1. © 2013 Direct One Communications, Inc. All rights reserved. 1 Pharmacotherapy of Medically Refractory Partial-Onset Epilepsy Cynthia M. Correll, MD Emory University School of Medicine, Atlanta, Georgia A REPORT FROM THE 66 th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY

2. © 2013 Direct One Communications, Inc. All rights reserved. 2 Eslicarbazepine Acetate in Patients Refractory to Carbamazepine

3. © 2013 Direct One Communications, Inc. All rights reserved. 3 Eslicarbazepine Acetate in Patients Refractory to Carbamazepine: Background and Rationale Eslicarbazepine acetate is a once-daily antiepileptic drug (AED) approved in Europe as adjunctive therapy in adults with partial-onset seizures. 1 Chemically related to carbamazepine Mechanism of action on voltage-gated sodium channels differs from that of carbamazepine 2 May be effective and tolerable when carbamazepine fails to control seizures completely

4. © 2013 Direct One Communications, Inc. All rights reserved. 4 Eslicarbazepine Acetate in Patients Refractory to Carbamazepine: Study Population and Methods Gil-Nagel et al 3 evaluated the effects of adjunctive eslicarbazepine acetate therapy on seizure frequency and treatment-emergent adverse events (TEAEs) in patients inadequately controlled with other AEDs, including carbamazepine. Patients were pooled from two phase III multicenter studies. Must have had four or more documented partial- onset seizures over 4 weeks while using 1–3 AEDs Randomized to 400, 800, or 1,200 mg/d of the drug or placebo and followed for a 12-week maintenance period and a 4-week tapering period

5. © 2013 Direct One Communications, Inc. All rights reserved. 5 Eslicarbazepine Acetate in Patients Refractory to Carbamazepine: Results Compared with placebo, 800 and 1,200 mg/d of eslicarbazepine acetate led to a significant reduction in seizure frequency in patients, including those taking carbamazepine. The frequency of TEAEs and TEAEs leading to drug discontinuation increased with the dose of eslicarbazepine acetate administered, especially among patients taking > 800 mg/d of carbamazepine concomitantly. Most frequent TEAEs observed with eslicarbazepine acetate: dizziness, diplopia, headache, somnolence, and nausea

6. © 2013 Direct One Communications, Inc. All rights reserved. 6 Eslicarbazepine Acetate in Patients With Symptoms of Mental Depression

7. © 2013 Direct One Communications, Inc. All rights reserved. 7 Eslicarbazepine Acetate in Patients With Mental Depression: Background and Rationale Depression and depressive symptoms are frequent comorbidities associated with epilepsy correlated with poor seizure control and increased AED side effects. 4–6 When given adjunctively to control partial-onset seizures in patients with epilepsy, eslicarbazepine acetate improved depressive symptoms during open- label extensions of two phase III multicenter trials. 7,8

8. © 2013 Direct One Communications, Inc. All rights reserved. 8 Eslicarbazepine Acetate in Patients With Mental Depression: Study Population and Methods Carreno et al 9 studied the efficacy and tolerability of eslicarbazepine acetate given for partial-onset seizures and depressive symptoms. Patients culled from two phase III multicenter studies who had four or more documented partial- onset seizures over 4 weeks Randomized to receive 400, 800, or 1,200 mg/d of eslicarbazepine acetate or placebo Analyzed over a 12-week maintenance period based on scores  10 or < 10 on the Montgomery-Asberg Depression Rating Scale (MADRS), respectively

9. © 2013 Direct One Communications, Inc. All rights reserved. 9 Eslicarbazepine Acetate in Patients With Mental Depression: Results Frequency of seizures was significantly less in patients with MADRS scores  10 and < 10 who received 800 or 1,200 mg/d of eslicarbazepine acetate. The reduction in seizure frequency was significantly greater in patients with a MADRS score < 10 compared wityh those having a MADRS score  10. The statistical significance of this difference was not discussed. Dose-dependent increases in TEAEs during eslicarbazepine acetate therapy were similar among patients with and without depressive symptoms.

10. © 2013 Direct One Communications, Inc. All rights reserved. 10 Perampanel as Adjunctive Therapy for Partial-Onset Seizures in Patients with Epilepsy

11. © 2013 Direct One Communications, Inc. All rights reserved. 11 Perampanel as Adjunctive Therapy for Partial-Onset Seizures: Background and Study Population Perampanel, a novel AED that specifically targets α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, was recently approved for use in both Europe and the United States as adjunctive therapy for partial-onset seizures, with or without secondarily generalized seizures, in patients  12 years of age The approval was based largely on safety and efficacy data that emerged from three global, placebo- controlled, double-blind phase III trials of adjunctive perampanel therapy in 1,478 patients with epilepsy. 10–14

12. © 2013 Direct One Communications, Inc. All rights reserved. 12 Perampanel as Adjunctive Therapy for Partial-Onset Seizures: Background and Study Population At the 66 th Annual Meeting of the American Epilepsy Society, Montouris et al 15 reported on the frequency of seizures, TEAEs, and serious adverse events (SAEs) in 1,218 of these patients who participated in an open-label extension trial.

13. © 2013 Direct One Communications, Inc. All rights reserved. 13 Perampanel as Adjunctive Therapy for Partial-Onset Seizures: Methods During the 23-week double-blind registration trials, patients were randomly assigned to 2, 4, 8, or 12 mg/d of perampanel or placebo. During the extension trial, all patients completed a 16-week blinded conversion period wherein the perampanel dosage was titrated from 2 to 12 mg once daily. The mean dose during the extension period was 10.2  2.3 mg. 71.6% of the patients remained in the study up to the cutoff date (week 52).

14. © 2013 Direct One Communications, Inc. All rights reserved. 14 Perampanel as Adjunctive Therapy for Partial-Onset Seizures: Results Before the extension trial, the median percent seizure reduction was 18.6% for patients receiving placebo and 31.7% for those taking perampanel. After conversion/titration of the perampanel dosage, a similar median percent seizure frequency reduction was seen in both groups of patients. Reductions in seizure frequency were maintained over 52 weeks.

15. © 2013 Direct One Communications, Inc. All rights reserved. 15 Perampanel as Adjunctive Therapy for Partial-Onset Seizures: Results The incidence of TEAEs and SAEs during the extension trial were not significantly different between the two groups. The withdrawal rate due to adverse events during the extension period was about 10% in both patients taking perampanel and those receiving placebo and did not differ significantly between the two groups. The most common TEAEs reported among patients taking perampanel were dizziness, somnolence, fatigue, and headache.

16. © 2013 Direct One Communications, Inc. All rights reserved. 16 Pregabalin as Monotherapy for Partial-Onset Seizures

17. © 2013 Direct One Communications, Inc. All rights reserved. 17 Pregabalin as Monotherapy for Partial-Onset Seizures: Methods Yurkewicz et al 16 evaluated the safety and efficacy of pregabalin monotherapy in an open-label extension study that followed a 20-week, randomized, double- blind, controlled study. 73 patients with partial-onset seizures transitioned from 150–600 mg/d to 300 mg/d over 7 days and continued on pregabalin alone for 24 weeks, allowing adjustments of 150–600 mg/d. 58 patients (79.5%) completed 24 weeks of pregabalin monotherapy (mean duration, 174 days; median average dose, 473.7 mg/d).

18. © 2013 Direct One Communications, Inc. All rights reserved. 18 Pregabalin as Monotherapy for Partial-Onset Seizures: Results 80% of patients completed 6 months of pregabalin monotherapy. 10 patients (13.7%) were seizure-free throughout the open-label study. 31 patients (42.5%) had a TEAE, most commonly headache, nausea, arthralgia, and weight gain. Four patients discontinued pregabalin monotherapy due to adverse events and five others for insufficient clinical response. The side-effect profile of pregabalin was similar to those of previous trials evaluating this medication.

19. © 2013 Direct One Communications, Inc. All rights reserved. 19 Adjunctive Lacosamide Therapy in the Elderly

20. © 2013 Direct One Communications, Inc. All rights reserved. 20 Adjunctive Lacosamide Therapy in the Elderly: Study Population and Methods Rosenfeld et al 17 studied the long-term safety and efficacy of lacosamide 18,19 in elderly patients with partial-onset seizures. Patients were enrolled in three open-label extension trials lasting up to 8 years. 20–23 33 of 1,054 patients were  65 years of age by the end of the trial. » 21 (63.6%) completed the open-label extension trial. » 18 (85.7%) continued on lacosamide after the trial ended.

21. © 2013 Direct One Communications, Inc. All rights reserved. 21 Adjunctive Lacosamide Therapy in the Elderly: Results 90.9%, 75.8%, and 42.4% of the 33 elderly patients continued taking lacosamide for more than 1, 3, and 5 years, respectively. Median percent reduction from baseline seizure frequency was 63%, 58%, and 67%, respectively. Dizziness, falls, contusion, sinusitis, cognitive disorder, tremor, headaches, depression, and cough were the most frequent TEAEs. Four patients (12.1%) withdrew due to TEAEs. No new types of TEAEs were reported over prolonged treatment.

22. © 2013 Direct One Communications, Inc. All rights reserved. 22 Converting from Immediate- to Extended-Release Lamotrigine

23. © 2013 Direct One Communications, Inc. All rights reserved. 23 Converting from Immediate- to Extended-Release Lamotrigine: Study Population and Methods Osborn et al 24 analyzed data on 55 patients converted from immediate-release lamotrigine to an extended-release form over 2 years. 19 patients converted to the same dose of extended- release lamotrigine, 21 converted to a higher dose, and 7 converted to a lower dose. A significant reduction in seizure frequency (46%) occurred after conversion to the extended-release form. Seven patients reported improvement in adverse effects after conversion to the extended-release form.

24. © 2013 Direct One Communications, Inc. All rights reserved. 24 Rufinamide Usage Patterns

25. © 2013 Direct One Communications, Inc. All rights reserved. 25 Rufinamide Usage Patterns: Study Population and Methods Silva et al 25 evaluated usage and dosing patterns of rufinamide among commercially insured patients using medical and pharmacy claims data from 2008 until 2011. Data were gathered on 495 patients (mean age, 16.9) initiating rufinamide therapy who had  6 months of pre- and post-enrollment date information. Examined were demographics (age, gender), clinical characteristics (comorbid illnesses, concomitant AEDs), persistence (time to rufinamide discontinuation), and rufinamide dose ratio (observed modal dose/calculated ideal dose)

26. © 2013 Direct One Communications, Inc. All rights reserved. 26 Rufinamide Usage Patterns: Results Clinical use of rufinamide was most common among patients already on a combination of three or more AEDs. Many patients (62%) did not reach 75% of the recommended daily dose of 45 mg/kg or the maximum dose of 3,200 mg/d of rufinamide. Since patients who took longer to reach their modal dose were less likely to discontinue therapy, slower titration may be more tolerable.

27. © 2013 Direct One Communications, Inc. All rights reserved. 27 Combining AEDs Based on Mechanism of Action

28. © 2013 Direct One Communications, Inc. All rights reserved. 28 Combining AEDs Based on Mechanism of Action: Methods Wang et al 26 analyzed duration of treatment and hospital or emergency room (ER) visits with AED combination regimens in a cross-sectional, retrospective analysis of medical and pharmacy claims from 2004 to 2011. Patients > 18 years of age who had a second AED added on at the index date were followed for at least 12 months. Patients (n = 8,165) used sodium-channel blockers,  -aminobutyric acid (GABA) analogs, a synaptic vesicle protein 2A binding (SV2) agent, and drugs with multiple mechanisms of action.

29. © 2013 Direct One Communications, Inc. All rights reserved. 29 Combining AEDs Based on Mechanism of Action: Results Patients using a sodium-channel blocker/SV2 agent had the longest mean treatment duration; those using a GABA analog/GABA analog had the shortest. Use of a sodium-channel blocker/SV2 agent wassignificantly less likely to lead to discontinuation; use of a GABA analog/GABA analog or GABA analog/drug with multiple mechanisms was more likely to be discontinued. Use of a sodium-channel blocker/SV2 agent led to lowest percentage requiring ER or hospital visits; use of a GABA analog/GABA analog led to highest.

30. © 2013 Direct One Communications, Inc. All rights reserved. 30 Combining AEDs Based on Mechanism of Action: Results Use of a GABA analog plus any AED led to significantly less likelihood of hospitalization when compared with a GABA analog/GABA analog. Use of a sodium-channel blocker with any other type of AED was significantly less likely to lead to ER visits when compared with a combination of a sodium-channel blocker with another sodium- channel blocker.

31. © 2013 Direct One Communications, Inc. All rights reserved. 31 Adherence to Antiepileptic Medication

32. © 2013 Direct One Communications, Inc. All rights reserved. 32 Adherence to Antiepileptic Medication: Study Population and Methods Economos et al 27 performed a critical review of adherence to antiepileptic regimens using a literature review of published databases. Reviewed 24 studies citing nonadherence rates of 25%–79% Factors affecting nonadherence included population demographics, medication side effects, medication dosing schedules, and number of medications used.

33. © 2013 Direct One Communications, Inc. All rights reserved. 33 Adherence to Antiepileptic Medication: Results Adherence to antiepileptic medication was worse among the elderly and adolescents. Children showed better adherence if they came from a higher socioeconomic background or if their parents were married. 28–33 Newer AEDs were associated with better compliance, presumably due to their better side-effect profiles. 34 Less frequent dosing was also associated with increased medication adherence. 35

34. © 2013 Direct One Communications, Inc. All rights reserved. 34 Adherence to Antiepileptic Medication: Results Conflicting reports on whether monotherapy or polytherapy led to better adherence left this issue unsettled. 35–37 A more tailored approach to prescribing AEDs may improve adherence. 38

35. © 2013 Direct One Communications, Inc. All rights reserved. 35 References 1.European Medicines Agency. Zebenix (eslicarbazepine acetate): summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/000988 /WC500047225.pdf. Accessed December 28, 2012. 2.Soares-da-Silva P, Hebeisen S. Slow and fast inactivation of voltage-gated sodium channels by eslicarbazepine and carbamazepine. Epilepsia. 2012; 53(suppl 5):54. 3.Gil-Nagel A, Trinka E, Chaves J, et al. A post- hoc exploratory analysis of the effect of eslicarbazepine acetate as adjunctive treatment in adult patients with partial-onset seizures refractory to carbamazepine. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster 3.228. 4.Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007;75:192–196. 5.Petrovski S, Szoecke CEI, Jones NC, et al. Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients. Neurology. 2010; 75:1015–1021. 6.Kanner AM, Barry JJ, Gilliam F, Hermann B, Meador KF. Depressive and anxiety disorders in epilepsy: do they differ in their potential to worsen common AED-related adverse events? Epilepsia. 2012;53:1104–1108. 7.Halasz P, Cramer JAM, Hodoba D, et al. Longer term efficacy and safety of eslicarbazepine acetate: results of a 1-year open-label extension study in partial-onset seizures in adults with epilepsy. Epilepsia. 2010; 51:1963–1969. 8.Hufnagel A, Ben-Menachem E, Gabbai AA, et al. Long term safety and efficacy of eslicarbazepine acetate as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy: results of a 1-year open- label extension study. Epilepsy Res. 2012. Epub ahead of print. 9.Carreno M, Ben-Menachem E, O’Brien TJ, et al. A post-hoc exploratory analysis of the effect of eslicarbazepine acetate as adjunctive treatment in adult patients with partial-onset seizures and comorbid clinically relevant depressive symptoms. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster 3.229.

36. © 2013 Direct One Communications, Inc. All rights reserved. 36 References 10.Fycompa [package insert]. Woodcliff Lake, NJ: Eisai, Inc; 2012. 11.Fycompa [package insert]. Hatfield, England: Eisai Europe Ltd; 2012. 12.French J. Global phase III trial of perampanel, a selective, non-competitive AMPA receptor antagonist, as adjunctive therapy in patients with refractory partial-onset seizures. Presented at the 63rd Annual Meeting of the American Academy of Neurology; April 9–16, 2011; Honolulu, HI. Abstract LBS 002. 13.Loring DW, Lowenstein DH, Barbaro NM, et al. Common data elements in epilepsy research: development and implementation of the NINDS epilepsy CDE project. Epilepsia. 2011;52:1186–1191. 14.Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78:1408–1415. 15.Montouris G, Yang H, Williams B, Zhou S, Laurenza A, Fain R. Efficacy and safety of perampanel in patients with treatment-resistant partial-onset seizures after conversion from double-blind placebo to open-label perampanel. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster 3.241. 16.Yurkewicz L, Kwan P, Fakhoury R, Pitman V, Knapp L. Long-term safety and efficacy of pregabalin monotherapy in patients with partial onset seizures: an open-label, extension study. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster 3.237. 17.Rosenfeld W, McShea C, Doty P. Evaluation of long-term treatment with lacosamide for partial-onset seizures in the elderly. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster 3.234. 18.European Medicines Agency. Vimpat (lacosamide): summary of product characteristics for lacosamide. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000863/WC500050338.pdf. May 22, 2012. Accessed December 28, 2012. 19.Vimpat [package insert]. Smyrna, GA:UCB, Inc; 2008.

37. © 2013 Direct One Communications, Inc. All rights reserved. 37 References 20.Rosenfeld W, Fountain N, Kaubrys G, et al. Lacosamide: long-term safety and efficacy in partial-onset seizures. Presented at the 29th International Epilepsy Congress, August 28–September 1, 2011; Rome, Italy. 21.Husain A, Chung S, Faught E, et al. Long-term safety and efficacy in patients with uncontrolled partial- onset seizures treated with adjunctive lacosamide: results from a phase III open-label extension trial. Epilepsia. 2012; 53:521–528. 22.Rosenow F, Kelemen A, Ben-Menachem E, et al. Long-term adjunctive lacosamide in patients with uncontrolled partial-onset seizures: results from the SP774 phase III open-label extension trial. Presented at the 29th International Epilepsy Congress, August 28–September 1, 2011; Rome, Italy. 23.Rosenfeld W, Husain A, Rosenow F, McShea C, Isojarvi J, Doty P. Evaluation of long-term treatment with lacosamide for partial-onset seizures: a pooled analysis of open-label extension trials, Presented at the 65th Annual Meeting of the American Epilepsy Society; December 2–6, 2011; Baltimore, MD. Abstract 3.233. 24.Osborn MR, Ramey P, Abou-Khalil B. Benefits of conversion from immediate release lamotrigine to extended release lamotrigine in individuals with drug-resistant epilepsy or adverse effects. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster 3.255. 25.Silva E, Margolis JM, Wang Z, Copher R, Labiner D. Rufinamide dosing patterns in commercially-insured pediatric and adult patients. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster 3.242. 26.Wang Z, Margolis JM, Copher R, Cavazos JE. Comparison of treatment duration of AED combination therapies base on mechanism of action in partial onset seizures. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster 3.248. 27.Economos A, Cheng J, Carrazana E. AEDs and adherence: a critical review. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster 3.262.

38. © 2013 Direct One Communications, Inc. All rights reserved. 38 References 28.Sander JW. The use of AEDs—principles and practice. Epilepsia. 2004(suppl 6);45:28–34. 29.Ettinger AB, Bater GA. Best clinical and research practice in epilepsy of old people: focus on AED adherence. Epilepsy Behav. 2009;15:S60–S63. 30.Zeber JE, Copeland LA, Pugh MJV. Variation in AED adherence among older patients with new-onset epilepsy. Ann Pharmacother. 2010;44:1896–1904. 31.Modi AC, Rausch JR, Glauser RA. Patterns of nonadherence to AED therapy in children with newly diagnosed epilepsy. JAMA. 2011; 305:1669–1676. 32.Kyngas H. Compliance with health regimens of adolescents with epilepsy. Seizure. 2000;9:598–604. 33.Michaud PA, Suris JC, Viner R. The Adolescent With a Chronic Condition: Epidemiology, Developmental Issues, and Health Care Provision. Geneva: World Health Organization, Department of Child and Adolescent Health and Development; 2007. http://whqlibdoc.who.int/publications/2007/9789241595704_eng.pdf. Accessed December 28, 2012. 34.Beghi, E, Beghi M, Cornaggia DM. The use of recently approved AEDs: use with caution, use in refractory patients or use as first-line indications? Expert Rev Neurother. 2011;11:1759–1767. 35.Reyna MD, Medina MT, Nicolas O et al. Adherence and complementary and alternative medicine use among Honduran people with epilepsy. Epilepsy Behav. 2009;14:645–650. 36.Carpay JA, Aldenkamp AP, Von Donselaar CA. Complaints associated with the use of AEDs: results from a community-based study. Seizure. 2005;14:198–206. 37.Buck D, Jacoby A, Baker GA, Chadwick DW. Factors influencing compliance with AED regimes. Seizure. 1997;6:87–93. 38.Al-Ageel S, Al-Sabhan J. Strategies for improving adherence to AED treatment in patients with epilepsy. Cochrane Database Syst Rev. 2011;(1):CD008312.