Transcript Morning Keynote Address: New Drugs and Rescue

New Antiepileptic drugs
Jacqueline A French MD
NYU Comprehensive Epilepsy Center
ANTIEPILEPTIC DRUG
DEVELOPMENT
eslicarbazepine
Retigabine
Number of Licensed Antiepileptic Drugs
Rufinamide
20
Perampanel
Vigabatrin
Pregabalin
Lacosamide
Zonisamide
Levetiracetam
Levetiracetam
Tiagabine
Oxcarbazepine
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
DO WE NEED MORE NEW
EPILEPSY 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
The course of drug development
• Pre-Clinical testing
10,000
Compounds
250
Get to Animal
Testing
10
Reach Human
Trials
• Phase I
– Testing in about 100 normal volunteers
– Developer needs to get approval from FDA in the
form of an NDA (new drug application)
• Phase II/III
– Tests to determine if therapy is safe and effective
Double-blind placebo-controlled
trial for FDA approval
Dose 2 + AEDs
Dose 1 + AEDs
1-2 AEDs
Baseline
Placebo + AEDs
Titration
Treatment
Taper
(double-blind)
+ follow up
What do we know about new epilepsy
drugs when they are approved by FDA?
• Ability to control seizures in one epilepsy type
(focal seizures) in patients who have failed
other drugs (treatment resistant) as measured
in randomized controlled trials (proof that
drug is better than placebo/sugar pill)
• Tolerability when use doses employed in trials,
over short term
• Safety in 1500-15,000 subjects
What don’t we know about epilepsy
drugs at time of FDA approval?
• Ability to control seizures in most seizure
syndromes
• Ability to control seizures in newly
diagnosed patients
• Comparative data vs new or old AEDs
• Effectiveness/tolerability in children
• Some safety issues (including long-term)
• Data on using the drug by itself
(monotherapy)
LEVEL OF KNOWLEDGE AT TIME OF APPROVAL
What we
know
What we don’t know
SERIOUS ISSUES IDENTIFIED BEFORE
AND AFTER FDA APPROVAL
Drug
BEFORE
APPROVAL
AFTER
APPROVAL
FELBAMATE
Rash, Serious rash
(Steven’s Johnson)
Fatal Aplastic Anemia
Liver failure
LAMOTRIGINE
Rash, Serious rash
(Steven’s Johnson)
Risk < 16 y.o
TOPIRAMATE
Acute Glaucoma, heat
stroke, Kidney Stones
TIAGABINE
Status Epilepticus
VIGABATRIN
Depression
Psychosis, Visual Field
Defects
How do we make progress?
• 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
– Includes sustained release
formulations
• Revolutionary Drugs
– Drugs that work with new
mechanisms never tried before
– Expectation: They will control
seizures that existing drugs can’t
control
What’s “new” in AEDs?
• One new drug approved June 2011
– Revolutionary
• Retigabine (Potiga)
• Two novel drug approved within last 12 months!
– Revolutionary:
• Perampanel (Fycompa)
– Evolutionary:
• Eslicarbazepine (Aptiom)
• Three sustained release formulations approved
– Oxtellar (sustained release oxcarbazepine)
– Trokendi (sustained release topiramate)
– Qudexy (sustained release topiramate)
Compounds which are second or third generation
derivatives of AEDs introduced before 1970
O
O
C
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
2nd Generation
C
O
NH
AED
Oxcarbazepine
2
O
N
O
CH 2OCH 3
T2000
CH3CH2CH2
CHCONHCH2CONH2
CH3CH2CH2
Valrocemide
(SPD–493)
CH3CH2
* CHCONH2
CH3CH2CH
CH3
H3 C
O
O
3rd
Generation
AED
Valnoctamide
*
N
O
C
NH 2
Eslicarbazepine
Acetate
Perucca et al, Lancet Neurol, 2007
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)
• Approved for add-on treatment in partial seizures
only
Patients with >50% Seizure Reduction during 3 month
study (USA)
% Patients
Study 301
18%
56 %
82 %
Placebo
2
44 %
French et al Neurology. 2011 May 3;76(18):1555-63
1200 RTG
Black Box Warning
• Initially approved in the US in 2010, with
concerns about bladder abnormalities
• In spring 2013 The FDA notified physicians about
risks of abnormalities to the retina (back of the
eye), potential vision loss, and skin discoloration,
all of which may become permanent.
• The revised label includes a new boxed warning,
the most serious type of warning FDA gives,
because of the risk of abnormalities in the retina.
Blue Discoloration
• They advise that Potiga use be limited to patients
who have not responded adequately to several
alternative therapies to decrease the frequency
of seizures, or epilepsy, and for whom the
benefits of treatment outweigh the risks.
• FDA recommends that patients have eye exams
by an ophthalmic professional before starting
Potiga and every six months during treatment.
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
Perampanel : Percent change in seizure
frequency during maintenance phase
(Study 304)
26 %
74 %
Placebo
(n=119)
French et al Neurology® 2012;79:589–596
37 %
64%
36 %
63 %
Perampane
l 8 mg/day
(n=132)
Perampanel 12
mg/day (n=130)
Side effects (add-on)1
Placebo
(n=121)
8 mg
(n=133)
12 mg
(n=134)
43
6.6
6.8
19.4
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
Unsteadiness
24
0
6.0
11.9
Treatment emergent Side effects %
Side effectss leading to study or study drug
withdrawal
N
Perampanel
Most common (≥10%)
TEAEs, treatment-emergent adverse events
• Several cases of “severe aggression”/homicidal ideation
(Black box warning)
French et al Neurology® 2012;79:589–596
What is exciting about Perampanel?
• First late-stage drug that works on excitatory
mechanisms
• Also has only be tried on focal seizures
– Study for (genetic) generalized tonic-clonic
seizures almost complete
• We have not explored the long-term potential
for drugs that impact excitatory, rather than
inhibitory mechanisms
What is Eslicarbazepine Acetate
• Not a completely new drug
• It is closely related to the drug
Oxcarbazepine (trileptal)
which has been on the market
for several decades
• When oxcarbazepine enters
the body, it is transformed into
2 mirror-image molecules
(R-licarbazepine and SLicarbazepine).
OXCARBAZEPINE
SLicarbaz
Repine
licarbaze
pine
What is Eslicarbazepine Acetate
• Eslicarbazepine acetate
enters the body and is
transformed into one of
these molecules (Slicarbazepine)
• Since everyone taking
oxcarbazepine has Slicarbazepine circulating in
their body, we don’t expect
any new surprise side effects
(but we do expect some of
the same side effects we
have already seen with
oxcarbazepine)
Eslicarbazepine Acetate
S-Licarbazepine
Is it better than Oxcarbazepine?
• Less effect on blood chemistry (sodium)
• Smoother release may reduce side effects
related to fluctuation of drug levels in
bloodstream
• Once daily administration
• Hopefully will work equally as well
• It remains to be seen whether it is better than
Trileptal overall
• Approved in Europe 18 months ago as
“Zebenix”.
Response Rate (%)
Results from 3 Eslicarbazepine Pivotal Trials:
50% Responder Rates
50
45
40
35
30
25
20
15
10
5
0
PL
ESL 400 mg od
ESL 800 mg od
ESL 1200 mg od
Study
BIA-2093-301
Study
BIA-2093-302
Study
BIA-2093-303
800 mg and 1200 mg doses were statistically significant; 400 mg was not.
Verrotti et al, Epilepsy Research 2014: 108:McCormack
1-10 PL, et al. CNS Drugs. 2009. 23(1):71-9.
Side effects
• Most common Side effects: dizziness, sleepiness,
headache, nausea, vomiting, double vision, abnormal
coordination
• Low incidence of low blood sodium(.6-1.3%)
• This is better than trileptal
• Not associated with changes in total cholesterol, low
density lipoprotein (LDL) levels, and glucose
• No effect on body weight
• Rash in 3%
Verrotti et al, Epilepsy Research 2014: 108: 1-10
Can a modified release formulation
of an AED be useful?
YES,
• If there are substantial ups and downs in medicine amounts
in the blood
• If either the peaks produce side effects, or the troughs
produce seizure breakthroughs
• If toxicity at the peak prevents ability to increase dose, and
increased dose is likely to improve seizure control
Immediate vs slow release
Cmax
Risk of side
effects
Risk of
seizure
breakthrough
12
6
Cloyd, 1998
Time
(hrs)
18
2
4
Immediate vs slow release: Dose
increase
Cmax
Risk of side
effects
Risk of
seizure
breakthrough
12
6
Cloyd, 1998
Time
(hrs)
18
2
4
Immediate Release Oxcarbazepine
Higher plasma [MHD] were associated with
larger decreases in seizures frequency p=0.0001
Seizure freedom
22%
10%*
3%*
.6%*
Barcs, Epilepsia, 41(12):1597–1607, 2000
OXC add on: Patients %
Discontinued
73%*
45%
28%
22%
*An additional 7% had to reduce dose to 1800 mg, leaving only 20%
who completed on 2400 mg/day
Barcs, Epilepsia, 41(12):1597–1607, 2000
Efficacy and safety of extended‐release oxcarbazepine (Oxtellar XR™)(Add-on focal
seizures, US population)
Acta Neurologica Scandinavica
Volume 129, Issue 3, pages 143-153, 21 DEC 2013 DOI: 10.1111/ane.12207
http://onlinelibrary.wiley.com/doi/10.1111/ane.12207/full#ane12207-fig-0003
Extended‐release oxcarbazepine
(Oxtellar) Side effects
Topiramate Sustained Release
• Topiramate, less
difference between
peak and trough
• Would it be enough to
make a difference?
PREVAIL: Titration and maintenance
phases
Chung et al. In preparation.
Topiramate immediate release
(Topamax) add-on study in focal
seizuresstudy
Median Percent Reduction from Baseline
in Weekly seizure Frequency
Reduction in seizure frequency
topiramate 200 mg sustained release
(Qudexy)
50
Combined titration and maintenance phase
40
39.5%
18.5% treatment
effect on seizure
reduction
30
20
21.65%
10
0
Chung et al. In preparation.
USL255
(N=124)
Placebo
(N=125)
Overall safety profile: Qudexy XR
(sustained release topiramate) vs
placebo
• Side effects deemed related to study drug
reported in ≥5% of subjects were:
– Somnolence (12.1% vs 2.4%)
– Dizziness (7.3% vs 5.6%)
– Paraesthesia (6.5% vs 2.4%)
– Weight decrease (6.5% vs 0)
– Fatigue (5.6% vs 4.8%)
Chung et al. In preparation.
Side effects related to cognitive and
neuropsychiatric functioning
Preferred Term, N (%)
USL255
N=124
Placebo
N=125
Any neurocognitive TEAE
16 (12.9)
5 (4.0)
Neurocognitive TEAEs
Aphasia
Dysarthria
Disturbance in attention
Memory impairment
Psychomotor retardation
Bradyphrenia
Amnesia
Cognitive disorder
Confusional state
Encephalopathy
Mental impairment
Speech disorder
Thinking abnormal
3 (2.4%)
3 (2.4%)
3 (2.4%)
3 (2.4%)
3 (2.4%)
2 (1.6%)
1 (0.8%)
1 (0.8%)
1 (0.8%)
1 (0.8%)
1 (0.8%)
1 (0.8%)
1 (0.8%)
0
1 (0.8%)
4 (3.2%)
1 (0.8%)
0
1 (0.8%)
0
0
0
0
0
0
0
Note: Preferred terms are in descending order of frequency as reported in the USL255 treatment group
Should you try a new antiepileptic
drug?
• Although there are many available drugs, many
may have features that make them a poor match
for a specific person
• For example:
– Drug does not treat the type of seizures the person
has
– Drug causes significant weight gain
– -Drug is associated with depression
– Drug interacts with another medication the person is
taking
Should you try a new antiepileptic
drug?
• If you have tried the available appropriate
AEDs, and they have not worked
– How do you know? Discuss with your physician
• Discuss the risks and benefits:
– data that is available about impact on seizures,
and what is known about the side effects.
• Discuss the epilepsy types that have been
studied in trials: Is yours among them?
Should you try a new antiepileptic
drug?
• How many people have taken the drug so far?
– Typically 3-5,000 have taken it before the FDA
approves it
– This would be enough to rule out an unexpected
side effect with a frequency of 1/1500
Summary
• There are interesting novel evolutionary and
revolutionary drugs in the pipeline, with more
coming behind
• Sometimes a small change (such as
formulation) can make a big difference
• Potential for new screening models makes the
future potentially even more promising