Objective: To evaluate the clinical effect of istradefylline as adjunctive treatment to LD in PD patients with or without additional PD medications (meds).

Background: Istradefylline, a selective adenosine A_2A receptor antagonist, acts in the indirect striatal outflow pathway. While monotherapy studies have not shown benefit, 20 and 40 mg/day doses were shown to decrease OFF-time when used adjunctively with LD in PD patients experiencing wearing-off.

Method: Istradefylline was evaluated in 12-wk double-blind, placebo-controlled randomized clinical studies. PD patients receiving LD and experiencing wearing-off received istradefylline or placebo. Other anti-PD meds could be continued at unchanged doses. Change from baseline in daily OFF-time was assessed using patient-completed 24-hr ON/OFF diaries. Adverse events (AEs) were recorded throughout the study. A pooled post-hoc analysis of 5 independent clinical trials assessed the reduction in OFF-time with istradefylline vs placebo when patients were divided into 2 subgroups: those receiving only LD and those receiving LD+other anti-PD meds. Data from 20 or 40 mg istradefylline dose groups were combined. Pooled analyses used a mixed-model repeated-measures approach.

Results: Following randomization, baseline clinical and demographic characteristics were similar across treatment groups (placebo, 20 or 40 mg istradefylline). Between subgroups, patients receiving LD+anti-PD meds vs treatment with LD only had lower mean daily LD doses (766 and 579 mg, respectively) and longer mean durations since: PD diagnosis (7.4 and 8.9 yrs), starting LD (7.2 and 8.2 yrs), and onset of motor complications (2.8 and 3.8 yrs). Baseline OFF-time was similar across treatments and subgroups (~6 hrs/day). In both subgroups, OFF-time was reduced from baseline with istradefylline treatment, and was significantly greater than for patients receiving placebo (Table). Overall, istradefylline was well-tolerated; dyskinesia was the most frequent reported AE. [table1]

Conclusion: Istradefylline has unique pharmacologic properties distinct from other currently-approved meds for PD. This post-hoc analysis demonstrates that, as compared with placebo, istradefylline as an adjunct to LD and other anti-PD meds reduced OFF-time from baseline beyond the effects of concomitant meds for PD. Sponsor of studies: Kyowa Hakko Kirin Co., Ltd.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/efficacy-of-istradefylline-an-a2a-receptor-antagonist-when-added-to-levodopa-ld-and-other-medications-for-parkinsons-disease-pd/