Development, Efficacy and Safety of Once-daily, Bedtime, Extended-release Amantadine (Gocovri®) to Treat Dyskinesia and OFF Time in Parkinson’s Disease

Abstract

Throughout the course of Parkinson’s disease, levodopa therapy becomes increasingly complicated by the development of OFF episodes and the emergence of dyskinesia. Both have a significant impact on activities of daily living, health-related quality of life, care-partner burden, the incidence of fall risk and healthcare costs. The approach to managing OFF episodes has been based on increasing the dosage and/or frequency of levodopa and/or adding adjunctive dopaminergic medication, all of which can increase dyskinesia as a trade-off to OFF episode improvement. In contrast, treatment of dyskinesia has centred on reducing levodopa and/or adjunctive dopaminergic therapy use, thus creating a treatment conundrum. Treatment with the glutamatergic antagonist amantadine has been reported to decrease dyskinesia, but the clinical utility of the amantadine immediate-release (IR) formulations can be limited by inadequate efficacy and dose-limiting side effects. Gocovri® (Adamas Pharmaceuticals; Emeryville, CA, USA) is a once-daily, bedtime, extended-release formulation of amantadine that provides peak plasma concentrations in the morning and are sustained throughout the day, while minimizing night-time exposure. In two randomized, placebo-controlled pivotal trials, Gocovri significantly reduced dyskinesia and improved OFF time, leading to its US Food and Drug Administration approval for levodopa-induced dyskinesia and OFF episodes. Additional analyses of Gocovri have demonstrated improvements in activities of daily living, reductions in daily transitions between motor states, less dyskinesia in patients switched from amantadine IR, and efficacy in patients with deep brain stimulation. In an open-label extension trial, Gocovri demonstrated durability in dyskinesia reduction and OFF time improvement over 2 years. Therefore, Gocovri represents a clinically significant advance in treating dyskinesia and OFF time.