This document discusses issues related to new and generic antiepileptic drugs (AEDs). It notes that while new AEDs have been introduced, the percentage of patients with uncontrolled seizures remains around 40%. Both new "revolutionary" drugs that work via novel mechanisms and "evolutionary" drugs that improve existing ones are needed. Several new AEDs are described including retigabine, brivaracetam and eslicarbazepine. Concerns about generic AED substitution include potential differences in formulations and lack of studies on risks of switching between generics. Physician oversight is recommended when changing AED preparations.

1. New Horizons and Old Dilemmas: New AEDs and Generics Jacqueline A. French, M.D. NYU Comprehensive Epilepsy Center

2. ANTIEPILEPTIC DRUG DEVELOPMENT 1840 1860 1880 1900 1920 1940 1960 1980 2000 0 5 10 15 20 Bromide Phenobarbital Phenytoin Primidone Ethosuximide Sodium Valproate Benzodiazepines Carbamazepine Zonisamide Felbamate Gabapentin Topiramate Fosphenytoin Oxcarbazepine Tiagabine Levetiracetam Rufinamide Lacosamide Pregabalin Retigabine Brivaracetam Eslicarbazepine Clobazam ? Calendar Year Number of Licensed Antiepileptic Drugs Lamotrigine Vigabatrin

3. SINCE 1998 2000 0 5 10 20 Zonisamide Felbamate Gabapentin Topiramate Fosphenytoin Oxcarbazepine Tiagabine Levetiracetam Pregabalin Calendar Year Number of Licensed Antiepileptic Drugs Lamotrigine 1990 Rufinamide Lacosamide 2010 Vigabatrin

4. DO WE NEED MORE NEW ANTIEPILEPTIC DRUGS? Problem with current AEDs: Seizure control Newly diagnosed well treated Still 40% with therapy resistance New AEDs over last 20 years have not changed this equation! Safety/tolerability Some new (and old) AEDs still have important safety and tolerability problems

5. How do we make progress? Revolutionary Drugs Drugs that work with new mechanisms never tried before Expectation: They will control seizures that existing drugs can ’ t control Evolutionary Drugs Improve on existing drugs Expectation: We can eliminate some of the problems/side effects of good drugs, without reducing their effect on seizures

6. Compounds which are second or third generation derivatives of AEDs introduced before 1970 1 st Generation AED CarbamazepineeTegretol TM Valproic Acid Depakote TM 2 nd Generation AED Oxcarbazepine Valrocemide (SPD–493) Valnoctamide 3 rd Generation AED Eslicarbazepine Acetate (BIA 2-093) Phenobarbital T2000 Perucca et al, Lancet Neurol , 2007

7. Compounds which are second generation derivatives of AEDs introduced after 1990 Gabapentin Levetiracetam Pregabalin Brivaracetam (ucb 34714) Precursor CNS Drug Piracetam 1 st Generation AED 2 nd Generation AED Perucca et al, Lancet Neurol , 2007

8. What ’s “ new ” this year? One “Old” drug finally coming to US Frisium (clobazam) Benzodiazepine which is for chronic use Has been available in Europe and Canada for decades Studies for Lennox-Gastaut, soon to be submitted to FDA One new drug to be approved Revolutionary Potiga (Retigabine) Three drugs in late trials Evolutionary Rikelta (brivaracetam) Stedesa (eslicarbazepine) Revolutionary: Perampanel

9. Retigabine Works on a NEW channel that other drugs don ’ t work on (Potassium channel) Defect in potassium channel linked to one inherited form of epilepsy (benign neonatal seizures) Will be approved for add-on treatment in partial seizures only Was reviewed at an FDA advisory panel, received “approval” by panel, awaiting resolution of manufacturing issues for full approval

10. Patients with > 50% Seizure Reduction in Overall Treatment Period (Titration + Maintenance) Study 302 Study 301 *p<0.005 **p<0.001 % Patients 179 181 178 152 153 Placebo 600 900 Placebo 1200 RTG RTG

11. Retigabine 1200 mg/day vs Placebo: Most Common Adverse Events ( > 10% incidence) % Patients Placebo (N=152) RTG (N=153) Dizziness 14 40 Somnolence 17 31 Fatigue 8 16 Confusion 2 14 Dysarthria 2 12 Headache 18 12 Ataxia 4 12 Urinary tract infection 9 12 Tremor 4 11 Vision blurred 3 11 Nausea 7 10

12. Discontinuations Due to Adverse Events *Dose-related Adverse event as primary reason for discontinuation RTG Placebo (N=331) 600 (N=181) 900 (N=178) 1200 (N=153) 8% 14% 26% 27% Cause for discontinuation in >3% of patients Dizziness* Confusion* Somnolence Fatigue Rare bladder issues will require monitoring

13. Perampanel First AED to work on excitation rather than inhibition or stabilization of membranes Inhibits excitatory chemical in the brain (AMPA) Will be approved for add-on treatment in partial seizures first Will be submitted to FDA this year

14. Perampanel : Percent change in seizure frequency during maintenance phase Median % change in seizure frequency -40 -30 -20 -10 0 -50 Placebo (n=119) Perampanel 8 mg/day (n=132) Perampanel 12 mg/day (n=130) -22.86 -32.13 ( P =0.08) -39.48 ( P =0.03)

15. Treatment-emergent side effects (add-on) TEAEs, treatment-emergent adverse events Placebo Perampanel Treatment emergent Side effects % N (n=121) 8 mg (n=133) 12 mg (n=134) TEAEs leading to study or study drug withdrawal 43 6.6 6.8 19.4 Most common (≥10%) Dizziness 113 9.9 37.6 38.1 Sleepiness 63 13.2 18.0 17.2 Irritability 35 5.0 7.5 14.2 Headache 54 13.2 15.0 13.4 Fall 38 6.6 9.8 12.7 Ataxia 24 0 6.0 11.9

16. OLD MECHANISM-MORE POWERFUL/SAFER Brivaracetam (Rikelta) Eslicarbazepine Acetate (Stedesa)

17. BRIVARACETAM (Rikelta) Similar mechanism to Levetiracetam (Keppra TM ) but much stronger in animal models Also has sodium channel blocking activity Keppra causes irritability/depression in some patients-unknown if Rikelta will have improved tolerability profile FDA trials underway. First study very positive, second study unclear, third trial underway First approval will be for add-on therapy for partial seizures. Other uses (eg for generalized seizures) will be explored later

18. Efficacy of Brivaracetam (5, 20 and 50 mg/day) Add-on Treatment in Refractory Partial-Onset Epilepsy SEIZURE-FREEDOM RATES RESPONDER RATES ITT population: n=208; 110M, 98F; age range 16–65 y PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) 0 10 20 30 40 50 60 16.7% p = 0.047 32.0% p = 0.002 44.2% p = 0.001 55.8% % Respondents PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) 0 10 % Patients 1.9% 1/54 8.0% 4/50 7.7% 4/52 7.7% 4/52

19. Brivaracetam Adverse Events PBO BRV5 BRV20 BRV50 Patients (N) 54 50 52 52 Permanent study drug discontinuation 2 (3.7) 3 (6.0) 1 (1.9) 0 Patients with ≥1 AE, n (%) 29 (53.7) 26 (52.0) 29 (55.8) 28 (53.8) Total AEs 59 50 72 56 AEs reported in ≥ 5% patients Headache Somnolence Influenza Dizziness Neutropenia Fatigue 4 (7.4) 4 (7.4) 4 (7.4) 3 (5.6) 1 (1.9) 2 (3.7) 4 (8.0) 1 (2.0) 4 (8.0) 1 (2.0) 4 (8.0) 0 2 (3.8) 3 (5.8) 0 0 2 (3.8) 2 (3.8) 1 (1.9) 3 (5.8) 1 (1.9) 4 (7.7) 0 3 (5.8)

20. Problems with Carbamazepine Effective drug but… Speeds metabolism through the liver, causing: Need for dose adjustment of other drugs that are taken simultaneously Changes (reduction) in levels of vitamins, hormones Increase in cholesterol levels, lipid levels Reduction in sodium (salt) levels in the blood that can lead to problems

21. Change in Cholesterol after removal of Tegretol or Dilantin (First to second blood draw) Mintzer S. et al Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann Neurol. 2009 Apr;65(4):448-56. Tegretol Dilantin CONTROL

22. Eslicarbazepine A “third generation” Carbamazepine (Tegretol TM ) Improves on second generation (Trileptal TM ) Less effect on sodium Smoother release may produce less side effects Does not have the same impact on the liver Hopefully will work equally as well Already approved in Europe as “ Zebenix ” . Will be submitted to FDA for approval as add-on therapy of partial seizures

23. Results from 3 Eslicarbazepine Pivotal Trials: 50% Responder Rates Study BIA-2093-301 Study BIA-2093-302 Study BIA-2093-303 Response Rate (%) 50 45 40 35 30 25 20 15 10 5 0 McCormack PL, et al. CNS Drugs . 2009. 23(1):71-9. 800 mg and 1200 mg doses were statistically significant; 400 mg was not. PL ESL 400 mg od ESL 800 mg od ESL 1200 mg od

24. Integrated Analysis of 3 Phase III Studies : Safety Results Most common Side effects: dizziness, sleepiness, headache, nausea, vomiting, double vision, abnormal coordination Low incidence of hyponatremia Not associated with changes in total cholesterol, low density lipoprotein (LDL) levels, and glucose No systematic effect on body weight

25. The Epilepsy Study Consortium Sponsored by Epilepsy Therapy Development Project and FACES Group of Epilepsy Centers who work together to write protocols, bring better drugs forward, Maintain the focus of drug development on helping people with epilepsy, NOT comercial concerns of pharmaceutical companies!

26. The future Need active pipeline with good compounds moving through Need better trial designs Shorten placebo period? Weed out effective drugs from non-effective Improve risk-benefit Acceptance by FDA of 2 new trial designs will speed good therapies

27. Many Drugs going off Patent This allows multiple (generic) companies to make the drug, in addition to the brand manufacturer At same dose, two formulations must be within 80%-125% of amount in brand, with 90% assurance. Different generic brands could be either high or low If a physician does not check the “do not substitute” box, insurance companies are at liberty to switch patients to generic

28. Generics Drugs off patent (available in generic) Dilantin (phenytoin) Tegretol (carbamazepine) Neurontin (gabapentin) Lamictal (lamotrigine) Topamax (topiramate) Trileptal (oxcarbazepine) Keppra (levetiracetam) Zonisamide (Zonegran)

29. Source: WKH PHAST TRX and Sales data factored by Verispan PDDA Note: Celexa included as a reference of typical generic erosion Prescription Generic Erosion Brand TRx as Percent of Total Molecule

30. Generics may be very good and close to the brand; The problem is that EACH TIME a new prescription is filled, it can be filled with a different company ’s generic, which could be high or low.

31. Different generics can also look different than the brand, causing confusion Tegretol Carbamazepine (Generic)

32. Cost Most insurance companies charge some additional cost for branded drugs Some companies will only pay for generics if they are available The cost differential for some patients may be hundreds of dollars a month, making brand name simply unaffordable

33. Generic Carbamazepine Products May Show Large Variations Five generic carbamazepine formulation-FDA-approval packets were assessed, data obtained using the Freedom of Information Act Looked at two properties: Overall exposure (AUC) and maximum blood concentration (Cmax) The AUC & Cmax of three generics were accurate copies of Tegretol® For two generics, the mean AUC & C max values were near the acceptance range of Tegretol ® Model of switches between two generic CBZ formulations produced AUC variations up to 21% & Cmax variations up to 40% Chuang et al.,

34. No well performed studies to assess risk from switching between generics Excipients and colorants may be different, leading to potential for allergic reactions Dissolution properties may vary

35. Drug Must Be in Solution to be Absorbed Drug in Blood Dissolution of Drug Drug in Solution Result Desired pharmacological effect achieved (seizure reduction) Solid Dosage Form

36. Active Drug Substances (continued) Seven Possible Components of a Tablet Active Drug Substance (ADS) Binders Fillers Disintegrants Lubricants Colors Flavors NOTE: The possible tablet components are rarely The same for the Brand and its Generic counterpart.

37. Bioavailability Physical characteristics of drug and composition of the tablet can effect the . . . Disintegration Dissolution This can effect the way the drug acts in the body

38. Understanding Components Active Drug Substances Properties/Attributes of Active Drug Substances (ADS) Polymorphic Crystal Form The Salt Form The Particle Size Hydrated vs. Anhydrous Form Wettability Solubility Impurity Profile Sources may be different resulting in differences that May or may not be important.

39. What Data Suggest Problems with Switching? Physician surveys Switchback data (Canada) More patients with epilepsy switch back to brand after using generic Increase usage of Emergency services and overall health care after switch from brand to generic Generic savings partially offset by increased dose and increased use of other AED and non-AED after switch

40. Are these sources reliable? All these sources are subject to bias Patients are anxious after switch and may be more aware of problems Remember emergent side effects on placebo)

41. Position Statement Epilepsy Foundation of America Foundation Opposes Mandatory Substitution for Antiepileptic Drugs The Epilepsy Foundation has had a historical position opposing mandatory substitution of generic drugs for brand name since generics first became available because of concerns about reported breakthrough seizures in some people with epilepsy when they are switched from one version of a medication to another. Other medical organizations focused on the treatment of epilepsy have had similar positions.

42. Position Statement American Academy of Neurology (AAN) The AAN, representing over 19,000 neurologists and neuroscience professionals, has taken an active interest in the clinical, ethical and policy considerations concerning the coverage of anticonvulsant drugs for people with epilepsy. The AAN opposes generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending physician ’ s approval. The FDA has allowed for significant differences between name-brand and generic drugs. This variation can be highly problematic for patients with epilepsy. Even minor differences in the composition of generic and name-brand anticonvulsant drugs for the treatment of epilepsy can result in breakthrough seizures.

43. Bottom Line Generic Substitution has not been shown definitively to cause a problem More studies needed Switching probably safe for most people May be a financial necessity for many

44. Who Should Be More Concerned? People whose seizures were controlled only after careful adjustment of one or more AEDs The elderly Patients taking multiple AEDs, who are at risk for drug interactions

45. Changing to Generic (or to Brand): Best practices Physician should get baseline drug levels Check level again when stable on new preparation Ideally limit changes between different generic manufacturers Report suspected problems (preferably with documentation) to FDA MedWatch (http://www.fda.gov/medwatch/)!