What’s new in clinical Trials

1. What’s new in clinical Trials Jacqueline A French MD NYU Epilepsy Center

2. Current issues to discuss • Why do we do clinical trials? • What to expect from a trial • Drugs/Devices currently in development

3. Why do we do clinical trials? • The American Public looks to its government for assurance that therapies developed to treat diseases are both SAFE and EFFECTIVE • The Food and Drug Administration (FDA) is charged with ensuring that safety and effectiveness are proven before a drug is put on pharmacy shelves, or before a device is marketed • They are also responsible for LABELING drugs so that the public is aware of risks and benefits • There are very strict rules that govern the conduct of clinical trials to determine safety and efficacy (effectiveness)

4. Who does clinical trials? • Early trials may be done by researchers at Universities • Most drugs and devices (even if the idea comes from research labs or the National Institutes of Health (NIH) will be tested by companies that eventually will sell the product • The cost of developing a new drug is $800 million to 2 Billion and takes 12-15 years • Companies need to partner with clinical researchers and doctors to perform good trials

5. The course of drug development • Pre-Clinical testing 10,000250 10 (compounds) (get to animal testing) (enter human tests) • 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

6. The course of drug development • Phase II/III (continued) • For a drug, At least 2 trials with a control group (usually placebo) • Drug must be better than “placebo” (how much?) • Can see how frequent dose-related side effects are compared to placebo • For a device a single trial may be sufficient • Overall, 1500-3000 pts exposed to drug, to look for “rare” side effects

7. The difficulty of clinical trials • Clinical trials cannot be exactly like clinical practice • Too much chance that events that occur by “chance” (good and bad) will be attributed to the novel intervention • Therefore, good clinical science requires that trials have a “control group”, that will provide data on what would have happened had the intervention NOT occurred • Studies without a control group usually over-estimate effectiveness of an intervention

8. DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL DOSE 2 +AEDS DOSE 1 +AEDS 1-2 AEDS PLACEBO +AEDS TAPER (DOUBLE BLIND) + FOLLOW-UP BASELINE TITRA- TION TREATMENT

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

10. Pregabalin Most Frequent Adverse Events *Weight gain AEs were not exclusively spontaneously reported. A query was generated for patients with a change in weight >7% to assess whether the body weight changes also needed to be reported as an AE. Data on file, Pfizer Inc

11. Precautionary tale: Cinromide • Promising potential AED in 1980’s • Highly effective in open-label trial of Lennox-Gastaut , a very severe childhood epilepsy with multiple seizures/day : Over 50% of children had seizures reduced by half • No difference from placebo in randomized controlled trial (significant response in both arms) The Group for the Evaluation of Cinromide in the Lennox-Gastaut Syndrome, 1989. Epilepsia, 30:422-429

12. The difficulty of clinical trials • Thus, patients who volunteer for trials will have to accept possibility of randomization to placebo. • Without this type of trial, we would never be able to know if a drug is truly working • New trial designs: attempt to limit placebo exposure as much as possible

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

14. 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

15. What’s new this year? • Two new drugs approved • Vimpat (lacosamide) (refractory partial-onset seizures) • Inovelon (rufinamide) (seizures associated with Lennox-Gastaut) • Four drugs in late trials (all for refractory partial onset seizures) • Eslicarbazepine • Rikelta (brivaracetam) • Carisbamate • Retigabine • One drug in development for acute clusters • Two devices in late trials • Responsive Neurostimulator (RNS) • Deep Brain Stimulator (DBS)

16. BRIVARACETAM • Similar mechanism to Levetiracetam (KeppraTM) but much stronger in animal models • Also has sodium channel blocking activity • Should work in many seizure types, including myoclonus • FDA trials underway

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

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

19. Responder Rates SEIZURE-FREEDOM RATES RESPONDER RATES p = 0.001 55.8 60 60 p = 0.002 44.2 50 50 40 40 p = 0.047 32.0 % Patients % Responders 30 30 16.7 20 20 8.0 4/50 7.7 4/52 7.7 4/52 10 1.9 1/54 10 0 0 PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) Results from logistic regression (50% responder rate); ITT population ITT population: n=208; 110M, 98F; age range 16–65 y; p-value versus PBO

20. Brivaracetam Adverse Events

21. Eslicarbazepine • A “third generation” Carbamazepine (TegretolTM) • Improves on second generation (TrileptalTM) • Less effect on sodium • Smoother release may produce less side effects • Hopefully will work equally as well • Ready to submit to FDA

22. Double-Blind Placebo-Controlled Add-on Trial of Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:50% Responder Rates (n=143) 54%* 41% (* P=0.008 vs PL) % Patients 28% Placebo ESL ESL 1200 mg/d 1200 mg/d o.i.d b.i.d. Bialer et al., Epilepsy Res 2007;73:1-52.

23. Carisbamate • Mechanism of action unknown • Performed very well in suppressing epileptic activity as a result of flashing lights (photosensitivity) • Two double-blind, placebo controlled trials in partial epilepsy, one positive and one negative • Side effects mild • Clinical trials are ongoing

24. CarisbamateSuppression of the Photoparoxismal Response Kasteleijn-Nolst Trenité et al, Epilepsy Res 2007;74:193-200

25. 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

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

27. Most Common Adverse Events (>10% Incidence)

28. Discontinuations Due to Adverse Events *Dose-related

29. Current pharmacologic therapy in epilepsy • Preventive (antiepileptic medications): • Standard for nearly all patients • Not effective for an “acute” seizure • Abortive or rescuemedications • Seizures in clusters • Prolonged seizures • One seizure after another (status epilepticus)

30. Options for abortive therapy • Current: • Rectal Diazepam (valium) • Mostly used in children • Often not feasible, or may be a delay in administration • Buccal or nasal preparations • Not FDA approved • Future • Intranasal Midazolam • Studies beginning soon

31. Advantages of Nasal Drug Delivery • Easy access with/without patient cooperation • Rapid and extensive absorption through the nasal mucosa • Convenient and easy administration • Needle-less

32. Comparative Efficacy of IN MDZ vs IV DZP N=47 children with febrile seizures (>10 min) Main outcome measures: Time from arrival at hospital to drug administration & time to seizure cessation Observation period = 60 minutes 5 min Dose = 0.2 mg/kg Dose = 0.3 mg/kg 3.5 min 8 min 6.1 min Lahat E, et al. BMJ. 2000;321:83-86.

33. What should I ask my doctor about a new drug? • How many patients have been exposed to date? • What are the common dose-related side effects • Were there any irreversible side effects, or will the problems go away when I lower the dose? • Was this drug studied for my seizure type? • How well did the drug do compared to placebo?

34. Devices under study NeuroPace “RNS” Trial Medtronic, “Sante” Trial

35. Medtronic SANTE Trial Stimulation of Anterior Thalamus for Epilepsy Electrodes surgically placed in the thalamus, a deep part of the brain, on both sides Stimulation every 5 minutes Strength and duration of stimulation can be adjusted Like Vagus nerve stimulator, patient can “trigger” stimulation for an aura or seizure

36. Electrode (4 contacts) Stimulating Electrode, 4 contacts

37. Deep Brain Stimulation Study • Of the 87 study participants who completed the diaries through month 13, 40 % experienced a ≥ 50 % reduction in their baseline rate of seizures 13 months after implant. • During this same long-term follow-up period (last three months of data for each patient), median seizure frequency was reduced by approximately two-thirds, 9% of study participants had no seizures and 19 % experienced a >90 % reduction in seizure frequency. • The infection rate was 10.9 % and the rate of asymptomatic intracranial hemorrhage was 1.3 % per lead implant. • There was a significantly higher incidence of spontaneously self-reported depression, memory impairment, and anxiety in the active group compared to the control group during the blinded phase,

38. Responsive Neurostimulator • The RNS is designed to detect abnormal electrical activity in the brain and to deliver small amounts of electrical stimulation to suppress seizures before there are any seizure symptoms. • The RNS is placed within the skull and underneath the scalp by a surgeon. The RNS is then connected to one or two wires containing electrodes that are placed within the brain or rest on the brain surface in the area of the seizure focus (where seizures start). • The RNS is designed to continuously monitor brain electrical activity from the electrodes and, after identifying the "signature" of a seizure's onset, deliver brief and mild electrical stimulation with the intention of suppressing the seizure. • Early trials are promising, and studies are ongoing

39. RNS with Leads

40. RNS

41. Anthony Murro, M.D. Medical College of Georgia

42. Other drugs/devices on the way • Drugs: • Ganaxalone • ICA-105665 • Perampanel (E2007) • T2000: (non-sedating barbiturate) • YKP3089 • Huperzine • NPY gene transfer • Devices • Drug Delivery Pumps • Seizure detection/prevention

43. Conclusion • Without volunteers for clinical trials, no new drugs or devices will be possible • Many new options are on the way, providing hope for all people with uncontrolled seizures