Objective: To evaluate the safety, pharmacokinetics (PK) and efficacy of single-dose apomorphine inhalation in PD patients.

Background: Apomorphine is a dopamine agonist, approved for treating disabling motor fluctuations (OFF periods) in PD patients, that persist despite current treatment with L-dopa or oral dopamine agonists. It is approved for subcutaneous use, which has several disadvantages such as difficult administration and pain at the injection site. Inhalation of thermally-generated aerosol (Staccato apomorphine) particles could provide a rapid and easy alternative.

Method: 24 PD patients with recognizable OFF periods were enrolled in 3 cohorts of 8 patients. Patients were randomized to receive a single inhaled dose of Staccato apomorphine (2, 3 or 4 mg) or placebo (6:2 ratio). Patients were treated with domperidone 20 mg TID from 2 days prior to dosing to prevent nausea/vomiting. To induce a morning OFF state prior to dosing, patients withheld their anti-Parkinson medication the evening prior to dosing. Treatment was administered in an OFF state only. Vital signs, ECGs and AEs were recorded, and PK samples were obtained throughout the study. MDS-UPDRS III was performed pre- and ~10, 30 and 60 min post-dose to assess efficacy.

Results: Apomorphine was rapidly absorbed with median t_max below 3.5 min. Mean t_1/2 was ~40 min. Apomorphine-treated groups showed a clear reduction (ranging from 10.3 to 12.8 pts depending on the dose) from baseline in mean MDS-UPDRS III total score already at 10 minutes post-dose. This reduction was larger than observed in the placebo group (~5 points). Inhaled apomorphine was relatively well tolerated by PD patients across doses with mostly mild and transient AEs. The most frequently reported AEs in the apomorphine-treated groups were throat irritation, orthostatic hypotension, yawning, nausea, somnolence and increased PD symptoms the days after dosing. Some patients in the placebo- and apomorphine-treated groups showed BP drops upon standing, mostly asymptomatic. No clinically relevant QTcF prolongation was observed.

Conclusion: PD patients tolerated apomorphine inhalation reasonably well. Inhaled apomorphine was rapidly absorbed into the systemic circulation with peak plasma concentrations below 3.5 min. Treatment effects could be shown with MDS-UPDRS III as early as 10 min post-dose at all 3 dose strengths.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/randomized-placebo-controlled-study-investigating-the-safety-pharmacokinetics-and-efficacy-of-inhaled-apomorphine-in-parkinsons-disease-patients/