Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, announced the statistically significant positive results in multiple preclinical models of alcohol use disorder.
The data was generated as part of the ongoing collaboration with the United States National Institute on Alcohol Abuse and Alcoholism (NIAAA), a component of the United States National Institutes of Health (NIH). Under the collaboration the pharmacology of ADX71441, a GABAB receptor positive allosteric modulator (PAM), is being evaluated in a battery of preclinical models to study its potential as a treatment for 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 per cent 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."
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. 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).
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 Organisation 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 per cent 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.