Addex Dipraglurant Normalizes Striatal Cholinergic Dysfunction in a Validated Preclinical Model of Primary Generalized Torsion Dystonia 1 (DYT1)
Dipraglurant, an mGlu5 negative allosteric modulator, currently in Phase 2 studies for levodopa-induced dyskinesia is on track for start of Phase 2 studies in rare dystonias in the first half of 2013
Geneva, Switzerland, 18 April 2013 – Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development announced today 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 torsinA protein. In a study conducted by Professor Antonio Pisani, University of Rome Tor Vergata and Fondazione Santa Lucia, dipraglurant dose-dependently prevented the abnormal excitatory effect observed on brain slices of transgenic DYT1 mice overexpressing the human mutant TOR1A gene by decreasing the paradoxical neuronal activity induced by the dopamine D2 receptor agonist quinpirole thus normalizing cholinergic over-excitability. These data together with previously reported results obtained with dipraglurant in the Tottering-mouse model for dystonia, the MPTP monkey of PD, as well as clinical trial observations in the Phase 2a study further validate the potential of mGlu5 inhibition as a novel approach for the treatment of certain forms of 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 in the first half of 2013. The DYT1 data will be presented at the Dystonia Meeting in Rome May 31st to June 1st 2013.
“The effects we’re seeing with dipraglurant in several validated preclinical mouse models of dystonia are very compelling,” stated Graham Dixon, Ph.D., Chief Scientific Officer at Addex. “These preclinical data as well as our findings in the Phase 2a clinical trial measuring levodopa-induced dyskinesia in Parkinson’s patients and the MPTP monkey model of Parkinson’s disease suggest that an mGlu5 negative allosteric modulator may potentially be an effective therapeutic approach for the treatment of certain dystonias. We plan to initiate a Phase 2 trial in the first half of the year to explore this hypothesis.”
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. Therefore 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.
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. There is presently no cure, and, although many drugs are utilized to try to treat dystonia, the leading treatment is botox injections and many patients are left with inadequate efficacy. Dipraglurant has been shown to effectively reduce dystonia in both a clinical study and preclinical models of Parkinson’s disease levodopa-induced dyskinesia (PD-LID). The neurophysiology of different forms of dystonia is thought to be similar and recent preclinical data in dystonia - suggesting that dipraglurant may also work for non-parkinsonian forms of dystonia.
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 (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 is also advancing 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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Disclaimer: The foregoing release may contain forward-looking statements that can be identified by terminology such as "not approvable", "continue", "believes", "believe", "will", "remained open to exploring", "would", "could", or similar expressions, or by express or implied discussions regarding Addex Therapeutics, formerly known as, Addex Pharmaceuticals, its business, the potential approval of its products by regulatory authorities, or regarding potential future revenues from such products. Such forward-looking statements reflect the current views of Addex Therapeutics regarding future events, future economic performance or prospects, and, by their very nature, involve inherent risks and uncertainties, both general and specific, whether known or unknown, and/or any other factor that may materially differ from the plans, objectives, expectations, estimates and intentions expressed or implied in such forward-looking statements. Such may in particular cause actual results with allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutic targets to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutics targets will be approved for sale in any market or by any regulatory authority. Nor can there be any guarantee that allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutic targets will achieve any particular levels of revenue (if any) in the future. In particular, management’s expectations regarding allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutic targets could be affected by, among other things, unexpected actions by our partners, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; competition in general; government, industry and general public pricing pressures; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Addex Therapeutics is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise, except as may be required by applicable laws.