SYDNEY, Australia — Treatment with a proprietary investigational extended-release version of amantadine (ADS-1502, Adamas Pharmaceuticals) led to a statistically significant improvement in the duration and severity of levodopa-induced dyskinesia (LID) in a phase 2/3 study.

For patients with Parkinson's disease (PD), reducing the time and severity of LID has been a "long-term goal in their treatment," study investigator Rajesh Pahwa, MD, professor of neurology, University of Kansas Medical Center, Kansas City, said in a statement.

He presented the results from the Extended Release Amantadine Safety and Efficacy Study in Levodopa-Induced Dyskinesia (EASED) clinical trial June 18 at the Movement Disorder Society (MDS) 17th International Congress of Parkinson's Disease and Movement Disorders. The EASED study was sponsored by Adamas Pharmaceuticals Inc.

Chronotherapeutic Pharmacokinetics

LID affects roughly 30% of patients taking levodopa, and there are currently no medications approved for the treatment of LID. "Amantadine has been around for ages and we know it helps dyskinesia," Dr. Pahwa noted in a telephone interview with Medscape Medical News.

"The limitations with immediate-release amantadine surround tolerability; patients have not been able to tolerate high enough doses or even just immediate-release amantadine per se, so the hope is the long-acting extended-release amantadine would be better tolerated and we could use higher doses with it," he explained.

ADS-5102, given once nightly, has a unique "chronotherapeutic" pharmacokinetic profile characterized by a slow increase in initial amantadine plasma concentrations, high plasma concentrations during the day when LID can be troublesome, and low plasma concentrations overnight, the company notes in a statement.

The low overnight amantadine plasma concentration may reduce the insomnia, sleep disturbances, and vivid dreams associated with immediate-release amantadine. Because of its altered pharmacokinetic profile, ADS-5102 is being investigated in clinical studies at daily doses 1.3- to 2.1-fold greater than the 100-mg twice-daily dose typically used with immediate-release amantadine.

The multicenter randomized, double-blind, placebo-controlled EASED trial enrolled 83 patients with PD and troublesome LID from 31 sites in the United States.

To participate, patients had to have a score of at least 2 on part IV, item 4.2 (functional impact of dyskinesia) of the MDS-United Parkinson's Disease Rating Scale (MDS-UPDRS) and be experiencing at least two 30-minute intervals of "on" time with troublesome dyskinesia during the day.

The patients were randomly assigned to receive 260 mg, 340 mg, or 420 mg of ADS-5102 or placebo once nightly for 8 weeks, with a 2-week safety follow-up.

Data "Promising"

The study met its primary endpoint, Dr. Pahwa said. Both the 340-mg and the 420-mg dose of ADS-5102 significantly reduced LID, as measured by the change in United Dyskinesia Rating Scale (UDysRS) total score over 8 weeks vs placebo (P =.005 and P =.013, respectively).

  ADS-5102 also significantly increased "on" time without troublesome dyskinesia as measured by patient diaries at the 260-mg dose (P =.004), the 340-mg dose (P =.008), and the 420-mg dose (P =.018).

Consistent with the changes observed in the UDysRS, ADS-5102 also led to statistically significant improvements in the functional impact of dyskinesia (MDS-UPDRS, item 4.2) at all 3 doses (P =.014, P =.002, and P <.001, respectively, for 260 mg, 340 mg, and 420 mg).

"These data are promising," Dr. Pahwa told Medscape Medical News. "However, this is not a comparative study with immediate-release amantadine so it's not possible to say head-to-head how it would do against immediate-release, but from the data we have it was efficacious and patients were able to tolerate higher doses relatively well."

Treatment with ADS-1502 did not lead to clinical worsening of PD by standard measures, and reported adverse events were consistent with PD and the known amantadine safety profile, the researchers say.

Treatment emergent adverse events were common in all treatment groups, but most were mild to moderate in severity. The most commonly reported adverse effects were constipation, dizziness, dry mouth, hallucination, fall, confusional state, headache, nausea, and asthenia, each reported in 2 or more patients in the active treatment groups.

Sixteen patients (19%) discontinued treatment. Two withdrew from the placebo group because of reasons unrelated to the study drug. The remainder of the discontinuations from the study were attributed to adverse events (260 mg, 3 patients; 340 mg, 3 patients; and 420 mg, 8 patients).

The company plans to take these data to the US Food and Drug Administration to obtain guidance on moving forward with additional studies.

The study was sponsored by Adamas Pharmaceuticals Inc. Dr. Pahwa and 3 coauthors are on the EASED steering committee and received compensation for this service.

Movement Disorder Society (MDS) 17th International Congress of Parkinson's Disease and Movement Disorders. Abstract 443. Presented June 18, 2013.

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