Long-Acting Drug Safe in Dyskinesia

June 23, 2016

BERLIN -- An extended-release formulation of amantadine for levodopa-induced dyskinesia is well tolerated in the long run, researchers reported here.

In an interim analysis of data from an ongoing open-label safety study, adverse event rates for those on ADS-5102 were similar to those in earlier studies over a total of 41 weeks, with the most common being falls (20%) and hallucinations (11%), Rajesh Pahwa, MD, Director of the Parkinson's Disease and Movement Disorder Center at the University of Kansas Medical Center, and colleagues reported at the International Congress of Parkinson's Disease and Movement Disorders.

For the side effects profile, the numbers aren't any different," Pahwa told MedPage Today. "The benefit is maintained long-term, and people tolerate the drug very well."

Amantadine is an old drug for Parkinson's disease that has been used to treat levodopa-induced dyskinesia, but it has to be taken two to three times a day, and its effects are not lasting, explained Claudia Trenkwalder, MD, of the University of Gottingen in Germany, who was not involved with the study.

Adamas Pharmaceuticals, therefore, developed a long-acting, extended-release version that can be taken before bedtime, before early-morning levodopa starts to produce dyskinesia, she explained: "This may be helpful and more efficient if you can give it at night as a sustained-release that works all day long," she told MedPage Today.

The EASE LID 2 trial was an open-label safety study conducted at 56 centers in North America and Western Europe. All patients either continued or started the 340-mg dose of ADS-5102 after the initial 24 weeks of the study, and the interim analysis also included data from patients with deep brain stimulation who still had levodopa-induced dyskinesia but had not been in the earlier trial.

The primary outcome was safety and tolerability, but the researchers also looked at efficacy as measured on the Unified Parkinson's Disease Rating Scale (UPDRS) Part IV, Pahwa said.

Overall, 129 patients had at least one post-baseline visit prior to the data cutoff date.

The researchers found rates of complications that were similar to those of the initial study, although patients who had originally been on placebo had slightly higher adverse event rates, which was expected, Pahwa said.

Discontinuation was also higher for those who had been on placebo initially compared with those who continued the study drug (17.6% versus 3.6%), which was also expected.

The most common adverse events overall were falls (20.2%), visual hallucinations (11.6%), abnormal dreams (7%), dizziness (7%), peripheral edema (7%), constipation (5.4%), and dry mouth (5.4%).

There was one urinary tract infection that was deemed to be drug-related, and the two deaths in the study were not thought to be related to extended-release amantadine, the researchers reported.

n terms of efficacy, the reductions on the UPDRS Part IV that were seen at the end of the randomized controlled trial were maintained in the follow-up period, and those who switched from placebo caught up to those who were on the drug the entire time, Pahwa said.

UPDRS scores were reduced from baseline by an average of 6 points for those who had been on placebo and by 6.6 points for those who had been on active drug. These reductions were driven by improvements in two items on the scale: functional impact of dyskinesia and functional impact of fluctuations, Pahwa said.

He added that the benefits were achieved without compromising the underlying control of Parkinson's symptoms, and concluded that the results demonstrate the long-term safety and efficacy of extended-release amantadine.

Adamas previously completed two pivotal phase III trials and is actively planning to file a New Drug Application with the U.S. Food and Drug Administration, according to a company spokesperson, although they would not disclose a timeline.

Trenkwalder noted that several other compounds have been evaluated for treating levodopa-induced dyskinesias, but this is one of the first to demonstrate safety and efficacy in phase III trials.

"It's difficult to measure dyskinesia, but this study relied on home diaries and succeeded," she said.

http://www.medpagetoday.com/MeetingCoverage/MDS/58734?xid=nl_mpt_DHE_2016-06-24&eun=g972365d0r