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

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

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)

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

The course of drug development Pre-Clinical testing 10,000 250 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

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

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

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

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

Pregabalin Most Frequent Adverse Events Preferred Term Placebo N=73 PGB 600 mg/d fixed dose N=137 PGB 150-600 mg/d flexible dose N=131 N (%) Dizziness 6 (8.2) 59 (43.1) 32 (24.4) Ataxia 3 (4.1) 29 (21.2) 12 (9.2) Weight gain* 5 (6.8) 28 (20.4) 25 (19.1) Asthenia (weakness) 10 (13.7) 25 (18.2) 22 (16.8) Somnolence 24 (17.5) Vertigo 2 (2.7) 19 (13.9) 14 (10.7) Diplopia 1 (1.4) 16 (11.7) 8 (6.1) Amblyopia 14 (10.2) 3 (2.3) Constipation 12 (8.8) 4 (3.1) Tremor 0 (0.0) *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

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

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

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

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

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)

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

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

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

SEIZURE-FREEDOM RATES Responder Rates RESPONDER RATES SEIZURE-FREEDOM RATES p = 0.001 55.8 60 60 p = 0.002 44.2 50 50 40 p = 0.047 32.0 40 % Patients % Responders 30 30 16.7 20 20 8.0 4/50 7.7 4/52 7.7 4/52 10 10 1.9 1/54 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

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

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

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.

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

Carisbamate Suppression of the Photoparoxismal Response Kasteleijn-Nolst Trenité et al, Epilepsy Res 2007;74:193-200

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

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

Most Common Adverse Events (>10% Incidence) % Patients Placebo (N=331) RTG 600 (N=181) RTG 900 (N=178) RTG 1200 (N=153) Dizziness 10 17 26 40 Somnolence 13 14 31 Fatigue 5 15 16 Confusion 1 2 Dysarthria 12 Headache 11 Ataxia / gait disturbance 3 Urinary tract infection Tremor 9 Vision blurred <1 Nausea 6 7

Discontinuations Due to Adverse Events Adverse event as primary reason for discontinuation 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 *Dose-related

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

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

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 Further studies to see if effect is due to transneural transport may be needed In a study by Hussain, et al in the Biological and Synthetic Membranes, 1989, IN administration in humans of lipophilic propranolol resulted in blood levels similar to those observed following IV administration (60 ng/ml)

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 Objective: To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. Design: Prospective randomized study. Setting: Pediatric emergency department in a general hospital. Subjects: 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. Interventions: Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). Main outcome measures: Time from arrival at hospital to starting treatment and cessation of seizures. Results: Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7.9 to 8.3). No significant side effects were observed in either group. Conclusion: Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centers but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home. 8 min 6.1 min Lahat E, et al. BMJ. 2000;321:83-86.

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?

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

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

Electrode (4 contacts) Stimulating Electrode, 4 contacts Greg: These 3 slides are from the ANTs patients. The first 2 show that focal discharges on the EEG can be seen focally on biopolar recordings from the ANTs electrodes (they are shown at a different gain in referential and bipolar montages. The last slide shows a delay from the right frontal to left frontal regions (across the callosum) to the ANTs: I.e. frontal regions to thalamus in this patient with a right frontal focus with rapid spread. The ANTs stimulator stopped her falls. This slide supports a proposed functional disruption of conduction from the frontal to more central regions, which might be responsible for the therapeutic effect (the stim. Was off the entire time these recordings were obtained).

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,

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

RNS with Leads

RNS

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

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

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