Addex Enters Collaboration with Prof. Pisani to Explore the Therapeutic use of Dipraglurant in the Treatment of Rare Inherited Forms of Dystonia
Geneva, Switzerland 7 May 2015 – Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development announced today entering a collaboration with Professor Antonio Pisani, University of Rome Tor Vergata to explore the use of dipraglurant to treat rare genetic forms of dystonia. The collaboration will evaluate the effect of chronic treatment with dipraglurant (ADX48621), on rescuing the synaptic plasticity deficits, in several models of genetic forms of dystonia, including the DYT1 knock-in mouse model.
DYT1 knock-in mice show a significant impairment of synaptic plasticity (enhanced long term potentiation (LTP) as well as lack of long term depotentiation (LTD) and synaptic depotentiation (SD)), consistent with the current pathophysiological hypothesis for dystonia. Dipraglurant has been reported to normalize the effects of the TOR1A/DYT1 dystonia mutation in the brains of mice (PR 18 april 2013, Sciamanna et al. Neuropharmacology 2014) and partially restored long-term depression and synaptic de-potentiation which are impaired in the DYT1 mutant mice over expressing the human mutant TOR1A gene. (PR 4 September 2013). Dipraglurant has already shown promise in the treatment of levodopa-induced dyskinesia and dystonia in Parkinson’s disease patients.
“With these studies we aim at strengthening the hypothesis that allosteric modulation of mGlu5 receptors may indeed represent an effective and novel approach in the pharmacological treatment of genetic forms of dystonia” said Prof Pisani.
"The collaboration with Prof. Pisani to explore rare inherited forms of dystonia will give us access to unique expertise and models to further validate the potential therapeutic use of dipraglurant to treat dystonia," said Tim dyer, CEO at Addex. “In parallel, we are planning to conduct an investigator led pilot study in cervical dystonia later this year as we launch clinical development of dipraglurant in this significant unmet medical need.”
Dystonia is a neurological disorder characterized by persistent or intermittent involuntary muscle contractions causing abnormal, often repetitive, patterned, twisting movements, postures or tremors. Symptoms originate from an imbalance of neurotransmitters in the brain. There are multiple forms of dystonia, and up to 100 diseases and conditions include dystonia as a prominent 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 fewer than 300,000 people are affected in the United States and Canada alone. Early onset primary dystonia are rare and frequently have a genetic basis (e.g. DYT1) and can progress to affect several parts of the body. Dystonia causes varying degrees of disability and pain, from mild to severe.
Dipraglurant is an oral, small molecule allosteric modulator that inhibits selectively the metabotropic glutamate receptor 5 (mGluR5), 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. In a double-blind, placebo-controlled, US and European Phase 2 study in PD-LID, data showed 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 reduced dystonia severity in addition to chorea, the two major LID components. 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 Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for central nervous system disorders. Addex lead drug candidate, dipraglurant (mGlu5 negative allosteric modulator or NAM) has successfully completed a Phase 2A POC in Parkinson’s disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter Phase 2B for PD-LID. In parallel, dipraglurant’s therapeutic use in dystonia and treatment resistant depression is being investigated. Addex second clinical program, ADX71149 (mGlu2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc. Addex also has several preclinical programs including: ADX71441 (GABAB receptor PAM) which has received regulatory approval to start Phase 1 and is being investigated for therapeutic use in Charcot-Marie-Tooth (Type 1A) disease, alcohol use disorder and nicotine dependence; mGlu4PAM for drug abuse and dependence, Parkinson’s disease and other neurodegenerative diseases; mGlu2NAM for treatment resistant depression and cognitive deficits; mGlu7NAM for psychosomatic disorders, TrkBPAM for neurodegenerative disorders; and GLP1PAM for type 2 diabetes. 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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