MIAMI—The sublingual apomorphine film APL-130277 (APL) is effective and well-tolerated for the acute management of off episodes in patients with Parkinson’s disease, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress.
APL is in development for the acute, intermittent treatment of off episodes associated with Parkinson’s disease, including end-of-dose wearing off (including early morning off); partial, delayed, or no on; and unpredictable off.
Evaluating the Efficacy and Safety of APL
To evaluate the efficacy and safety of APL, C. Warren Olanow, MD, Professor Emeritus and Chair Emeritus of Neurology and Professor of Neuroscience at the Mount Sinai School of Medicine in New York City, and colleagues conducted a double-blind, placebo-controlled trial.
Eligible participants were 18 or older, had idiopathic Parkinson’s disease according to UK Brain Bank criteria, were stage I–III according to the modified Hoehn and Yahr scale when on, and had a clinically meaningful response to levodopa with well-defined, early-morning off episodes. They had one or more off episodes per day and a total daily off time of two or more hours when receiving stable doses of levodopa qid or carbidopa–levodopa extended-release capsules tid for four or more weeks, or monoamine oxidase B inhibitors for eight or more weeks.
Patients with atypical or secondary parkinsonism, a major psychiatric disorder, or mouth cankers or sores were excluded. Patients who had undergone a neurosurgical procedure for Parkinson’s disease, received continuous subcutaneous apomorphine infusion, or received Duopa also were excluded. Finally, patients currently taking 5-HT3 antagonists, selective dopamine antagonists (excluding quetiapine or clozapine), or dopamine-depleting agents were excluded.
The APL dose (10 mg to 35 mg) to produce a full on was determined during the open-label titration phase. During the double-blind treatment phase, researchers randomized patients to the dose of APL identified during the titration phase or placebo that could be self-administered as many as five times per day for 12 weeks. Movement Disorder Society Unified Parkinson’s Disease Rating Scale, Part III (MDS-UPDRS-III) scores were determined monthly before dosing and at 15, 30, 45, 60, and 90 minutes post dose. The primary end point was the change in MDS-UPDRS-III score at 30 minutes post dose at 12 weeks. The key secondary end point was the percentage of patients with a patient-determined full on response within 30 minutes at 12 weeks. Safety assessments were also performed.
Treated Patients Were More Likely to Be On
A total of 109 patients were randomized to the double-blind treatment phase, and had a mean of 3.9 off episodes per day. Participants’ mean age was 62.7, and 37.6% of participants were female. More than 90% of participants were white.
In all, 80 patients completed the study. The least squares mean change from predose to 30 minutes post dose for the MDS-UPDRS-III score at 12 weeks was –11.1 and –3.5 for the APL and placebo groups, respectively (mean difference, –7.6). Similar results were observed at day 1 and weeks 4 and 8.
The difference between treatment arms in motor score became significant at 15 minutes and remained significant until 90 minutes. There was a significant difference favoring APL over placebo in the percentage of patients achieving a self-rated full on response at 30 minutes post dose at week 12. A home dosing diary showed that a larger percentage of patients receiving APL were on within 30 minutes post dose (least squares mean, 78.70%), compared with controls (least squares mean, 31.10%).
In the double-blind treatment phase, the overall discontinuation rate was 16.4% for placebo and 37.0% for APL. The discontinuation rate due to adverse events was 9.1% and 27.8% for placebo and APL, respectively. Discontinuation due to adverse events was the most common reason. During the double-blind treatment phase of APL, the most frequent adverse events were nausea (27.8%), somnolence (13%), and dizziness (9.3%). Most treatment-emergent adverse events were mild to moderate. Six patients experienced severe adverse events in the placebo and APL groups combined. Three patients experienced serious adverse events combined. One patient in the APL group died from cardiac arrest considered possibly related to treatment by the investigator. Oral adverse events occurred in 31.5% of patients in the APL group versus 7.3% of controls. These events were generally mild and reversible, said the researchers.