Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, as Adjunctive Therapy to Levodopa in Parkinson’s Disease: A Pooled Analysis of 8 Phase 2b/3 Trials

Abstract

Background: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson’s disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Objective: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline. Methods: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline’s FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor. Results: Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], –0.38 h [–0.61, –0.15]) and 40 mg/day (–0.45 h [–0.68, –0.22], p < 0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, –0.75 h [–1.10, –0.40]; 40 mg/day, –0.82 h [–1.17, –0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%). Conclusion: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.

The Pharmacological Potential of Adenosine A2A Receptor Antagonists for Treating Parkinson’s Disease

“…Taken along with the evidence from animal models of PD, an improvement of motor disability would be predicted when adenosine A 2A antagonists are used in combination with levodopa therapy [ 32 , 91 ]. Not surprisingly, a number of selective adenosine A 2A receptor antagonists have been developed [ 92 ] with the aim of increasing the duration of motor improvement seen during the time when symptoms are adequately controlled by medication (ON time) and decreasing the periods of inadequate control of PD symptoms (OFF time) in patients receiving levodopa but where insufficient efficacy is occurring [ 18 , 32 , 93 ]. Surprisingly, however, clinical development has proved challenging.…”

“…To date, istradefylline has received approval in the US and Japan for the treatment of adult PD patients experiencing OFF time who are currently taking levodopa (plus a decarboxylase inhibitor) [ 109 , 110 ]. The efficacy of istradefylline was evaluated in a pooled analysis of eight multicenter, phase IIb/III double blind, placebo-controlled trials of patients experiencing motor fluctuations taking 20 or 40 mg/day of istradefylline [ 93 ]. The overall effect size in reducing OFF time (−0.38 to −0.82 h) was in the same range as those achieved by other adjuncts to levodopa therapy—such as MAO-B inhibitors and COMT-inhibitors [ 93 ].…”

“…The efficacy of istradefylline was evaluated in a pooled analysis of eight multicenter, phase IIb/III double blind, placebo-controlled trials of patients experiencing motor fluctuations taking 20 or 40 mg/day of istradefylline [ 93 ]. The overall effect size in reducing OFF time (−0.38 to −0.82 h) was in the same range as those achieved by other adjuncts to levodopa therapy—such as MAO-B inhibitors and COMT-inhibitors [ 93 ].…”

Istradefylline: A novel agent in the treatment of “off” episodes associated with levodopa/carbidopa use in Parkinson disease

“… 6 - 9 All 4 trials examined reduction of daily awake “off” time (percentage or hours) as the primary endpoint over a 12-week period, and istradefylline reduced “off” time by approximately 1 to 2 hours in these trials. Furthermore, a recently published pooled analysis 10 of 8 randomized, placebo-controlled, double-blind phase 2b/3 studies (including the studies in the Table ) showed that istradefylline significantly improved “off” time as well as “on” time without troublesome dyskinesia relative to placebo. However, some placebo-controlled studies 11 , 12 have failed to show efficacy of istradefylline in PD, including a phase-3 trial examining istradefylline as adjunctive therapy to L/C in PD patients with motor-response complications to reduce “off” time and a trial that studied istradefylline as monotherapy for improving motor symptoms in early PD.…”

“…The 4 trials that led to FDA approval for istradefylline showed a mean reduction in daily “off” time relative to placebo of −0.75 hour for the 20-mg/d dose and −0.82 hour for the 40-mg/d dose. 10 A previous meta-analysis 27 that assessed the efficacy of dopamine agonists, MAO-B inhibitors, and COMT inhibitors through indirect comparison (ie, because of a lack of head-to-head clinical trials) showed a reduction in daily “off” time relative to placebo of −1.54 hour, −0.93 hour, and −0.83 hour, respectively. However, indirect comparisons between istradefylline and these other drug classes may be susceptible to bias, so the results should be interpreted cautiously.…”