Date: 2015-01-07
Type of information: Collaboration agreement
Compound: ADX71441
Company: Addex Therapeutics (Switzerland) National Institute on Alcohol Abuse and Alcoholism (NIAAA) (USA)
Therapeutic area: CNS diseases
Type agreement: collaboration
Action mechanism: ADX71441 is a GABA-B receptor positive allosteric modulator (PAM) oral small molecule. 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, used off label for overactive bladder (OAB) and alcohol use disorder, but use is limited due to variety of side effects of the drug 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 molecule that has demonstrated excellent preclinical efficacy and tolerability in several rodent models of pain, anxiety, addiction and OAB and has 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).
Disease: alcohol use disorder
Details: * On January 7, 2015, Addex Therapeutics, a Swiss company pioneering allosteric modulation-based drug discovery and development announced entering a collaboration with the National Institute on Alcohol Abuse and Alcoholism (NIAAA), a component of the National Institutes of Health (NIH), to evaluate the pharmacology of ADX71441, a GABAB receptor positive allosteric modulator (PAM), in preclinical models of alcohol use disorder. The collaboration will evaluate Addex drug candidate, ADX71441, in a battery of preclinical models to study its potential as a treatment for alcohol use disorder. Both clinical and pre-clinical data suggest that activation of GABAB receptors offers a unique therapeutic opportunity to address the needs of patients with alcohol use disorder by suppressing multiple alcohol-related behaviors, including intake, reward and motivation, and seeking behavior. GABAB receptor PAMs have a similar pharmacological profile to the orthosteric agonist, baclofen, while showing a more favorable tolerability profile. 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).
Financial terms:
Latest news: * On October 13, 2015, Addex Therapeutics announced the statistically significant positive results in multiple preclinical models of alcohol use disorder. 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% 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.
