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Partnering to treat dystonia
GENEVA, Switzerland and CHICAGO—Addex Therapeutics, a company pioneering allosteric modulation-based drug discovery and development, and the Dystonia Medical Research Foundation (DMRF) are collaborating to explore the use of dipraglurant to treat dystonia, the third most common movement disorder following essential tremor and Parkinson's disease.
Dipraglurant, a novel small molecule inhibitor of the metabotropic glutamate receptor 5, has shown promise in the treatment of levodopa-induced dyskinesia and dystonia in Parkinson's disease. Dipraglurant has also been shown to normalize the effects of the TOR1A/DYT1 dystonia mutation in the brains of mice. The objective of the collaboration is to design a detailed development plan and regulatory path as well as identifying key option leaders and patients for a Phase 2 clinical trial. In addition, Addex on January 9 plans to start clinical testing of the therapeutic effect of dipraglurant in patients with cervical dystonia in collaboration with Professor Dirk Dressler of The Hannover Medical School in Germany.
"The DMRF and Addex each embody spheres of expertise that complement the other very well," said DMRF President Art Kessler, who was diagnosed with dystonia as a child. "This drug represents an important opportunity for the dystonia community to examine a potential new treatment option in collaboration with established experts in drug discovery and development."
"The collaboration with the DMRF will give Addex access to unique networks of research and clinical experts in the field of dystonia" said Sonia Poli, CSO at Geneva-based Addex. "Dipraglurant has shown robust efficacy in multiple models of dystonia and we look forward to collaborating with DMRF to evaluate dipraglurant in dystonia patients."
Dystonia is a neurological disorder characterized by persistent or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. The movements are usually patterned and twisting, and may resemble a tremor. 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 is rare and frequently has 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 selectively inhibits 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, U.S. 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.
The Dystonia Medical Research Foundation is a 501c3 non-profit organization dedicated to advancing research for improved dystonia treatments and ultimately a cure, promoting awareness, and supporting the well-being of affected individuals and families. Since 1976, the DMRF has supported and stimulated the dystonia research field. Work supported by the DMRF has led to an overall better understanding of dystonia as well as breakthroughs in genetics and therapeutics. The Foundation also provides patient education and support resources.
Addex Therapeutics is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for central nervous system disorders. Dipraglurant (mGlu5 negative allosteric modulator or NAM), its lead drug candidate, 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.