Add-on amantadine lessens “off” episodes in Parkinson’s disease

A delayed release/extended release (DR/ER) formulation of amantadine can help reduce breakthrough symptoms in Parkinson’s disease (PD) patients when the effect of levodopa therapy wears off, as shown in a recent study.

In a pooled analysis of two phase III trials (the 25-week EASE LID and the 12-week EASE LID 3) and a 2-year open-label extension trial (EASE LID 2), 12 weeks of treatment with amantadine-DR/ER produced a mean reduction in “off” episodes of 1 hour per day in the overall modified intent-to-treat (mITT) population (n=196) as compared with placebo. An “off” episode was defined as when levodopa/carbidopa did not seem to work and symptoms returned or became worse. [NPJ Parkinsons Dis 2022;8:29]

The results were consistent in the subgroup analysis, with “off” episodes decreasing by a mean of 1.2 hours/day among patients with baseline “off” time of ≥2.5 hours/day (n=102) and a mean of 0.77 hour/day among patients with baseline “off” time of <2.5 hours/day (n=94) at week 12.

Amantadine-DR/ER-treated patients also saw a reduction in the MDS-UPDRS* Part IV motor fluctuation subscores that became evident by week 2 and kept below baseline through week 100.

At baseline, 173 of 196 (88 percent) patients reported experiencing “off” episodes on their home diaries. Mean daily “off” time prior to amantadine-DR/ER treatment was 2.8 hours in the mITT population, 4.4 hours in the ≥2.5-hour subgroup, and 1.0 hour in the <2.5-hour subgroup.

The present data confirm and extend the findings from previous trials, showing that patients with significant motor fluctuations at baseline experienced a clinically relevant reduction in the magnitude of “off” time, with the reduction at least as large as that achieved with other adjunct therapies aimed at managing motor fluctuations, the investigators said.

Furthermore, the parallel reductions in MDS-UPDRS Part IV motor fluctuation items that were sustained throughout 100 weeks of open-label amantadine-DR/ER treatment suggested that the benefit conferred for “off” episodes was persistent and did not result simply from levodopa dose adjustment, they added.

FDA approval nabbed

“Current treatment algorithms [in PD] often present a difficult trade-off between managing ‘off’ time and managing dyskinesia,” the investigators said. “Of all the medications available … only amantadine has established efficacy against levodopa-induced dyskinesia.” [Neurol Clin 2020;38:255-267; Oncotarget 2017;8:57316-57326]

A DR/ER capsule formulation of amantadine contains coated pellets that provide a reliable delivery profile, with an initial delay in exposure, followed by sustained amantadine delivery over the dosing interval. This formulation was specifically developed to address the issue with immediate-release amantadine, where higher doses have been associated with greater efficacy but worse tolerability, according to the investigators.

“Based on the consistently statistically significant and clinically meaningful ‘off’ time reductions demonstrated in phase III trials, the US Food and Drug Administration has now approved amantadine-DR/ER for adjunctive use with levodopa/carbidopa in patients with PD experiencing ‘off’ episodes,” they said. [tinyurl.com/y88xv2uv]

Moreover, in light of the additional reductions in dyskinesia observed with amantadine-DR/ER, the drug is the only medication to receive FDA-approval for treating both types of complications, the investigators noted. [JAMA Neurol 2017;74:941-949; Mov Disord 2017;32:1701-1709]

 *Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale