Introduction
Istradefylline is an adenosine 2A receptor (A2AR) antagonist approved as an adjunctive therapy for Parkinson’s disease. It was first approved in Japan in 2013, followed later by approval in the United States in 2019. It is not yet approved in Europe. The drug is promising given its unique mechanism of action, but clinical trial results were mixed. We asked two experts to discuss the evidence for istradefylline and which patients may be most likely to benefit from it.
1) What pre-clinical evidence supports A2AR antagonists as possible therapeutics in PD?
Dr. Sako:
A2ARs are predominantly expressed in the striatum,1 and A2AR antagonist reduced extracellular GABA concentrations in the globus pallidus of the 6-hydroxydopamine-lesioned rats.2 In addition, reduced locomotor activities in D2R knock-out mice were restored by administration of KW-6002 (istradefylline).3 These results support the notion that A2AR antagonist could suppress hyperactivity of the indirect pathway to provide therapeutic benefit in patients with PD. Potential for neuroprotection has also been suggested by animal studies. An A2AR antagonist protected against MPTP-induced dopaminergic neurotoxicity.4 The loss of dopaminergic neurons in double mutant alpha-synuclein transgenic mice were significantly attenuated by A2AR depletion.5
Dr. Schwarzschild:
Multiple lines of preclinical evidence converge in support of A2AR antagonism as a now established therapeutic strategy for treating motor symptoms and disability of PD
- Anatomically, within the brain adenosine A2A receptor expression is largely restricted to the striatum, and within the striatum it is largely restricted to the dopamine D2 receptor-expressing GABAergic projection neurons. This relatively discrete expression accounts for the low risk of CNS side effects experienced with A2AR antagonists.
- Physiologically, A2AR’s stimulate while D2R’s inhibit adenylate cyclase and electrophysiological activity of these striatal neurons. Accordingly, through this cellular interaction A2AR antagonism can counterbalance the loss of dopaminergic D2R-mediated motor inhibition characteristic of Parkinson’s.
- Behaviorally, A2AR antagonists consistently reverse parkinsonian motor deficits across a variety of hypodopaminergic rodent and primate models of PD.
A couple of intriguing lines of preclinical evidence converge in support A2AR antagonism as possible therapeutic strategy for treating the underlying neurodegeneration and progression of PD
- Epidemiologically, one of the most robust ‘reduced risk’ factors for PD is caffeine, which has many of its effects on the brain through adenosine A2AR antagonism.
- Neurobiologically, A2AR’s blockade confers protection against dopaminergic neuron loss across a wide range of PD neurodegeneration models.
The long-term effects of istradefylline or other adenosine A2AR blockers on PD progression have not yet been determined in randomized clinical trials.
2) What clinical trial evidence supports istradefylline in PD?
Dr. Sako:
The effect of istradefylline on motor symptoms in PD was controversial because the results of clinical trials were heterogeneous.6, 7 However, a meta-analysis has demonstrated that 40 mg/day istradefylline significantly reduced off time and improved UPDRS part III in homogeneous studies.7 In contrast, 20mg/day istradefylline only improved UPDRS part III in homogeneous studies.
Dr. Schwarzschild:
On balance, the results from eight phase 2 or 3 placebo-controlled, randomized clinical trials of istradefylline as adjunctive treatment demonstrated partially improved movement in people with PD already being treated with levodopa. Most of these studies found that istradefylline produced benefit from the patient’s perspective in the form of reduced ‘off’ time, and generally less consistently as assessed by ‘on’ time without troublesome dyskinesia. The complementary clinician-based assessment of the motor part of the Unified Parkinson’s Disease Rating Scale similarly demonstrated better scores on istradefylline in several but not in all studies.
3) What symptoms does istradefylline help with, and what doesn’t it help with? In what type of patients is it most likely to be of benefit?
Dr. Sako:
Istradefylline was reported to improve axial symptoms including postural abnormalities and gait disorders in Japan.8, 9 These were case series studies, and randomized controlled studies are needed to demonstrate the effect of istradefylline on axial symptoms in PD. Patients with dyskinesia showed increased binding to A2AR in the striatum, which might indicate the association of dyskinesia with A2AR, and therapeutic effect of A2AR antagonists on dyskinesia;10 however, a meta-analysis indicated that dyskinesia was aggravated by the use of istradefylline with homogeneous studies.7 Furthermore, a pooled analysis revealed features of patients who benefited from istradefylline treatment, such as age more than 65, daily off time more than 8 hours, lack of dyskinesia, and modified H & Y scale more than 3.11 Collectively, istradefylline is expected to provide therapeutic benefit for elderly patients without dyskinesia at an advanced stage, together with levodopa.
Dr. Schwarzschild:
Adjunctive istradefylline helps typical motor symptoms such as bradykinesia by reducing the duration of ‘wearing off’ episodes, when these symptoms typically emerge or worsen. Despite the potential of A2AR antagonism to offer a levodopa-sparing strategy that reduces motor complications of levodopa, that possibility has not been realized as a practical application. Accordingly, simply adding on istradefylline to a dopaminergic regimen that’s already producing dyskinetic side effects is likely to exacerbate them. However, based on substantial pre-clinical as well as epidemiological data the possibility that dyskinesias may be prevented by initiating A2AR antagonism earlier, concurrent with dopaminergic drug treatment may be worth pursuing in clinical trials. In theory, heavier caffeine consumers may respond less well given that caffeine at concentrations achieved with typical consumption displaces adenosine antagonists like istradefylline from their striatal A2AR binding sites. However, randomized trials of istradefylline in PD did not routinely measure or report caffeine intake, leaving uncertain the utility of this potential response determinant.
4) Why did istradefylline take so much longer to get approved in the US than in Japan, and what can we learn from this in terms of drug development?
Dr. Sako:
The difference in time for approval was attributed to inconsistent results of clinical trials. Istradefylline provided consistent therapeutic effect in Japanese trials, while several studies in other regions failed to demonstrate a significant benefit of istradefylline. The results of clinical trials can be easily affected by confounding factors including genetics, medication, and other circumstances if drugs have only small effects. For example, average dose of levodopa in the clinical trial in Japan was lower than that in North America. It is almost impossible to control all these confounding factors in clinical trials, and consequently heterogeneous results are obtained for the primary outcome. A small number of heterogeneous studies should not be assessed individually for drugs with limited benefit because confounding factors significantly contribute to results. A meta-analysis and/or pooled analysis will help to find small effects and cause of heterogeneity as istradefylline has been assessed.7, 11
Dr. Schwarzschild:
Regulatory approval for use of istradefylline to treat PD was sought in the US prior to its 2013 approval in Japan. However in 2008 the FDA issued a Not Approvable letter in response to a New Drug Application for istradefylline due to a lack of demonstrated effectiveness and non-inferiority to approved products at the time.
Although regulatory approval in the US was achieved in 2019 after completion of additional trials and with overall evidence deemed supportive of sufficient efficacy and safety, the individual study results were mixed. The lack of efficacy is some studies has been attributed in part to challenges of clinical trial design and execution, which can amplify confounding placebo effects for example, and are more critical when assessing interventions with relatively modest efficacy.
A drug like istradefylline is particularly attractive because of the clear mechanism of action and strong pre-clinical evidence. It is logical that antagonism of inhibition in the indirect pathway within the striatum will shift the balance of the neural circuitry favorably for the patient with Parkinson’s disease. Further, the low density of A2ARs outside of the striatum provide hope that minimal side effects will occur. However, the story of the mixed outcomes in clinical trials is a reminder that what works logically and in animal models does not always translate perfectly into humans. As istradefylline gains regulatory approval around the world, further studies will provide the needed insight into how to optimally leverage this therapy and for which patients it can offer the most benefit.
References
- Svenningsson P, Le Moine C, Aubert I, et al. Cellular distribution of adenosine A2A receptor mRNA in the primate striatum. J Comp Neurol 1998;399(2):229-240.
- Ochi M, Koga K, Kurokawa M, et al. Systemic administration of adenosine A(2A) receptor antagonist reverses increased GABA release in the globus pallidus of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study. Neuroscience 2000;100(1):53-62.
- Aoyama S, Kase H, Borrelli E. Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. J Neurosci 2000;20(15):5848-5852.
- Yu L, Shen HY, Coelho JE, et al. Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms. Ann Neurol 2008;63(3):338-346.
- Kachroo A, Schwarzschild MA. Adenosine A2A receptor gene disruption protects in an alpha-synuclein model of Parkinson's disease. Ann Neurol 2012;71(2):278-282.
- Jenner P, Mori A, Aradi SD, et al. Istradefylline - a first generation adenosine A(2A) antagonist for the treatment of Parkinson's disease. Expert Rev Neurother 2021;21(3):317-333.
- Sako W, Murakami N, Motohama K, et al. The effect of istradefylline for Parkinson's disease: A meta-analysis. Sci Rep 2017;7(1):18018.
- Suzuki K, Miyamoto T, Miyamoto M, et al. Could istradefylline be a treatment option for postural abnormalities in mid-stage Parkinson's disease? J Neurol Sci 2018;385:131-133.
- Iijima M, Orimo S, Terashi H, et al. Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson's disease: A single-arm, open-label, prospective, multicenter study. Expert Opin Pharmacother 2019;20(11):1405-1411.
- Ramlackhansingh AF, Bose SK, Ahmed I, et al. Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology 2011;76(21):1811-1816.
- Hattori N, Kitabayashi H, Kanda T, et al. A Pooled Analysis From Phase 2b and 3 Studies in Japan of Istradefylline in Parkinson's Disease. Mov Disord 2020;35(8):1481-1487.