VANCOUVER – An extended-release amantadine formulation reduced levodopa-induced dyskinesia in a phase III Parkinson’s disease trial from the drug’s developer, Adamas Pharmaceuticals.
Amantadine extended release (ER) is a once-daily, 340-mg capsule taken at bedtime. Patients wake up with the drug on board and achieve peak plasma concentrations during the waking hours. Concentrations drop off in the evening, which might help with sleep, said investigator Dr. Rajesh Pahwa, a neurology professor at the University of Kansas Medical Center, Kansas City.
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Generic immediate-release amantadine is usually dosed at 100 mg twice daily, “but 200 mg is [often] not an effective dose” for levodopa-induced dyskinesia, Dr. Pahwa noted. “The effective dose is closer to 340 mg.”
It’s hoped that the ER formulation, by smoothing out the peaks and troughs in plasma concentrations, might make higher dosing more tolerable, he said at the annual meeting of the American Academy of Neurology.
The study randomized 126 patients with Parkinson’s disease and levodopa dyskinesia evenly to placebo or amantadine ER for 24 weeks.
Compared with placebo and based on patient diaries, amantadine ER reduced on-time with troublesome dyskinesias by about 1.5 hours per day, from a baseline of about 4.6 hours. Amantadine ER also increased on-time without troublesome dyskinesias by about 2.5 hours, from a baseline of about 8.4 hours, and reduced off-time by almost an hour, from a baseline of about 3.1 hours – with the greatest benefits coming at 12 weeks.
The drug also reduced Unified Dyskinesia Rating Scale scores about 8 points over placebo at week 12, and 9 points at week 24, from a baseline mean of about 40 points. At week 12, 60% of the ER patients, compared with 19% of placebo subjects, had moderately to markedly improved scores on the Clinical Global Impression of Change. Pharmacokinetics were not reported.
“All the efficacy parameters are going in the same direction,” Dr. Pahwa said.
About 21% of amantadine ER patients dropped out of the study because of side effects, most frequently hallucinations, peripheral edema, dizziness, dry mouth, constipation, and falls. Side effects led to the withdrawal of about 7% of placebo patients.
“We had some dropouts, but at least we were able to show that the majority of patients were able to tolerate 340 mg and have efficacy,” Dr. Pahwa said.
Food and Drug Administration labeling of an immediate-release amantadine formulation reported nausea, dizziness, and insomnia in up to 10% of patients, with more serious side effects in fewer patients, in doses generally of 100 mg twice daily.
Adamas plans to submit an approval package to the FDA in 2016, with possible amantadine ER approval in 2017.
The trial excluded patients who had used immediate-release amantadine within 30 days, along with people who had deep brain stimulation and those who had hallucinated within a year for any reason.
The mean baseline levodopa dose was 862 mg, and mean duration of levodopa-induced dyskinesia was about 4 years. The mean age of patients in the trial was 65 years.
Adamas Pharmaceuticals funded the study. Dr. Pahwa is a paid consultant and a researcher for the company.