Apomorphine (Apokyn) is a dopamine delivered by multi-dose glass cartridges, 30 mg/3 mL with a multiple dose pen injector (APOKYN Pen). Apokyn is FDA approved in the U.S. for the acute, intermittent treatment of hypomobility, OFF episodes, and unpredictable ON/OFF episodes associated with advanced Parkinson disease (PD). It is used by a relatively small number of patients in the U.S. However, different formulations of apomorphine are available outside the U.S., and different formulations are under investigation within our borders.
One study evaluated APL-130277, a sublingual (beneath the tongue) apomorphine oral strip, as an acute, effective, noninvasive treatment for OFF episodes (1). This was a phase II, open-label, proof-of-concept study.
In open-label studies, patients know they are taking the study drug and there is no placebo, thus no blind. Proof-of-concept studies are designed to verify that some concept has practical potential, such as using a sublingual version of the drug for a certain indication.
In this study patients presented to clinic in the morning hours “in the practically defined OFF state” (before taking their morning medications) and were given APL-130277 10 mg. PD motor scores using MDS-UPDRS III were recorded before dosing and at 15, 30, 45, 60, and 90 minutes. If a full ON state was not achieved within 3 hours, the dose was increased in 5 mg increments until the patient was either ON, or had taken 30 mg. Of the 19 people with PD treated, 15 (78.9%) reached a full ON response within 30 minutes, and 6 of the 15 patients reached ON within 15 minutes. Average duration of ON was 50 minutes, and nine patients remained fully ON for 90 or more minutes. No patients discontinued the drug due to adverse event, though dizziness occurred in 36.8%, sleepiness in 31.6%, and nausea in 21.1%.
NCT0254269 is an open-label phase III study to examine long-term safety, tolerability, and efficacy of APL-1320277 in doses ranging from 10-35 mg for the treatment of OFF episodes in patients with PD (2). Estimated enrollment will be 226 patients and recruitment is ongoing at many centers in the U.S. and Canada.
Apomorphine has also been developed as a drug which may be administered by pump. Already available in some countries, it is currently in trials in the U.S. The apomorphine pump is being tested as a method to avoid fluctuations in the motor symptoms of PD. In a study published in 2017, authors noted that people with advanced PD and contraindications for deep brain stimulation (DBS) might benefit from apomorphine as an add-on to existing medications, and evaluated the motor and nonmotor symptoms in advanced PD (3).
A small cohort of 12 patients with advanced PD were assessed before and after 6 months of apomorphine with a type of brain imaging called 18F-fluorodeoxyglucose positron emission tomography (PET scan) and “exhaustive clinical assessments.” Authors noted that after 6 months of therapy they were able to significantly reduce oral PD meds (and thus reduce risk of side effects from those meds), and that motor and nonmotor scores improved “with a beneficial effect on executive functions, quality of life and apathy.” Brain PET scan of these patients reportedly revealed significant metabolic changes consistent with the improvements in clinical scores. The authors noted, “these preliminary results have to be confirmed by further studies.”
NCT02339064 is a phase III, 52-week safety study being called INFUS-ON, which is an actively recruiting, multicenter, open-label trial to assess the long-term safety and tolerability of continuous subcutaneous infusion of apomorphine in advanced PD patients with unsatisfactory motor fluctuations while using levodopa and at least one other class of drugs or mode of therapy for PD (4). The study will also evaluate reductions in OFF time and improvements in ON time without troublesome dyskinesias.
REFERENCES
- Hauser, et al. Sublingual apomorphine (APL-130277) for the acute conversion of OFF to ON in Parkinson’s disease. Mov Disord. 2016;31(9):1366-72.
- https://clinicaltrials.gov/ct2/show/NCT02542696?term=sublingual+apomorphine&cond=Parkinson+Disease&rank=36
- Auffret, et al, Apomorphine pump in advanced Parkinson’s disease: Effects on motor and nonmotor symptoms with brain metabolism correlations. J Neurol Sci. 2017;372:279-287.
- https://clinicaltrials.gov/ct2/show/NCT02339064?term=apomorphine+pump&cond=Parkinson+Disease&rank=6
