Research Area Position Papers

mGluR5

One promising approach to dyskinesia involves the glutamate receptor mGluR5. In five years the Foundation's de-risking efforts have chaperoned mGluR5 from basic discovery to clinical testing and attracted industry interest in the target. In August 2010, Addex Pharmaceuticals of Geneva received Foundation funding for a Phase 2 clinical trial of an mGluR5-targeting agent that has shown promise in pre-clinical trials and a Phase 1 clinical study. The Addex medicine, called ADX48621, is aimed at treating both aspects of dyskinesia, which comprises jerky movements known as chorea and slow, sometimes painful, writhing movements known as dystonia. The company's compound is the only experimental drug to have shown an impact on both aspects in pre-clinical testing.

The initial data on mGluR5 and dyskinesia came from a research group at Lund University in Sweden funded by the Foundation in 2005 to demonstrate that blocking the action of mGluR5 prevented levodopa-induced dyskinesias in rodent models of PD. Follow-on funding from MJFF allowed the researchers to collaborate with the University of Bordeaux in France, taking these to invest in mGluR5 development. Today, in addition to the Addex-funded trial, MJFF is supporting a team at The Institute for Neurodegenerative Disorders in New Haven, Connecticut, to verify the action of an mGluR5-targeting compound and determine a safe and effective dose for use in additional future clinical trials.

mu Opioid Receptors

One promising approach to dyskinesia involves the glutamate receptor mGluR5. In five years the Scientific evidence suggests that increased opioid peptide transmission in the basal ganglia might underlie dyskinesia after chronic levodopa treatment and that opioid antagonists might be useful as adjuncts to levodopa therapy for Parkinson's disease. Preclinical evaluation of opioid antagonists in relevant models of dyskinesia suggests that antagonism of the mu opioid receptor may be effective for alleviating these levodopa-induced motor complications.

Exton, Pennsylvanie-based biotech Adolor has discovered a family of novel, selective mu opioid receptors. These compounds have been shown to be highly efficacious, after oral administration, in well-validatedpre-clinical models of dyskinesia. The robust antidyskinetic efficacy of these compounds was confirmed by three independent laboratories. Adolor's mu opioid receptors represent first-in-class compounds with a novel mechanism of action for the potential treatment of levodopa-induced dyskinesia associated with Parkinson's disease. MJFF is currently funding Adolor's ongoing lead compound optimization development efforts.

Serotonin

Researchers at Lund University in Sweden have been funded by MJFF since 2005 to develop a new treatment for dyskinesia targeting the brain's serotonin system, better known for its role in clinical depression. With Foundation funding, the researchers recently demonstrated that abnormal, dyskinesia-inducing dopamine release can be effectively blocked by drugs that act on two specific receptors, known as 5-HT1A and 5-HT1B, located on the serotonin neurons. They have also shown that this technique is particularly effective when the two receptors are activated simultaneously.

Based on these results, Dr. Björklund's team is now conducting an MJFF-funded pilot clinical trial in 24 Parkinson's patients at Lund University Hospital and Karolinska Hospital Huddinge (both in Sweden). The trial is being carried out in collaboration with the U.S. biotech company PsychoGenics, using their proprietary drug Eltoprazine, which activates both 5-HT1A and 5-HT1B, and has shown promising results in pre-clinical trials to date.

Validation of Clinical Rating Scales for Dyskinesia

The Michael J. Fox Foundation is funding a $1-million clinical study aiming to establish a framework for testing novel anti-dyskinesia treatments by validating clinical scales used to measure changes in dyskinesia severity.

Significant problems in measuring dyskinesia and assessing the efficacy of potential new therapies have created major roadblocks to clear-cut trial results and, therefore, industry investment leading to new and better interventions. The establishment of validated tools for use in dyskinesia clinical trials would significantly reduce the barrier for biotech and pharmaceutical companies to invest in trials to address this debilitating aspect of living with Parkinson's.

The study holds two primary aims: quantitatively establish the degree of changes in dyskinesia severity as a result of treatment with amantadine; and conclusively determine which scale or scales most accurately detect these changes. Patients will be treated with amantadine or placebo, and then have their dyskinesia rated over the course of several weeks using numerous dyskinesia measurement scales. The researchers will examine the response to placebo as well in order to favor scales that maximally separate placebo-associated changes from amantadine-associated changes. The results will establish a path for clinical testing of future promising novel dyskinesia treatments.

The double-blind, placebo-controlled trial, enrolling 66 PD patients at up to eight sites in the United States, Canada and Europe, will be led by coordinating principal investigators Christopher G. Goetz, MD, and Glenn T. Stebbins, PhD, of Rush University Medical Center in Chicago.