© 2016 Direct One Communications, Inc. All rights reserved. 1 Recent Research Expands Our Understanding of Perampanel Christian M. Cabrera Kang, MD Emory University School of Medicine, Atlanta, Georgia A REPORT FROM THE 69 th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY

© 2016 Direct One Communications, Inc. All rights reserved. 2 Mechanism of Action and Indications Perampanel is a novel selective, noncompetitive antagonist of the  -amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) glutamate receptor. It was originally approved by the FDA in October 2012 for adjunctive treatment of partial-onset epilepsy, with or without secondarily generalized seizures, in patients  12 years of age. In June 2015, perampanel was also approved for adjunctive treatment of primary generalized tonic- clonic seizures (PGTCS) in the same age group.

© 2016 Direct One Communications, Inc. All rights reserved. 3 Effect of Baseline Seizure Frequency Patients with partial epilepsy who had  7.5 seizures over 6 weeks prior to treatment with perampanel (4–12 mg/d) experienced a greater reduction in seizure frequency than did those with more frequent seizures before being treated with perampanel. Williams B et al. AES 2015, Poster 1.188

© 2016 Direct One Communications, Inc. All rights reserved. 4 Effect of Baseline Seizure Frequency continued Likewise, patients with partial epilepsy who had  7.5 seizures prior to treatment with perampanel had higher responder rates (50% or greater reduction in seizure frequency) to perampanel than those who had more frequent seizures. Williams B et al. AES 2015, Poster 1.188

© 2016 Direct One Communications, Inc. All rights reserved. 5 Combination Antiepileptic Therapy Treatment with perampanel plus only one other antiepileptic drug (AED) produced a greater reduction in frequency of PGTCS (87.6%) than did using perampanel with two (64.1%) or three (66.6%) other AEDs, as would be expected if it is assumed that patients using one AED are less refractory to pharmacotherapy. None of the five most common AEDs used to treat PGTCS—valproic acid, lamotrigine, levetiracetam, topiramate, and zonisamide—was more effective than another when given together with perampanel. Kirmani B et al. AES 2015, Poster 1.191

© 2016 Direct One Communications, Inc. All rights reserved. 6 Duration of Partial Epilepsy Patients with uncontrolled partial seizures who were diagnosed  20 years ago were more likely to respond to therapeutic doses of perampanel (8–12 mg/d) than those who had a longer history of epilepsy. Halford J et al. AES 2015, Poster 1.193

© 2016 Direct One Communications, Inc. All rights reserved. 7 Long-term Efficacy and Safety In all, 1,217 patients patients with drug-resistant partial seizures were included in the open-label extension trial; 681 of these were treated with perampanel for  2 years. The majority of patients who were  75% responders (71.2%) or who were free of seizures (78.7%) were taking 12 mg/d of perampanel. More than half of the 47 patients achieving seizure- freedom did so within 26 weeks of beginning therapy. The rate and type of treatment-emergent adverse events (10% overall) in these groups were similar to those in the entire study population. Yang H et al. AES 2015, Poster 1.196

© 2016 Direct One Communications, Inc. All rights reserved. 8 Perampanel in Generalized Seizures Patients with secondarily generalized seizures (SGS) or PGTCS given 8 mg/d of perampanel experienced a significant reduction in monthly seizure frequency when compared with those taking placebo (–65.5% vs –24.6%, respectively; P < ) and higher 50% and 75% responder rates, irrespective of the number of concomitant AEDs being used. Generalized seizure freedom rates were 26.9% with perampanel therapy versus 12.6% with placebo. Treatment-emergent adverse effects were experienced by 79% of patients taking perampanel and 67.5% of the placebo group. O’Brien T et al. AES 2015, Poster 2.250

© 2016 Direct One Communications, Inc. All rights reserved. 9 Adolescents With Partial Seizures Fifty-three adolescents with inadequately controlled partial seizures exposed to perampanel for  52 weeks experienced a 50% responder rate (66%) and a median reduction in seizure frequency of –74.1% within 40–52 weeks. Treatment-related adverse events were observed in 70.2% of patients and led to discontinuation in 6.1%. Dizziness, somnolence, and aggression were the most common adverse events. No clinically important changes in mean laboratory values were seen during the study. Villanueva V et al. AES 2015, Poster 2.263

© 2016 Direct One Communications, Inc. All rights reserved. 10 Asians and Pacific Islanders Treatment with 8 or 12 mg/d of perampanel of Asian and Pacific Islander patients with uncontrolled partial seizures led to a significant reduction in seizure frequency and higher 50% responder rate compared with placebo. Patients with SGS seemed to have a greater response with a higher seizure-freedom rate than did the partial-seizure group, with or without SGS. Dizziness, somnolence, and headache were the most frequently reported adverse events, and their frequency seemed to increase with escalation in the dose of perampanel. Nishida T et al. AES 2015, Poster 3.256

© 2016 Direct One Communications, Inc. All rights reserved. 11 Psychiatric and Behavioral Events Psychiatric and behavioral adverse events were seen in 24.7% of 163 patients with PGTCS taking perampanel and 19.5% of those on placebo. Most of these events were mild to moderate in severity. Dobrinsky C et al. AES 2015, Poster 1.190

© 2016 Direct One Communications, Inc. All rights reserved. 12 Falls In all, 163 patients with inadequately controlled PGTCS who were taking one to three concomitant AEDs were randomized to receive perampanel (maximum dose, 8 mg/d) or placebo. The titration period lasted for 4 weeks, and maintenance therapy lasted for 13 weeks. Nonseizure-related falls occurred in one placebo- treated and two perampanel-treated subjects. Most of the falls occurred during the maintenance period; none of them led to removal of the patient from the study. Leppik IE et al. AES 2015, Poster 1.194

© 2016 Direct One Communications, Inc. All rights reserved. 13 Laboratory Abnormalities In the same study, no clinically relevant changes in mean laboratory values from baseline to the end of the treatment period were found in patients with PGTCS taking perampanel or placebo. The data did not suggest a need for routine clinical laboratory monitoring. McElveen WA et al. AES 2015, Poster 1.195

© 2016 Direct One Communications, Inc. All rights reserved. 14 Long-Term Cognitive Effects Perampanel therapy had no significant long-term (up to 52 weeks) cognitive effects in 114 adolescents with partial seizures. Only power of attention, one of the five domains of the Cognitive Drug Research System, was impaired—and then only very mildly. Fain R et al. AES 2015, Poster 3.260

© 2016 Direct One Communications, Inc. All rights reserved. 15 Growth and Development No remarkable change in height or weight from baseline was noted in 114 adolescents with uncontrolled partial seizures who were treated with up to 12 mg/d of perampanel for up to 104 weeks. A slight reduction in bone age (–2 months) was not considered to be clinically important. The majority of patients advanced by more than one Tanner stage or remained stable; changes in TSH and IGF-1 levels were not clinically important. Overall, treatment with perampanel did not seem to have a clinically meaningful effect on growth or development in adolescents. Kumar D et al. AES 2015, Poster 3.262

© 2016 Direct One Communications, Inc. All rights reserved. 16 Conclusions Overall, perampanel therapy seems to be similarly effective in patients with partial or generalized seizures when compared with other AEDs, and it offers a relatively favorable side-effect profile. Its novel mechanism of action provides another option for physicians treating patients with epilepsy. Treatment with perampanel outperformed the use of placebo in terms of decreasing seizure frequency, increasing the responder rate, and showing greater efficacy in patients with less-refractory epilepsy. Among adolescents with partial seizures, efficacy was directly related to length of perampanel exposure.

© 2016 Direct One Communications, Inc. All rights reserved. 17 Conclusions continued The drug appears to be more effective in patients who have: » A lower frequency of partial seizures at baseline; » PGTCS and were taking fewer concomitant AEDs; » Been diagnosed with partial epilepsy shortly before treatment began; and » Treatment-responsive partial seizures. Dizziness, somnolence, and aggression observed in adolescents had no apparent relationship to dose. Asian/Pacific Islanders with SGS seemed to have a greater response rate and higher freedom from seizures than other patients with partial seizures.

© 2016 Direct One Communications, Inc. All rights reserved. 18 Conclusions continued In Asian/Pacific Islanders with partial seizures, dizziness, somnolence, and headache were directly related to dose escalation. Psychiatric and behavioral events occurred in one fourth of patients with PGTCS taking perampanel; most were mild to moderate in severity. Laboratory abnormalities, including elevated ALT and cholesterol/triglyceride levels, were clinically insignificant in patients with PGTCS. Perampanel had no clinically meaningful effect on growth or development in adolescents with partial seizures.