New Horizons and Old Dilemmas: New AEDs and

Generics

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

Rufinamide

Lacosamide Pregabalin

RetigabineBrivaracetamEslicarbazepineClobazam

?

Calendar Year

Nu

mb

er o

f L

icen

sed

An

tiep

ilep

tic

Dru

gs

Lamotrigine

Vigabatrin

SINCE 1998

20000

5

10

20

Zonisamide

Felbamate

GabapentinTopiramate

Fosphenytoin

Oxcarbazepine

Tiagabine

Levetiracetam

Pregabalin

Calendar Year

Nu

mb

er o

f L

icen

sed

An

tiep

ilep

tic

Dru

gs

Lamotrigine

1990

RufinamideLacosamide

2010

Vigabatrin

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

Eslicarbazepine Acetate

(BIA 2-093)

N

CNH2O

CH3CH2CH2

CH3CH2CH2

CHCOOH

N

CNH2O

O

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 Levetiracetam

Pregabalin Brivaracetam

(ucb 34714)

Precursor CNS Drug Piracetam

COOHNH2

COOHNH2

*

HCH3

CH3

NO

H

H

O

NH2

NO

H

O

NH2

*

NO

H

O

NH2

*

*

1st Generation AED

2nd Generation AED

Perucca et al, Lancet Neurol, 2007

What’s “new” this year?

• One “Old” drug finally coming to US– Frisium (clobazam)

• Benzodiazepine which is for chronic use• Has been available in Europe and Canada for decades• Studies for Lennox-Gastaut, soon to be submitted to FDA

• One new drug to be approved – Revolutionary

• Potiga (Retigabine)

• Three drugs in late trials– Evolutionary

• Rikelta (brivaracetam)• Stedesa (eslicarbazepine)

– Revolutionary:• Perampanel

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)

• Will be approved for add-on treatment in partial seizures only

• Was reviewed at an FDA advisory panel, received “approval” by panel, awaiting resolution of manufacturing issues for full approval

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

44%**

18%

39%**

31%*

17%

0

10

20

30

40

50

60Study 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– Rare bladder issues will require monitoring

Discontinuations Due to Adverse Events

*Dose-related

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 first

• Will be submitted to FDA this year

Placebo (n=119)

Perampanel 8 mg/day (n=132)

Perampanel 12 mg/day

(n=130)

Perampanel : Percent change in seizure frequency during maintenance

phase

Median % change in seizure frequency -22.86

-32.13 (P=0.08)

-39.48 (P=0.03)

-40

-30

-20

-10

0

-50

Treatment-emergent side effects (add-on)

TEAEs, treatment-emergent adverse events

Placebo Perampanel

Treatment emergent Side effects %N

(n=121)

8 mg(n=133)

12 mg (n=134)

TEAEs 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

Ataxia 24 0 6.0 11.9

OLD MECHANISM-MORE POWERFUL/SAFER

Brivaracetam (Rikelta)

N

CNH2O

*

O

H3CO

Eslicarbazepine Acetate (Stedesa)

BRIVARACETAM (Rikelta)

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

• Also has sodium channel blocking activity• Keppra causes irritability/depression in some

patients-unknown if Rikelta will have improved tolerability profile

• FDA trials underway. First study very positive, second study unclear, third trial underway

• First approval will be for add-on therapy for partial seizures. Other uses (eg for generalized seizures) will be explored later

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)

Problems with Carbamazepine

• Effective drug but…– Speeds metabolism through the liver,

causing:• Need for dose adjustment of other drugs that are

taken simultaneously• Changes (reduction) in levels of vitamins,

hormones• Increase in cholesterol levels, lipid levels• Reduction in sodium (salt) levels in the blood that

can lead to problems

Change in Cholesterol after removal of Tegretol or Dilantin

(First to second blood draw)

Mintzer S. et al Effects of antiepileptic drugs on lipids, homocysteine, andC-reactive protein. Ann Neurol. 2009 Apr;65(4):448-56.

Tegretol Dilantin CONTROL

Eslicarbazepine• A “third generation” Carbamazepine (TegretolTM)• Improves on second generation (TrileptalTM)

– Less effect on sodium– Smoother release may produce less side effects– Does not have the same impact on the liver

• Hopefully will work equally as well• Already approved in Europe as “Zebenix”. Will

be submitted to FDA for approval as add-on therapy of partial seizures

Results from 3 Eslicarbazepine Pivotal Trials:50% Responder Rates

PLESL 400 mg odESL 800 mg odESL 1200 mg od

StudyBIA-2093-301

Study BIA-2093-302

StudyBIA-2093-303

Res

po

nse

Rat

e (%

) 50454035302520151050

McCormack PL, et al. CNS Drugs. 2009. 23(1):71-9.800 mg and 1200 mg doses were statistically significant; 400 mg was not.

Integrated Analysis of 3 Phase III Studies : Safety Results

• Most common Side effects: dizziness, sleepiness, headache, nausea, vomiting, double vision, abnormal coordination

• Low incidence of hyponatremia

• Not associated with changes in total cholesterol, low density lipoprotein (LDL) levels, and glucose

• No systematic effect on body weight

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

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

Generics

• Drugs off patent (available in generic)– Dilantin (phenytoin)– Tegretol (carbamazepine)– Neurontin (gabapentin)– Lamictal (lamotrigine)– Topamax (topiramate)– Trileptal (oxcarbazepine)– Keppra (levetiracetam)– Zonisamide (Zonegran)

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

• 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.

Different generics can also look different than the brand, causing

confusion

Tegretol Carbamazepine (Generic)

Cost

• Most insurance companies charge some additional cost for branded drugs

• Some companies will only pay for generics if they are available

• The cost differential for some patients may be hundreds of dollars a month, making brand name simply unaffordable

Generic Carbamazepine Products May Show Large Variations

• Five generic carbamazepine formulation-FDA-approval packets were assessed, data obtained using the Freedom of Information Act

• Looked at two properties: Overall exposure (AUC) and maximum blood concentration (Cmax)

• The AUC & Cmax of three generics were accurate copies of Tegretol®

• For two generics, the mean AUC & CFor two generics, the mean AUC & Cmaxmax values were near values were near

the acceptance range of the acceptance range of TegretolTegretol®®

• Model of switches between two generic CBZ formulations produced AUC variations up to 21% & Cmax variations up to 40%

Chuang et al.,

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

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

• Dissolution properties may vary

Drug Must Be in Solution to be Absorbed

Drug in Blood

Solid Dosage Form

Dissolutionof Drug

Drug inSolution

ResultDesired pharmacological effect achieved (seizure reduction)

Active Drug Substances(continued)

Seven Possible Components of a Tablet

• Active Drug Substance (ADS)

• Binders

• Fillers

• Disintegrants

• Lubricants

• Colors

• Flavors

NOTE: The possible tablet components are rarely

The same for the Brand and its Generic counterpart.

Bioavailability

Physical characteristics of drug and composition of the tablet can effect the . . .

• Disintegration

• Dissolution

This can effect the way the drug acts in the body

Understanding Components

Active Drug SubstancesProperties/Attributes of Active Drug Substances (ADS)

• Polymorphic Crystal Form

• The Salt Form

• The Particle Size

• Hydrated vs. Anhydrous Form

• Wettability

• Solubility

• Impurity Profile

Sources may be different resulting in differences that

May or may not be important.

What Data Suggest Problems with Switching?

• Physician surveys• Switchback data (Canada)

– More patients with epilepsy switch back to brand after using generic

• Increase usage of Emergency services and overall health care after switch from brand to generic

• Generic savings partially offset by increased dose and increased use of other AED and non-AED after switch

Are these sources reliable?

• All these sources are subject to bias

• Patients are anxious after switch and may be more aware of problems– Remember emergent side effects on placebo)

Position StatementEpilepsy Foundation of America

Foundation Opposes Mandatory Substitution for Antiepileptic Drugs

The Epilepsy Foundation has had a historical position opposing mandatory substitution of generic drugs for brand name since generics first became available because of concerns about reported breakthrough seizures in some people with epilepsy when they are switched from one version of a medication to another. Other medical organizations focused on the treatment of epilepsy have had similar positions.

Position StatementAmerican Academy of Neurology (AAN)

The AAN, representing over 19,000 neurologists and neuroscience professionals, has taken an active interest in the clinical, ethical and policy considerations concerning the coverage of anticonvulsant drugs for people with epilepsy. The AAN opposes generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending physician’s approval.

The FDA has allowed for significant differences between name-brand and generic drugs. This variation can be highly problematic for patients with epilepsy. Even minor differences in the composition of generic and name-brand anticonvulsant drugs for the treatment of epilepsy can result in breakthrough seizures.

Bottom Line

• Generic Substitution has not been shown definitively to cause a problem– More studies needed

• Switching probably safe for most people

• May be a financial necessity for many

Who Should Be More Concerned?

• People whose seizures were controlled only after careful adjustment of one or more AEDs

• The elderly

• Patients taking multiple AEDs, who are at risk for drug interactions

Changing to Generic (or to Brand): Best practices

• Physician should get baseline drug 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/)!