At 10 minutes post dose, all 3 AZ-009 dose groups showed a clear reduction from baseline in mean MDS-UPDRS part III score that was greater than for placebo.
Data from a randomized, 3-part trial suggests that AZ-009 (Alexza Pharmaceuticals), a formulation of inhaled apomorphine, could provide an easier and faster-acting way of treating OFF episodes in patients with Parkinson disease (PD) than traditional subcutaneous apomorphine. All told, the medication was rapidly absorbed into the systemic circulation and well-tolerated by both healthy volunteers (HV) and patients with PD.1
Part A of the study was a randomized, open-label crossover study that assessed singled doses of AZ-009 (1 mg) and subcutaneous apomorphine (2 mg) in 8 HVs. After examining safety data, part B (n = 16) was a randomized, single-ascending dose study with planned doses of 2 mg, 3 mg, and 4 mg in HVs. Part C (n = 25) had the same study design as part B but was performed in patients with PD after overnight anti-PD medication withdrawal.
Senior author Geert Jan Groeneveld, MD, PhD, professor of clinical neuropharmacology, Leiden University Medical Center, and colleagues documented peak plasma concentrations at 2 minutes for those on AZ-009. In comparison, apomorphine concentrations after subcutaneous injection increased over time with a median Tmax of 30 minutes. The authors noted the significance of these findings, writing "even though subcutaneous apomorphine is efficacious, it can be painful and/or difficult to self-administer and often results in injection-site reactions."
For part B, the median Tmax in HVs were similar to those in part A. For those with PD in part C, the median Tmax was 2 or 3 minutes depending on the dose group. Additionally, Cmax and area under the curve (AUC)0-inf after 2 mg and 3 mg of AZ-009 were similar for HVs and patients with PD. The 4-mg cohort was canceled because of incidence of adverse events (AEs) in the 3-mg cohort.
Between the 2 medications, 62.5% of those who received AZ-009 reported moderate AEs, compared to 100% of those after treatment with subcutaneous apomorphine. Nausea and presyncope and somnolence and headache were the most frequently reported treatment-emergent AEs in the study. Patients on AZ-009 tended to report their first AE within 2-3 minutes after inhalation whereas those who received subcutaneous apomorphine reported AEs around 20 minutes.
AZ-009 was relatively well-tolerated by patients with PD, with mostly mild TEAEs reported. Of them included throat irritation, orthostatic hypotension, and yawning. Most of these were resolved without treatment, except for 1 case of severe hypotension in the 3-mg group that was treated with ephedrine, and 2 cases where the number of PD medication doses was increased for several days after study participation because of increased PD symptoms.
Investigators assessed motor function using part III of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Patients with PD in all 3 AZ-009-treated dose groups demonstrated a reduction in MDS-UPDRS part III total score at the first assessment 10 minutes post dose. At that time point, the mean change was –10.7 (SD, 13.6) for the 2-mg group, –12.8 (SD, 7.9) for the 3-mg group, –10.3 (SD, 3.7) for the 4-mg group, and –4.8 (SD, 4.9) for the placebo group.
AZ-009 was most effective until 30 minutes post dose, where the treated groups started to see decreases in effect sizes. This further decreased at 1 hour post dose to less than half of the maximum effect observed 10 minutes post dose; however, those on placebo no longer showed a reduction compared with baseline at the 1-hour mark. Notably, the highest percentage of patients in an ON state occurred 10 minutes post dose for the 3-mg AZ-009 group and 20 minutes post dose for the 2-mg and 4-mg AZ-009 groups.
Apomorphine subcutaneous injection has been available in the US for almost 15 years. Watch below, as a panel of experts, including Stuart Isaacson, MD, and William Ondo, MD, discussed the use of the medication for managing PD.