Safety, Tolerability and Efficacy of ADX48621 in the Treatment of Levodopa-induced Dyskinesia in Parkinson's Disease

Objective/Rationale: 
The main objective of this study is to evaluate the effect of ADX48621 (dipraglurant) in reducing levodopa-induced dyskinesia in patients with Parkinson’s disease (PD). ADX48621 is a modulator (non-competitive inhibitor) of the metabotropic glutamate receptor 5 (mGluR5), which is found abundantly in the brain. Blockade of this receptor has been shown to have anti-parkinsonian and anti-dyskinetic effects in a variety of pre-clinical models. ADX48621 in particular has shown significant effects in reducing both the chorea and dystonia components of dyskinesia in a pre-clinical model of PD levodopa-induced dyskinesia.

Project Description: 
The study will include around 90 patients with PD in the USA and Europe, being treated with levodopa and experiencing moderate to severe dyskinesia. Patients who agree to participate will be randomly assigned in a proportion of 2:1 to take ADX48621 or placebo for four weeks. For the first two weeks, patients will receive either 50mg of ADX48621 three times a day or placebo. If after this initial period the study drug is well tolerated, patients will proceed to take 100 mg of ADX48621 or placebo three times a day for the subsequent two weeks. The study will comprise five visits: Screening; Visit 1; Treatment Allocation (one week later) Visit 2; Interim Visit 3 (after two weeks of treatment); End of Treatment (after four weeks of treatment) Visit 4 and Follow up Visit 5. At Visits 2, 3 and 4 patients will take a dose of their levodopa with study medication, and the effect on their abnormal movements (dykinesias) will be rated by a trained observer for the three hours after dosing. Other PD rating scales will be used to collect information on the effects of study medication on dyskinesias, PD symptoms and quality of life in between the clinical visits.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
Levodopa, the primary treatment for Parkinson’s disease, is highly effective, but after a few years of treatment, patients tend to experience reduced effectiveness and abnormal body movements known as dyskinesias following dosing. These dyskinesias have a negative impact on quality of life and can restrict the dosing of levodopa, resulting in an inadequate control of parkinsonian symptoms. There are no marketed medications indicated specifically for the treatment of levodopa-induced dyskinesia. Amantadine is partially effective, but has significant dose limiting side effects. An effective, well tolerated treatment for dyskinesia, could significantly advance the treatment of PD.

Anticipated Outcome: 
The results from this proof-of-concept study will determine whether ADX48621 has any clinically meaningful effect in the treatment of PD levodopa-induced dyskinesia and whether the drug is well tolerated by patients with PD. The data will be used to optimize the design and dosing regimen for subsequent larger studies in this indication.

PARTNERING PROGRAM

This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.

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