Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, has reported positive preclinical data for its GABA-B receptor positive allosteric modulator (PAM) oral small molecule, ADX71441, in a validated rodent model of alcohol binge drinking. ADX71441 demonstrated robust, dose-dependent and long-lasting suppression of alcohol intake in animals compared to naltrexone, the most-commonly prescribed treatment of alcoholism on the market.
"These data are extremely encouraging and superior to naltrexone in our pre-clinical model, and warrant further exploration as a novel treatment for alcoholism," said Professor Klaus Miczek at Tufts University (USA) in whose laboratory the study was performed.
Both clinical and pre-clinical data suggest that activation of the GABA-B receptor offers a unique therapeutic opportunity to address largely unmet needs of patients with alcohol and drug abuse by reducing the alcohol or drug intake; alleviating many physical signs (pain, Gastrointestinal/urinary disturbances) and emotional symptoms (anxiety) associated with withdrawal; and maintaining abstinence by reducing alcohol or drug craving.
ADX71441, which has potential for once daily dosing and selectively activates the GABA-B receptor, was evaluated in a mouse model of alcohol binge drinking. Acute, oral administration of ADX71441 (3, 10, 30 mg/kg) resulted in a dose-dependent suppression of alcohol intake, achieving 80% reductions at higher doses (10, 30 mg/kg) in comparison to vehicle treatment. Reductions in alcohol consumption in response to ADX71441 treatment were present for the entire 4hour alcohol access period. The effect of ADX71441 in this model was more robust and longer-lasting than that seen in mice treated with naltrexone, which was used in the study as a positive control. This is the first study showing efficacy of a GABA-B receptor PAM in a rodent model of alcohol binge drinking.
"Alcoholism is an important unmet medical need as current treatments offer marginal efficacy in reducing alcohol intake and are associated with significant side effects," noted Dr Graham Dixon, CSO at Addex. "We are excited by the robustness of the data and look forward to the filing of a CTA for ADX71441 by the end of 2012 and initiating phase I testing in Q1 2013."
Oral small molecule GABA-B receptor PAMs have potential in treating multiple indications and Addex has previously demonstrated positive proof of concept in a broad range of preclinical models, including those of pain, anxiety, obsessive-compulsive disorder and overactive bladder (OAB). Addex is positioning ADX71441 as a treatment for spasticity, with multiple sclerosis (MS) being an initial focus of the clinical development programme.
"The advancement of ADX71441 towards the clinic clearly illustrates our strategy to bring forward innovative oral small molecule NCEs addressing validated targets with broad therapeutic potential," said Bharatt Chowrira, CEO at Addex. "GABA-B receptor is one such exciting target whose activation has been validated in a broad range of indications. We plan to initially focus on evaluating ADX71441 for the treatment of spasticity in MS patients who currently are not adequately treated for this debilitating disease."
Alcoholism 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. Patients with alcoholism 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 current standard of care typically being prescribed to patients with heavy drinking but largely being unable to prevent them from relapsing.
Activation of gamma-aminobutyric acid subtype B receptor (GABABR), a Family C class of GPCR, is clinically and commercially validated by a generic GABA-BR agonist, baclofen, which is marketed for spasticity in spinal cord injury patients. Baclofen has also shown clinical relevance in a number of other indications including overactive bladder, pain and is in early stage clinical development for alcohol dependence and autism. Despite baclofen's broad clinical validation, it is not commonly used due to multiple side effects, rapid clearance, development of tolerance to the drug, rebound and withdrawal syndromes. Orthosteric GABA-BR agonists have also shown clinical validation in gastroesophageal reflux disease (GERD). Addex' GABA-BR PAMs have shown efficacy in multiple preclinical models including: OAB, pain, osteoarthritis pain, anxiety and alcoholism.
Addex Therapeutics discovers and develops an emerging class of small molecule drugs, called allosteric modulators, which have the potential to be more specific and confer significant therapeutic advantages over conventional "orthosteric" small molecule or biological drugs.