Date: 2013-09-04
Type of information: Results
phase: preclinical studies
Announcement: results
Company: Addex Therapeutics (Switzerland)
Product: dipraglurant
Action
mechanism: mGluR5 negative allosteric modulator. 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.
Disease: dystonia, primary generalized torsion dystonia 1 (DYT1)
Therapeutic area: Neuromuscular diseases - Rare diseases - CNS diseases - Neurological diseases
Country:
Trial details:
Latest
news: * On September 4, 2013, Addex Therapeutics, a company pioneering allosteric modulation-based drug discovery and development, has announced additional positive preclinical data for its mGlu5 negative allosteric modulator (NAM) oral small molecule, dipraglurant, in a validated model for primary generalized torsion dystonia 1 (DYT1), a common and severe genetic form of dystonia, caused by a mutation in the TOR1A gene encoding the torsin A protein. In the study, that is part of an ongoing collaboration with Professor Antonio Pisani, University of Rome Tor Vergata and Fondazione Santa Lucia, chronic treatment with dipraglurant (50 mg/kg i.p. for 8 days) partially restored long-term depression and synaptic de-potentiation which are impaired in the DYT1 mutant mice over expressing the human mutant TOR1A gene. These data together with previously reported results obtained with dipraglurant in in vitro and in in vivo preclinical behavioral models, as well as observations made in the Phase 2a study of dipraglurant in Parkinson's disease patients, further support the hypothesis that inhibition of mGlu5 could be beneficial in counteracting the abnormal electrophysiological function observed in dystonia. In keeping with the Company's rare disease development strategy, Addex plans to initiate a Phase 2a study with dipraglurant in a rare dystonia.
* On April 18, 2013, Addex Therapeutics has announced positive preclinical data for its mGlu5 negative allosteric modulator (NAM) oral small molecule, dipraglurant, in a validated model for primary generalized torsion dystonia 1 (DYT1). In a study conducted by Professor Antonio Pisani, University of Rome Tor Vergata and Fondazione Santa Lucia, dipraglurant dose-dependently prevented the abnormal excitatory effect observed on brain slices of transgenic DYT1 mice overexpressing the human mutant TOR1A gene (gene that encodes the protein torsin A) by decreasing the paradoxical neuronal activity induced by the dopamine D2 receptor agonist quinpirole thus normalizing cholinergic over-excitability. These data together with previously reported results obtained with dipraglurant in the Tottering-mouse model for dystonia, the MPTP monkey of PD, as well as clinical trial observations in the Phase 2a study further validate the potential of mGlu5 inhibition as a novel approach for the treatment of certain forms of dystonia. In keeping with the Company's rare disease development strategy, Addex plans to initiate a Phase 2a study with dipraglurant in a rare dystonia in the first half of 2013. The DYT1 data will be presented at the Dystonia Meeting in Rome May 31st to June 1st 2013.
* On January 29, 2013, Addex Therapeutics has announced positive preclinical data for 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. 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 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. The study has been performed at Emory University (USA) in the laboratory of Professor Hess. The validation of the tottering mouse model has been funded in part by the Bachmann-Strauss Dystonia and Parkinson Foundation.
Addex has also announced that it continues to seek a partner to advance dipraglurant in Parkinson's levodopa-induced-dyskinesia. The company looks forward to starting Phase 2 clinical testing in the second half of 2013 with this potentially important movement disorder therapeutic.
