Istradefylline (Nourianz™) New Drug Update

Istradefylline (Nourianz™) New Drug Update September 2019 Nonproprietary Name istradefylline Brand Name Nourianz Manufacturer Kyowa Kirin Form Tablets Strength 20 mg, 40 mg FDA Approval August 27, 2019 Market Availability TBD FDA Approval Classification Standard Review FDB Classification: TBD Specific Therapeutic Class (HIC3) INDICATION1

Istradefylline (Nourianz) is an adenosine A2A receptor antagonist approved as adjunctive treatment to levodopa/carbidopa (LD/CD) in adults with Parkinson’s disease (PD) experiencing “off” episodes. CONTRAINDICATIONS/WARNINGS Istradefylline does not have any contraindications. In combination with LD, istradefylline may cause dyskinesia or exacerbate existing dyskinesia. Istradefylline carries a warning for hallucinations and psychotic behavior; if these occur, a dosage reduction or discontinuation of istradefylline is recommended. Patients who have a major psychotic disorder should not be treated with istradefylline, due to the potential risk for exacerbating psychosis. Patients taking istradefylline may experience impulse control and compulsive behaviors including 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. Healthcare providers (HCPs) should inquire about these impulses from patients and caregivers (particularly since patients may not view these behaviors as abnormal). DRUG INTERACTIONS Co-administration with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin) may increase istradefylline exposure; therefore, the maximum istradefylline dose with concomitant use is 20 mg once daily. Conversely, co-administration with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, rifampin, phenytoin, St. John’s wort) should be avoided due to the potential for reduced therapeutic effect of istradefylline.

Proprietary Information. Restricted Access – Do not disseminate or copy without approval.

COMMON ADVERSE EFFECTS The most common adverse reactions reported in clinical trials (incidence ≥ 5%) for istradefylline relative to placebo are: dyskinesia (20 mg 15%, 40 mg 17%, placebo 8%), dizziness (20 mg 3%, 40 mg 6%, placebo 4%), constipation (20 mg 5%, 40 mg 6%, placebo 3%), nausea (20 mg 4%, 40 mg 6%, placebo 5%), hallucination (20 mg 2%, 40 mg 6%, placebo 3%), and insomnia (20 mg 1%, 40 mg 6%, placebo 4%). The percentage of patients discontinuing istradefylline for any adverse effect was 5%, 6%, and 5% for the 20 mg dose, 40 mg dose, and placebo, respectively. The most frequent adverse effect leading to study discontinuation was dyskinesia. SPECIAL POPULATIONS Pregnancy Available data for use in pregnant women are insufficient to inform of drug-related fetal or maternal risks. Based on animal studies, istradefylline was teratogenic and caused embryo-fetal harm when administered during pregnancy. Use of istradefylline is not recommended during pregnancy. Women of reproductive potential should use adequate contraception during treatment. Pediatrics Safety and efficacy of istradefylline have not been established in pediatric patients. Geriatrics In clinical trials, no differences in effectiveness were reported for istradefylline between patients ≥ 65 years of age and younger patients. No dose adjustments are recommended based on age. Renal Impairment No dose adjustment is required in patients with mild, moderate, or severe renal impairment. It has not been evaluated in end-stage renal disease (ESRD). Hepatic Impairment No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh A). The maximum dosage in moderate hepatic impairment (Child-Pugh B) is 20 mg once daily. Istradefylline has not been studied in severe hepatic impairment (Child-Pugh C), and its use in this population should be avoided. Tobacco Smokers Tobacco smoking can decrease the efficacy of istradefylline due to steady-state systemic exposures being decreased (by 38% to 54%). The recommended dose of istradefylline in patients who smoke ≥ 20 cigarettes daily (or the equivalent of another tobacco product) is 40 mg once daily.

DOSAGES The recommended dose of istradefylline is 20 mg orally once daily without regard to food. The dosage may be increased to 40 mg once daily (maximum dose) based on patient need and tolerability. Initial dose titration is not required. CLINICAL TRIALS2,3,4,5,6,7,8,9,10 A literature search was performed using “istradefylline” and “Parkinson’s disease.” The efficacy of istradefylline was studied in 4 randomized, double-blind, placebo-controlled, multicenter, 12-week trials in patients (n=1,143) with PD experiencing “off” episodes: Study 1, NCT00456586, phase 2; Study 2, NCT00199407, phase 3; Study 3, NCT00455507, phase 2; and Study 4, NCT00955526, phase 3. The primary efficacy endpoint was change from baseline in daily awake percentage of “off” time or the change from baseline in total daily “off” time (based on patient- completed, 24-hour diaries). The secondary endpoint was a change from baseline in “on” time without troublesome dyskinesia. The mean age was 65 years (range 33 to 84 years old); 50% were male, 32% of patients were Caucasian, and 67% of Asian decent. Patients enrolled had a mean duration of PD of 9 years (1 month to 37 years) with Hoehn and Yahr Stage II to IV. They were experiencing a minimum of 2 hours (mean of about 6 hours) of “off” time daily, and they were on levodopa for at least 1 year and on a stable dose for at least 4 weeks before screening (mean total daily dose range: 416 to 785 mg). Study patients were on levodopa with or without concomitant medications (as long as stable for at least 4 weeks before screening and throughout study) for PD. These included dopamine agonists (85%), catechol-O-methyl transferase (COMT) inhibitors (38%), monoamine oxidase B (MAO-B) inhibitors (40%), anticholinergics (13%), and/or amantadine (33%). Patients who had received a neurosurgical treatment for PD (e.g., pallidotomy, thalamotomy, deep brain stimulation) were excluded. Studies 1 and 2 were conducted in the United States (US)/Canada and US, respectively, and istradefylline was administered as once-daily 40 mg and 20 mg, respectively. Studies 3 and 4 were conducted in Japan; patients were randomized to both doses (20 mg and 40 mg once-daily) of istradefylline or placebo. All 4 studies showed a statistically significant decrease in least square means difference (LSMD) from baseline in daily “off” time compared to placebo. Table 1 provides a summary of the results.

Table 1 Study/Design Baseline (mean +/- SD) % of awake LSMD versus placebo (change from “off” hours baseline daily awake “off” time % hours) (p-value) Study 1 (NCT00456586) placebo (n=66) 37.2 +/- 13.8 istradefylline 40 mg (n=129) 38.4 +/- 16.2 -6.78 (p=0.007) Study 2 (NCT00199407) placebo (n=113) 38.7 +/- 11.6 istradefylline 20 mg (n=112) 39.8 +/- 14 -4.57 (p=0.025) Study/Design Baseline (mean +/- SD) % of “off” LSMD versus placebo (change from hours baseline daily “off” time) hours (p-value) Study 3 (NCT00455507) placebo (n=118) 6.4 +/- 2.7 istradefylline 20 mg (n=115) 6.8 +/- 2.9 -0.65 (p=0.028) istradefylline 40 mg (n=124) 6.6 +/- 2.5 -0.92 (p=0.002) Study 4 (NCT00955526) placebo (n=123) 6.3 +/- 2.5 istradefylline 20 mg (n=120) 6.6 +/- 2.7 -0.76 (p=0.006) istradefylline 40 mg (n=123) 6 +/- 2.5 -0.74 (p=0.008) SD= standard deviation; LSMD= least squares mean difference

OTHER DRUGS USED FOR CONDITION11 A number of adjunctive therapies are approved for use in PD to help reduce “off” episodes including dopamine agonists (pramipexole, ropinirole, rotigotine), catechol-O-methyl transferase [COMT] inhibitors (entacapone, tolcapone), monoamine oxidase B [MAO B] inhibitors (rasagiline, selegiline, safinamide). Injectable apomorphine and inhaled levodopa (Inbrija) are also approved. PLACE IN THERAPY12,13,14,15 Per the National Institutes of Health (NIH), PD is the second most common neurodegenerative disorder in the US after Alzheimer’s. In the US, approximately 50,000 people are diagnosed with PD each year and about 1 million Americans suffer from the condition. It typically occurs in people over age 60 years, although it can occur earlier. Levodopa remains the cornerstone in the treatment of PD; however motor complications can occur with long-term use; add-on treatments are aimed to reduce the “off episodes” - periods of the day when PD symptoms return. Updated PD guidelines from the American Academy of Neurology (AAN) are under development; however, international guidelines from the International Parkinson and Movement Disorder Society were published in 2018. These guidelines detail a number of potential options for treating motor fluctuations as add-on therapy to optimized oral levodopa and address the role of istradefylline. The following therapies are considered to be clinically useful: non-ergot dopamine agonists (pramipexole, ropinirole, rotigotine, apomorphine intermittent injections), levodopa extended release, COMT inhibitors (entacapone), MAO B inhibitors (rasagiline, safinamide). The ergot dopamine agonist, bromocriptine, as well as the COMT inhibitor, tolcapone, and non-ergot dopamine agonist, apomorphine infusion, are considered to be possibly useful. Istradefylline is also included in the guidelines as a possibly useful therapy for treating motor fluctuations. Choice of agent is dependent on patient characteristics as well as safety, cost, and availability. In general, oral agents are utilized first, followed by parenteral and surgical treatment modalities as motor fluctuations advance.

Istradefylline (Nourianz) is an oral once-daily adenosine A2A receptor antagonist approved as an adjunct to levodopa for the wearing off symptoms in patients with PD. The exact mechanism of its therapeutic effect is unknown, but it is a nondopaminergic option for the treatment of “off” episodes. While it has shown a reduction in daily “off” times relative to placebo, more studies are needed to elucidate its risk versus benefit profile compared to other available adjunctive options.

SUGGESTED UTILIZATION MANAGEMENT Anticipated Therapeutic Class Review Parkinson’s Disease (TCR) Placement Clinical Edit Initial Approval Criteria: ▪ Patient age ≥ 18 years old; AND ▪ Documented diagnosis of Parkinson’s disease (PD); AND ▪ Patient is experiencing “off” episodes of PD at least 2 hours/day on average; AND ▪ Patient must be on a concomitant stable levodopa-based therapy regimen; AND ▪ Patient has tried and failed adequate adjunctive therapies (e.g., dopamine agonists, monoamine oxidase-B [MOA-B] inhibitors, catechol-O-methyltransferase [COMT] inhibitors) to control “off” symptoms; AND ▪ Patient is monitored for tobacco smoking and the dose adjusted accordingly (40 mg once daily); AND ▪ Patient does NOT have a major psychotic disorder; AND ▪ Patient is NOT pregnant AND is using proper contraception; AND ▪ Patient does NOT have severe hepatic impairment (Child-Pugh C); AND ▪ Patient does NOT have end stage renal disease (ESRD) (estimated creatinine clearance (CrCL) by Cockcroft-Gault equation: <15 mL/min) OR ESRD requiring hemodialysis; AND ▪ Patient on strong CYP3A4 inhibitors will be on a maximum dosage of 20 mg once daily; AND ▪ Patient will avoid concomitant use with strong CYP3A4 inducers (e.g., rifampin, etc.) Renewal Criteria: ▪ Patient continues to meet the above initial criteria; AND ▪ Absence of unacceptable toxicity or treatment related adverse event from the drug (e.g., dyskinesias exacerbation, hallucinations/psychotic behavior, impulse control/compulsive behaviors); AND ▪ Patient has clinically meaningful response to treatment (e.g., patient shows a reductions in time of “off” episodes.) Quantity Limit 30 tablets/30 days Duration of Approval Initial and renewal: 12 months Drug to Disease Hard Edit None

REFERENCES

1 Nourianz [package insert]. Bedminster, NJ, Kyowa Kirin; August 2019. 2 Nourianz [package insert]. Bedminster, NJ, Kyowa Kirin; August 2019. 3 Study 1. NCT00456586. Available at https://clinicaltrials.gov/ct2/show/NCT00456586?term=NCT00456586&rank=1. Accessed September 25, 2019. 4 Study 2. NCT00199407. Available at https://clinicaltrials.gov/ct2/show/NCT00199407?term=NCT00199407&rank=1. Accessed September 25, 2019. 5 Study 3. NCT00455507. Available at https://clinicaltrials.gov/ct2/show/NCT00455507?term=NCT00455507&rank=1. Accessed September 25, 2019. 6 Study 3. NCT00955526. Available at https://clinicaltrials.gov/ct2/show/NCT00955526?term=NCT00955526&rank=1. Accessed September 25, 2019. 7 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. DOI: 10.1002/ana.21315. 8 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. DOI: 10.1002/mds.22095. 9 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): 1437-1443. DOI: 10.1002/mds.23107. 10 Mizuno Y, Kondo T. Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson’s disease. Mov Disord. 2013; 28(8): 1138– 1141. DOI: 10.1002/mds.25418 11 Clinical Pharmacology. Available at: https://www.clinicalkey.com/pharmacology/. Accessed September 25, 2019. 12 National Institutes of Health. Parkinson’s disease. Fact Sheet. Available at: https://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=109. Accessed September 25, 2019. 13 American Academy of Neurology. Guidelines under development. Available at: https://www.aan.com/policy-and-guidelines/guidelines/guidelines- under-development/. Accessed September 25, 2019. 14 Stacy M, Bowron A, Guttman M, et al. Identification of motor and nonmotor wearing-off in Parkinson's disease: comparison of a patient questionnaire versus a clinician assessment. Mov Disord. 2005; 20(6): 726-733. DOI: 10.1002/mds.20383. 15 Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and Movement Disorder Society Evidence-Based Medicine Review: Updates on treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2018;33(8):1248-1266. DOI: 10.1002/mds.27372. Available at: https://www.movementdisorders.org/MDS-Files1/Resources/PDFs/TreatmentsforMotorSymptomsofPD-2018.pdf. Accessed November 6, 2019.