Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations

Abstract

The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A(2A) receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…L-DOPA while eliciting significantly less dyskinesia than L-DOPA alone (Bara-Jimenez et al, 2003;Bibbiani et al, 2003). However, istradefylline slightly exacerbated dyskinesia severity in placebo-controlled studies (Hauser et al, 2008;LeWitt et al, 2008), but another A 2A antagonist, preladenant, significantly increased duration of ontime without troublesome dyskinesia in a phase II study (Hodgson et al, 2010).…”

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update

“…Selective A 2A blockers are being evaluated for the treatment of Parkinson's disease and for drug addiction on the basis of these compounds' ability to simulate activation of dopamine D 2 receptors (Svenningsson et al, 1999;Jenner et al, 2009;Pinna, 2009). The selective A 2A antagonists (E)-1,3-diethyl-8-(m,p-dimethoxystyryl)xanthine [KW6002 (43); istradefylline; Kyowa-Hakko Kogyo, Tokyo, Japan] has been extensively studied in large phase III studies (Hauser et al, 2008;LeWitt et al, 2008;Stacy et al, 2008) Investigators at the National Institute on Drug Abuse are conducting An fMRI Study of SYN115 in Cocaine Dependent Subjects (www.clinicaltrials.gov identifier NCT00783276). The dopamine system is critical in modulation of reward and has been implicated in the initiation and maintenance of addiction.…”

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.…”