Addex' ADX71441 Demonstrates Robust Efficacy in Multiple Preclinical Models of Alcohol Use Disorder
In an alcohol self-administration model in rats, ADX71441 dose dependently demonstrated statistical significant efficacy in reducing alcohol self-administration at doses as low as 1 mg/kg i.p.. ADX71441 reduced motivation to consume alcohol in both normal and alcohol dependent animals, with a stronger effect in alcohol dependent animals. It was shown that the efficacy was due to a decrease in immediate reward rather than modulation of the caloric value of liquid reinforcers, in a self-administration paradigm using 0.2% Saccharin. In addition, it was shown that the effects were not due to sedation as locomotor activity remained unchanged up to 10 mg/kg i.p.. In models of alcohol relapse, ADX71441 blocked cue-induced relapse to alcohol seeking and blocked stress-induced relapse to alcohol seeking at all doses. It was also shown that ADX71441 attenuates neuronal activity in the central amygdala and the nucleus accumbens shell by c-Fos staining of brain slices obtained from the alcohol relapse models.
"We are delighted by these results which combined with the fact that GABAB activation is a clinically validated mechanism in alcohol use disorder, clearly show the value of ADX71441 in this indication.", commented Sonia Poli, CSO of Addex. "We thank NIAAA and their team for the outstanding job they have done in generating this data and look forward to continuing our collaboration."
"In 2013, we executed a strategy to drive forward our research efforts through collaborations with patient advocacy groups, academic institutions and governmental organizations to efficiently access both expertise and generate data," said Tim Dyer, CEO of Addex. "The data from this collaboration with NIAAA is a clear demonstration of the value we can build through this collaborative research strategy."
About GABAB Activation and ADX71441
Activation of gamma-aminobutyric acid subtype B (GABAB) receptor, a Family C class of GPCR, is clinically & commercially validated. Generic GABAB receptor agonist, baclofen, is marketed for spasticity and some spinal cord injuries, and French health authorities have approved its use for the treatment of alcoholism on a "case by case" basis. Baclofen is also used off label for a number of other indications including overactive bladder (OAB), but its utility is limited due to variety of side effects and rapid clearance. ADX71441 is a potent selective positive allosteric modulator (PAM) which potentiates GABA responses at the GABAB receptor. ADX71441 is a novel, first-in-class, oral, small molecules that has demonstrated excellent preclinical efficacy and tolerability in several rodent models of pain, anxiety, addiction and OAB and have also proven efficacy in a genetic model of Charcot-Marie-Tooth Type 1A disease (CMT1A). ADX71441 differs from the generic drug baclofen in that it is a positive allosteric modulator rather than an orthosteric agonist at the GABAB receptor. ADX71441 only acts when the natural ligand (GABA) activates the receptor, and therefore respecting the physiological cycle of activation. It has been proposed that PAMs produce less adverse effects and lead to less tolerance than direct agonists (May and Christopoulos 2003; Langmead and Christopoulos 2006; Perdona et al. 2011; Urwyler 2011; Gjoni et al., 2008; Ahnaou et al). Addex has published positive data with ADX71441 in two models of alcohol abuse in mice, the ethanol binge-like drinking, drinking-in-the-dark (DID) and a model of long-term, excessive drinking, intermittent access to alcohol (IAA) (Hwa et al. Psychopharmacology 2014;231(2):333-343).
About Alcohol Use Disorder
Problem drinking that becomes severe is given the medical diagnosis of "alcohol use disorder" or AUD. AUD is a broad term for problems with alcohol, and is generally indicative of compulsive and uncontrolled consumption of alcoholic beverages. It is medically considered a disease, specifically an addictive illness. The World Health Organization estimates that about 140 million people throughout the world suffer from alcohol dependence. Patients with alcohol use disorder suffer major changes to the brain structure and chemistry. Excessive alcohol consumption damages almost every organ in the body and the cumulative toxic effects can cause both medical (cirrhosis of the liver, pancreatitis, heart disease, peptic ulcers, sexual dysfunction) and psychiatric (epilepsy, dementia, psychosis, anxiety & depression) problems. Treatment of alcoholism is complex with a current standard of care typically being prescribed to patients with heavy drinking but largely being unable to prevent them from relapsing. Approximately 7.2 percent or 17 million adults in the United States age 18 and older had an AUD in 2012. This includes 11.2 million men and 5.7 million women. In addition, an estimated 855,000 adolescents age 12-17, in the United States, had an AUD in 2012.
About Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for neurological disorders. Addex lead drug candidate, dipraglurant (mGluR5 negative allosteric modulator or NAM) has successfully completed a Phase IIa POC in Parkinson's disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter Phase IIb for PD-LID. In parallel, dipraglurant's therapeutic use in dystonia and treatment resistant depression is being investigated. Addex second clinical program, ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc. Addex also has several preclinical programs including: ADX71441 (GABAB receptor PAM) which has received regulatory approval to start Phase I and is being investigated for therapeutic use in Charcot-Marie-Tooth (Type 1A) disease, alcohol use disorder and nicotine dependence; mGluR4PAM for drug abuse and dependence, Parkinson's disease and other neurodegenerative diseases; mGluR2NAM for treatment resistant depression and cognitive deficits; mGluR7NAM for psychosomatic disorders, TrkBPAM for neurodegenerative disorders; and GLP1PAM for type 2 diabetes. Allosteric modulators are an emerging class of small molecule drugs which have the potential to be more specific and confer significant therapeutic advantages over conventional "orthosteric" small molecule or biological drugs. Addex allosteric modulator drug discovery platform targets receptors and other proteins that are recognized as essential for therapeutic intervention - the Addex pipeline was generated from this pioneering allosteric modulator drug discovery platform.