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CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202834Orig1s000 MEDICAL REVIEW(S) Safety Team Leader Memo NDA 202834 Review and Evaluation of Clinical Data Safety Team Leader Memorandum ________________________________________________________________ NDA: 202834 Drug: Perampanel (FYCOMPA) Route: Oral Indication: Adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization Sponsor: Eisai, Inc. Submission Date: 12/22/11 Review Date: 8/30/12 Reviewer: Sally Usdin Yasuda, Safety Team Leader Division of Neurology Products _______________________________________________________________ 1. Background Perampanel is, according to the Sponsor, a non-competitive antagonist of the AMPA glutamate receptor. The mechanism of action in epilepsy is not fully established. In addition to the clinical trials for epilepsy, clinical trials have been performed in patients with Parkinson’s disease, multiple sclerosis, migraine, and neuropathic pain. Fycompa has been approved since July 2012 in Europe for the indication proposed in this NDA. The proposed dose is 4-12 mg per day, given as a single daily dose before bedtime in patients aged 12 years and older. Treatment is to be initiated with a dose of 2 mg/day, increasing in increments of 2 mg/day at intervals no more frequently than weekly. In terms of the clinical pharmacology of perampanel, Tmax ranges from 0.5 to 4 hours. Perampanel is extensively metabolized, primarily by CYP3A followed by glucuronidation. In clinical studies, the CYP3A4 inducers carbamazepine, oxcarbazepine, and phenytoin caused large, 2-3 fold increases in perampanel clearance. Mean elimination half-life is 105 hours (based on a population PK analysis of pooled data from 19 Phase 1 studies). Renal clearance is a minor route of elimination. Steady state is typically achieved by Day 21. This memorandum primarily summarizes the findings of Dr. Mary Doi’s primary safety review of the perampanel NDA. Please refer to Dr. Doi’s review for more detail. 2. Summary of Findings from the Safety Review 2.1 Sources of Data, Exposure, and Demographics Sources of Data The NDA summarized safety data from 52 clinical trials. These include 27 Phase 1 trials (including a thorough QT study) evaluating single (0.2 to 36 mg) or multiple doses (1 to 12 mg), 10 studies performed in the primary indication of epilepsy, and 15 studies in non-epilepsy indications (Parkinson’s disease, neuropathic pain, migraine, and multiple sclerosis). The Safety analysis pools in Dr. Doi’s review were the Epilepsy Phase 3 Double-blind (DB) Pool, the Epilepsy Phase 2 DB Pool, the Epilepsy All Treated Pool (DB studies and open label extensions); the Nonepilepsy All Treated Pool 1 Reference ID: 3197631 Safety Team Leader Memo NDA 202834 and the Nonepilepsy DB Pool; and the Phase 1 Pool (pooled into single dose studies and multiple dose studies; n=916)). The Epilepsy Phase 3 DB trials (Studies 304, 305, and 306) were randomized, double- blind, placebo-controlled, dose-escalation, parallel-group studies to evaluate the efficacy and safety of perampanel given as adjunctive therapy in subjects with refractory partial seizures aged 12 years and older1. As described in Dr. Doi’s review, the three phases of the studies were the pre-randomization, double-blind (with 6 week titration period followed by a 13 week maintenance period) and follow-up phases. Subjects could be on stable doses of up to 3 approved antiepileptic drugs (AEDs); only 1 inducer AED (defined as carbamazepine, phenytoin, phenobarbital, or primidone) was allowed. Concomitant use of vigabatrin was excluded. Dose was not stratified by concomitant use of enzyme inducing AEDs. The maintenance doses in Studies 304 and 305 were 8- 12 mg/day and in Study 306 they were 2-8 mg/day. During the titration period in each study, doses were increased in 2 mg increments (beginning with a 2 mg dose) on a weekly basis until the randomly assigned dose was attained. Down-titration was permitted for subjects experiencing intolerable adverse events (AEs) anytime during the double-blind phase. Following the DB studies, approximately 86% of placebo subjects and 81% of perampanel subjects subsequently enrolled in the open label extension (OLE) Study 307. In Study 307 subjects were titrated to 12 mg/day or the maximum tolerated dose (MTD) and remained on that dose unless further titration was necessary for efficacy or tolerability; in this study concomitant AEDs and doses could be changed at the discretion of the investigator. In the Epilepsy Phase 2 DB pool, Study 203 evaluated doses of 1 and 2 mg/day, Study 206 evaluated doses of 4 mg/day (or the MTD) in 101 subjects, and Study 208 evaluated doses of 12 mg/day (or the MTD) in 38 subjects. Approximately 70% of the placebo group and 68% of the perampanel group of Study 206/208 subsequently enrolled in OLE Study 207. The Nonepilepsy DB pool included safety data from six Phase 2 and Phase 3 studies in Parkinson’s disease, evaluating doses of ≤4mg/day (n=1462) except for Study 214 that evaluated doses of > 4 mg-8 mg (n=55). It also included the Neuropathic Pain DB pool with doses of > 4-8 mg/day (n= 236) and ≤4mg/day (n=141), and the Multiple Sclerosis and Migraine in DB studies that contributed 119 subjects to < 4 mg/day. The Nonepilepsy all-treated pool (n=2717) also included the OLE studies for Parkinson’s disease and Neuropathic Pain. Exposure According to Dr. Doi’s review, as of the 120 day Safety Update cutoff date 1651 subjects with epilepsy had received perampanel in the Phase 2 and 3 DB, placebo controlled trials and in the open-label extension studies. A total of 1231 subjects were exposed for at least 6 months and 996 subjects were exposed for at least 1 year. Dr. Doi notes that even after restricting the epilepsy population to subjects who received SSites in Bulgaria, China, France, Germany, India, Lithuania, the Netherlands, and Portugal only enrolled subjects 18 years of age and older. 2 Reference ID: 3197631 Safety Team Leader Memo NDA 202834 maximum daily doses at or above the proposed lowest dose for marketing (4 mg), the total number of subjects was 1573. She also notes that in the Epilepsy All Treated Pool, mean duration of exposure for the highest modal dose group (> 8 to 12 mg) was 89.1 weeks, and that 739 of the 952 subjects in this dose group were treated for over 51 weeks. Thus the Sponsor has met the ICH guidance recommendations of 1500 total, 300 for 6 months, and 100 for 1 year for the Epilepsy pools alone. A total of 104 pediatric subjects (12 to ≤ 16 years old) were exposed to perampanel, all in the epilepsy Phase 3 trials, with 82 subjects exposed for greater than 6 months and 65 subjects exposed for greater than 1 year. The Sponsor recently initiated Study 235, a randomized, DB, placebo controlled study of the effects of adjunctive therapy with perampanel on cognition, growth, safety, tolerability, and PK in adolescents (12 to < 18 y.o). As of October 1, 0211, 39 subjects had been enrolled in Study 235, with an enrollment goal of 132 subjects. Dr. Doi notes that fewer subjects completed the trial in the higher dose groups in the Epilepsy Phase 3 DB Pool (discussed in more detail in section 2.3.3 of this memo under Dropouts). In addition, she notes that subjects assigned in the higher dose groups were more likely to be unable to reach and maintain the randomized dose, with the target dose being the last dose taken by 98.3%, 93.6%, 81%, and 61.2% of subjects in the 2mg, 4mg, 8mg, and 12 mg dose groups, respectively. Of those randomized to the 12 mg group, 72.5% (n=185) reach the assigned dose, although 24.3% of those subjects later down-titrated or discontinued (twice the placebo rate of 11.3%). Of those randomized to the 8 mg group, 96% (n=414) reached the assigned dose, although 25.1% later down-titrated or discontinued. In the 2mg and 4 mg dose groups, 99% and 98%, respectively, reached their assigned doses and subjects in those groups down- titrated or discontinued at rates similar to placebo. Fewer subjects receiving non- enzyme inducing AEDs reached and maintained doses of 8-12 mg for the entire double- blind treatment phase when compared to subjects receiving enzyme-inducing AEDs. She also notes a lower mean duration of exposure in the ≥ 65 years age category compared to ≤17 to < 65 years or < 17 years in the 12 mg group. In the Phase 2 DB pool, subjects randomized to the >8-12 mg dose group were taking lower doses (median 6 mg, mean 7.5 mg). Dr. Doi notes that these subjects will likely not have the same AE profile as Phase 3 subjects in the highest dose group, and she shows (Table 32, p. 170 of her review) that the risk of discontinuation due to AEs was lower in the Phase 2 DB Pool than the Phase 3 DB pool at this dose. Demographics – In the Phase 3 epilepsy pool, the age range was 12 to 77 y.o. (ISS p. 69) and the mean age was 34.9 years. Approximately 47% of the pediatric patients were ages 15 and 16, while approximately 36% were ages 12 and 13. Approximately 2% of patients were 65 years or older. Forty-seven to 51% were male. Subjects were predominantly white (75%) or Asian (19%), with the mean BMI in the overweight category. Subjects were enrolled in sites worldwide, with 44% from Europe, 22% from North American, 18% from Asia-Pacific, and 11% from Central/South America. Among subjects from North America, 81.4% were white, 9.4% were black/African American, and 1.3% were Asian.