Geneva, Switzerland, 4 September 2013 - Addex Therapeutics (ADXN.SW), a leading company pioneering allosteric modulation-based drug discovery and development announced today additional positive preclinical data for its mGlu5 negative allosteric modulator (NAM) oral small molecule, dipraglurant, in a validated model for primary generalized torsion dystonia 1 (DYT1), a common and severe genetic form of dystonia, caused by a mutation in the TOR1A gene encoding the torsin A protein. In the study, that is part of an ongoing collaboration with Professor Antonio Pisani, University of Rome Tor Vergata and Fondazione Santa Lucia, chronic treatment with dipraglurant (50 mg/kg i.p. for 8 days) partially restored long-term depression and synaptic de-potentiation which are impaired in the DYT1 mutant mice over expressing the human mutant TOR1A gene. These data together with previously reported results obtained with dipraglurant in in vitro and in in vivo preclinical behavioral models, as well as observations made in the Phase 2a study of dipraglurant in Parkinson`s disease patients, further support the hypothesis that inhibition of mGlu5 could be beneficial in counteracting the abnormal electrophysiological function observed in dystonia. In keeping with the Company`s rare disease development strategy, Addex plans to initiate a Phase 2a study with dipraglurant in a rare dystonia.
"These findings in the DYT1 mutant mice over expressing the human mutant TOR1A gene are very promising," stated Professor Antonio Pisani, University of Rome Tor Vergata and Fondazione Santa Lucia, and principal investigator on the study. "These results are consistent with previous observations obtained with mGlu5 tool compounds and provide additional support for further exploration of dipraglurant in preclinical and clinical studies of dystonia."
"We are pleased to continue to build positive data to support developing dipraglurant in dystonia and our collaboration with Professor Pisani, is a great example of how we continue to advance our portfolio in a capital efficient manner." said Tim Dyer, CEO at Addex.
About Dystonia and DYT1
Dystonia is a movement disorder that causes the muscles to contract and spasm involuntarily, according to the Dystonia Medical Research Foundation. The involuntary muscle contractions force the body into repetitive and often twisting movements as well as awkward, irregular postures. There are approximately 13 forms of dystonia, and dozens of diseases and conditions include dystonia as a major symptom. Dystonia may affect a single body area or be generalized throughout multiple muscle groups. Dystonia affects men, women, and children of all ages and backgrounds. Estimates suggest that no less than 300,000 people in North America are affected. Dystonia causes varying degrees of disability and pain, from mild to severe. Early-onset primary dystonia (DYT1) is the most common form of hereditary primary dystonia. Usually first symptoms occur in the limbs and dystonia generalizes within a few years of onset. Onset can be during adolescence and early adulthood. DYT1 is caused by mutations in the TOR1A gene, a gene that encodes the protein torsin A. Torsin A is widely expressed in human tissues, particularly in neurons where mutations in TOR1A selectively alter normal functioning. One of the characteristics of DYT1 dystonia is significant impairment of plasticity in the striatum where a close functional link between mGlu5 receptors, adenosine (A2A) and dopamine (D2) receptors has been shown. It has been observed that defective D2 receptor function in striatal neurons could be blocked by antagonizing A2A receptors which in turn were able to restore alterations in synaptic plasticity. On the basis of a close interplay with D2 and A2A receptors, mGlu5 receptor antagonism has the potential to contribute to the restoration of plasticity deficits as observed in mutant animals. Preliminary data demonstrated that an mGlu5 receptor antagonist, MPEP, was able to restore physiological levels of long-term potentiation. mGlu5 receptor inhibition with an allosteric modulator could potentially be a novel approach in the pharmacological treatment of dystonia, as an attractive alternative to anticholinergics. Anticholinergics have significant compliance-limiting side effects such as dry mouth, cognitive impairment, changes in blood pressure, pulse rate or ECG, constipation, dizziness and somnolence. Consequently, there is a significant unmet medical need for a safe and effective oral small molecule for the treatment of these dystonias.
Dipraglurant is an oral, small molecule allosteric modulator that inhibits selectively the metabotropic glutamate receptor 5 (mGlu5), a Class C G-Protein Coupled Receptor (GPCR), with potential to be used in combination with levodopa or dopamine agonists or as a standalone treatment for Parkinson`s disease levodopa-induced dyskinesia (PD-LID), motor and non-motor symptoms of Parkinson`s disease and other movement disorders. Data from a recent Phase 2a show that dipraglurant met the primary objective of the study by exhibiting a good safety and tolerability profile. Dipraglurant also demonstrated a statistically significant reduction in LID severity with both 50 and 100 mg doses. Dipraglurant appears to reduce dystonia severity in addition to chorea, the two major LID components. In a double-blind, placebo-controlled study conducted in the US and Europe, the primary objective was to demonstrate safety and tolerability in PD-LID patients. In addition, the trial was designed to evaluate exploratory efficacy as a secondary objective. Efficacy was measured using the modified Abnormal Involuntary Movement Scale (mAIMS), patient diaries documenting "off-time" (impaired voluntary movement), "on-time" (with or without dyskinesia) and sleep. Additional endpoints include the Unified Parkinson`s Disease Rating Scale (UPDRS), the Clinician & Patient Global Impression of Change (CGIC & PGIC), and an evaluation of the patients` mood using the Hospital Anxiety & Depression Score. The trial was supported by a grant from The Michael J. Fox Foundation for Parkinson`s Research.
About mGlu5 Inhibition
There is an increasing body of evidence that mGlu5 inhibition may be a valuable new strategy for treating a number of important diseases and conditions, such as Parkinson`s disease, Parkinson`s disease levodopa-induced dyskinesia (PD-LID), anxiety, depression, pain, tardive dyskinesia, dystonia, addiction, autism and Fragile X syndrome. With regards to Parkinson`s disease, recent clinical and preclinical evidence suggest that mGlu5 inhibition may have an effect on parkinsonian motor symptoms as well as dyskinesia. MGlu5 is found in regions of the brain considered to be key control points in the neuronal movement circuits affected by abnormal signaling by the neurotransmitter glutamate in Parkinson`s disease. Perturbations in glutamate signaling (along with disruptions in dopaminergic signaling) are believed to be an underlying cause of movement disorders like Parkinson`s disease. As such, inhibiting mGlu5 could act to re-establish normal movement via a non-dopaminergic mechanism. Separately, preclinical findings also suggest that mGlu5 inhibitors may be neuroprotective and may, therefore, hold potential as disease modifying agents that can slow or prevent progression of Parkinson`s disease.
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: GABA-BR 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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