Addex Pharmaceuticals is moving forward with a Phase IIa study evaluating the metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, called dipraglurant (ADX48621), in reducing levodopa-induced dyskinesia in patients with Parkinson’s disease (PD). The study is not impacted by Merck’s recent announcement that they were pulling out of a partnership with Addex to develop positive allosteric modulators on a closely related receptor called mGluR4, said Chris Maggos, who handles business development and communication at Addex. According to a recent article in SCRIPIntelligence, while Merck continues to acknowledge that mGluR4 is an exciting target for PD, it has decided to instead focus its resources on a product in late stage clinical testing for Parkinson’s as part of its merger with Schering-Plough.
The Addex mGluR5 study, which is partially funded by The Michael J. Fox Foundation (MJFF), is currently recruiting and running on schedule. Top-line data are expected to be reported during the first half of 2012.
MJFF has funded studies on mGluR5 since 2005, when Angela Cenci-Nilsson, MD, PhD, of Lund University in Sweden received a Target Validation award to demonstrate that blocking the action of mGluR5 prevented levodopa-induced dyskinesias in pre-clinical models of PD. MJFF research staff then helped forge a collaboration between Cenci-Nilsson and Erwan Bezard, PhD, of the Université de Bordeaux, to identify a compound capable of reducing mGluR5 activity. Having already found an mGluR5 inhibitor in human clinical testing for another disease, they adapted their studies to this compound to accelerate development toward the clinic. Building on the success of their collaboration, the Foundation then funded Danna Jennings, MD, of the Institute for Neurodegenerative Disorders in New Haven, Connecticut, to verify the action of this compound and determine a safe and effective dose for use in future clinical trials. Using PET scans and a fluorescent imaging molecule that binds to mGluR5, Dr. Jennings is imaging PD patients’ brains before and after treatment to determine if the compound is reaching the brain at appropriate levels and to determine the most effective dose of the drug for use in future PD clinical trials.
As a result of the strong pre-clinical and clinical evidence supporting mGluR5 as a highly promising target to treat dyskinesia, Addex applied for a $900,000 grant from MJFF to help fund its Phase II study, which is testing efficacy in the drug ADX48621 for treating both aspects of dyskinesia: Jerky movements known as chorea and slow, sometimes painful, writhing movements known as dystonia. The company's compound is the only experimental drug to date to have been reported to have an impact on both of these aspects in pre-clinical testing.
MJFF continues to support research into mGluR4, funding a project led by principal investigator Jeff Conn, PhD, director of the Vanderbilt Center for Neuroscience Drug Discovery. Addex also is continuing to invest in its mGluR4 program and may strike another collaboration on the compound with a new partner in the future.