Oral Inhalation of Apomorphine May Relieve "Off" Periods in PD

Susan Jeffrey

November 15, 2006

November 16, 2006 (Kyoto) — A new powdered formulation of apomorphine, administered by oral inhalation, may provide rapid, noninvasive relief from "off" periods for patients with Parkinson's disease, a phase 2 study suggests.

Donald Grosset, MD, a consultant neurologist at the Institute of Neurological Sciences, Southern General Hospital, in Glasgow, Scotland, was the principal investigator for this first clinical trial of the inhaled formulation, presented November 2 at the Movement Disorders Society's 10th International Congress on Parkinson's Disease and Movement Disorders.
"The clinical implications of the finding are that patients with more advanced Parkinson's disease could benefit from a noninvasive route of administration and a faster response when they enter an 'off' period," he told Medscape.

Further testing will be required for product license approval, Dr. Grosset added. Vectura Group PLC, the sponsor of this study, is continuing with the clinical trial development program for this application of inhaled apomorphine, he said.

New Administration Route

Apomorphine is a powerful dopamine agonist that is already used clinically as a subcutaneous injection, as intermittent injections to rescue from off periods, or as an infusion to stabilize treatment with constant-dose levels, Dr. Grosset pointed out. While both of these formulations are available in Europe, only the intermittent injections are available in North America and are used for the same indication as inhaled apomorphine.

However, the inhaled route gives the potential advantage of a more rapid response, because peak levels reach the bloodstream more quickly than other oral treatments for off periods, such as dispersible dopa, and it is noninvasive, unlike subcutaneous injections, he noted.

The current phase 2 study aimed to evaluate the clinical tolerability, pharmacokinetics, and efficacy of a powdered formulation of apomorphine called VR040, delivered using a breath-actuated delivery device (Aspirair, Vectura Group PLC, Chippenham, United Kingdom).

The trial was a double-blind, 4-parallel-group, dose-escalation, placebo-controlled study. A total of 24 patients with idiopathic PD and motor fluctuations first omitted their dopaminergic therapy and received 3 days of treatment with domperidone 20 mg three times daily to induce an off state, confirmed by the patient and scored using the United Parkinson's Disease Rating Scale (UPDRS III).

Patients then received 1 of 6 doses of apomorphine —200, 300, 500, 750, 800 or 1200 µg — or placebo, receiving 6 active and 2 placebo doses. A second identical dose could be given at 12 minutes if the patient did not respond to the initial dose.

They report that all 24 patients completed the study, with no serious adverse events reported. No patient experienced vomiting, symptomatic hypotension, or syncope, and no clinically relevant changes in lung function or abnormal electrocardiograms were seen. Peak plasma concentrations occurred between 1 and 3 minutes postdose.

Although the authors note that this study is not powered to evaluate efficacy, their results showed a clear dose-response with the "on" response observed, correlating with improvement in UPDRS upper-arm scores. Symptoms and signs of PD were improved at higher doses of 500, 750, and 1200 µg.

Five of 12 patients at these doses received a full on response, compared with 0 of 6 at 400 µg and 1 of 6 on placebo. The median onset of therapeutic effect was 10 minutes, with some patientsfully converting at 4 minutes, they note. Median duration of effect was 25 minutes, ranging out to 60 minutes for some patients.

Patients successfully used the device, the authors point out, and reported it was easy to use.

Dr. Grosset and colleagues conclude that consecutive doses of this inhaled formulation are well tolerated. "VR040 has the potential as a noninvasive, rapidly acting, and user-friendly treatment for patients suffering motor complications associated with advanced PD," they write. "Further development of VR040, including higher dose strengths, will be pursued."

Dr. Donald Grosset disclosed that he has worked on a consultancy basis for Vectura Group PLC.

Movement Disorder Society 10th International Congress on Parkinson's Disease and Movement Disorders: Poster P1142. Presented November 2, 2006.


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