Addex Dipraglurant Demonstrates Anxiolytic- and Antidepressant-like Activity in Multiple Preclinical Models Relevant for Non-Motor Symptoms in Parkinson’s Disease
Geneva, Switzerland 14 August 2015 – Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development announced today that its lead compound dipraglurant, a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator (NAM) demonstrated robust efficacy in multiple preclinical models of anxiety and depression. The studies were conducted in collaboration with the laboratory of Professor Andrzej Pilc of the department of Neurobiology, Institute of Pharmacology at the Polish Academy of Sciences in Krakow, Poland.
Dipraglurant is a novel small molecule inhibitor of the metabotropic glutamate receptor 5 (mGluR5) that has successfully completed Phase II proof-of-concept testing in Parkinson's disease (PD) patients suffering from debilitating levodopa-induced dyskinesia (LID). Dipraglurant given orally showed anxiolytic effects in the elevated plus maze test (EPM) and the stress-induced hyperthermia test (SIH) in mice at the dose of 50 mg/kg, and antidepressant effects in the forced swim test (FST) in rats (at doses of 10 and 30 mg/kg) and mice (at doses of 30 and 50 mg/kg) . These data will be presented at the XIX International Congress of the Polish Pharmacological Society, 17-19 September 2015 being held in Świnoujście, Poland.
“The consistent effects across a battery of different preclinical models provides further evidence that excessive glutamate activity mediated through mGluR5 can contribute to the development of anxiety and depression symptoms” commented Professor Andrzej Pilc of the department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
“There remains a significant unmet medical need for medications to treat the full range of motor and non-motor complications of PD” said Sonia Poli, CSO at Addex, “dipraglurant may represent an attractive approach to treat not only levodopa induced dyskinesia, but also the concomitant non-motor symptoms which are present in almost all PD patients and can have a greater negative impact on the quality of life than motor complications.
"The collaboration with Prof. Pilc, a world leader in fundamental research on mGlu receptors is a further demonstration of our strategy to drive forward our research in collaboration with leading academic institutions." said Tim Dyer, CEO at Addex. “While we continue to prioritize the development of dipraglurant for Parkinson’s disease levodopa induced dyskinesia and dystonia, these data provide evidence of additional utility for dipraglurant in PD patients.”
About non-motor symptoms in PD
Parkinson’s disease (PD) patients suffer not only from the primary motor symptoms of the disease, but also from a range of non-motor symptoms (NMS) that cause disability and have a significant negative impact on the quality of their life. A wide range of non-motor symptoms (NMS) including psychiatric, cognitive, sleep and autonomic disturbances has been recognized as an integral feature of PD. Non-motor symptoms are experienced by nearly all PD patients, are often present at diagnosis, may precede the onset of motor symptoms and can cause disability (Bernal-Pacheco et al., 2012). Affective disorders are among the most common NMS in PD patients with average reported prevalence for anxiety disorders of approximately 40% (Quelhas and Costa, 2009; Richard, 2005) while prevalence of depression ranges from 31-45%, depending on diagnostic criteria (Lemke, 2008; Slaughter et al., 2001), with significant percentages exhibiting co-morbid anxiety and depression (Dissanayaka et al., 2010; Nuti et al., 2004). Excessive glutamate activity in the basal ganglia resulting from degeneration of the nigrostriatal dopamine pathway has been implicated in motor symptoms, NMS and dyskinesias in PD patients.
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 neurological disorders. Addex lead drug candidate, dipraglurant (mGluR5 negative allosteric modulator or NAM) has successfully completed a Phase IIa POC in Parkinson’s disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter Phase IIb for PD-LID. In parallel, dipraglurant’s therapeutic use in dystonia is being investigated. Addex second clinical program, ADX71149 (mGluR2 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 I and is being investigated for therapeutic use in Charcot-Marie-Tooth (Type 1A) disease, alcohol use disorder and nicotine dependence; mGluR4PAM for drug abuse and dependence, Parkinson’s disease and other neurodegenerative diseases; mGluR2NAM for treatment resistant depression and cognitive deficits; mGluR7NAM 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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