The subcutaneous infusion resulted in 1.89 fewer hours per day spent in “off” periods compared to placebo.
Regina Katzenschlager, MD
Subcutaneous apomorphine infusion (APO-go/Movapo) has been shown to result in a meaningful reduction in “off” time in patients with Parkinson disease who are still facing persistent motor fluctuations despite optimized oral or transdermal therapy.
New findings from the TOLEDO study, published in The Lancet Neurology, have revealed that the therapy was associated with a difference of -1.89 hours per day in off time for patients with Parkinson in comparison with placebo.1 These reductions were observed within the first week of treatment with the infusion.
"The results of the TOLEDO study provide level 1 evidence for the first time and confirm what clinicians had observed and reported in uncontrolled studies for several decades: good efficacy and tolerability of apomorphine SC infusion in PD patients whose motor fluctuations have become difficult to manage by adjusting oral treatment," Regina Katzenschlager, MD, of the Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Danube Hospital, told NeurologyLive. "The effect size is similar to the other infusion therapy, intestinal levodopa gel, and the improvement in OFF duration is not achieved at the expense of increased dyskinesia."
Led by Katzenschlager, the randomized, double-blind, multicenter study included 128 patients with Parkinson disease at 23 sites, of which 106 were included in the full analysis. Patients were randomly assigned 1:1 to either received a 3- to 8-mg/hour dose of apomorphine (n = 53) or placebo saline infusion (n = 53) during waking hours for 12 weeks. The mean final dose of the intervention drug was 4.68 mg/hour (standard deviation [SD], 1.50).
Data revealed that the intervention group experienced a reduction in “off” time from baseline of -2.47 hours/day (SD, 3.70) compared to only -0.58 hours/day (SD, 2.80) in the placebo group (95% CI, -3.16 to -0.62; P = .0025). Additionally, there were greater increases in “on” time without troublesome dyskinesia for the apomorphine group from baseline compared to placebo. The treatment group experienced a 2.77 hours/day increase in “on” time compared to a 0.80 hours/day increase observed in the placebo group (P = .0008).
Previous data from the TOLEDO study, presented last year at the 21st International Congress of Parkinson’s Disease and Movement Disorders in Vancouver, British Columbia, revealed that proportion of responders in the apomorphine group, 62%, was higher than those in the placebo group, 29% (P = .0008).
Katzenschlager and colleagues noted that the patients’ assessment of the therapy’s success was reflective of the clinical improvements. Those treated with the apomorphine infusion rated themselves as “improved” at a rate of 71% compared to only 18% of patients treated with placebo (P <.0001). According to the Patient Global Impression of Change assessment, the apomorphine group scored 4.4 compared to 3.2 with placebo. "The findings add clinically valuable information on a treatment option which helps to better control 'off' periods and which offers improvements without the need for any surgical procedure," Katzenschlager explained.
The therapy was relatively well-tolerated as well, as no unexpected safety signals were observed, which Katzenschlager credited to each center's "longstanding experience with apomorphine treatment and its often remarkable clinical efficacy." All told, 6 patients in the apomorphine group withdrew from the trial due to treatment-associated adverse events (AEs). AEs included moderate gait disturbance, severe hypotension, and visual hallucination, although the most common AEs (≥10% of patients) were nausea or somnolence (22% for both) and infusion site reactions such as erythema (17%) and skin nodules (44%). "The spectrum and the frequency of AEs had also reflected what may be seen in clinical practice, without unexpected safety signals," Katzenschlager added.
"We hope the positive results of the TOLEDO study will help ensure apomorphine infusion, which is delivered using a small, ambulatory mini-pump, is incorporated into national [Parkinson disease] treatment guidelines," said Andrew Lees, MD, FMedSci, an investigator in the pivotal clinical trial that led to apomorphine being licensed for Parkinson treatment, in a statement.2
Many open-label studies have shown efficacy with an apomorphine infusion in reducing “off” time in patients with Parkinson, but these findings, the authors noted, add to an otherwise much-needed set of confirmatory data from a double-blind phase trial.
1. Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018. E-Pub July 25, 2018. doi: 10.1016/S1474-4422(18)30239-4.
2. Phase 3 TOLEDO Study Shows Apomorphine Infusion Provides Effective Relief of Persistent Motor Fluctuations in Parkinson's Disease (PD) Patients Whose Symptoms are Uncontrolled with Oral Medication [press release]. London, UK: Britannia Pharmaceuticals Ltd; August 3, 2018. prnewswire.com/news-releases/britannia-pharmaceuticals-ltd-phase-3-toledo-study-shows-apomorphine-infusion-provides-effective-relief-of-persistent-motor-fluctuations-in-parkinsons-disease-pd-patients-whose-symptoms-are-uncontrolled-with-oral-medication-689967281.html. Accessed August 3, 2018.