Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies

Abstract

BACKGROUND Immediate Release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER ® ) contains an IR outer layer and ER core for once-daily dosing. OBJECTIVEReport individual and pooled results for the similarly designed double-blind, placebocontrolled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID. METHODS PD patients with LID were randomized to IR/ER-amantadine 193mg, 258mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II+III and Fatigue Severity Scale. RESULTSOverall, 222 individuals enrolled (N=87 ALLAY-LID I, N=135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193mg and 258mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were −5.5[−9.8,−1.2], p=0.012 and −5.2[-9.5,-0.9], p=0.017, respectively. IR/ER-amantadine 258mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193mg), 18.7% (258mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively).CONCLUSIONS IR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

Downregulation of striatal CaV1.3 inhibits the escalation of levodopa-induced dyskinesia in male and female parkinsonian rats of advanced age

“…The management of levodopa-induced dyskinesia (LID) remains a significant unmet need in the treatment of Parkinson’s disease (PD) ( Huot et al, 2022 ; Bastide et al, 2015 ; Bove and Calabresi, 2022 ; Huot et al, 2013 ). Levodopa, the biosynthetic precursor to dopamine (DA), has been the predominant symptomatic treatment for PD for more than five decades ( Bastide et al, 2015 ; Rascol et al, 2022 ; Tanner et al, 2020 ; Belujon et al, 2010 ). Though the dyskinetic side effects of long-term levodopa use are well-documented, effective therapies for LID remain elusive (for review ( Huot et al, 2022 ; Bastide et al, 2015 )).…”

“…Though the dyskinetic side effects of long-term levodopa use are well-documented, effective therapies for LID remain elusive (for review ( Huot et al, 2022 ; Bastide et al, 2015 )). Currently, extended-release amantadine is the only FDA-approved drug available to individuals with PD suffering from LID, which, though partially effective, is not without its own side effects ( Rascol et al, 2022 ; Tanner et al, 2020 ).…”