Addex and NIDA enter collaboration to advance ADX71441 & ADX88178 in drug abuse and addiction
Geneva, Switzerland, 4 November 2013 – Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development announced today entering a collaboration with the National Institute on Drug Abuse (NIDA), a component of the National Institutes of Health (NIH) to evaluate the pharmacology of ADX71441, a GABAB receptor positive allosteric modulator (PAM), and ADX88178, an mGlu4 PAM in preclinical models of drug abuse and addiction. The collaboration will evaluate Addex drug candidates, ADX71441 and ADX88178 in a battery of preclinical models to study their potential as treatments for nicotine and cocaine addiction.
“NIDA has made significant contributions to our understanding of the underlying pathology of drug abuse and addiction and has coordinated development and validation of a large battery of preclinical models which will provide Addex with invaluable information for the further development of ADX71441 and ADX88178,” said Tim Dyer, CEO at Addex. “This is our first collaboration with NIDA and another example of us executing our strategy to advance our pipeline through collaborations with cutting edge academic and governmental research groups.”
Both pre-clinical and clinical data suggest that activation of GABAB receptors offers a unique therapeutic opportunity to address the needs of drug abuse patients by reducing drug intake, by maintaining abstinence, and by reducing drug craving. Moreover treatment with a GABAB activator can alleviate many physical signs (GI/urinary disturbances) and emotional symptoms (anxiety) associated with withdrawal. Addex recently reported 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). The data have been published online on August 22 (L.S. Hwa et al. Psychopharmacology).
“Alcohol and nicotine addiction are often comorbid, and therefore the data from this collaboration with NIDA will help us define the best clinical development path for our lead programs,” said Sonia Poli, VP translational science at Addex. “We are also excited to learn more about the potential utility of both GABAB PAM and mGlu4 PAM in further aspects of drug addiction”
About Drug Abuse and Drug Addiction
Scientific advances have revolutionized our understanding of addiction as a chronic, relapsing disease and not a moral failure. Drug addiction is a complex illness which is characterized by intense and, at times, uncontrollable drug craving, along with compulsive drug seeking and use that persist even in the face of devastating consequences. Addiction affects multiple brain circuits, including those involved in reward and motivation, learning and memory, and inhibitory control over behavior. While a person initially chooses to take drugs, over time the effects of prolonged exposure on brain functioning compromise that ability to choose, and seeking and consuming the drug become compulsive, often eluding a person’s self-control or willpower. Because drug abuse and addiction have so many dimensions and disrupt so many aspects of an individual’s life, treatment is not simple. Addiction treatment must help the individual stop using drugs, maintain a drug-free lifestyle, and achieve productive functioning in the family, at work, and in society. Patients typically require long-term or repeated episodes of care to achieve the ultimate goal of sustained abstinence and recovery of their lives.
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 used for overactive bladder (OAB), but is not commonly used 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 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).
About mGlu4 Activation and ADX88178
The metabotropic glutamate receptor 4 (mGlu4) belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Gαi/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in transmitter release from presynaptic terminals. MGlu4 is currently receiving much attention based primarily upon its unique distribution in key brain region involved in many CNS disorders. MGlu4 PAM is emerging as a promising target for the treatment of motor and non motor symptoms as well as a disease-modifying agent in Parkinson’s disease through a non-dopaminergic approach. Emerging data for other therapeutic indications such as anxiety, multiple sclerosis, neuropathic and inflammatory pain, schizophrenia and diabetes make mGlu4 a highly promising target for both CNS and non CNS diseases. In particular, anxiety disorders are among the most prevalent psychiatric disorders in the world. Addex has reported in 2010 that ADX88178 demonstrated oral efficacy in two preclinical rodent models of anxiety: the marble burying test in mice and EPM in mice and rats. The mGlu4-mediated specific effect has been also confirmed in knock-out mice. Therefore, mGlu4 activators may represent a new generation of anxiolytic therapeutics. More recently, mGlu4 PAM PHCCC demonstrated efficacy in a neuroinflammation model, the remitting-relapsing EAE model, by promoting regulatory T-cell (Treg) formation and reverse pro-inflammatory T-cell release. Therefore, positive modulation of mGlu4 could potentially stop the destruction of myelin in MS in a robust and durable manner.
About Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) is a development stage company focused on advancing innovative oral small molecules against rare diseases utilizing its pioneering allosteric modulation-based drug discovery platform. The Company’s two lead products are being investigated in Phase 2 clinical testing: dipraglurant (an mGlu5 negative allosteric modulator or NAM) is being developed by Addex to treat Parkinson’s disease levodopa-induced dyskinesia (PD-LID) and rare forms of dystonia; and ADX71149 (mGlu2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc., to treat both schizophrenia and anxiety as seen in patients suffering from major depressive disorder. Addex also has several preclinical programs including: GABAB receptor positive allosteric modulator (PAM) for Charcot-Marie-Tooth (type 1a) disease, spasticity in patients with multiple sclerosis (MS), pain, overactive bladder and other disorders; and mGlu4 PAM for MS, Parkinson’s disease, anxiety and other diseases. 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. The Company uses its proprietary discovery platform to target receptors and other proteins that are recognized as essential for the therapeutic modulation of important diseases with unmet medical needs.
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