Amantadine Improves Motor Function, Dyskinesia in Parkinson Disease

Robert A. Hauser, MD, MBA

When treated with amantadine extended-release capsules (Gocovri; Adamas), patients with Parkinson disease saw improvements in both dyskinesia and motor aspects of experiences of daily living (M-EDLs), namely tremor, freezing, eating, and getting in and out of the seated position, according to findings from 2 randomized phase 3 trials published in Neurology Therapy.¹

Changes from baseline to week 12 were analyzed via the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), with a treatment difference of –2.0 (P = .004) for amantadine versus placebo. Additionally, at the 12-week mark, the amantadine group’s change from baseline exceeded a published minimal clinically important difference threshold of 3.05 points.

“For people living with Parkinson disease, motor complications often have a broad impact on daily activities,” study author Robert A. Hauser, MD, MBA, professor of neurology, and director, Parkinson’s Disease and Movement Disorders Center, University of South Florida, said in a statement.² “The improvements in patient-perceived disability associated with motor aspects of PD–such as freezing of gait, tremors, and getting out of bed–support the use of Gocovri as an important treatment option for PD motor complications.”

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Following an initial screening, a total of 198 patients were treated, with 100 receiving amantadine and 98 receiving placebo. The modified intent-to-treat group consisted of 196 patients, including all randomized subjects from both studies, with 100 receiving amantadine and 96 receiving placebo. Among these patients, 187, 173, and 169 provided MDS-UPDRS Part II data at 2, 8, and 12 weeks, respectively (amantadine: 97, 84, and 82; placebo: 90, 89, and 87). Participants had a mean age of 64.7 years and had, on average, been taking levodopa for 7.7 years and experiencing dyskinesia for 3.8 years. 

At the 12-week mark, patients treated with amantadine reported a least-squares mean change from baseline on the MDS-UPDRS of –3.4 points, compared to –1.4 points for those treated with placebo (treatment difference, –2.0 [95% CI, –3.3 to –0.7]; P = .004). Specifically, for freezing; tremor; and getting up from bed, chairs, and deep seats, patients reported statistically significant improvements, with amantadine-related treatment differences of –0.4 (P <.0001), –0.4 (P = .002), and –0.3 (P = .002), respectively. Additionally, patients treated with amantadine showed significant improvements in eating tasks (–0.2; P = .016). Of participants that reported freezing, 61.7% of those receiving amantadine and 31.5% receiving placebo showed improvement, while those with at least mild impact at baseline also moved to nonproblematic scores (0 or 1), notably 53.8% of those treated with amantadine and 17.1% of those with the placebo.

“The substantial treatment effect (−0.4) for the freezing M-EDL may represent an important outcome because effective treatment for freezing of gait is a significant unmet need in PD,” the authors noted. “Because the pathophysiology of freezing appears to be separate from the primary motor symptoms of PD, the effect of Gocovri on this aspect of disease is particularly interesting.”

The authors noted 2 primary limitations, the post hoc aspect of the study, as well as presence of only mild impairment for most at baseline, which they noted potentially affected their ability to detect responses. In addition, the extended-release pill is specific to the study, with a higher recommended dosage than other amantadine regimens. “As most patients with dyskinesia also suffer from OFF episodes, future studies/analyses should evaluate the performance of Gocovri in patients with higher levels of baseline OFF and in those without dyskinesia,” the authors wrote.

Of the adverse events (AEs) reported, visual and auditory hallucinations were the most common, particularly in order participants and those with lower renal function. Dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypertension were additional AEs reported, occurring in more than 10% of patients treated with amantadine.

A second indication was approved for amantadine extended-release capsules by the FDA in February 2021, making it the only approved therapy in the US to treat both OFF episodes and dyskinesia in patients with Parkinson disease. As noted by the investigators, further investigation is necessary, as the recent study contains one of the few sources of controlled data on the effectiveness of amantadine in treating both tremor and freezing. 

REFERENCES
1. Hauser RA, Mehta SH, Kremens D, et al. Effects of Gocovri (amantadine) extended-release capsules on motor aspects of experiences of daily living in people with Parkinson’s disease and dyskinesia. Neurol Ther. Published online May 22, 2021. doi:10.1007/s40120-021-00256-1
2. New data analysis supports Gocovri as an important treatment for motor complications for people with Parkinson’s disease. News release. Adamas. June 10, 2021. Accessed July 6, 2021. https://www.biospace.com/article/releases/new-data-analysis-supports-gocovri-as-an-important-treatment-for-motor-complications-for-people-with-parkinson-s-disease/