Once-Daily Oral Med May Reduce Levodopa-Induced Dyskinesia

Megan Brooks

October 06, 2016

An investigational extended-release (ER) formulation of amantadine hydrochloride (ADS-5102, Adamas Pharmaceuticals) led to a statistically significant reduction in levodopa-induced dyskinesia (LID) and "off" time and was well tolerated in EASE LID 3, a phase 3 trial.

"Our results were positive for the primary endpoint, which was the reduction in the Unified Dyskinesia Rating Scale [UDysRS], but also for our main secondary endpoint, which was off time," study investigator Rajesh Pahwa, MD, professor of neurology and director, Parkinson's Disease and Movement Disorder Center, University of Kansas Medical Center, Kansas City, told Medscape Medical News.

The study results were presented at the 4th World Parkinson Congress in Portland, Oregon.

More Convenient, Better Pharmacokinetics

ADS-5102 is intended for once-daily administration at bedtime. According to the company, it's designed to improve upon the pharmacokinetic profile of immediate-release (IR) amantadine, to boost efficacy without compromising the known tolerability profile. In pharmacokinetic studies, ADS-5102 achieved high plasma amantadine concentrations during the daytime, when dyskinesia is most apt to occur.

The EASE LID 3 trial was a 13-week, double-blind, placebo-controlled study conducted at 39 sites in the United States and Europe. Seventy-seven patients with Parkinson's disease (PD) and LID were randomly allocated to take a 340-mg capsule of ADS-5102 once daily at bedtime (n = 38) or matching placebo (n = 39).

To be included in the trial, patients had to have a score of at least 2 on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part IV, Item 4.2 (functional impact of dyskinesia), and at least two 30-minute intervals of "on" time with troublesome dyskinesia during the day documented on 2 consecutive 24-hour home diaries. Inclusion criteria also required that current medications, including levodopa preparations taken at least 3 times daily, remain unchanged for 30 days before screening and during the study.

Exclusion criteria included a history of deep-brain stimulation; clinically significant hallucinations due to PD medications, underlying PD, or other/unknown cause within the year before enrollment; use of amantadine within the prior 30 days; or documented inability to tolerate or lack of response to prior amantadine treatment for dyskinesia.

The results showed that ADS-5102 significantly decreased the UDysRS total score at week 12 compared with placebo. The percentage reduction from the mean UDysRS total score at baseline compared with that at week 12 was 46% in the ADS-5102 group vs 16% in the placebo group. Improvement in LID was evident at the first post-baseline UDysRS assessment at week 2 and was maintained through week 12. The reduction in UDysRS total score was consistent across subgroups, including baseline dyskinesia severity and daily levodopa dose, the investigators say.

The study also met key secondary endpoints.

According to home diaries, ADS-5102 increased "on" time without troublesome dyskinesia by 1.9 hours per day, adjusted for placebo (P = .0168), and decreased "off" time by 1.1 hours per day (P = .0199).

At week 12, the MDS-UPDRS Part IV (motor complications) score decreased by 4.3 with ADS-5102 and 1.3 with placebo (P < .0001) and the MDS-UPDRS combined score (Parts I, II, and III) decreased by 8.4 and 2.0, respectively (P = .0398).

Also at 12 weeks, 51.4% of patients in the ADS-5102 group had moderate to marked improvement in PD symptoms, including but not limited to LID, based on the Clinical Global Impression-Change scale, compared with 10.5% of those in the placebo group.

ADS-5102 was generally well tolerated, with the types of adverse events consistent with the known safety profile of amantadine IR, the investigators say. The most common adverse events, occurring in more than 5% of patients, were dry mouth, nausea, decreased appetite, insomnia, orthostatic hypotension, falls, and visual hallucination. One patient in the ADS-5102 group reported two related serious adverse events (constipation and urinary retention) but opted to stay on the treatment and completed the study. No patients died during the study.

These findings from the EASE LID 3 trial confirm findings from the previous phase 2/3 EASED and phase 3 EASE LID studies of ADS-5102, the investigators note.

In a separate poster presentation, Dr Pahwa and colleagues reported results of a post hoc analysis of the EASE LID study, suggesting that treatment with ADS-5102 improves activities of daily living (ADLs).

At baseline, at least 40% of patients reported mild to moderate impairment due to LID in 9 of 10 ADLs. Additionally, more than 70% reported mild to moderate impairment due to dyskinesia in public and social settings, as well as in walking and balance at baseline.

The post hoc analysis showed that treatment with ADS-5102 improved ADLs, as evidenced by a 7.0-point reduction from baseline in the UDysRS, Part 1B total score, which gauges the effect of dyskinesia on ADLs, compared with a 4.0-point reduction for placebo.

Adamas Pharmaceuticals said it plans to submit a new drug application for amantadine ER for treatment of LID in PD to the US Food and Drug Administration later this year.

"If approved, this drug would become the only drug available for Parkinson's that not only reduces dyskinesia but also reduces off time," Dr Pahwa told Medscape Medical News. "We have drugs that reduce off time, but their side effect is worsening of dyskinesias. Right now, there is no drug that has been approved for dyskinesias, so if approved it would be the first drug for LID."

High-Quality Study

Reached for comment, Olivier Rascol, MD, PhD, from INSERM, Clinical Investigation Center and Department of Neurology, University Hospital of Toulouse, France, told Medscape Medical News that this is a "nice study of good quality with good methodology and validated endpoints. And it's a study that was needed because there was no such large and good-quality data to document the effect of amantadine on dyskinesia."

The results are "confirmatory of something that we already knew, which is that amantadine, a drug available for more than 40 years now as an IR formulation for the treatment of Parkinson disease, improves dyskinesia. In terms of practice, such new data, obtained with a now ER formulation, hopefully will allow better communication to general neurologists and will raise their interest in such a property to improve the management of dyskinetic patients," said Dr Rascol, who was not involved in the study.

With the ER formulation, he noted, "there is the added convenience of taking it once daily rather than three times daily as this is the rule with the IR formulation. It is also conceivable that amantadine ER plasma profile may induce less side effects or better tolerability than the IR formulation. However, this remains to be proven clinically, as no direct head-to-head comparison has been performed yet between the old IR and the new ER formulation."

The studies were sponsored by Adamas Pharmaceuticals Inc. Dr Pahwa is on the Adamas LID Steering Committee and received compensation for this service. Dr Rascol serves as an advisor to the company.

4th World Parkinson Congress. Abstracts 1331 and 1233. Presented September 20, 2016.

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