienced immediately prior to tics, and in the ATQ, a self-assessment of tics, where tic intensity was reduced an average of 30%. Standardized video assessment (the MRVS) also showed improvement, but did not reach statistical significance. ABX-1431 was generally safe and well-tolerated. There were no serious adverse events, and all adverse events (AE) resolved. Headache, somnolence, and fatigue were the most common AE.
This Phase 1b study in adults was a randomized, blinded, placebocontrolled crossover, single dose design. Patients were evaluated for their Tourette Syndrome (TS) symptoms by changes in rating in the following measures over time (pre-dose, 4 hours post-dose, 8 hours post-dose) in four co-primary endpoints: Yale Global Tic Severity Scale (YGTSS), Adult Tic Questionnaire (ATQ), Premonitory Urge for Tics Scale (PUTS), Modified Rush Video Scale (MRVS). Secondary endpoints of the study were Clinician Global Impression-Severity of Tourette Syndrome (CGI-TS), safety, pharmacokinetics, and pharmacodynamics. The study also included exploratory endpoints for patients with attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), which are common co-morbidities of TS. The study was amended to give eligible patients the option to continue for an additional dose; eight patients continued. Additional data from this set and data from the extension will be available at a later date.
Tourette Syndrome (TS) is a neuropsychiatric disorder that first appears during childhood. People with TS experience sudden, involuntary, and repetitive motor and vocal tics, as well as an uncomfortable urge that precedes tics. Obsessive Compulsive Disorder (OCD) and Attention Deficit Hyperactivity Disorder (ADHD) commonly accompany TS. Current medications approved for TS include antipsychotic drugs; however, these therapies are associated with significant side effects such as tardive dyskinesia, sedation, nausea, weight gain, and metabolic effects. The need exists for therapies with a better side-effect profile, as well as for those that provide shorter-acting symptomatic treatment.
ABX-1431 is a first-in-class, small-molecule inhibitor of monoacylglycerol lipase (MGLL) for the treatment of neurological disorders. MGLL is a serine hydrolase which regulates one of the body's key natural activators of the cannabinoid receptors, 2-arachidonoylglycerol (2-AG), which signals through the cannabinoid receptors CB1 and CB2 to modulate neurotransmission and inflammatory signaling, respectively. Potent and selective inhibition of MGLL by ABX-1431 prevents the breakdown of 2-AG and amplifies cannabinoid receptor signaling in neural circuits, which are often dysregulated in disease states.
Direct cannabinoid receptor activation by cannabis derivatives and synthetic agonists has demonstrated clinical benefits in a number of central nervous system (CNS) diseases associated with overactive neurotransmission including spasticity associated with multiple sclerosis, chronic pain and Tourette syndrome. However, exocannabinoid use is limited by its broad activity and concomitant CNS adverse effects, and by challenges with administration and dosing precision. ABX-1431, as an oral therapy, provides the ability to modulate the endocannabinoid receptors selectively with the right dose in areas where circuits are activated, potentially increasing efficacy and limiting safety issues. The ability to safely correct aberrant neurotransmission suggests that ABX-1431 will have broad utility in a wide range of neurological diseases.
In September 2016, Celgene Corporation exercised its option to obtain ex-US rights to ABX-1431, while Abide retains US rights.