New Antiepileptic drugs Jacqueline A French MD - PowerPoint Presentation

Slide1

New Antiepileptic drugs

Jacqueline A French MD

NYU Comprehensive Epilepsy Center

Slide2

ANTIEPILEPTIC DRUG DEVELOPMENT

1840

1860

1880

1900

1920

1940

1960

1980

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

P

erampanel

R

etigabine

Levetiracetam

eslicarbazepine

Slide3

DO WE NEED MORE NEW

EPILEPSY DRUGS

?

Problem with current AEDs:Seizure controlNewly diagnosed well treatedStill 40% with therapy resistanceNew AEDs over last 20 years have not changed this equation!Safety/tolerability

Some new (and old) AEDs still have important safety and tolerability problems

Slide4

The course of drug development

Pre-Clinical testing

10,000Compounds

Phase ITesting in about 100 normal volunteersDeveloper needs to get approval from FDA in the form of an NDA (new drug application)

Phase II/IIITests to determine if therapy is safe and effective

250

Get to Animal

Testing

10Reach Human

Trials

Slide5

Double-blind placebo-controlled

trial for FDA approval

Baseline

Titration

1-2 AEDs

Placebo + AEDs

Dose 1 + AEDs

Dose 2 + AEDs

Taper

(double-blind)

+ follow up

Treatment

Slide6

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 termSafety in 1500-15,000 subjects

Slide7

What don

’

t we know about

epilepsy drugs at time of FDA approval?Ability to control seizures in most seizure syndromesAbility to control seizures in newly diagnosed patientsComparative data vs new or old AEDsEffectiveness/tolerability in children

Some safety issues (including long-term)Data on using the drug by itself (monotherapy)

Slide8

What we don

’

t know

What we

know

LEVEL

OF

KNOWLEDGE AT TIME OF APPROVAL

Slide9

SERIOUS

ISSUES IDENTIFIED BEFORE AND AFTER FDA APPROVAL

Drug

BEFORE APPROVAL

AFTER APPROVAL

FELBAMATE

Rash,

Serious rash (Steven’s Johnson)

Fatal Aplastic

Anemia

Liver failure

LAMOTRIGINE

Rash,

Serious rash (Steven’s Johnson)

Risk < 16 y.o

TOPIRAMATE

Acute Glaucoma, heat stroke,

Kidney Stones

TIAGABINE

Status

Epilepticus

VIGABATRIN

Depression

Psychosis, Visual

Field Defects

Slide10

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 seizuresIncludes sustained release formulations

Revolutionary DrugsDrugs that work with new mechanisms never tried beforeExpectation: They will control seizures that existing drugs can’

t control

Slide11

What

’

s “new” in AEDs?

One new drug approved June 2011RevolutionaryRetigabine (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)

Slide12

Compounds which are second or third generation derivatives of AEDs introduced before 1970

1

st

Generation

AED

CarbamazepineeTegretol

TM

Valproic Acid

Depakote TM

2

nd Generation AED

Oxcarbazepine

Valrocemide

(SPD–493)

Valnoctamide

3rd

Generation AED

Eslicarbazepine Acetate(BIA 2-093)

Phenobarbital

T2000

Perucca et al, Lancet Neurol

,

2007

Slide13

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

Slide14

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 %

Slide15

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.

Slide16

Blue Discoloration

Slide17

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.

Slide18

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 firstWill be submitted to FDA this year

Slide19

Placebo

(n=119)

Perampanel

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

Slide20

Side effects (add-on)

1

Several cases of “severe aggression”/homicidal ideation

(Black box warning)

TEAEs, treatment-emergent adverse events

Placebo

Perampanel

Treatment emergent Side effects %

N

(n=121)

8 mg

(n=133)

12 mg

(n=134)

Side

effectss

leading to study or study drug withdrawal

43

6.6

6.8

19.4

Most common

(

≥10%)

Dizziness

113

9.9

37.6

38.1

Sleepiness

63

13.2

18.0

17.2

Irritability

35

5.0

7.5

14.2

Headache

54

13.2

15.0

13.4

Fall

38

6.6

9.8

12.7

Unsteadiness

24

0

6.0

11.9

French et al Neurology® 2012;79:589–596

Slide21

What is exciting about

Perampanel

?

First late-stage drug that works on excitatory mechanismsAlso has only be tried on focal seizuresStudy for (genetic) generalized tonic-clonic seizures almost completeWe have not explored the long-term potential for drugs that impact excitatory, rather than inhibitory mechanisms

Slide22

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 decadesWhen oxcarbazepine enters the body, it is transformed into 2 mirror-image molecules(R-licarbazepine and S-Licarbazepine).

R-licarbazepine

OXCARBAZEPINE

S-Licarbazepine

Slide23

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

Slide24

Is it better than

Oxcarbazepine

?

Less effect on blood chemistry (sodium)Smoother release may reduce side effects related to fluctuation of drug levels in bloodstreamOnce daily administrationHopefully will work equally as wellIt remains to be seen whether it is better than Trileptal overallApproved in Europe 18 months ago as “Zebenix

”.

Slide25

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

Slide26

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 glucoseNo effect on body weightRash in 3%

Verrotti et al, Epilepsy Research 2014: 108: 1-10

Slide27

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,

Slide28

12

Drug Concentration

Time (hrs)

6

24

18

Risk of

side effects

Risk of seizure breakthrough

Immediate vs slow release

Cmax

Cloyd, 1998

Slide29

12

Drug Concentration

Time (hrs)

6

24

18

Risk of

side effects

Risk of seizure breakthrough

Immediate

vs

slow

release: Dose increase

Cmax

Cloyd, 1998

Slide30

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

Slide31

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

Slide32

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.12207http://onlinelibrary.wiley.com/doi/10.1111/ane.12207/full#ane12207-fig-0003

Slide33

Extended‐release

oxcarbazepine

(Oxtellar

) Side effects

Slide34

Topiramate Sustained Release

Topiramate

, less difference between

peak and troughWould it be enough to make a difference?

Slide35

PREVAIL: Titration and maintenance phases

Chung et al. In preparation.

Slide36

Topiramate

immediate release (Topamax) add-on study in focal

seizuresstudy

Slide37

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.

Slide38

Overall safety profile:

Qudexy

XR (sustained release topiramate

) vs placeboSide 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.

Slide39

Side effects

related to cognitive and

neuropsychiatric functioning

Preferred Term, N (%)USL255N=124

PlaceboN=125Any neurocognitive TEAE

16 (12.9)5 (4.0)

Neurocognitive TEAEs

Aphasia3 (2.4%)

0 Dysarthria

3 (2.4%)1 (0.8%)

Disturbance in attention3 (2.4%)

4 (3.2%) Memory impairment

3 (2.4%)1 (0.8%) Psychomotor retardation

3 (2.4%)0 Bradyphrenia

2 (1.6%)1 (0.8%) Amnesia

1 (0.8%)0 Cognitive disorder

1 (0.8%)0 Confusional state

1 (0.8%)0 Encephalopathy

1 (0.8%)0 Mental impairment 1 (0.8%)

0 Speech disorder1 (0.8%)

0 Thinking abnormal1 (0.8%)

0Note: Preferred terms are in descending order of frequency as reported in the USL255 treatment group

Slide40

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 hasDrug causes significant weight gain-Drug is associated with depressionDrug interacts with another medication the person is taking

Slide41

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?

Slide42

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 itThis would be enough to rule out an unexpected side effect with a frequency of 1/1500

Slide43

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