NOURIANZ significantly decreased “off” time from baseline compared to placebo¹

Change from baseline in daily “off” time at 12 weeks (hours)^1,2

In study 3, the change in OFF time from baseline was -0.66 in the placebo group and -1.58 in the NOURIANZ 20 mg/d group. In study 4, the change in OFF time from baseline was -0.23 in the placebo group, -0.99 in the NOURIANZ 20 mg/d group, and -0.96 in the NOURIANZ 40 mg/d group.

Study description: Randomized, 12-week, multicenter, double-blind, placebo-controlled studies of NOURIANZ 20 mg and 40 mg as adjunctive treatment to levodopa treatment in patients with Parkinson's disease (PD) (mean age=65 years) experiencing “off” time (mean approximately 6 hours/day). Primary endpoint was change from baseline in total daily “off” time. Secondary endpoint was change from baseline in “on” time without troublesome dyskinesia. Endpoints measured using 24-hour patient diaries.¹All enrolled patients were on stable doses of baseline therapy for the duration of the study. Baseline therapy was levodopa/carbidopa (Studies 1, 2, 3, and 4) or levodopa/benserazide (Studies 3 and 4) for all patients with or without other concomitant medications for PD, including dopamine agonists (85%), COMT inhibitors (38%), MOA-B inhibitors (40%), anticholinergics (13%), and/or amantadine (33%).^1,2 ^aLeast squares (LS) mean change from baseline (ANCOVA). ANCOVA, analysis of covariance; COMT, catechol-o-methyl transferase; MAO, monoamine oxidase.

Change in “off” time from baseline to endpoint
(12-weeks), daily awake “off” time
(% of awake hours)^1,2

Concomitant Treatments of Parkinson's Disease

Pre-specified analysis for Study 1 was ANOVA, and for study 2 was ANCOVA^*

^*LS mean change from baseline (ANOVA in Study 1, ANCOVA in Study 2). ANOVA, analysis of variance.

Decreased “off” time and increased “on” time without troublesome dyskinesia at Week 12^1,2

NOURIANZ decreased OFF time and increased ON time without troublesome dyskinesia at Week 12

^a LS mean change from baseline (ANOVA in Study 1, ANCOVA in Studies 2, 3, and 4). Baseline therapy was levodopa/carbidopa and/or levodopa/benserazide for all patients with or without concomitant PD medications.

NOURIANZ was evaluated in patients taking levodopa treatment with or without concomitant medications¹

NOURIANZ Concomitant Treatments of Parkinson's Disease

NOURIANZ increased daily “on” time, without troublesome dyskinesia^1,2†‡

Patients treated with NOURIANZ experienced an increase in “on” time without troublesome dyskinesia.

Increases from baseline with NOURIANZ 20 mg ranged from 0.90 to 1.35 hours^†
Increases from baseline with NOURIANZ 40 mg ranged from 0.85 to 1.45 hours^‡
Increases from baseline with placebo ranged from 0.28 to 0.80 hours

^†Nominal P values: P=0.135 in Study 2; P=0.085 in Study 3; P=0.008 in Study 4. ^‡Nominal P values: P=0.026 in Study 1; P=0.048 in Study 3; P=0.008 in Study 4.
Least squares mean change from baseline (ANOVA in Study 1; ANCOVA in Studies 2, 3, and 4).

NOURIANZ was evaluated in patients taking levodopa treatment with or without other concomitant medications for PD.

Indication

NOURIANZ^™ (istradefylline) is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes.

Important Safety Information

Warnings and Precautions

Dyskinesia: NOURIANZ in combination with levodopa may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical trials, 1% of patients treated with either NOURIANZ 20 mg or 40 mg discontinued treatment because of dyskinesia, compared to 0% for placebo.

Hallucinations / Psychotic Behavior: Because of the potential risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with NOURIANZ. Consider dosage reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking NOURIANZ.

Impulse Control / Compulsive Behaviors: Patients treated with NOURIANZ and one or more medication(s) for the treatment of Parkinson’s disease (including levodopa) may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges. In clinical trials, 1 patient treated with NOURIANZ 40 mg was reported to have impulse control disorder, compared to no patient on NOURIANZ 20 mg or placebo.

Drug Interactions

The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily. Avoid use of NOURIANZ with strong CYP3A4 inducers.

Specific Populations

Pregnancy: Based on animal data, may cause fetal harm.

Hepatic impairment: The maximum recommended dosage of NOURIANZ in patients with moderate hepatic impairment is 20 mg once daily. Avoid use in patients with severe hepatic impairment.

Adverse Reactions

The most common adverse reactions with an incidence ≥5% and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%) for NOURIANZ 20 mg, 40 mg, and placebo, respectively.

You are encouraged to report suspected adverse reactions to Kyowa Kirin, Inc. at 1-844-768-3544 or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information for NOURIANZ.

Reference: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Bedminster, NJ, USA.

References: 1. Hickey P, Stacy M. Available and emerging treatments for Parkinson’s disease: a review. Drug Des Devel Ther. 2011;5:241-254. 2. The voice of the patient: Parkinson’s disease. Silver Spring, MD: US Food and Drug Administration; April 2016. https://www.fda.gov/media/124392/download. Accessed June 11, 2019. 3. Parkinson’s Foundation. Statistics. https://parkinson.org/Understanding-Parkinsons/Statistics. Accessed May 5, 2019. 4. Stocchi F, Antonini A, Barone P, et al. Early DEtection of wEaring off in Parkinson disease: the DEEP study. Parkinsonism Relat Disord. 2014;20(2):204-211. 5. NOURIANZ [package insert]. Kyowa Kirin, Inc., Bedminster, NJ, USA.

References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Bedminster, NJ, USA. 2. Kalia LV, Brotchie JM, Fox SH. Novel nondopaminergic targets for motor features of Parkinson's disease: review of recent trials. Mov Disord. 2013;28(2):131-144. 3. Morelli M, Di Paolo T, Wardas J, Calon F, Xiao D, Schwarzschild MA. Role of adenosine A_2A receptors in parkinsonian motor impairment and L-DOPA-induced motor complications. Prog Neurobiol. 2007;83(5):293-309. 4. Mishina M, Ishiwata K, Naganawa M, et al. Adenosine A_2A receptors measured with [¹¹C]TMSX PET in the striata of Parkinson's disease patients. PLoS One. 2011;6(2):e17338. doi:10.1371/journal.pone.0017338. 5. Varani K, Vincenzi F, Tosi A, et al. A_2A adenosine receptor overexpression and functionality, as well as TNF-α levels, correlate with motor symptoms in Parkinson’s disease. FASEB J. 2010;24(2):587-598. doi:10.1096/fj.09-141044. 6. Brooks DJ. Dopamine agonists: their role in the treatment of Parkinson’s disease [editorial]. J Neurol Neurosurg Psychiatry. 2000;68(6):685-689. 7. Brichta L, Greengard P, Flajolet M. Advances in the pharmacological treatment of Parkinson’s disease: targeting neurotransmitter systems. Trends Neurosci. 2013;36(9):543-554. 8. Ishibashi K, Miura Y, Wagatsuma K, Toyohara J, Ishiwata K, Ishii K. Occupancy of adenosine A_2A receptors by istradefylline in patients with Parkinson’s disease using ¹¹C-preladenant PET. Neuropharmacology. 2018;143:106-112. 9. Ossola B, Schendzielorz N, Chen SH, et al. Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GDNF in astroglia. Neuropharmacology. 2011;61(4):574-582. 10. Kaakkola S, Wurtman RJ. Effects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study. Brain Res. 1992;587(2):241-249. 11. Kong P, Zhang B, Lei P, et al. Neuroprotection of MAO-B inhibitor and dopamine agonist in Parkinson disease. Int J Clin Exp Med. 2015;8(1):431-439. 12. GOCOVRI^® (amantadine) [Prescribing Information]. Emeryville, CA: Adamas Pharma LLC; 2017. 13. Gerlach M, Double K, Arzberger T, Leblhuber F, Tatschner T, Riederer P. Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum. J Neural Transm (Vienna). 2003;110(10):1119-1127. 14. Rubí B, Maechler P. Minireview: new roles for peripheral dopamine on metabolic control and tumor growth: let's seek the balance. Endocrinology. 2010;151(12):5570-5581. doi:10.1210/en.2010-0745. 15. Jenner P. Istradefylline, a novel adenosine A_2A receptor antagonist, for the treatment of Parkinson's disease. Expert Opin Investig Drugs. 2005;14(6):729-738.

References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Bedminster, NJ, USA. 2. Data on file. Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ.

References: 1. Data on file. Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ. 2. NOURIANZ [package insert]. Kyowa Kirin, Inc., Bedminster, NJ, USA.