What’s New In Antiepileptic Drugs

Jacqueline A. French, M.D.

NYU Comprehensive Epilepsy Center

ANTIEPILEPTIC DRUG DEVELOPMENT

1840 1860 1880 1900 1920 1940 1960 1980 20000

5

10

15

20

BromidePhenobarbital

Phenytoin Primidone

Ethosuximide

Sodium Valproate

Benzodiazepines

Carbamazepine

Zonisamide

Felbamate

Gabapentin

Topiramate Fosphenytoin

OxcarbazepineTiagabine

Levetiracetam

RufinamideLacosamideBrivaracetam

Pregabalin

Retigabine

?

Calendar Year

Nu

mb

er o

f L

icen

sed

An

tiep

ilep

tic

Dru

gs

Lamotrigine

SINCE 1998

20000

5

10

20

Zonisamide

Felbamate

Gabapentin

Topiramate Fosphenytoin

OxcarbazepineTiagabineLevetiracetam

Pregabalin

Calendar Year

Nu

mb

er o

f L

icen

sed

An

tiep

ilep

tic

Dru

gs

Lamotrigine

1990

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

How do we make progress?

• Revolutionary Drugs– Drugs that work with new mechanisms never

tried before– Expectation: They will control seizures that

existing drugs can’t control

• Evolutionary Drugs– Improve on existing drugs– Expectation: We can eliminate some of the

problems/side effects of good drugs, without reducing their effect on seizures

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

1st Generation AED

CarbamazepineeTegretol TM

Valproic AcidDepakote TM

2nd Generation AED

OxcarbazepineValrocemide

(SPD–493)

Valnoctamide3rd Generation AED

Licarbazepine

(MHD)

Eslicarbazepine Acetate

(BIA 2-093)

N

CNH2O

CH3CH2CH2

CH3CH2CH2

CHCOOH

N

CNH2O

O

N

CNH2O

HO

*

N

CNH2O

*

O

H3CO

Phenobarbital

T2000

NH

NH

O

O

O

N

N

O

O

O

CH2OCH3

CH2OCH3

*

CH3CH2CH

CHCONH2

CH3

CH3CH2

CH3CH2CH2

CH3CH2CH2

CHCONHCH2CONH2

Perucca et al, Lancet Neurol, 2007

Compounds which are second generation derivatives of AEDs introduced after 1990

Gabapentin Lamotrigine Levetiracetam

Pregabalin JZP-4 Brivaracetam

(ucb 34714)

Seletracetam

(ucb 44212)XP-13512

Precursor CNS Drug Piracetam

COOHNH2

COOHNH2

*

HCH3

CH3

NO

H

H

O

NH2

NO

H

O

NH2

*

NO

H

O

NH2

*

*

NO

H

O

NH2

*

F2C *

1st Generation AED

2nd Generation AED

N

NN

ClNH2

Cl

H2N

N

N

ClNH2

Cl

H2N

Cl

COOHNH

OO

OO

Perucca et al, Lancet Neurol, 2007

What’s new this year?

• Two new drugs to be approved – Revolutionary

• Vimpat (lacosamide)• Inovelon (rufinamide)

• Four drugs in late trials– Evolutionary

• Rikelta (brivaracetam)• Eslicarbazepine

– Revolutionary:• Carisbamate• Retigabine

What’s new this year?

• Many drugs off/going off patent (going generic)– Neurontin (gabapentin)– Lamictal (lamotrigine)– Topamax (topiramate)– Trileptal (oxcarbazepine)– Keppra (levetiracetam)

What’s new this year?

• Two new trial designs endorsed by FDA– “Withdrawal to monotherapy”: Speed approval

for monotherapy– “Time to Nth seizure”: Create more “patient-

friendly trials

DRUGS THAT WORK IN NEW WAYS

retigabinelacosamide rufinamide

Lacosamide (RIKELTATM)

• Works on sodium channels, like Carbamazepine (Tegretol TM) and Phenytoin (DilantinTM)

• However, It selectively enhances slow inactivation of sodium channels, whereas the older drugs work on fast inactivation

• Approved in Europe, expected to be approved in US by December 2008

Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy:50% Responder Rates (n=418)

Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy:50% Responder Rates (n=418)

0

20

40

60

22%

41%*38%*

% P

atie

nts

33%

Placebo LCS 200mg LCS 400mg LCS 600mg

(* P<0.05 vs PL)

Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

 

Percentages are based on the number of patients in the randomized dose group who received at least one dose of trial

medication.

Lacosamide Treatment-emergent adverse events (%) leading to discontinuation in at least 5% of

patients in any treatment group

Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

RUFINAMIDE (INOVELONTM)

• Also works on sodium channels with new mechanism

• Approved in Europe for treatment of a severe form of epilepsy (Lennox-Gastaut syndrome)– “Orphan drug”

• In Front of FDA for Lennox-Gastaut and Partial seizures

Rufinamide Lennox-Gastaut Responder Rate:

Tonic-Atonic Seizure Frequency

21.9%

42.5%

60.3%

3.3%

28.3%

16.7%

0%

10%

20%

30%

40%

50%

60%

70%

Rufinamide Placebo

% o

f S

ub

jec

ts

≥75% ≥50% ≥25%

Seizure Reduction

P=0.0003

P=0.006

P=0.002

Rufinamide AEs With Incidence ≥3% vs Placebo: All Treated Subjects With

Epilepsy (Double-blind Only)

RufinamideN (%)

PlaceboN (%)

Subjects 1465 635

Subjects with an AE 1180 (80.5) 497 (78.3)

Somnolence 36 (17) 16 (8.1)

Vomiting 35 (16.5) 14 (7.1)

Headache 34 (16.0) 16 (8.1)

Nausea 16 (7.5) 7 (3.6)

Ataxia 10 (4.7) 1 (0.5)

Diplopia 10 (4.7) 1 (0.5

What we don’t know

What we know

LEVEL OF KNOWLEDGE AT TIME OF APPROVAL

What do we know about AEDs at time of approval?

• How the drug works in difficult to control seizures (proof that drug is better than placebo)

• Side effects when used at titration rates and doses employed in trials, over short term

• Safety in 1500-15,000 subjects

• Drug interactions

What don’t we know about AEDs at time of approval?

• How the drug works in other types of epilepsy• How the drug works in newly diagnosed

patients• Comparative data vs new or old AEDs• Impact at different ages

– Pediatric– Elderly

• Best dose, titration schedule• Some safety issues (including long-term)• How well the drug works by itself• Pregnancy effects

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)

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

Retigabine 1200 mg/day vs Placebo: Most Common Adverse Events (>10% incidence)

% Patients

Placebo

(N=152)RTG

(N=153)

Dizziness 14 40

Somnolence 17 31

Fatigue 8 16

Confusion 2 14

Dysarthria 2 12

Headache 18 12

Ataxia 4 12

Urinary tract infection 9 12

Tremor 4 11

Vision blurred 3 11

Nausea 7 10

• Adverse event as primary reason for discontinuationRTG

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

Discontinuations Due to Adverse Events

*Dose-related

OLD MECHANISM-MORE POWERFUL/SAFER

Brivaracetam

N

CNH2O

*

O

H3CO

Eslicarbazepine Acetate

BRIVARACETAM

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

• Also has sodium channel blocking activity

• FDA trials underway

reference 0-20 20-40 40-60 60-80 80-100 100-1200

100

200

300

400

500

Control5.4 mg/kg i.p.17.0 mg/kg i.p.170 mg/kg i.p.

periodMinutes of testing

Me

an

du

ratio

n o

f S

WD

s (s

)

Values given are means ± S.D. (n=8)

Genetic Absence Epilepsy Rats from Strasbourg

Levetiracetam

Genetic Absence Epilepsy Rats from Strasbourg

reference 0-20 20-40 40-60 60-80 80-100 100-1200

100

200

300

400

500

Control

2.1 mg/kg i.p.

6.8 mg/kg i.p.

68 mg/kg i.p.

periodMinutes of testing

Mea

n du

ratio

n of

SW

Ds

(s)

Values given are means ± S.D. (n=8)

seletracetam

Efficacy of Brivaracetam (5, 20 and 50 mg/day) Add-on Treatment in Refractory Partial-Onset

Epilepsy SEIZURE-FREEDOM

RATES

RESPONDER RATES

ITT population: n=208; 110M, 98F; age range 16–65 yITT population: n=208; 110M, 98F; age range 16–65 y

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

den

ts

PBO(n=54)

BRV5(n=50)

BRV20(n=52)

BRV50(n=52)

0

10

% P

atie

nts

1.9%1/54

8.0%4/50

7.7%4/52

7.7%4/52

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

• 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

Many Drugs going off Patent

• This allows multiple (generic) companies to make the drug, in addition to the brand manufacturer

• At same dose, two formulations must be within (80%-125%) of amount in brand, with 90% assurance.

• Different generic brands could be either high or low

• If a physician does not check the “do not substitute” box, insurance companies are at liberty to switch patients to generic

Source: WKH PHAST TRX and Sales data factored by Verispan PDDANote: Celexa included as a reference of typical generic erosion

Pres

crip

tion

Generic Erosion

Bra

nd T

Rx

as P

erce

nt o

f Tot

al M

olec

ule

0%

20%

40%

60%

80%

100%

Month

0

Month

4

Month

8

Month

12

Month

16

Month

20

Month

24

Celexa (REF) Neurontin

Zonegran Trileptal

Many Drugs going off Patent

• Generics may be very good and close to the brand; The problem is that EACH TIME a new prescription is filled, it can be filled with a different company’s generic, which could be high or low.

• No well performed blinded studies to assess risk from switching between generics

• Excipients and colorants may be different, leading to potential for allergic reactions

• Dissolution properties may vary

• Risks of generics should be weighed against cost benefits1

1Epilepsy Foundation. Statement on substitution of generic antiepileptic drugs.

Changing to Generic (or to Brand)

• Baseline levels• Check level again when stable on new

preparation• Ideally limit changes between different generic

manufacturers• Report suspected problems (preferably with

documentation) to FDA MedWatch (http://www.fda.gov/medwatch/)!

The Epilepsy Study Consortium

• Sponsored by Epilepsy TherapyDevelopment Project and FACES• Group of Epilepsy Centers who work together to write protocols, bring better

drugs forward, Maintain the focus of drug development on

helping people with epilepsy, NOT comercial concerns of pharmaceutical companies!

The future

• Need active pipeline with good compounds moving through

• Need better trial designs– Shorten placebo period?– Weed out effective drugs from non-effective– Improve risk-benefit

• Acceptance by FDA of 2 new trial designs will speed good therapies