Transcript Advances in Epilepsy Research

What’s New In Antiepileptic
Drugs
Jacqueline A. French, M.D.
NYU Comprehensive Epilepsy
Center
Number of Licensed Antiepileptic Drugs
ANTIEPILEPTIC DRUG
DEVELOPMENT
?
20
Retigabine
Rufinamide
Lacosamide
Brivaracetam
Pregabalin
Zonisamide
Levetiracetam
Oxcarbazepine
Tiagabine
15
Fosphenytoin
Topiramate
Lamotrigine
Gabapentin
10
Felbamate
Sodium Valproate
Carbamazepine
Ethosuximide
5
Phenytoin
Phenobarbital
Benzodiazepines
Primidone
Bromide
0
1840
1860
1880
1900
1920
1940
Calendar Year
1960
1980
2000
Number of Licensed Antiepileptic Drugs
SINCE 1998
20
Pregabalin
10
Zonisamide
Levetiracetam
Tiagabine Oxcarbazepine
Topiramate
5
Fosphenytoin
Lamotrigine
Gabapentin
Felbamate
0
1990
2000
Calendar Year
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
O
C
O
CH 3CH2CH 2
NH
N
O
NH
NH 2
O
1st
Generation
AED
Carbamazepinee
Tegretol TM
Phenobarbital
CHCOOH
CH 3CH2CH 2
Valproic Acid
Depakote TM
O
O
CH 2OCH 3
N
N
O
2nd Generation
C
O
NH
AED
Oxcarbazepine
N
2
O
T2000
H3 C
O
(SPD–493)
CH3CH2
* CHCONH2
CH3CH2CH
CH3
*
*
Valnoctamide
N
N
O
Valrocemide
O
HO
3rd Generation
AED
CH 2OCH 3
CH3CH2CH2
CHCONHCH2CONH2
CH3CH2CH2
C
NH 2
Licarbazepine
(MHD)
O
C
NH 2
Eslicarbazepine
Acetate
(BIA 2-093)
Perucca et al, Lancet Neurol, 2007
Compounds which are second generation
derivatives of AEDs introduced after 1990
N
O
O
H
Precursor CNS
Drug
NH2
H
Piracetam
NH 2
COOH
N
N
Cl
1st Generation
AED
Cl
H2N
Gabapentin
*
N
O
NH2
H
N
O
NH2
Lamotrigine
Levetiracetam
O
O
Cl
O
NH2
*
2nd Generation
AED
COOH
O
NH
COOH
CH3
N
CH3
XP-13512
Perucca et al, Lancet Neurol, 2007
O
*
Cl
H2N
N
JZP-4
NH2
H
*
O
N
Cl
H
Pregabalin
F2C
*
N
*
NH2
H
O
O
NH2
Brivaracetam Seletracetam
(ucb 34714)
(ucb 44212)
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 “patientfriendly trials
DRUGS THAT WORK IN
NEW WAYS
lacosamide
rufinamide
retigabine
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)
60
% Patients
41%*
38%*
40
33%
(* P<0.05
vs PL)
22%
20
0
Placebo
LCS 200mg
LCS 400mg
LCS 600mg
Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive
Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007
Lacosamide Treatment-emergent adverse events
(%) leading to discontinuation in at least 5% of
patients in any treatment group
Percentages are based on the number of patients in the
randomized dose group who received at least one dose of trial
medication.
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
Rufinamide
Placebo
P=0.0003
70%
60.3%
% of Subjects
60%
P=0.002
50%
40%
30%
42.5%
P=0.006
28.3%
21.9%
16.7%
20%
10%
3.3%
0%
≥75%
≥50%
Seizure Reduction
≥25%
Rufinamide AEs With Incidence ≥3% vs
Placebo: All Treated Subjects With
Epilepsy (Double-blind Only)
Rufinamide
N (%)
Placebo
N (%)
1465
635
1180 (80.5)
497 (78.3)
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
Subjects
Subjects with an AE
Somnolence
LEVEL OF KNOWLEDGE AT TIME OF APPROVAL
What we
know
What we don’t know
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)
Study 302
Study 301
% Patients
60
50
44%**
39%**
40
31%*
30
20
18%
17%
10
0
179
181
178
Placebo
600
900
152
Placebo 1200 RTG
RTG
Intent-to-treat
*p<0.005
153
**p<0.001
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
Discontinuations Due to Adverse
Events
• Adverse event as primary reason for discontinuation
RTG
Placebo
(N=331)
600
(N=181)
900
(N=178)
1200
(N=153)
8%
14%
26%
27%
• Cause for discontinuation in >3% of patients
–
–
–
–
*Dose-related
Dizziness*
Confusion*
Somnolence
Fatigue
OLD MECHANISM-MORE
POWERFUL/SAFER
H3 C
O
O
*
N
O
Brivaracetam
C
NH 2
Eslicarbazepine Acetate
BRIVARACETAM
• Similar mechanism to Levetiracetam
(KeppraTM) but much stronger in animal
models
• Also has sodium channel blocking activity
• FDA trials underway
Genetic Absence Epilepsy Rats from Strasbourg
Mean duration of SWDs (s)
500
Levetiracetam
400
300
Control
5.4 mg/kg i.p.
17.0 mg/kg i.p.
170 mg/kg i.p.
200
100
0
reference 0-20
period
Values given are means ± S.D. (n=8)
20-40
40-60
60-80
Minutes of testing
80-100 100-120
Genetic Absence Epilepsy Rats from Strasbourg
seletracetam
Mean duration of SWDs (s)
500
400
300
Control
2.1 mg/kg i.p.
6.8 mg/kg i.p.
68 mg/kg i.p.
200
100
0
reference 0-20
period
Values given are means ± S.D. (n=8)
20-40
40-60
60-80 80-100 100-120
Minutes of testing
Efficacy of Brivaracetam (5, 20 and 50 mg/day)
Add-on Treatment in Refractory Partial-Onset
Epilepsy
RESPONDER RATES
p = 0.001
55.8%
60
40
8.0%
4/50
7.7%
4/52
7.7%
4/52
BRV5
(n=50)
BRV20
(n=52)
BRV50
(n=52)
% Patients
% Respondents
10
p = 0.002
44.2%
50
p = 0.047
32.0%
30
20
SEIZURE-FREEDOM
RATES
16.7%
1.9%
1/54
10
0
0
PBO
(n=54)
BRV5
(n=50)
BRV20
(n=52)
BRV50
(n=52)
ITT population: n=208; 110M, 98F; age range 16–65 y
PBO
(n=54)
Brivaracetam Adverse Events
Patients (N)
Permanent study drug
discontinuation
Patients with ≥1 AE, n (%)
Total AEs
PBO
BRV5
BRV20
BRV50
54
50
52
52
2 (3.7)
3 (6.0)
1 (1.9)
0
26
(52.0)
50
29
(55.8)
72
28
(53.8)
56
29 (53.7)
59
AEs reported in ≥ 5% patients
Headache
4 (7.4)
4 (8.0)
2 (3.8)
1 (1.9)
Somnolence
4 (7.4)
1 (2.0)
3 (5.8)
3 (5.8)
Influenza
4 (7.4)
4 (8.0)
0
1 (1.9)
Dizziness
3 (5.6)
1 (2.0)
0
4 (7.7)
Neutropenia
1 (1.9)
4 (8.0)
2 (3.8)
0
Fatigue
2 (3.7)
0
2 (3.8)
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
100%
80%
60%
40%
20%
Celexa (REF)
Neurontin
Zonegran
Trileptal
Source: WKH PHAST TRX and Sales data factored by Verispan PDDA
Note: Celexa included as a reference of typical generic erosion
Month 24
Month 20
Month 16
Month 12
Month 8
Month 4
0%
Month 0
Brand TRx as Percent of Total Molecule
Prescription
Generic Erosion
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 Therapy
Development 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