Regulatory Decision Summary for MOVAPO

The clinical pharmacology and efficacy/safety studies included in the Movapo NDS indicated that following subcutaneous injection, the pharmacokinetic properties of apomorphine and its effects on motor symptoms that occur with hypomobility/"off" episodes in patients with advanced Parkinsons disease (PD) make it suitable for use as an acute/"rescue" treatment for "off" episodes in this patient population. Pharmacokinetic studies demonstrated that following subcutaneous injection, apomorphine maximum plasma concentrations were achieved by 20 to 30 minutes; the terminal half-life was approximately 40 to 50 minutes; and, by 90 minutes to 2 hours plasma concentrations were very low. In a pharmacokinetic/pharmacodynamic (PK/PD) study and in three pivotal efficacy/safety studies (all conducted in patients with advanced PD), significant improvement in motor symptoms associated with "off" episodes occurred in a timeframe that closely follows the pharmacokinetics. The onset of the treatment effect occurs within approximately 20 minutes of dosing and the maximum improvement occurs by approximately 40 minutes post-dose. By approximately 90 minutes post-dose, when apomorphine plasma concentrations are very low, motor scores increase to pre-dose levels. Doses above 6 mg do not lead to a greater treatment effect but rather slightly prolong the duration of the effect, while increasing the risk of adverse events (AEs). The primary efficacy evaluations in the pivotal studies were generally after single dose administration of apomorphine to treat "off" episodes that were induced or that developed at the end of a dosing interval (oral medications) in an inpatient setting, but one study also included a 4-week outpatient period. The outpatient data indicated that 95% of "off" episodes that were treated with apomorphine were reversed/aborted compared to 23% with placebo. Total daily "off" time was reduced from an average of 5.9 hours at baseline to 4.2 hours during outpatient treatment (mean reduction 1.7 hours). These outpatient data, which most closely reflected outcomes from apomorphine being used as it is normally needed, to treat "off episodes that occur as a result of end of dose wearing off or unpredictable "on/off" episodes, suggested the effects of apomorphine for reversing "off" episodes are likely to be clinically meaningful to patients. The increase in "on" time in any state was approximately half the decrease in "off" time, and the reason for this gap remains uncertain.

The safety data from the clinical studies generally confirmed observations reported in published studies. The most common AEs associated with apomorphine included nausea, vomiting, dizziness, somnolence, dyskinesia, yawning, decreases in blood pressure, and falls. Mild to moderate dyskinesia and blood pressure lowering effects follow a time course that coincides with the improvement in motor symptoms and maximum plasma concentrations, i.e., maximum effects at 20 to 40 minutes post-dose. The hypotensive effects are dose-related at doses above 6 mg. Based on the hypotensive effects of apomorphine, treatment should be initiated in a clinic where patients can be monitored closely. Apomorphine was also shown to produce a small prolongation of the QTc interval in a Holter monitoring study, with the greatest increases being observed at doses of 8 mg and 10 mg. With respect to the types of AEs that occur with apomorphine subcutaneous injections, the apomorphine AE profile is not unlike that of other dopamine agonists. However, some of these AEs are more pronounced with apomorphine than with other dopamine agonists (for example [e.g.], hypotensive effects, dizziness). This is likely due to apomorphine being a potent agonist at D₁ and D₂ dopamine receptors, and also possibly due to its rapid increase in plasma concentrations and rapid onset of pharmacodynamic effects following administration. Based on the relationship to dose for some adverse effects, the maximum recommended dose for a single injection is 6 mg. Apomorphine maximum plasma concentrations were increased by 25% and 50% with moderate hepatic impairment and moderate renal impairment, respectively. As such, caution is recommended for treating patients with mild or moderate hepatic impairment and for patients with mild or moderate renal impairment the recommended starting dose is lowered by half (1 mg) compared to what is recommended for patients with normal renal function (2 mg).

Uncertainties that remain after review of the Movapo NDS which have all been addressed in the Movapo PM include:

1. The hypotensive effects of apomorphine could be exacerbated by concomitant use with antihypertensive medications or alcohol and, in patients with advanced PD, concomitant use of antihypertensives may not be uncommon. The seriousness of this uncertainty was addressed with a contraindication for concomitant use of antihypertensives and vasodilators, and a warning for use with alcohol.
2. A study that used Holter monitoring showed a small QTc prolonging effect with apomorphine. The largest increases were observed with the 8 mg and 10 mg doses, which suggest a possible relationship to dose. The Movapo PM describes findings from the Holter monitoring study and includes recommendations to assess patients for risk factors for QTc interval prolongation prior to prescribing.
3. Treatment with apomorphine requires use of an antiemetic, at least during the initial treatment period. The options for antiemetics that can be used with apomorphine are limited for a variety of reasons, including no availability in Canada of the antiemetic used in the clinical development program. The use of other antiemetics has not been systematically evaluated in interaction studies. Domperidone is a potent antiemetic that is used with apomorphine in other jurisdictions (e.g., Europe), and is available in Canada. Since antiemetic options may be limited with apomorphine, a recommendation for caution and careful consideration of the dose, duration of treatment and the QT prolonging effect of domperidone has been incorporated in the Movapo PM to ensure that prescribers are aware of this information, should they choose to prescribe domperidone as an antiemetic to use with Movapo.

For patients with advanced PD who continue to experience hypomobility/"off" episodes (end of dose wearing off, unpredictable "on/off" episodes) despite attempts to optimize their treatment regimen with oral and/or transdermal antiparkinson medications, there are limited treatment options to manage these often debilitating symptoms. These tend to be therapies that many patients are not candidates for (e.g. levodopa/carbidopa intestinal gel infusion; deep brain stimulation) because they involve surgery, are invasive, and are associated with several serious complications. Pharmacokinetic and efficacy and safety studies in the Movapo NDS have provided evidence to support the use of Movapo subcutaneous injections (in the dose range of 2 mg to 6 mg/injection) for acute, intermittent treatment for hypomobility, "off" episodes (end of dose wearing-off and unpredictable "on/off" episodes) in patients with advanced PD. Although doses in the range of 2 mg to 10 mg were evaluated in clinical trials, there is no evidence that doses greater than 6 mg provide an increased effect and doses greater than 6 mg were associated with dose-related hypotensive effects and potentially dose-related effects on the QTc interval. Therefore, Movapo may provide a "rescue" medication option for these patients. Based on the characterization of the safety profile in the clinical development program and any remaining uncertainties about the safety, the use of Movapo intermittent subcutaneous injections should be initiated and supervised only by neurologists and specialized healthcare professionals who are experienced and trained in the diagnosis and treatment of patients with PD and who are familiar with the efficacy and safety profile of Movapo. The benefit-harm profile for this patient population can be considered acceptable when Movapo is used as described in the approved Movapo PM.