jacqueline french, md
DESCRIPTION
New Concepts, Old Dilemmas: Drugs on the Horizon and Generic SubstitutionTRANSCRIPT
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/)!