Extended-Release Amantadine Effective for Dyskinesia in PD

Pauline Anderson

June 21, 2017

Amantadine extended-release (ER) capsules reduce levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD), a phase 3 placebo-controlled trial has shown.

"Our study showed that this medication significantly reduced not only the severity of dyskinesia as measured by the United Dyskinesia Rating Scale, but also the duration of dyskinesia during the day as measured by patient diaries," lead author, Rajesh Pahwa, MD, professor, neurology, and director, Parkinson's Disease and Movement Disorders Center, University of Kansas Medical Center, Kansas City, told Medscape Medical News

Another important finding of the study, published online June 12 in JAMA Neurology, was that the medication reduced "off" times — periods during the day when anti-PD medication isn't working optimally, said Dr Pahwa.

"All the current medications we have to reduce off time increase dyskinesia; not only did this drug reduce dyskinesia, but it also reduced the off time."

The study was halted early, and data were submitted to the US Food and Drug Administration (FDA) for approval.

Amantadine is a nonselective low-affinity noncompetitive N-methyl-d-aspartate receptor antagonist with antiglutamatergic properties. It also exerts some control over the release of dopamine and is believed to induce anticholinergic effects.

It's estimated that LID occurs in more than 50% of patients who have received levodopa therapy for 4 to 6 years and in more than 90% of patients treated for a decade.

In addition to the duration of levodopa therapy, disease duration, disease severity, and age at onset are other important risk factors for LID, according to experts.

Unmet Need

Dyskinesia "is a major unmet need in Parkinson's disease," said Dr Pahwa, adding that there are no approved treatments for the condition.

"There is a generic amantadine immediate release available, but it has never been well studied for dyskinesia," he said.

The ER capsules, administered at bedtime, are specifically formulated so that the plasma concentration increases slowly during sleep, with peak concentration in the morning and sustained concentrations throughout the day.

"Levels go up slowly and you have a benefit as soon as you wake up and throughout the day," said Dr Pahwa.

Researchers randomly assigned 126 patients with PD taking levodopa from 44 North American sites to a treatment or a placebo group. Study patients had to have at least mild functional impact of dyskinesia (score of 2 on a scale of 0 to 4, where 0 is no impact and 4 is severe impact).

During the first week of treatment, patients assigned to receive amantadine received a daily dose of 137 mg, which was increased to 274 mg during weeks 2 to 24 before being reduced back to 137 mg during the last week of dosing.

Antiparkinsonian medications, including levodopa preparations, were to be unchanged for at least 30 days before screening and during the study.

The primary outcome was change in the United Dyskinesia Rating Scale (UDysRS) total score at 12 weeks.

The modified intent-to-treat analysis, which included 121 patients, showed a significantly greater decrease in UDysRS total score (reduction in duration, severity, and impact of dyskinesia) in the amantadine group than in the placebo group at week 12 (least-squares mean treatment difference, –7.9; 95% confidence interval [CI], –12.5 to –3.3; P < .001).

Similarly, at week 24, the decrease in UDysRS total score was significantly greater in the treatment group compared with the placebo group (least-squares mean treatment difference, –9.3; 95% CI, –14.7 to –4.0; P < .001).

The treatment effect of amantadine on the UDysRS total score was consistent across subgroups. For example, it was effective in younger (under age 65 years) as well as older patients and in men and women.

"Whichever subgroup analysis we did, it showed that it worked," said Dr Pahwa.

The treatment also provided significant improvement on several key secondary endpoints. For example, patient diary entries showed improvement over placebo for mean "on" time without troublesome dyskinesia.

As well, off time decreased by a mean of 0.6 hours for the treatment group and increased by 0.3 hours for the placebo group, for a treatment difference of  –0.9 hours (95% CI, –1.6 to –0.2 hours; P = .02).

Adverse Events

Overall, adverse events (AEs) were reported in 88.9% of the treatment group and 60.0% of the placebo group. Most of these were mild to moderate.

The most common AEs, occurring in 5% or more of the treatment group, included visual hallucinations, peripheral edema, dizziness, dry mouth, and constipation.

"Physicians need to be aware that, as with all medications, there are side effects with this drug, and in this case, they need to be aware of hallucinations, which can be seen with all Parkinson's medications," said Dr Pahwa.

Other AEs, occurring in less than 5% of patients in the treatment group, included nausea, confusion, and orthostatic hypotension. Impulse control disorder was not reported in the treatment group.

No serious AEs were associated with the study drug.

When the trial was stopped, assessment at 12 weeks had been completed for all patients and the sponsor felt there were enough data to 24 weeks to submit to the FDA, said Dr Pahwa.

The sponsor also submitted data from another phase 3 study of the agent to the FDA. That study, which included North American as well as European sites and continued for only 12 weeks, will be published within the next few months, said Dr Pahwa.

Major Advantage

In an accompanying editorial, Aparna Wagle Shukla, MD, assistant professor, Department of Neurology, University of Florida, Gainesville, noted that the study "had a moderately large sample of patients with PD and LID" and that "the investigators used a validated scale that incorporated both patient and physician ratings."

Once-daily dosing is a major advantage when it comes to reducing pill burden, which is "exceedingly common in PD," said Dr Wagle Shukla.

"As pill burden is a major reason for medication nonadherence, once-daily dosing with extended-release amantadine is expected to present an attractive option for patients and prescribers."

Dr Wagle Shukla pointed out several limitations of the study. There was no active comparison with immediate-release amantadine, and there was an "early and unexpected" termination of the trial. In addition, the analysis did not shed light on responders to amantadine therapy vs nonresponders, she said.

Patients with young-onset PD were underrepresented in the sample; these patients in general tend to have more severe LID, she added.

Despite the many advantages of this pill, "until a true comparison with a generic amantadine pill is performed, it remains unclear whether the potential benefits justify the cost," Dr Wagle Shukla concluded.

"It is important that regulatory agencies give due consideration to what requirements and comparator groups are most appropriate for pharmaceutical companies that are interested in manufacturing extended-release formulations."

Dr Pahwa reported receiving honoraria or payments for consulting from AbbVie, Acadia, Acorda, Adamas, Sunovion, Impax, Lundbeck, Neurocrine, Sage, St Jude Medical, Teva Neuroscience, Union Chimique Belge, US WorldMeds, and Global Kinetics; receiving research grants from Acadia, Acorda, Adamas, Avid, Biotie, Boston Scientific, Civitas, Cynapsus, Kyowa, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, National Parkinson Foundation, Pfizer, and Parkinson Study Group/University of Rochester; serving on the data monitoring committee for Ionis; and receiving personal compensation as the co-editor-in-chief of the International Journal of Neuroscience. Dr Wagle Shukla has disclosed no relevant financial relationships.

JAMA Neurol. Published online June 12, 2017. Abstract, Editorial

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