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Parkinson’s Drug Rytary (Carbidopa/Levodopa) Resubmitted for FDA Review

Company provides updated safety and stability data

Impax Pharmaceuticals has resubmitted a new drug application (NDA) for Rytary (IPX066) to the FDA. The drug is an extended-release capsule formulation of carbidopa and levodopa for the symptomatic treatment of Parkinson’s disease (PD).

After discussions with the FDA, the company provided updated safety and stability information. The FDA will require an inspection of manufacturing facilities involved in the production of Rytary in connection with the resubmission. The agency has 14 calendar days to officially accept the NDA resubmission.

Results from three phase III studies of IPX066 — APEX-PD (in patients with early PD), ADVANCE-PD (in patients with advanced PD), and ASCEND-PD (in patients with advanced PD) — have been reported.

The APEX-PD trial was a randomized, double-blind, placebo-controlled, parallel-group, fixed-dose phase III study comparing IPX066 with placebo in patients with early PD. A total of 381 subjects in North America and Europe were randomly assigned to receive one of three doses of IPX066 or matching placebo administered orally three times per day for 30 weeks.

The study met its primary efficacy endpoint of a change from baseline in the sum of the United Parkinson’s Disease Rating Scale (UPDRS) Parts II and III score at the end of the study. The study also met several secondary endpoints, including the Clinician Global Impression of Change and the Patient Global Impression of Change. The most commonly reported adverse events in the IPX066 treatment arms included nausea, headache, and dizziness, which were consistent with carbidopa/levodopa products.

The ADVANCE-PD trial was a randomized, double-blind, active-control, parallel-group phase III study of the safety and efficacy of IPX066 compared with that of immediate-release (IR) carbidopa/levodopa in patients with advanced PD with motor fluctuations. The trial enrolled 471 subjects in North America and Europe. Of these subjects, 393 were randomly assigned to participate in the 13-week trial. Before randomization, subjects receiving a stable IR carbidopa/levodopa regimen entered a 3-week dose-adjustment period for IR carbidopa/levodopa, followed by a 6-week dose-conversion period to IPX066.

IPX066 produced significantly improved control of motor symptoms compared with IR carbidopa/levodopa in multiple clinical measures in subjects with advanced PD. Treatment with IPX066 resulted in a 37% improvement from baseline compared with a 17% improvement for IR carbidopa/levodopa (P < 0.0001). Additional clinical and patient-reported outcome measures in the study consistently demonstrated the improved efficacy profile of IPX066 compared with that of IR carbidopa/levodopa. During the double-blind portion of the trial, IPX066 had an adverse event (AE) rate of 43% compared with 40% for IR carbidopa/levodopa. The most common AEs reported for IPX066 included insomnia, nausea, falls, dizziness, and dyskinesia.

The ASCEND-PD trial was a randomized, double-blind, two-treatment, 2-week crossover phase III study of IPX066 and CLE (a combination treatment of carbidopa/levodopa and entacapone, an enzyme inhibitor of levodopa breakdown). Subjects taking a stable dose of CLE were converted to IPX066 over a 6-week period. They were then randomly assigned to one of the two treatments (IPX066 or CLE) for 2 weeks and were crossed over to the other treatment for an additional 2 weeks after a 1-week washout with IPX066. The study enrolled 110 subjects with advanced PD. Of these, 84 subjects completed the randomized double-blind comparative phase of the study. Following this phase, the subjects were enrolled into a 6-month open-label extension study.

The study’s primary endpoint was the percentage of “off time” during waking hours, as measured by patients’ diaries. “Off time” is the functional state when the effect of the patients’ medication has worn off, and there is a return of the motor symptoms of PD.

Patients entered the study with a baseline “off time” of 36.1% (5.9 hours). At the end of the randomized IPX066 treatment phase, patients had an “off time” of 24.0% (3.8 hours) during waking hours compared with 32.5% (5.2 hours) with CLE (P < 0.0001). This represented a 33.5% decrease in the percent “off time” for IPX066 from baseline compared with a 10.0% decrease for CLE.

Sources: Impax Pharmaceuticals; April 11, 2014; GlaxoSmithKline; August 15, 2011; and Impax Labs; June 1, 2011.

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