Addex ADX71441 Demonstrates Positive Results in Highly Translational Preclinical Model of Spasticity.
Geneva, Switzerland, 27 July 2016 – Addex Therapeutics (SIX: ADXN) announced today that ADX71441, a positive allosteric modulator (PAM) of the GABAB receptor demonstrated positive results in a highly translational preclinical model of spasticity. The results were obtained at a specialist in vivo pharmacology research organization, NSrepair, in Marseille, France, under the supervision of Dr. Philippe Marino.
ADX71441 was evaluated in a leading model of muscle spasticity, the rat transection spinal cord injury (SCI) model. Muscle hyperactivity was measured by a translational electrophysiological marker, the rate- dependent depression of the Hoffmann’s reflex (H-reflex), a measurement that is also used to evaluate spasticity in patients. The SCI procedure significantly induced spasticity in rats within 5 weeks (P < 0.001; Mann-Whitney test), after which a single intravenous administration of ADX71441 (1, 3 or 10 mg/kg) or vehicle was administered and the degree of spasticity response was measured.
ADX71441 demonstrated a significant anti-spasticity therapeutic effect in the SCI model and more specifically:
“Activation of the GABAB receptor is a well-proven mechanism for treatment of spasticity and baclofen, a GABAB agonist is marketed for spasticity and some spinal cord injuries” said Sonia Poli, CSO at Addex “The remarkable data obtained at NSrepair provide the first evidence that the positive allosteric modulator ADX71441 might be a promising therapeutic compound to treat spasticity.”
Spasticity is a common debilitating complication characterized by a velocity-dependent increase in the tonic stretch reflex, an increase in muscle tone and spasms, which might interfere with movement, speech, or be associated with discomfort or pain. Spasticity is usually caused by damage to nerve pathways within the brain or spinal cord that control muscle movement. It may occur in association with spinal cord injury, multiple sclerosis, cerebral palsy, stroke, brain or head trauma, amyotrophic lateral sclerosis, hereditary spastic paraplegias, and metabolic diseases such as adrenoleukodystrophy, phenylketonuria, and Krabbe disease. Symptoms may include hypertonicity (increased muscle tone), clonus (a series of rapid muscle contractions), exaggerated deep tendon reflexes, muscle spasms, scissoring (involuntary crossing of the legs), and fixed joints (contractures). The degree of spasticity varies from mild muscle stiffness to severe, painful, and uncontrollable muscle spasms. Spasticity can interfere with rehabilitation in patients with certain disorders, and often interferes with daily activities. Treatment may include baclofen, diazepam, tizanidine or clonazepam. Physical therapy regimens may include muscle stretching and range of motion exercises to help prevent shrinkage or shortening of muscles and to reduce the severity of symptoms. Targeted injection of botulinum toxin into muscles with the most tome can help to selectively weaken these muscles to improve range of motion and function. Surgery may be recommended for tendon release or to sever the nerve-muscle pathway.
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 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, 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 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.
About Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for neurological disorders. Addex lead drug candidate, dipraglurant (mGluR5 negative allosteric modulator or NAM) has successfully completed a phase IIa POC in Parkinson’s disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter phase III 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 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 I 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 for neurodegenerative diseases, mGluR7NAM for psychosomatic disorders and TrkBPAM for neurodegenerative disorders which are being advanced in collaboration with the Universities of Lausanne and Geneva under the Swiss CTI grant program; and mGluR3PAM which is being advanced in collaboration with Pierre Fabre Pharmaceuticals. 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 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.
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