1. New Antiepileptic drugs Jacqueline A French MD 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 Pregabalin Calendar Year Number of Licensed Antiepileptic Drugs Lamotrigine Vigabatrin Perampanel Retigabine Levetiracetam eslicarbazepine

3. DO WE NEED MORE NEW EPILEPSY 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

4. The course of drug development Pre-Clinical testing 10,000 Compounds Phase I – Testing in about 100 normal volunteers – Developer needs to get approval from FDA in the form of an NDA (new drug application) Phase II/III – Tests to determine if therapy is safe and effective 250 Get to Animal Testing 10 Reach Human Trials

5. Double-blind placebo-controlled trial for FDA approval BaselineTitration 1-2 AEDsPlacebo + AEDs Dose 1 + AEDs Dose 2 + AEDs Taper (double-blind) + follow up Treatment

6. What do we know about new epilepsy drugs when they are approved by FDA? Ability to control seizures in one epilepsy type (focal seizures) in patients who have failed other drugs (treatment resistant) as measured in randomized controlled trials (proof that drug is better than placebo/sugar pill) Tolerability when use doses employed in trials, over short term Safety in 1500-15,000 subjects

7. What don ’ t we know about epilepsy drugs at time of FDA approval? Ability to control seizures in most seizure syndromes Ability to control seizures in newly diagnosed patients Comparative data vs new or old AEDs Effectiveness/tolerability in children Some safety issues (including long-term) Data on using the drug by itself (monotherapy)

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

9. SERIOUS ISSUES IDENTIFIED BEFORE AND AFTER FDA APPROVAL DrugBEFORE APPROVAL AFTER APPROVAL FELBAMATERash, Serious rash (Steven’s Johnson) Fatal Aplastic Anemia Liver failure LAMOTRIGINERash, Serious rash (Steven’s Johnson) Risk < 16 y.o TOPIRAMATEAcute Glaucoma, heat stroke, Kidney Stones TIAGABINE Status Epilepticus VIGABATRINDepressionPsychosis, Visual Field Defects

10. How do we make progress? 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 – Includes sustained release formulations Revolutionary Drugs – Drugs that work with new mechanisms never tried before – Expectation: They will control seizures that existing drugs can ’ t control

11. What ’ s “new” in AEDs? One new drug approved June 2011 – Revolutionary Retigabine (Potiga) Two novel drug approved within last 12 months! – Revolutionary: Perampanel (Fycompa) – Evolutionary: Eslicarbazepine (Aptiom) Three sustained release formulations approved – Oxtellar (sustained release oxcarbazepine) – Trokendi (sustained release topiramate) – Qudexy (sustained release topiramate)

12. 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 Eslicarbazepine Acetate (BIA 2-093) Phenobarbital T2000 Perucca et al, Lancet Neurol, 2007

13. 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) Approved for add-on treatment in partial seizures only

14. Patients with >50% Seizure Reduction during 3 month study (USA) Study 301 % Patients 1200 RTG 2 French et al Neurology. 2011 May 3;76(18):1555-63 82 % 18% Placebo 44 % 56 %

15. Black Box Warning Initially approved in the US in 2010, with concerns about bladder abnormalities In spring 2013 The FDA notified physicians about risks of abnormalities to the retina (back of the eye), potential vision loss, and skin discoloration, all of which may become permanent. The revised label includes a new boxed warning, the most serious type of warning FDA gives, because of the risk of abnormalities in the retina.

16. Blue Discoloration

17. They advise that Potiga use be limited to patients who have not responded adequately to several alternative therapies to decrease the frequency of seizures, or epilepsy, and for whom the benefits of treatment outweigh the risks. FDA recommends that patients have eye exams by an ophthalmic professional before starting Potiga and every six months during treatment.

18. 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

19. Placebo (n=119) Perampane l 8 mg/day (n=132) Perampanel 12 mg/day (n=130) Perampanel : Percent change in seizure frequency during maintenance phase (Study 304) 37 % 36 % 64% 26 % French et al Neurology® 2012;79:589–596

20. Side effects (add-on) 1 Several cases of “severe aggression”/homicidal ideation (Black box warning) TEAEs, treatment-emergent adverse events PlaceboPerampanel Treatment emergent Side effects % N (n=121) 8 mg (n=133) 12 mg (n=134) Side effectss leading to study or study drug withdrawal 436.66.819.4 Most common (≥10%) Dizziness 1139.937.638.1 Sleepiness 6313.218.017.2 Irritability 355.07.514.2 Headache 5413.215.013.4 Fall386.69.812.7 Unsteadiness2406.011.9 French et al Neurology® 2012;79:589–596

21. What is exciting about Perampanel? First late-stage drug that works on excitatory mechanisms Also has only be tried on focal seizures – Study for (genetic) generalized tonic-clonic seizures almost complete We have not explored the long-term potential for drugs that impact excitatory, rather than inhibitory mechanisms

22. What is Eslicarbazepine Acetate Not a completely new drug It is closely related to the drug Oxcarbazepine (trileptal) which has been on the market for several decades When oxcarbazepine enters the body, it is transformed into 2 mirror-image molecules (R-licarbazepine and S- Licarbazepine). R- licarbaze pine OXCARBAZEPINE S- Licarbaz epine

23. What is Eslicarbazepine Acetate Eslicarbazepine acetate enters the body and is transformed into one of these molecules (S- licarbazepine) Since everyone taking oxcarbazepine has S- licarbazepine circulating in their body, we don’t expect any new surprise side effects (but we do expect some of the same side effects we have already seen with oxcarbazepine) Eslicarbazepine Acetate S-Licarbaz- epine

24. Is it better than Oxcarbazepine? Less effect on blood chemistry (sodium) Smoother release may reduce side effects related to fluctuation of drug levels in bloodstream Once daily administration Hopefully will work equally as well It remains to be seen whether it is better than Trileptal overall Approved in Europe 18 months ago as “Zebenix”.

25. Results from 3 Eslicarbazepine Pivotal Trials: 50% Responder Rates PL ESL 400 mg od ESL 800 mg od ESL 1200 mg od 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. Verrotti et al, Epilepsy Research 2014: 108: 1-10

26. Side effects Most common Side effects: dizziness, sleepiness, headache, nausea, vomiting, double vision, abnormal coordination Low incidence of low blood sodium(.6-1.3%) This is better than trileptal Not associated with changes in total cholesterol, low density lipoprotein (LDL) levels, and glucose No effect on body weight Rash in 3% Verrotti et al, Epilepsy Research 2014: 108: 1-10

27. Can a modified release formulation of an AED be useful? If there are substantial ups and downs in medicine amounts in the blood If either the peaks produce side effects, or the troughs produce seizure breakthroughs If toxicity at the peak prevents ability to increase dose, and increased dose is likely to improve seizure control YES,

28. 12 Drug Concentration Time (hrs) 6 2424 18 Risk of side effects Risk of seizure breakthrough Immediate vs slow release Cmax Cloyd, 1998

29. 12 Drug Concentration Time (hrs) 6 2424 18 Risk of side effects Risk of seizure breakthrough Immediate vs slow release: Dose increase Cmax Cloyd, 1998

30. Immediate Release Oxcarbazepine Median % sz reduction.6%* 3%* 10%* 22% Higher plasma [MHD] were associated with larger decreases in seizures frequency p=0.0001 Seizure freedom Barcs, Epilepsia, 41(12):1597–1607, 2000

31. OXC add on: Patients % Discontinued 28% 22% 45% 73%* *An additional 7% had to reduce dose to 1800 mg, leaving only 20% who completed on 2400 mg/day Barcs, Epilepsia, 41(12):1597–1607, 2000

32. Efficacy and safety of extended‐release oxcarbazepine (Oxtellar XR™)(Add-on focal seizures, US population) Acta Neurologica Scandinavica Volume 129, Issue 3, pages 143-153, 21 DEC 2013 DOI: 10.1111/ane.12207 http://onlinelibrary.wiley.com/doi/10.1111/ane.12207/full#ane12207-fig-0003 Volume 129, Issue 3, http://onlinelibrary.wiley.com/doi/10.1111/ane.12207/full#ane12207-fig-0003

33. Extended‐release oxcarbazepine (Oxtellar) Side effects

34. Topiramate Sustained Release Topiramate, less difference between peak and trough Would it be enough to make a difference?

35. PREVAIL: Titration and maintenance phases Chung et al. In preparation.

36. Topiramate immediate release (Topamax) add-on study in focal seizuresstudy

37. Reduction in seizure frequency topiramate 200 mg sustained release (Qudexy) 18.5% treatment effect on seizure reduction Combined titration and maintenance phase Chung et al. In preparation.

38. Overall safety profile: Qudexy XR (sustained release topiramate) vs placebo Side effects deemed related to study drug reported in ≥5% of subjects were: – Somnolence (12.1% vs 2.4%) – Dizziness (7.3% vs 5.6%) – Paraesthesia (6.5% vs 2.4%) – Weight decrease (6.5% vs 0) – Fatigue (5.6% vs 4.8%) Chung et al. In preparation.

39. Side effects related to cognitive and neuropsychiatric functioning Preferred Term, N (%) USL255 N=124 Placebo N=125 Any neurocognitive TEAE 16 (12.9)5 (4.0) Neurocognitive TEAEs Aphasia3 (2.4%)0 Dysarthria3 (2.4%)1 (0.8%) Disturbance in attention3 (2.4%)4 (3.2%) Memory impairment3 (2.4%)1 (0.8%) Psychomotor retardation3 (2.4%)0 Bradyphrenia2 (1.6%)1 (0.8%) Amnesia1 (0.8%)0 Cognitive disorder1 (0.8%)0 Confusional state1 (0.8%)0 Encephalopathy1 (0.8%)0 Mental impairment1 (0.8%)0 Speech disorder1 (0.8%)0 Thinking abnormal1 (0.8%)0 Note: Preferred terms are in descending order of frequency as reported in the USL255 treatment group

40. Should you try a new antiepileptic drug? Although there are many available drugs, many may have features that make them a poor match for a specific person For example: – Drug does not treat the type of seizures the person has – Drug causes significant weight gain – -Drug is associated with depression – Drug interacts with another medication the person is taking

41. Should you try a new antiepileptic drug? If you have tried the available appropriate AEDs, and they have not worked – How do you know? Discuss with your physician Discuss the risks and benefits: – data that is available about impact on seizures, and what is known about the side effects. Discuss the epilepsy types that have been studied in trials: Is yours among them?

42. Should you try a new antiepileptic drug? How many people have taken the drug so far? – Typically 3-5,000 have taken it before the FDA approves it – This would be enough to rule out an unexpected side effect with a frequency of 1/1500

43. Summary There are interesting novel evolutionary and revolutionary drugs in the pipeline, with more coming behind Sometimes a small change (such as formulation) can make a big difference Potential for new screening models makes the future potentially even more promising