PRIMARY ENDPOINTS
- Study 1
- Study 2
- Study 3
- Study 4
NOURIANZ® (istradefylline) is the first and only adjunctive therapy that reduces “off” time by lifting the brake of adenosine1-3
Study 1
STUDY DESIGN
Study description
- 12-week study conducted in the U.S. and Canada1
- NOURIANZ 40 mg (n=129) or placebo (n=66), once-daily1
Study design
- Randomized, multi-center, double-blind, placebo-controlled1
- 40 mg as adjunctive treatment to levodopa/carbidopa1
Patient population
- 195 patients with PD experiencing “off” time1
- Mean age=63.2 years4
Primary endpoint
- Change from baseline in the daily awake percentage of “off” time or the change from baseline in total daily “off” time based on 24-hour diaries completed by patients1
Secondary endpoint
- Change from baseline in “on” time without troublesome dyskinesia (ie, “on” time without dyskinesia plus “on” time with non-troublesome dyskinesia)1
- Endpoints measured using 24-hour patient diaries1
Baseline therapy
- Levodopa/carbidopa with or without other concomitant medications for PD1
- Across all 4 pivotal trials: concomitant medications included dopamine agonists (85%), COMT inhibitors (38%), MAO-B inhibitors (40%), anticholinergics (13%), and/or amantadine (33%)1
- Across all 4 pivotal trials: patients were enrolled who had a mean duration of Parkinson’s disease of 9 years (range: 1 month to 37 years), were Hoehn and Yahr Stage II to IV, experiencing at least 2 hours (mean approximately 6 hours) of “off” time per day, and were treated with levodopa for at least 1 year, with stable dosage for at least 4 weeks before screening (mean total daily dosage range: 416 to 785 mg)1
Limitations
- The study was conducted in highly pretreated patients. Understanding of earlier use in disease management is not possible to derive from the data set4
COMT, catechol-o-methyltransferase; MAO-B, monoamine oxidase B.
KEY TAKEAWAY
Nearly
3x
Nearly
3x
reduction in % of awake time spent in the “off” state vs placebo4
NOURIANZ 40 mg: 10.49% reduction compared with placebo: 3.71% (95% CI: -11.63, -1.92; P=0.007)*
RESULTS
Significant decrease in % of awake time spent in the “off” state at Week 124
Magnify
Nearly 3x reduction in % of awake time spent in the “off” state vs placebo
Patients treated with NOURIANZ 40 mg once daily experienced a statistically significant decrease from baseline in percentage of daily awake “off” time (-10.49%), compared with patients on placebo (-3.71%) at Week 12.4*
- *Least square mean changes from baseline.
- Cl, confidence interval.
Study 2
STUDY DESIGN
Study description
- 12-week study conducted in the U.S.1
- NOURIANZ 20 mg (n=112) or placebo (n=113), once-daily1
Study design
- Randomized, double-blind, placebo-controlled1
- 20 mg as adjunctive treatment to levodopa/carbidopa1
Patient population
- 225 patients with PD experiencing “off” time1
- Mean age=63.5 years3
Primary endpoint
- Change from baseline in the daily awake percentage of “off” time or the change from baseline in total daily “off” time based on 24-hour diaries completed by patients1
Secondary endpoint
- Change from baseline in “on” time without troublesome dyskinesia (ie, “on” time without dyskinesia plus “on” time with non-troublesome dyskinesia)1
- Endpoints measured using 24-hour patient diaries1
Baseline therapy
- Levodopa/carbidopa with or without other concomitant medications for PD1
- Across all 4 pivotal trials: concomitant medications included dopamine agonists (85%), COMT inhibitors (38%), MAO-B inhibitors (40%), anticholinergics (13%), and/or amantadine (33%)1
- Across all 4 pivotal trials: patients were enrolled who had a mean duration of Parkinson’s disease of 9 years (range: 1 month to 37 years), were Hoehn and Yahr Stage II to IV, experiencing at least 2 hours (mean approximately 6 hours) of “off” time per day, and were treated with levodopa for at least 1 year, with stable dosage for at least 4 weeks before screening (mean total daily dosage range: 416 to 785 mg)1
Limitations
- The study was conducted in highly pretreated patients. Understanding of earlier use in disease management is not possible to derive from the data set4
COMT, catechol-o-methyltransferase; MAO-B, monoamine oxidase B.
KEY TAKEAWAY
Nearly
2x
Nearly
2x
reduction in % of awake time spent in the “off” state vs placebo4
NOURIANZ 20 mg: 9.49% reduction compared with placebo: 4.92% (95% CI: -8.55, -0.59; P=0.025)*
RESULTS
Significant decrease in % of awake time spent in
the “off” state at Week 124
Magnify
Nearly 2x reduction in % of awake time spent in the “off” state vs placebo
Patients treated with NOURIANZ 20 mg once daily experienced a statistically significant decrease from baseline in percentage of daily awake “off” time (-9.49%), compared with patients on placebo (-4.92%) at Week 12.4*
- *Least square mean changes from baseline.
- Cl, confidence interval.
Study 3
STUDY DESIGN
Study description
- 12-week study conducted in Japan1
- NOURIANZ 20 mg (n=115), NOURIANZ 40 mg (n=124), or placebo (n=118), once-daily1
Study design
- Randomized, multi-center, double-blind, placebo-controlled1
- 20 mg or 40 mg as adjunctive treatment to levodopa/carbidopa1
Patient population
- 357 patients with PD experiencing “off” time1
- Mean age=65.0 years4
Primary endpoint
- Change in the total hours of awake time per day spent in the “off” state compared with placebo based on 24-hour diaries completed by patients4
Secondary endpoint
- Change from baseline in “on” time without troublesome dyskinesia (ie, “on” time without dyskinesia plus “on” time with non-troublesome dyskinesia)1
- Endpoints measured using 24-hour patient diaries1
Baseline therapy
- Levodopa/carbidopa or levodopa/benserzide with or without other concomitant medications for PD4
- Across all 4 pivotal trials: concomitant medications included dopamine agonists (85%), COMT inhibitors (38%), MAO-B inhibitors (40%), anticholinergics (13%), and/or amantadine (33%)1
- Across all 4 pivotal trials: patients were enrolled who had a mean duration of Parkinson’s disease of 9 years (range: 1 month to 37 years), were Hoehn and Yahr Stage II to IV, experiencing at least 2 hours (mean approximately 6 hours) of “off” time per day, and were treated with levodopa for at least 1 year, with stable dosage for at least 4 weeks before screening (mean total daily dosage range: 416 to 785 mg)1
Limitations
- The study was conducted in highly pretreated patients. Understanding of earlier use in disease management is not possible to derive from the data set4
COMT, catechol-o-methyltransferase; MAO-B, monoamine oxidase B.
KEY TAKEAWAY
Up to
Up to
2x
reduction in “off” time vs placebo4
NOURIANZ 20 mg reduced “off” time by
0.65 hours4*
(95% CI: -1.23, -0.07; P=0.028)
NOURIANZ 40 mg reduced “off” time by
0.92 hours4*
(95% CI: -1.49, -0.35; P=0.002)
Data represents placebo corrected reduction in “off” time for 20 mg and 40 mg doses
RESULTS
Significant decrease in “off” time at Week 124
Magnify
Approximately 2x reduction in “off” time vs placebo
In Study 3, patients treated with NOURIANZ 20 mg or NOURIANZ 40 mg once daily experienced a statistically significant decrease from baseline in “off” time (-1.31 hours, -1.58 hours, respectively) compared with patients on placebo (-0.66 hours) at Week 12.4*
- *Least square mean changes from baseline.
- Cl, confidence interval.
Study 4
STUDY DESIGN
Study description
- 12-week study conducted in Japan1
- NOURIANZ 20 mg (n=120), NOURIANZ 40 mg (n=123), or placebo (n=123), once-daily1
Study design
- Randomized, multi-center, double-blind, placebo-controlled1
- 20 mg or 40 mg as adjunctive treatment to levodopa/carbidopa1
Patient population
- 366 patients with PD experiencing “off” time1
- Mean age=65.8 years4
Primary endpoint
- Change in the total hours of awake time per day spent in the “off” state compared with placebo based on 24-hour diaries completed by patients1,4
Secondary endpoint
- Change from baseline in “on” time without troublesome dyskinesia (ie, “on” time without dyskinesia plus “on” time with non-troublesome dyskinesia)1
- Endpoints measured using 24-hour patient diaries1
Baseline therapy
- Levodopa/carbidopa or levodopa/benserzide with or without other concomitant medications for PD4
- Across all 4 pivotal trials: concomitant medications included dopamine agonists (85%), COMT inhibitors (38%), MAO-B inhibitors (40%), anticholinergics (13%), and/or amantadine (33%)1
- Across all 4 pivotal trials: patients were enrolled who had a mean duration of Parkinson’s disease of 9 years (range: 1 month to 37 years), were Hoehn and Yahr Stage II to IV, experiencing at least 2 hours (mean approximately 6 hours) of “off” time per day, and were treated with levodopa for at least 1 year, with stable dosage for at least 4 weeks before screening (mean total daily dosage range: 416 to 785 mg)1
Limitations
- The study was conducted in highly pretreated patients. Understanding of earlier use in disease management is not possible to derive from the data set4
COMT, catechol-o-methyltransferase; MAO-B, monoamine oxidase B.
KEY TAKEAWAY
More than
More than
4x
reduction in “off” time vs placebo4
NOURIANZ 20 mg reduced “off” time by
0.99 hours4*
(95% CI: -1.30, -0.22; P=0.006)
NOURIANZ 40 mg reduced “off” time by
0.96 hours4*
(95% CI: -1.27, -0.20; P=0.008)
Compared with 0.23 hours for placebo
RESULTS
Significant decrease in “off” time at Week 124
Magnify
More than 4x reduction in “off” time vs placebo
In Study 4, patients treated with NOURIANZ 20 mg or NOURIANZ 40 mg once daily experienced a statistically significant decrease from baseline in “off” time (-0.99 hours, -0.96 hours, respectively) compared with patients on placebo (-0.23 hours) at Week 12.4*
- *Least square mean changes from baseline.
- Cl, confidence interval.
See NOURIANZ safety
Safety
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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.
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.
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.
References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540. 2. Chen J-F, Cunha RA. The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease. Purinergic Signal. 2020;16(2):167-174. 3. Isaacson SH, Betté S, Pahwa R. Istradefylline for OFF episodes in Parkinson’s disease: a US perspective of common clinical scenarios. Degener Neurol Neuromuscul Dis. 2022;12:97-109.
References: 1. Parkinson’s disease. National Institutes of Health. Updated June 26, 2023. Accessed April 9, 2024. https://www.nih.gov/research-training/accelerating-medicines-partnership-amp/parkinsons-disease 2. Olanow CW, Poewe W, Rascol O, Stocchi F. From OFF to ON—treating OFF episodes in Parkinson’s disease. US Neurol. 2020;16(suppl 1):2-10.
References: 1. 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. 2. Mori A. Mode of action of adenosine A2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int Rev Neurobiol. 2014;119:87-116. 3. Varani K, Vincenzi F, Tosi A, et al. A2A 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. 4. Fuxe K, Marcellino D, Genedani S, Agnati L. Adenosine A2A receptors, dopamine D2 receptors and their interactions in Parkinson's disease. Mov Disord. 2007;22(14):1990-2017. doi: 10.1002/mds.21440. 5. Morelli M, Di Paolo T, Wardas J, Calon F, Xiao D, Schwarzschild MA. Role of adenosine A2A receptors in parkinsonian motor impairment and L-DOPA-induced motor complications. Prog Neurobiol. 2007;83(5):293-309. 6. Morelli M, Blandini F, Simola N, Hauser RA. A2A receptor antagonism and dyskinesia in Parkinson's disease. Parkinsons Dis. 2012;2012:489853. doi: 10.1155/2012/489853. 7. Mishina M, Ishiwata K. Adenosine receptor PET imaging in human brain. Int Rev Neurobiol. 2014;119:51-69. doi:10.1016/B978-0-12-801022-8.00002-7. 8. 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. 9. Hickey P, Stacy M. Available and emerging treatments for Parkinson’s disease: a review. Drug Des Devel Ther. 2011;5:241-254. 10. 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.
References: 1. Kulisevsky J, Poyurovsky M. Adenosine A2A-receptor antagonism and pathophysiology of Parkinson’s disease and drug-induced movement disorders. Eur Neurol. 2012;67(1):4-11. 2. Mori A. Mode of action of adenosine A2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int Rev Neurobiol. 2014;119:87-116. 3. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540. 4. DHIVY [package insert]. Alpharetta, GA: Avion Pharmaceuticals, LLC; 2021. 5. Morelli M, Blandini F, Simola N, Hauser RA. A2A receptor antagonism and dyskinesia in Parkinson’s disease. Parkinsons Dis. 2012;2012:489853. 6. Liu Y-J, Chen J, Li X, et al. Research progress on adenosine in central nervous system diseases. CNS Neurosci Ther. 2019;25(9):899-910. 7. Mishina M, Ishiwata K. Adenosine receptor PET imaging in human brain. Int Rev Neurobiol. 2014;119:51-69. 8. Isaacson SH, Betté S, Pahwa R. Istradefylline for OFF episodes in Parkinson’s disease: a US perspective of common clinical scenarios. Degener Neurol Neuromuscul Dis. 2022;12:97-109. 9. Chen J-F, Cunha RA. The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease. Purinergic Signal. 2020;16(2):167-174. 10. 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. 11. Kaakkola S, Wurtman RJ. Effects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study. Brain Res.1992;587(2):241-249. 12. 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. 13. Barrett MJ, Sargent L, Nawaz H, Weintraub D, Price ET, Willis AW. Antimuscarinic anticholinergic medications in Parkinson disease: to prescribe or deprescribe? Mov Disord Clin Pract. 2021;8(8):1181-1188. 14. Vanle B, Olcott W, Jimenez J, Bashmi L, Danovitch I, IsHak WW. NMDA antagonists for treating the non-motor symptoms in Parkinson’s disease. Transl Psychiatry. 2018;8(1):117. 15. Rascol O, Fabbri M, Poewe W. Amantadine in the treatment of Parkinson’s disease and other movement disorders. Lancet Neurol. 2021;20:1048-1056. 16. 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. 17. 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. 18. Jenner P. Istradefylline, a novel adenosine A2A receptor antagonist, for the treatment of Parkinson’s disease. Expert Opin Investig Drugs. 2005;14(6):729-738. 19. Ishibashi K, Miura Y, Wagatsuma K, Toyohara J, Ishiwata K, Ishii K. Occupancy of adenosine A2A receptors by istradefylline in patients with Parkinson’s disease using 11C-preladenant PET. Neuropharmacology. 2018;143:106-112.
References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540. 2. Isaacson SH, Betté S, Pahwa R. Istradefylline for OFF episodes in Parkinson’s disease: a US perspective of common clinical scenarios. Degener Neurol Neuromuscul Dis. 2022;12:97-109. 3. Mori A. Mode of action of adenosine A2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int Rev Neurobiol. 2014;119:87-116. 4. Data on file. Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ.
References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc. Princeton, NJ 08540. 2. Data on file. Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ. 3. Wadhwa RR, Cascella M. Steady state concentration. StatPearls Publishing; 2023.
References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc. Princeton, NJ 08540. 2. Data on file. Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ. 3. Hauser RA, Hattori N, Fernandez H, et al. 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. J Park Dis. 2021;11:1663-1675.
Reference: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540.
References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540. 2. Isaacson SH, Betté S, Pahwa R. Istradefylline for OFF episodes in Parkinson’s disease: a US perspective of common clinical scenarios. Degener Neurol Neuromuscul Dis. 2022;12:97-109. 3. Kulisevsky J, Poyurovsky M. Adenosine A2A-receptor antagonism and pathophysiology of Parkinson’s disease and drug-induced movement disorders. Eur Neurol. 2012;67(1):4-11. 4. Mori A. Mode of action of adenosine A2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int Rev Neurobiol. 2014;119:87-116. 5. DHIVY [package insert]. Alpharetta, GA: Avion Pharmaceuticals, LLC; 2021. 6. Olanow CW, Poewe W, Rascol O, Stocchi F. From OFF to ON—treating OFF episodes in Parkinson’s disease. US Neurol. 2020;16(suppl 1):2-10. 7. Chou KL, Stacy M, Simuni T, et al. The spectrum of “off” in Parkinson’s disease: what have we learned over 40 years? Parkinsonism Relat Disord. 2018;51:9-16.
Reference: 1. NOURIANZ. Prescribing Information. Kyowa Kirin, Inc; 2020. Accessed April 1, 2021. https://www.nourianzhcp.com/assets/pdf/nourianz-full-prescribing-information.pdf
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