Adenosine A_2A receptor antagonist istradefylline (KW‐6002) reduces “off” time in Parkinson's disease: A double‐blind, randomized, multicenter clinical trial (6002‐US‐005)

Abstract

Objective: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A 2A receptor antagonist, istradefylline, shows promise for the treatment of PD. Methods: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. Results: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off" time for istradefylline was a mean (Ϯ standard deviation) of Ϫ10.8 Ϯ 16.6% (95% confidence interval, Ϫ13.46 to Ϫ7.52) and for placebo, Ϫ4.0 Ϯ 15.7% (95% confidence interval, Ϫ7.73-0.31; p ϭ 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off" time of Ϫ1.8 Ϯ 2.8 hours for istradefylline and Ϫ0.6 Ϯ 2.7 hours for placebo ( p ϭ 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. Interpretation: Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off" time without increased troublesome dyskinesia. Neurol 2008;63:295-302 Although Parkinson's disease (PD) has several treatment options that initially can provide excellent symptomatic relief, 1 control of its disabilities typically declines over time. Because PD is characterized by loss of dopaminergic neurons projecting from substantia nigra to striatal nuclei, the most rational and effective therapy for restoring dopaminergic neurotransmission has been the dopamine precursor L-dopa. Ann2 Two years after starting L-dopa therapy, however, many patients start to experience fluctuations that interrupt control of parkinsonism, sometimes for up to several hours per day. 3,4 Adjusting the effects of L-dopa (by dosing changes or extenders such as catechol-Omethyltransferase or monoamine oxidase B inhibitors) or adding other dopaminergic drugs can improve "off" (undermedicated) states. Despite these options, inadequate control of motor fluctuations is a major source of disability for chronically treated PD.Beyond restoring dopaminergic input to striatal neurons, other pharmacological interventions can influence From the

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…In these studies, istradefylline was utilized as add-on therapy to 1500 PD patients with motor fluctuations and dyskinesia. These studies demonstrated a statistically significant, but modest decrease of 0.7-1.2 h 'off ' time, associated with a similar increase in 'on' time (LeWitt et al, 2008;Stacy et al, 2008). The frequency of dyskinesia in the treated group was actually greater than that observed in the group treated with placebo.…”

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…Moreover, on the basis of the apparent protective effect of coffee in PD, adenosine receptor (A 2A ) antagonists have also been tested and there is evidence that they improve parkinsonian symptoms in animal models [670] and clinical trials [671][672][673][674]. Lastly, the more recently indicated protective effect of uric acid, together with its ability to slow disease progression, has led to the initiation of a clinical trial of inosine, a precursor that increases uric acid levels.…”

Extracellular adenosine triphosphate and adenosine in cancer

“…Potential side effects of A2A receptor antagonists might include increased blood pressure and inflammation. However, based on the results of recent clinical trials with A2A receptor antagonists against Parkinson's disease, A2A antagonists seem to be welltolerated (LeWitt et al, 2008).…”