, Volume 73, Issue 8, pp 875–882 | Cite as

Istradefylline: First Global Approval

  • Rosselle DungoEmail author
  • Emma D. Deeks


Kyowa Hakko Kirin is developing istradefylline, a selective adenosine A2A receptor antagonist, for the once-daily oral treatment of Parkinson’s disease (PD). Adenosine A2A receptors are considered to be present particularly in the basal ganglia of the brain; the degeneration or abnormality observed in PD is believed to occur in the basal ganglia, which is recognized to play a significant role in motor control. Commercially available dopamine replacement therapies effectively treat the early motor symptoms of PD; however, these agents are associated with development of motor complications, limiting usefulness in late stages of the disease. Istradefylline is proposed to possess a clearly distinct action site from existing agents which act on dopamine metabolism or dopamine receptors. Kyowa Hakko Kirin has received approval for istradefylline in the adjunctive treatment of PD in Japan. A New Drug Application was filed in the USA, but the FDA issued a non-approvable letter in February 2008. This article summarizes the milestones in the development of istradefylline leading to its first approval for the treatment of patients with PD.


Levodopa Motor Fluctuation Awake Time Biovail Corporation 
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  1. 1.
    Wu SS, Frucht SJ. Treatment of Parkinson’s disease: what’s on the horizon? CNS Drugs. 2005;19(9):723–43.PubMedCrossRefGoogle Scholar
  2. 2.
    Jenner P. Istradefylline, a novel adenosine A2A receptor antagonist, for the treatment of Parkinson’s disease. Expert Opin Investig Drugs. 2005;14(6):729–38.PubMedCrossRefGoogle Scholar
  3. 3.
    Morelli M, Carta AR, Jenner P. Adenosine A2A receptors and Parkinson’s disease. Handb Exp Pharmacol. 2009;193:589–615.PubMedCrossRefGoogle Scholar
  4. 4.
    Kyowa Hakko Kirin Co. Ltd. Approval for manufacturing and marketing of NOURIAST® tablets 20 mg, a novel antiparkinsonian agent [media release]. Accessed 25 Mar 2013.
  5. 5.
    Kyowa Hakko Kirin Co. Ltd. Submission of New Drug Application for Istradefylline (KW-6002), an investigational anti-Parkinson's disease drug [media release]. 27 Apr 2007.
  6. 6.
    Kyowa Hakko Kirin Co. Ltd. Kyowa Hakko receives not approvable letter from FDA for Istradefylline (KW-6002) [media release]. 28 Feb 2008.
  7. 7.
    Biovail Corporation. Biovail enters into license agreement with Kyowa Hakko Kirin [media release]. 3 Jun 2010.
  8. 8.
    Valeant Pharmaceuticals International Inc. Valeant and Biovail agree to merge [media release]. 21 Jun 2010.
  9. 9.
    Kyowa Hakko Kirin Co. Ltd. Termination of the North American licensing agreement for KW-6002 (Istradefylline) [media release]. Accessed 3 Jun 2011.
  10. 10.
    Harper LK, Beckett SR, Marsden CA, et al. Effects of the A2A adenosine receptor antagonist KW6002 in the nucleus accumbens in vitro and in vivo. Pharmacol Biochem Behav. 2006;83(1):114–21.PubMedCrossRefGoogle Scholar
  11. 11.
    Brooks DJ, Doder M, Osman S, et al. Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain. Synapse. 2008;62(9):671–81.PubMedCrossRefGoogle Scholar
  12. 12.
    Aoyama S, Koga K, Mori A, et al. Distribution of adenosine A2A receptor antagonist KW-6002 and its effect on gene expression in the rat brain. Brain Res. 2002;953(1–2):119–25.PubMedCrossRefGoogle Scholar
  13. 13.
    Ochi M, Shiozaki S, Kase H. Adenosine A2A receptor-mediated modulation of GABA and glutamate release in the output regions of the basal ganglia in a rodent model of Parkinson’s disease. Neuroscience. 2004;127(1):223–31.PubMedCrossRefGoogle Scholar
  14. 14.
    Ochi M, Koga K, Kurokawa M, et al. Systemic administration of adenosine A2A 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Kanda T, Jackson MJ, Smith LA, et al. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol. 1998;43:507–13.PubMedCrossRefGoogle Scholar
  16. 16.
    Kanda T, Tahiro T. Antiparkinsonian activities of istradefylline (KW-6002), pramipexole and entacapone in MPTP-treated common marmosets [abstract no. Tu-258]. Mov Disord. 2009;24(Suppl. 1):S353–4.Google Scholar
  17. 17.
    Kanda T, Jackson MJ, Smith LA, et al. Combined use of the adenosine A2A antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp Neurol. 2000;162(2):321–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Grondin R, Bedard PJ, Hadj Tahar A, et al. Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys. Neurology. 1999;52(8):1673–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Bibbiani F, Oh JD, Petzer JP, et al. A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson’s disease. Exp Neurol. 2003;184(1):285–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Lundblad M, Vaudano E, Cenci MA. Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of L-DOPA-induced dyskinesia. J Neurochem. 2003;84(6):1398–410.PubMedCrossRefGoogle Scholar
  21. 21.
    Koga K, Kurokawa M, Ochi M, et al. Adenosine A2A receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats. Eur J Pharmacol. 2000;408(3):249–55.PubMedCrossRefGoogle Scholar
  22. 22.
    Shiozaki S, Ichikawa S, Nakamura J, et al. Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP. Psychopharmacology (Berl). 1999;147(1):90–5.CrossRefGoogle Scholar
  23. 23.
    Betz AJ, Vontell R, Valenta J, et al. Effects of the adenosine A2A antagonist KW 6002 (istradefylline) on pimozide-induced oral tremor and striatal c-Fos expression: comparisons with the muscarinic antagonist tropicamide. Neuroscience. 2009;163(1):97–108.PubMedCrossRefGoogle Scholar
  24. 24.
    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):5848–52.PubMedGoogle Scholar
  25. 25.
    Kanda T, Kadowaki T, Shiozaki S. Effect of istradefylline (KW-6002) on the ON/OFF-like phenomenon in 6-OHDA- lesioned rats [abstract no. 741.14/T6]. 38th Annual Meeting of the Society for Neuroscience; 15–19 Nov 2008; Washington (DC).Google Scholar
  26. 26.
    Ikeda K, Kurokawa M, Aoyama S, et al. Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson’s disease. J Neurochem. 2002;80(2):262–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Pierri M, Vaudano E, Sager T, et al. KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse. Neuropharmacology. 2005;48(4):517–24.PubMedCrossRefGoogle Scholar
  28. 28.
    Lo DC, Park LC, Leeds J, et al. The adenosine 2A receptor antagonist istradefylline (KW-6002) is neuroprotective in a chronic brain slice explant model and improves performance in the R6/2 mouse model of Huntington disease [abstract no. 798.13/P11]. 37th Annual Meeting of the Society for Neuroscience; 3–7 Nov 2007; San Diego.Google Scholar
  29. 29.
    Kadowaki T, Shiozaki S, Kanda T. Effect of istradefylline (KW-6002) on cognitive function in an object recognition test in mPFC-lesioned rats [abstract no. 832.2/J4]. 38th Annual Meeting for the Society for Neuroscience; 15–19 Nov 2008; Washington (DC).Google Scholar
  30. 30.
    Knebel W, Rao N, Uchimura T, et al. Population pharmacokinetic analysis of istradefylline in healthy subjects and in patients with Parkinson’s disease. J Clin Pharmacol. 2011;51(1):40–52.PubMedCrossRefGoogle Scholar
  31. 31.
    Rao N, Uchimura T, Mori A. Evaluation of safety, tolerability, and multiple-dose pharmacokinetics of istradefylline in Parkinson’s disease patients [abstract no. PIII-88]. Clin Pharmacol Ther. 2008;83(Suppl. 1):S99.Google Scholar
  32. 32.
    Rao N, Uchimura T, Mori A. Evaluation of safety, tolerability, and multiple-dose pharmacokinetics of istradefylline in healthy subjects [abstract no. PIII-89]. Clin Pharmacol Ther. 2008;83(Suppl 1):S99.Google Scholar
  33. 33.
    Rao N, Chaikin P, Dvorchik B, et al. Effective of moderate hepatic impairment and cigarette smoking on the pharmacokinetics of istradefylline [abstract no. 2.224]. Parkinsonism Relat Disord. 2007;13(Suppl. 2):S104.Google Scholar
  34. 34.
    Rao N, Chaikin P, Dvorchik B, et al. Evaluation of the pharmacokinetic interaction of istradefylline and ketoconazole [abstract no. 2.225]. Parkinsonism Relat Disord. 2007;13(Suppl. 2):S104.Google Scholar
  35. 35.
    Rao N, Dvorchik B, Sussman N, et al. A study of the pharmacokinetic interaction of istradefylline, a novel therapeutic for Parkinson’s disease, and atorvastatin. J Clin Pharmacol. 2008;48(9):1092–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Rao N, Allenby K, Uchimura T. Steady state administration of istradefylline does not affect the pharmacokinetics of levodopa/carbidopa [abstract no. 618]. Mov Disord. 2007;22(Suppl. 16):S188–9.Google Scholar
  37. 37.
    Kyowa Hakko Kirin Co. Ltd. Kyowa Hakko Kirin announces results of phase lll clinical study of KW-6002 (istradefylline) for Parkinson’s disease in Japan [media release]. 10 May 2011.
  38. 38.
    Hauser RA, Shulman LM, Trugman JM, et al. Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord. 2008;23(15):2177–85.PubMedCrossRefGoogle Scholar
  39. 39.
    Pourcher E, Fernandez HH, Stacy M, et al. Istradefylline for Parkinson’s disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Parkinsonism Relat Disord. 2012;18(2):178–84.PubMedCrossRefGoogle Scholar
  40. 40.
    Kyowa Hakko Kogyo Co. Ltd. Results of phase-III clinical studies of an anti-Parkinson’s disease drug Istradefylline/KW-6002 conducted overseas [media release]. 7 Mar 2006.
  41. 41.
    Factor S, Mark MH, Watts R, et al. A long-term study of istradefylline in subjects with fluctuating Parkinson’s disease. Parkinsonism Relat Disord. 2010;16(6):423–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A(2A) receptor antagonist treatment of Parkinson’s disease. Neurology. 2003;61(3):293–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Hauser RA, Hubble JP, Truong DD, et al. Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD. Neurology. 2003;61(3):297–303.PubMedCrossRefGoogle Scholar
  44. 44.
    Mizuno Y, Hasegawa K, Kondo T, et al. Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: a randomized, controlled study. Mov Disord. 2010;25(10):1437–43.PubMedCrossRefGoogle Scholar
  45. 45.
    LeWitt PA, Guttman M, Tetrud JW, et al. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces “off” time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol. 2008;63(3):295–302.PubMedCrossRefGoogle Scholar
  46. 46.
    Stacy M, Silver D, Mendis T, et al. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease [Erratum appears in Neurology. 2008;71(12): 953]. Neurology. 2008;70(23):2233–40.PubMedCrossRefGoogle Scholar
  47. 47.
    Fernandez HH, Greeley DR, Zweig RM, et al. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord. 2010;16(1):16–20.PubMedCrossRefGoogle Scholar
  48. 48.
    DeCerce J, Smith LF, Gonzalez W, et al. Effectiveness and tolerability of istradefylline for the treatment of restless legs syndrome: an exploratory study in five female patients. Current Ther Res. 2007;68(5):349–59.CrossRefGoogle Scholar
  49. 49.
    Bertoni JM, 6002-INT-001 study group. The long-term safety and tolerability of istradefylline as adjunctive therapy to levodopa in patients with Parkinson’s disease and motor complications [abstract no. 635]. Mov Disord. 2008;23(Suppl. 1):209–10.Google Scholar
  50. 50.
    Knebel W, Rao N, Uchimura T, et al. Population pharmacokinetic-pharmacodynamic analysis of istradefylline in patients with Parkinson disease. J Clin Pharmacol. 2012;52(10):1468–81.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Adis R&D InsightAucklandNew Zealand
  2. 2.AdisAucklandNew Zealand

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