What

1
Whats 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
• 10,000 250
  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

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
Epilepsy50 Responder Rates
41
38
33
( Plt0.05 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
Adverse Event Preferred Term PlaceboN73 PGB600 mg/d fixed doseN137 PGB 150-600 mg/d flexible doseN131
N () N () 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 6 (8.2) 24 (17.5) 25 (19.1)
Vertigo 2 (2.7) 19 (13.9) 14 (10.7)
Diplopia 1 (1.4) 16 (11.7) 8 (6.1)
Amblyopia 1 (1.4) 14 (10.2) 3 (2.3)
Constipation 3 (4.1) 12 (8.8) 4 (3.1)
Tremor 0 (0.0) 12 (8.8) 4 (3.1)
Weight gain AEs were not exclusively
spontaneously reported. A query was generated for
patients with a change in weight gt7 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 1980s
• 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,
30422-429
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
2000
1990
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
Whats 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. (n8)
18
Genetic Absence Epilepsy Rats from Strasbourg
Values given are means S.D. (n8)
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
10
1.9 1/54
0
0
PBO (n54)
BRV5 (n50)
BRV20 (n52)
BRV50 (n52)
PBO (n54)
BRV5 (n50)
BRV20 (n52)
BRV50 (n52)
Results from logistic regression (50 responder
rate) ITT population ITT population n208
110M, 98F age range 1665 y p-value versus PBO
20
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 AEs reported in 5 patients AEs reported in 5 patients AEs reported in 5 patients 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)
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
Epilepsy50 Responder Rates (n143)
54
41
( P0.008 vs PL)
Patients
28
Placebo ESL
ESL 1200 mg/d
1200 mg/d
o.i.d b.i.d.
Bialer et al., Epilepsy Res 2007731-52.
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
Carisbamate Suppression of the Photoparoxismal
Response
Kasteleijn-Nolst Trenité et al, Epilepsy Res
200774193-200
25
Retigabine

• Works on a NEW channel that other drugs dont
  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 gt50 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
plt0.005 plt0.001
27
Most Common Adverse Events (gt10 Incidence)
Patients Patients Patients Patients
Placebo(N331) RTG 600 (N181) RTG 900(N178) RTG 1200(N153)
Dizziness 10 17 26 40
Somnolence 13 14 26 31
Fatigue 5 17 15 16
Confusion 1 2 5 14
Dysarthria 1 5 2 12
Headache 16 11 17 12
Ataxia / gait disturbance 2 3 5 12
Urinary tract infection 5 1 2 12
Tremor 3 2 9 11
Vision blurred 2 lt1 5 11
Nausea 5 6 7 10
28
Discontinuations Due to Adverse Events
Adverse event as primary reason for discontinuation Adverse event as primary reason for discontinuation Adverse event as primary reason for discontinuation Adverse event as primary reason for discontinuation
Placebo(N331) 600(N181) 900(N178) 1200(N153)
8 14 26 27
Cause for discontinuation in gt3 of patients Cause for discontinuation in gt3 of patients Cause for discontinuation in gt3 of patients Cause for discontinuation in gt3 of patients
Dizziness Dizziness Dizziness Dizziness
Confusion Confusion Confusion Confusion
Somnolence Somnolence Somnolence Somnolence
Fatigue Fatigue Fatigue Fatigue
Dose-related
29
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)

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
N47 children with febrile seizures (gt10 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. 200032183-86.
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 gt90 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