New Antiepileptic drugs Jacqueline A French MD NYU Comprehensive Epilepsy Center
Dec 22, 2015
New Antiepileptic drugs
Jacqueline A French MDNYU 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
Calendar Year
Nu
mb
er o
f L
icen
sed
An
tiep
ilep
tic
Dru
gs
Lamotrigine
Vigabatrin
Perampanel
Retigabine
Levetiracetam
eslicarbazepine
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 10,000Compounds
• 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
250
Get to AnimalTesting
10
Reach Human Trials
Double-blind placebo-controlled trial for FDA approval
Baseline Titration
1-2 AEDs Placebo + AEDs
Dose 1 + AEDs
Dose 2 + AEDs
Taper(double-blind)
+ follow upTreatment
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)
What we don’t know
What we know
LEVEL OF KNOWLEDGE AT TIME OF APPROVAL
SERIOUS ISSUES IDENTIFIED BEFORE AND AFTER FDA APPROVAL
Drug BEFORE APPROVAL
AFTER APPROVAL
FELBAMATE Rash, Serious rash (Steven’s Johnson)
Fatal Aplastic AnemiaLiver 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
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
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)
Study 301
% P
atien
ts
1200 RTG
2 French et al Neurology. 2011 May 3;76(18):1555-63
82 %
18%
Placebo
44 %56 %
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
Placebo (n=119)
Perampanel 8 mg/day
(n=132)
Perampanel 12 mg/day (n=130)
Perampanel : Percent change in seizure frequency during maintenance phase
(Study 304)
74 %63 %
37 %36 %
64%
26 %
French et al Neurology® 2012;79:589–596
Side effects (add-on)1
• Several cases of “severe aggression”/homicidal ideation (Black box warning)
TEAEs, treatment-emergent adverse events
Placebo Perampanel
Treatment emergent Side effects %N
(n=121)
8 mg(n=133)
12 mg (n=134)
Side effectss 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
Unsteadiness 24 0 6.0 11.9
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 S-Licarbazepine).
R-licarbaze
pine
OXCARBAZEPINE
S-Licarbazepine
What is Eslicarbazepine Acetate
• Eslicarbazepine acetate enters the body and is transformed into one of these molecules (S-licarbazepine)
• Since everyone taking oxcarbazepine has S-licarbazepine 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-Licarbaz-epine
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”.
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.
Verrotti et al, Epilepsy Research 2014: 108: 1-10
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?
• 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
YES,
12
Dru
g C
once
ntra
tion
Time (hrs)
6 24
18
Risk of side effects
Risk of seizure
breakthrough
Immediate vs slow release
Cmax
Cloyd, 1998
12
Dru
g C
once
ntra
tion
Time (hrs)
6 24
18
Risk of side effects
Risk of seizure
breakthrough
Immediate vs slow release: Dose increase
Cmax
Cloyd, 1998
Immediate Release Oxcarbazepine
Median %
sz reduction .6%*
3%*
10%*22%
Higher plasma [MHD] were associated withlarger decreases in seizures frequency p=0.0001
Seizure freedom
Barcs, Epilepsia, 41(12):1597–1607, 2000
OXC add on: Patients % Discontinued
28%22%
45%
73%*
*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 ScandinavicaVolume 129, Issue 3, pages 143-153, 21 DEC 2013 DOI: 10.1111/ane.12207http://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
Reduction in seizure frequency topiramate 200 mg sustained release
(Qudexy)
USL255(N=124)
Placebo(N=125)
0
10
20
30
40
50
39.5%
21.65%
Me
dia
n P
erc
en
t R
ed
uc
tio
n f
rom
Ba
se
lin
e
in W
ee
kly
se
izu
re F
req
ue
nc
y
18.5% treatment effect on seizure
reduction
Combined titration and maintenance phase
Chung et al. In preparation.
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 (%) USL255N=124
PlaceboN=125
Any neurocognitive TEAE 16 (12.9) 5 (4.0)Neurocognitive TEAEs Aphasia 3 (2.4%) 0 Dysarthria 3 (2.4%) 1 (0.8%) Disturbance in attention 3 (2.4%) 4 (3.2%) Memory impairment 3 (2.4%) 1 (0.8%) Psychomotor retardation 3 (2.4%) 0 Bradyphrenia 2 (1.6%) 1 (0.8%) Amnesia 1 (0.8%) 0 Cognitive disorder 1 (0.8%) 0 Confusional state 1 (0.8%) 0 Encephalopathy 1 (0.8%) 0 Mental impairment 1 (0.8%) 0 Speech disorder 1 (0.8%) 0 Thinking abnormal 1 (0.8%) 0Note: 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