Date: 2013-05-02
Type of information: Initiation of preclinical development
phase: non clinical study
Announcement: results
Company: Addex Therapeutics (Switzerland)
Product: dipraglurant
Action
mechanism: mGluR5 negative allosteric modulator. Dipraglurant is a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator. The product has the potential to be used in combination with levodopa or dopamine agonists or as a standalone treatment for Parkinson's disease (debilitating levodopa-induced dyskinesia (PD-LID), PD-related motor symptoms, non-motor symptoms of PD and other movement disorders.
Disease: Parkinson's disease
Therapeutic area: Neurodegenerative diseases - CNS diseases
Country:
Trial
details: The non-human primate PET study measured the mGlu5 receptor occupancy after bolus/i.v. infusion of dipraglurant followed by administration of 18F-FPEB, a high-quality, high affinity, high specificity mGlu5 PET tracer. The treatment comprised 4 different dose levels of dipraglurant (4.34, 1.52, 0.6 and 0.2 mg/kg) and two baseline PET scans. Dynamic PET images were acquired for 2 hours and plasma samples were drawn during the PET scan and analysed for drug levels. The study was performed by Molecular NeuroImaging (MNI) in New Haven, CT, USA .
Latest
news: * On May 2, 2013, Addex Therapeutics, a company pioneering allosteric modulation-based drug discovery and development, has announced that dipraglurant demonstrated dose-dependent mGlu5 receptor occupancy in a non-human primate positron emission tomography (PET) study. The study demonstrated the correlation between the plasma concentration of dipraglurant and occupancy of dipraglurant on mGlu5 receptors in the brain. The results support efficacy data as observed in a preclinical non-human primate model of levodopa-induced dyskinesia and will be used to inform dosing in future clinical studies. In addition, the study results reinforce data seen in the Phase 2a trial supporting dipraglurant as a potent, selective and brain penetrant mGlu5 negative allosteric modulator (NAM).
The results demonstrated that dipraglurant penetrates the blood-brain barrier and dose-dependently blocks the binding of 18F-FPEB. The dissociation constant (KD) was determined to be 0.82 mg/kg and at the highest dose nearly complete blockade of the receptor was achieved (81% RO). The receptor occupancy data combined with the dipraglurant plasma concentration was used to analyse the previously reported data obtained in the non-human primate model of Parkinson\'s disease Levodopa induced dyskinesia (PD-LID). There was a clear and direct relationship between mGlu5 receptor occupancy and efficacy as demonstrated by decreasing dyskinesia in the MPTP-PD-LID model. This invaluable information relating the receptor occupancy to the therapeutic dose is a step forward in the understanding of the pharmacology of dipraglurant and will be translated into dose selection for the future clinical development of dipraglurant.
The study was supported by a $1 million grant from the Michael J. Fox Foundation for Parkinson\'s Research.
