what’s new in antiepileptic drugs jacqueline a. french, m.d. nyu comprehensive epilepsy center
TRANSCRIPT
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