Pooled efficacy analyses of eight randomized, placebo-controlled studies of istradefylline combined with levodopa in patients with PD and motor fluctuations.

Istradefylline, a well-tolerated selective adenosine A_2A receptor antagonist, acts via the indirect basal ganglia outflow pathway. In 2013, doses of 20 and 40mg/day were approved in Japan as adjunctive treatment to levodopa-containing products in patients with PD experiencing wearing-off phenomena.

The pooled analysis included 2719 treated patients (placebo, n=992; 20 mg/day, n=848; 40 mg/day, n=879). At week 12, OFF-hours/day with 20 and 40mg istradefylline was reduced (LS mean difference from placebo in reduction from baseline [95%CI], -0.38 [-0.61, -0.15] and -0.45 [-0.68, -0.22], respectively). ON-hours/day without troublesome dyskinesia increased from baseline with istradefylline compared with placebo (LS mean difference from placebo [95%CI], 20mg, 0.40 [0.15, 0.66]; 40mg, 0.33 [0.08, 0.59]). Istradefylline was well-tolerated, with an average completion rate of 89% across all studies. Dyskinesia was the most frequent AE (8% higher incidence with istradefylline than placebo). Five studies showed statistical improvement with istradefylline over placebo for OFF-time; additional analysis of these five studies and other secondary outcomes will be presented.

Istradefylline offers an adenosine A_2A receptor-mediated, nondopaminergic mechanism for patients with PD on levodopa with motor fluctuations. Istradefylline significantly improved OFF-time and ON-time without troublesome dyskinesia in the pooled analysis of eight studies, as well as in five individual trials.