Addex ADX71441 Preclinical Results for Treatment of Alcohol Use Disorder Published in Journal of Psychopharmacology
Study Conducted in Collaboration with National Institute on Alcohol Abuse and Alcoholism
Geneva, Switzerland, 4 May 2017 – Addex Therapeutics (SIX: ADXN) announced today that the results of a preclinical study evaluating ADX71441 in animal models of alcohol use disorder were published in the Journal of Psychopharmacology. The study was led by Prof. Markus Heilig of Linköping University, Sweden, and was conducted in collaboration with the National Institute on Alcohol Abuse and Alcoholism (NIAAA), a division of National Institutes of Health.
The results of the study demonstrated that ADX71441, a positive allosteric modulator (PAM) of the gamma-aminobutyric acid subtype B (GABAB) receptor, dose-dependently suppressed alcohol self-administration of both dependent and non-dependent animals, but its potency was higher in alcohol-dependent rats. This effect was robust, appearing at a dose of 3 mg/kg in non-dependent animals, and reached a >80% reduction of self-administration at a dose of 10 mg/kg; the dose of 1 mg/kg was sufficient in animals with a history of dependence. Furthermore, both cue- and stress-induced alcohol seeking were blocked by ADX71441. Suppression of responding for alcohol was not the result of non-specific sedative or otherwise performance-impairing properties of the drug, as ADX71441 did not impair locomotor activity at doses between 1 and 10 mg/kg. ADX71441 displayed a 10-fold separation between specific behavioral effects and sedation.
The data indicated that ADX71441 may be beneficial in treating alcohol use disorder in humans, as it retains the efficacy of the GABAB receptor agonist, baclofen, while potentially having a better therapeutic index. The results also indicated that maximal efficacy of ADX71441 can be expected in severely dependent patients. Finally, the data provided a basis for developing a functional magnetic resonance imaging(fMRI) based translational biomarker that could advance clinical development of ADX71441 in alcohol use disorder more rapidly and reliably.
“These data are very encouraging and strongly support the further development of ADX71441 in alcohol use disorder.” said Prof. Markus Heilig of Department of Clinical and Experimental Medicine, Linköping University “GABA B activation is a well validated target for alcohol use disorder through the work performed with baclofen and we look forward to studying ADX71441 in patients.”
“The publication of Prof Heilig’s research in this prestigious scientific journal further validates the development of ADX71441 in alcohol use disorder,” said Sonia Poli, CSO of Addex. “We look forward to leveraging the results of this study in our clinical development plan for ADX71441. We expect to initiate a Phase I study for ADX71441 as a potential treatment for alcohol and cocaine addiction in the third quarter of this year.”
“We thank the NIAAA for their support and Prof. Heilig and his team for their work accomplished with ADX71441 in this study,” commented Tim Dyer, CEO of Addex. “These new data are indicative of how we are informing our clinical development programs through collaborations with leading academic institutions.”
Augier et al.: “The GABAB positive allosteric modulator, ADX71441 attenuates alcohol self-administration and relapse to alcohol seeking in rats”, Neuropsychopharmacology, 2017, Mar 15 - Epub ahead of print
About GABA B receptor
The GABAB receptor 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. 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, requiring frequent administration of higher doses.
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 molecule that demonstrated excellent preclinical efficacy and tolerability in rodent models of pain, anxiety, OAB, alcohol use disorders, nicotine dependence and in a non-human primate model of cocaine use disorder. ADX71441 has also proven efficacy in a genetic model of Charcot-Marie-Tooth Type 1A disease (CMT1A). ADX71441 has a different molecular mechanism from the generic drug baclofen in that it is a positive allosteric modulator, rather than an orthosteric agonist at the GABAB receptor, with a longer half-life, suitable for once daily administration. ADX71441 only acts when the natural ligand (GABA) activates the receptor, 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 Therapeutics (www.addextherapeutics.com) is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for neurological disorders. 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's 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. Addex's lead drug candidate, dipraglurant (mGluR5 negative allosteric modulator or NAM) has successfully completed a Phase 2a POC in Parkinson's disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter registration trials for PD-LID with support from the Michael J. Fox Foundation for Parkinson's Research (MJFF). In parallel, dipraglurant's therapeutic use in dystonia is being investigated with support from the Dystonia Medical Research Foundation (DMRF). Addex's second clinical program, ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc for epilepsy. In addition, ADX71441 (GABAB receptor PAM) has received regulatory approval to start Phase 1 and is being investigated for its therapeutic use in Charcot-Marie-Tooth Type 1A disease (CMT1A), cocaine and alcohol use disorder and nicotine dependence. Discovery programs include mGluR4PAM, mGluR7NAM, TrkBPAM and mGluR3NAM & PAM.
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