Randomized, placebo‐controlled trial of ADS‐5102 (amantadine) extended‐release capsules for levodopa‐induced dyskinesia in Parkinson's disease (EASE LID 3)

Abstract

BackgroundThe treatment of levodopa‐induced dyskinesia in Parkinson's disease (PD) is an unmet need with no approved drug therapy.ObjectiveThe purpose of this study was to investigate the efficacy and safety of 274 mg ADS‐5102 (amantadine) extended‐release capsules (equivalent to 340‐mg amantadine HCl) for levodopa‐induced dyskinesia in a randomized controlled trial.MethodsPD patients with ≥1 hour of troublesome dyskinesia and at least mild functional impact were randomized to placebo or ADS‐5102 once daily at bedtime for 13 weeks. The primary efficacy analysis was based on change from baseline to week 12 on the Unified Dyskinesia Rating Scale total score in the modified intent‐to‐treat population. OFF time was a key secondary measure.ResultsAt week 12, least‐squares mean change in the Unified Dyskinesia Rating Scale was −20.7 (standard error 2.2) for ADS‐5102 (n = 37) and –6.3 (standard error 2.1) for placebo (n = 38; treatment difference −14.4, 95% confidence interval −20.4 to −8.3, P < .0001), indicating improvement in levodopa‐induced dyskinesia. OFF time decreased 0.5 hours (standard error 0.3) for ADS‐5102 from a baseline mean of 2.6 hours and increased 0.6 hours (standard error 0.3) for placebo from a baseline mean of 2.0 hours (treatment difference −1.1 hours, 95% confidence interval −2.0 to −0.2, P = .0199). The most common adverse events (ADS‐5102 versus placebo) included dry mouth (13.5% versus 2.6%), nausea (13.5% versus 2.6%), decreased appetite (10.8% versus 0%), insomnia (10.8% versus 0%), orthostatic hypotension (10.8% versus 0%), constipation (8.1% versus 0%), falls (8.1% versus 5.3%), and visual hallucinations (8.1% versus 5.3%). Adverse events led to treatment discontinuation in 19% versus 8%, respectively.ConclusionADS‐5102 274 mg is an oral pharmacotherapy demonstrating a significant decrease in levodopa‐induced dyskinesia and improving OFF time. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates

“…Because the infusion into the putamen was unilateral and centered on the posterolateral motor territory using a discrete volume to avoid overflow to surrounding extrastriatal areas, most likely the covered area did not extend to the whole target region, but nevertheless, dyskinesias were reduced by 71%. In line with our results, the only drug in clinical use to treat dyskinesias is amantadine, an agent with actions at multiple sites, including the NMDAR (Oertel et al, 2017). On the basis of the effects of selective agents, the antidyskinetic effect of amantadine is likely mediated by NMDAR block.…”

Parkinson's Patients with Dyskinesia Switched from Immediate Release Amantadine to Open‐label ADS‐5102

“…Mean duration of dyskinesia in previous amantadine IR patients was 7.4 years, compared with 4.6 and 4.0 years in the previous active and previous placebo subgroups, respectively. Baseline MDS‐UPDRS Part IV scores for previous amantadine IR subgroup were similar to scores of the previous placebo subgroup (∼9.5–10) …”

“…Patients were recruited after completing participation in one of the ADS‐5102 controlled, double‐blind trials (EASE LID or EASE LID 3), or the dose‐finding EASED study . Patients who were ineligible to enroll in an ADS‐5102 trial because they had undergone deep brain stimulation (DBS) were recruited to this open‐label trial.…”

“…Recently, two phase 3, double‐blind, placebo‐controlled efficacy studies demonstrated that ADS‐5102 significantly reduced dyskinesia, with a secondary benefit of reduction in OFF time, when administered once daily at bedtime . In the current analysis, we assess the tolerability and efficacy of open‐label ADS‐5102 (amantadine) extended release capsules in the subgroup of patients who were receiving amantadine IR and then directly switched to ADS‐5102 at enrollment in the EASE LID 2 open‐label study.…”

Pharmacokinetics of ADS-5102 (Amantadine) Extended Release Capsules Administered Once Daily at Bedtime for the Treatment of Dyskinesia

“…In all three studies, the reduction in dyskinesia was significant at the first visit (2 weeks) and was durable for up to 24 weeks. Moreover, benefits for dyskinesia and OFF time were observed throughout the waking day [14,15]. While dose-dependent increases in sleep-related AEs were reported in early studies with amantadine IR in PD patients [21] and healthy elderly volunteers [26], the incidence of sleep-related AEs (e.g., insomnia) was low in the ADS-5102 clinical program despite the high dose of amantadine used.…”