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Addex Dipraglurant Reduces Motor Abnormalities in a Preclinical Model Relevant for Several Rare types of Dystonia
By: Marketwired .
Jan. 29, 2013 01:11 AM
GENEVA -- (Marketwire) -- 01/29/13 -- Addex Therapeutics / Addex Dipraglurant Reduces Motor Abnormalities in a Preclinical Model Relevant for Several Rare types of Dystonia.
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Dipraglurant, a novel oral small molecule negative allosteric modulator of mGlu5 receptor, on track for Phase 2 clinical testing in the second half of 2013
Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development, announced positive preclinical data for its mGlu5 negative allosteric modulator (NAM) oral small molecule, dipraglurant, in a validated rodent model of dystonia, a spectrum of disorders, that includes several rare diseases and is characterized by debilitating involuntary muscle contractions and body movements. This is an area of high unmet medical need where many patients are left inadequately treated with the current standard of care. Dipraglurant demonstrated a robust and dose-dependent reduction in severity of a dystonia-like attack, induced by caffeine in the tottering mouse model. These data are consistent with earlier reported Addex findings in a Phase 2a clinical trial measuring levodopa-induced dyskinesia in Parkinson's patients as well as a non-human primate model of Parkinson's-related dystonia.
"The effects of dipraglurant in the mouse model are very compelling. They provide additional support for further exploration of mGlu5 inhibitors as a novel treatment for dystonia and also open new therapeutic avenues" said Professor Ellen Hess at Emory University (USA) in whose laboratory the study was performed.
The validation of the tottering mouse model in the laboratory of Professor Hess has been funded in part by the Bachmann-Strauss Dystonia and Parkinson Foundation. The model recapitulates key genetic and phenotypic features of so called episodic neurological disorders, that involve aberrant calcium channel functioning and susceptibility to neurological attacks in response to stress, alcohol or caffeine. In the study, acute, oral administration of dipraglurant (10, 30, 50 mg/kg) resulted in dose-dependent reductions of dystonia scores, achieving significant reductions at the highest dose in comparison to vehicle treatment. In a sub-group of experimental animals, dipraglurant fully blocked the onset of dystonia. These results demonstrate the potential of mGlu5 inhibition as a novel approach for the treatment of multiple types of dystonias, as well as other rare neurological conditions including familial hemiplegic migraine type 1, episodic ataxia type 2, and periodic paralysis.
"We are pleased that we continue to see broad therapeutic application for dipraglurant," said Bharatt Chowrira, CEO at Addex. "As we continue to seek a partner to advance dipraglurant in Parkinson's levodopa-induced-dyskinesia, we see great opportunity to take the compound forward in several rare disease indications including certain forms of dystonias. We look forward to starting Phase 2 clinical testing in the second half of 2013 with this potentially important movement disorder therapeutic".
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.
There is increasingly convincing 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.
Addex Therapeutics (www.addextherapeutics.com) discovers and develops an emerging class of small molecule drugs, called allosteric modulators, 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 address receptors and other proteins that are recognized as attractive targets for modulation of important diseases with unmet medical needs. The Company's two lead products are being investigated in Phase 2 clinical testing: dipraglurant (ADX48621, an mGlu5 negative allosteric modulator or NAM) is being developed by Addex to treat Parkinson's disease levodopa-induced dyskinesia (PD-LID) and dystonia; and ADX71149 (mGlu2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals Inc. to treat schizophrenia and anxiety seen in patients suffering from major depressive disorder. Addex also is 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; mGlu4 PAM for MS, Parkinson's disease, anxiety and other diseases. In addition, Addex is applying its proprietary discovery platform to identify highly selective and potent allosteric modulators of a number of both GPCR and non-GPCR targets that are implicated in diseases of significant unmet medical need.
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.
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