Parkinson's Disease Levodopa-Induced Dyskinesia
Parkinson's disease (PD) is a chronic and progressive movement disorder, meaning that symptoms continue and worsen over time. According to the Parkinson's Disease Foundation, as many as one million Americans live with PD and more than 10 million people worldwide are living with PD. The cause of PD is unknown, and there is presently no cure.
PD involves the malfunction and death of certain nerve cells in the brain that produce dopamine, a key chemical that sends messages to the part of the brain that controls movement and coordination. As PD progresses, the amount of dopamine produced in the brain decreases, leaving a person unable to control movement normally.
Levodopa (L-DOPA) therapy increases brain levels of dopamine and is the gold standard for treating symptoms of PD in nearly all phases of the disease. Currently, it is considered the most effective drug for controlling the symptoms of PD. However, L-DOPA-induced dyskinesia (LID) is a common, and generally disabling, complication of long-term L-DOPA treatment in PD patients. Studies published in the New England Journal of Medicine and Movement Disorders have shown that LID develops in approximately 45% of L-DOPA-treated PD patients after five years and 80% after 10 years of L-DOPA treatment. This dyskinesia, or uncontrollable muscle movement, induced by L-DOPA therapy, is not part of PD, but instead a complication of L-DOPA therapy. LID interferes not only with L-DOPA treatment of PD, but also negatively impacts the quality of life of PD patients and is a major contributor to disability later in the ordinary course of the disease. While amantadine, a low-affinity NMDA receptor antagonist, has been shown to offer some relief for certain PD patients suffering from LID, more effective and better tolerated pharmacologic management of LID remains a significant unmet medical need.
In a monkey model of PD, AV-101 (250 mg/kg and 450 mg/kg) reduced by 30% the mean dyskinesia score associated with L-DOPA treatment of PD. Maximum dyskinesia scores were also reduced by 17%. Importantly, AV-101 did not reduce the anti-parkinsonian therapeutic benefit of L-DOPA. Moreover, the duration of L-DOPA response and delay to L-DOPA effect were not affected by treatment with AV-101. We believe these preclinical monkey data warrant Phase 2 clinical development of AV-101 in L-DOPA-treated PD patients suffering from LID.