New Therapies and News fromClinical Trials

Jacqueline A French MDNYU Epilepsy Center

Current issues to discuss

• How are we doing with our current treatments?

• Drugs/Devices recently approved• Drugs/devices in development

Definition of Drug Resistant Epilepsy (International League Against Epilepsy)• “Drug resistant epilepsy may be defined as

failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.”

• No seizure frequency requirement

How Common is Drug Resistant Epilepsy?

Long-Term Follow-Up of Mixed Population (N=525)*

*Epilepsy Unit, Glasgow, Scotland 1984-1997 Kwan P, Brodie MJ. N Engl J Med 342:314, 2000

Seizure-free63% (n=333)

Uncontrolled37% (n=192)

Resistance vs Syndrome

Difficult to controlEasy to control

Semah F et al. Neurology 51:1256, 1998

45%

35%

82%

27%

% of Seizure-Free

Patients

n 33 337 445 294Global disturbanceGeneticKnown Cause Unknown cause

Generalized Focal

0

20

40

60

80

100

0

20

40

60

80

100

Seizure Control vs Lesion Location / Etiology% of Seizure-Free

Patients

54% 50% 46%42%

30%24%

11%3%

n 26 57 50 268 50 81 22438 Post-stroke Vascular Tumor Normal Head Cortical Isolated Dual

malformation MRI trauma dysgenesis hippocampal pathology*

sclerosis

Difficult to controlEasy to control

*HS + another lesion Semah F et al. Neurology 51:1256, 1998

0

20

40

60

80

100

How do new therapies get on the market?

• 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

SINCE 1998

20000

5

10

20

Zonisamide

FelbamateGabapentin

Topiramate

Oxcarbazepine

Tiagabine

Levetiracetam

Pregabalin

Calendar Year

Nu

mb

er o

f L

icen

sed

An

tiep

ilep

tic

Dru

gs

Lamotrigine

1990 2010

LacosamideRufinamide

DO WE NEED MORE NEW THERAPIES?

• Problem with current AEDs:– Seizure control

• 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

Recent Drug approvals

Drugs• Vimpat (Lacosamide): Approved October 2008

– Approved for partial-onset (focal) seizures

• Banzel (rufinamide) Approved November 2008– Approved for Lennox-Gastaut Syndrome (a form

of severe epilepsy, often associated with intellectual impairment)

Recent Drug approvals

• Sabril (Vigabatrin): August 2009– Available in Europe for over a decade– Known to cause permanent vision problems

(seeing to the sides) in 30% of people– Approved for infantile spasms and treatment-

resistant partial onset (focal) seizures

Drugs in late stages of Development

• Brivaracetam (Rikelta)• Eslicarbazepine (Stedesa)• Retigabine (Ezogabine)

BRIVARACETAM(Rikelta)

• Similar mechanism to Levetiracetam (KeppraTM) but much stronger in animal models

• Also has sodium channel blocking activity• Should work in many seizure types• Trials underway at NYU and elsewhere

Responder Rates Responder Rates

SEIZURE-FREEDOM RATES50% SZ REDUCTION RATES

Results from logistic regression (50% responder rate); ITT populationResults from logistic regression (50% responder rate); ITT populationITT population: n=208; 110M, 98F; age range 16–65 y; ITT population: n=208; 110M, 98F; age range 16–65 y; pp-value versus PBO-value versus PBO

PBO(n=54)

BRV5(n=50)

BRV20(n=52)

BRV50(n=52)

0

10

20

30

40

50

60

16.7

p = 0.04732.0

p = 0.00244.2

p = 0.00155.8

% R

esp

on

de

rs

PBO(n=54)

BRV5(n=50)

BRV20(n=52)

BRV50(n=52)

0

60

% P

atie

nts

1.91/54

8.04/50

7.74/52

7.74/52

10

20

30

40

50

Brivaracetam Adverse EventsBrivaracetam Adverse Events

PBO BRV5 BRV20 BRV50

Patients (N) 54 50 52 52Permanent 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

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)

Eslicarbazepine(Stedesa)

• A “third generation” Carbamazepine (TegretolTM)

• Improves on second generation (TrileptalTM)– Less effect on blood tests (sodium)– Smoother release may produce less side

effects

• Hopefully will work equally as well• Trials underway at NYU and elsewhere

Double-Blind Placebo-Controlled Add-on Trial of Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

50% Responder Rates (n=143)

28%

41%

% P

atie

nts

54%*

Placebo ESL ESL 1200 mg/d 1200 mg/d o.i.d b.i.d.

(* P=0.008 vs PL)

Bialer et al., Epilepsy Res 2007;73:1-52.

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, submitted to FDA for approval

Patients with >50% Seizure Reduction in Overall Treatment Period (Titration + Maintenance)

44%**

18%

39%**

31%*

17%

0

10

20

30

40

50

60

Intent-to-treat

Study 302 Study 301

*p<0.005 **p<0.001

% P

atie

nts

179 181 178 152 153

Placebo 600 900 Placebo 1200 RTGRTG

% Patients

Placebo(N=331)

RTG 600 (N=181)

RTG 900(N=178)

RTG 1200(N=153)

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 <1 5 11

Nausea 5 6 7 10

Most Common Adverse Events (>10% Incidence)

Discontinuations Due to Adverse Events

Adverse event as primary reason for discontinuationPlacebo(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 at NYU

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

Lahat E, et al. BMJ. 2000;321:83-86.

Dose = 0.3 mg/kg

Dose = 0.2 mg/kg

N=47 children with febrile seizures (>10 min)

3.5 min

5 min

6.1 min8 min

Main outcome measures: Time from arrival at hospital to drug administration & time to seizure cessation

Observation period = 60 minutes

Comparative Efficacy of IN MDZ vs IV DZP

Who can be in a clinical trial of a new therapy?

• People on 2-3 stable antiepileptic drugs, still experiencing more than one seizure/month (often requires 3-4)

• Able to keep seizure counts

• Usually over 18, unless trial is specifically for children

• Not planning pregnancy

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

Medtronic, “Sante” Trial

NeuroPace “RNS” Trial

Medtronic SANTE TrialStimulation 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

Stimulating Electrode, 4 contactsElectrode (4 contacts)

Results of stimulation

(sham)

Deep Brain Stimulation Study

• Treatment worked better for people with epilepsy from the temporal lobe, and did not work as well in those with frontal, parietal and occipital epilepsy.

• Treatment worked just as well after surgery and VNS.• 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,

Seizure frequency changes 2 years after randomization

Radiosurgery

• “Gamma Knife”• Alternative to open

surgery• Using a special helmet,

radiation is focused on a single spot in the brain-the spot where seizures arise, destroying the focus, while passing harmlessly through normal tissue. Less invasive than standard surgery

• So far produces seizure freedom about 2/3 of the time, about the same as open surgery.

Gamma Knife• Advantages

– Less invasive– Recovery usually faster– May cause less harm to normal surrounding tissue, leading

to fewer neuropsychological problems in the longterm

• Disadvantages– Takes a while to work (up to a year), and seizures may get

worse before they improve– Swelling may cause nausea, headache, psychiatric problems– 2/3 need anti-swelling meds (steroids) temporarily

Temporal lobectomy

What happens now?

• Randomized trial of Gamma knife vs temporal lobectomy

• Could be a good alternative in some patients who do not want to have open surgery

Responsive Neurostimulator

• 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.

• Electrodes are placed within the brain or rest on the brain surface in the area of the seizure focus (where seizures start).

• 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.

RNS with Leads

RNS

Anthony Murro, M.D.Medical College of Georgia

RNS Clinical trial

• 171 patients implanted-half got “sham” stimulation, the other half got true stimulation

• During the last 2 months, mean 29 % percent decrease vs 14 % decrease in the sham stimulation group.

• In the long term (last 12 weeks of treatment): 47 % of subjects experienced a ≥ 50 % decrease in seizure frequency, as compared to their baseline.

• Few adverse events

What happens now?

• FDA expert panel voted to approve Deep Brain Stimulator (Medtronics) in March 2010– Should be on market shortly

• Responsive Neurostimulator (Neuropace) will be evaluated for approval by FDA

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

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