1. What’s New In Antiepileptic Drugs Jacqueline A. French, M.D. NYU Comprehensive Epilepsy Center

2. ANTIEPILEPTIC DRUG DEVELOPMENT 18401860188019001920194019601980 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 Brivaracetam Pregabalin Retigabine ? Calendar Year Number of Licensed Antiepileptic Drugs Lamotrigine

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

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 Carbamazepinee Tegretol TM Valproic Acid Depakote TM 2 nd Generation AED Oxcarbazepine Valrocemide (SPD–493) Valnoctamide 3 rd Generation AED Licarbazepine (MHD) 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 GabapentinLamotrigineLevetiracetam Pregabalin JZP-4 Brivaracetam (ucb 34714) Seletracetam (ucb 44212) XP-13512 Precursor CNS Drug Piracetam 1 st Generation AED 2 nd Generation AED Perucca et al, Lancet Neurol, 2007

8. What’s new this year? Two new drugs to be approved –Revolutionary Vimpat (lacosamide) Inovelon (rufinamide) Four drugs in late trials –Evolutionary Rikelta (brivaracetam) Eslicarbazepine –Revolutionary: Carisbamate Retigabine

9. What’s new this year? Many drugs off/going off patent (going generic) –Neurontin (gabapentin) –Lamictal (lamotrigine) –Topamax (topiramate) –Trileptal (oxcarbazepine) –Keppra (levetiracetam)

10. What’s new this year? Two new trial designs endorsed by FDA –“Withdrawal to monotherapy”: Speed approval for monotherapy –“Time to Nth seizure”: Create more “patient- friendly trials

11. DRUGS THAT WORK IN NEW WAYS retigabinelacosamiderufinamide

12. Lacosamide (RIKELTA TM ) Works on sodium channels, like Carbamazepine (Tegretol TM ) and Phenytoin (Dilantin TM ) However, It selectively enhances slow inactivation of sodium channels, whereas the older drugs work on fast inactivation Approved in Europe, expected to be approved in US by December 2008

13. Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy: 50% Responder Rates (n=418) 22% 41%* 38%* % Patients 33% Placebo LCS 200mg LCS 400mg LCS 600mg (* P<0.05 vs PL) Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

14. Percentages are based on the number of patients in the randomized dose group who received at least one dose of trial medication. Lacosamide Treatment-emergent adverse events (%) leading to discontinuation in at least 5% of patients in any treatment group Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

15. RUFINAMIDE (INOVELON TM ) Also works on sodium channels with new mechanism Approved in Europe for treatment of a severe form of epilepsy (Lennox-Gastaut syndrome) –“Orphan drug” In Front of FDA for Lennox-Gastaut and Partial seizures

16. Rufinamide Lennox-Gastaut Responder Rate: Tonic-Atonic Seizure Frequency % of Subjects ≥ 75% ≥ 50% ≥ 25% Seizure Reduction P=0.0003 P=0.006 P=0.002

17. Rufinamide AEs With Incidence ≥ 3% vs Placebo: All Treated Subjects With Epilepsy (Double-blind Only) Rufinamide N (%) Placebo N (%) Subjects1465635 Subjects with an AE1180 (80.5)497 (78.3) Somnolence36 (17)16 (8.1) Vomiting35 (16.5)14 (7.1) Headache34 (16.0)16 (8.1) Nausea16 (7.5)7 (3.6) Ataxia10 (4.7)1 (0.5) Diplopia10 (4.7)1 (0.5

18. What we don’t know What we know LEVEL OF KNOWLEDGE AT TIME OF APPROVAL

19. What do we know about AEDs at time of approval? How the drug works in difficult to control seizures (proof that drug is better than placebo) Side effects when used at titration rates and doses employed in trials, over short term Safety in 1500-15,000 subjects Drug interactions

20. What don’t we know about AEDs at time of approval? How the drug works in other types of epilepsy How the drug works in newly diagnosed patients Comparative data vs new or old AEDs Impact at different ages –Pediatric –Elderly Best dose, titration schedule Some safety issues (including long-term) How well the drug works by itself Pregnancy effects

21. 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) Trials completed, ready to submit to FDA for approval

22. Patients with >50% Seizure Reduction in Overall Treatment Period (Titration + Maintenance) Intent-to-treat Study 302Study 301 *p<0.005 **p<0.001 % Patients 179181178152153 Placebo 600900Placebo1200 RTG RTG

23. Retigabine 1200 mg/day vs Placebo: Most Common Adverse Events (>10% incidence) % Patients Placebo (N=152) RTG (N=153) Dizziness1440 Somnolence1731 Fatigue816 Confusion214 Dysarthria212 Headache1812 Ataxia412 Urinary tract infection912 Tremor411 Vision blurred311 Nausea710

24. 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 Discontinuations Due to Adverse Events *Dose-related

25. OLD MECHANISM-MORE POWERFUL/SAFER Brivaracetam Eslicarbazepine Acetate

26. BRIVARACETAM Similar mechanism to Levetiracetam (Keppra TM ) but much stronger in animal models Also has sodium channel blocking activity FDA trials underway

27. Values given are means ± S.D. (n=8) Genetic Absence Epilepsy Rats from Strasbourg Levetiracetam

28. Genetic Absence Epilepsy Rats from Strasbourg Values given are means ± S.D. (n=8) seletracetam

29. 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

30. Brivaracetam Adverse Events PBOBRV5BRV20BRV50 Patients (N)545052 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 AEs59507256 AEs reported in ≥ 5% patients Headache Somnolence Influenza Dizziness Neutropenia Fatigue 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 2 (3.8) 1 (1.9) 3 (5.8) 1 (1.9) 4 (7.7) 0 3 (5.8)

31. Eslicarbazepine A “third generation” Carbamazepine (Tegretol TM ) Improves on second generation (Trileptal TM ) –Less effect on sodium –Smoother release may produce less side effects Hopefully will work equally as well Ready to submit to FDA

32. 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

33. 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

34. Many Drugs going off Patent 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.

35. No well performed blinded studies to assess risk from switching between generics Excipients and colorants may be different, leading to potential for allergic reactions Dissolution properties may vary Risks of generics should be weighed against cost benefits 1 1 Epilepsy Foundation. Statement on substitution of generic antiepileptic drugs.

36. Changing to Generic (or to Brand) Baseline 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/)!

37. 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!

38. 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