The Importance of Clinical Trials: Getting New Therapies for
Epilepsy on the Market Jacqueline A. French, M.D. NYU Comprehensive
Epilepsy Center
Slide 2
The first randomized controlled trial: Lind s treatise on
scurvey Six groups (2 patients/group): 2pts : a quart of cider a
day 2pts: elixir of vitriol 2 pts: vinegar 2 pts: seawater 2pts:
mixture of garlic, mustard, spices 2pts: oranges and lemons Group
receiving oranges and lemons fit for duty in 6 days and began to
tend the other patients
Slide 3
Why do we do clinical trials? The American Public looks to its
government for assurance that therapies developed to treat diseases
are both SAFE and EFFECTIVE The Food and Drug Administration (FDA)
is charged with ensuring that safety and effectiveness are proven
before a drug is put on pharmacy shelves, or before a device is
marketed They are also responsible for LABELING drugs so that the
public is aware of risks and benefits There are very strict rules
that govern the conduct of clinical trials to determine safety and
efficacy (effectiveness) Without clinical trials, no new therapy
would be marketed!
Slide 4
The course of drug development Pre-Clinical testing 10,000
Compounds 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 Animal Testing 10 Reach Human Trials
Slide 5
The course of drug development Phase II/III (continued) For a
drug, at least 2 trials, (usually as add-on, i.e. new drug added on
to existing therapy) with a control group (usually placebo(sugar
pill)) Drug must be better than placebo Can see how frequent
dose-related side effects are compared to placebo It is essential
to make these trials as safe and patient-friendly as possible
Slide 6
How do new therapies get on the market? The cost of developing
a new drug is $800 million to 2 Billion and takes 12-15 years Most
drugs and devices (even if the idea comes from research labs or the
National Institutes of Health (NIH) will be tested by companies
that eventually will sell the product Private sector companies need
to partner with clinical researchers and doctors to perform good
trials People with epilepsy must enroll in trials in order for
drugs to obtain approval from FDA
Slide 7
Anti-seizure drugs All available therapies only treat symptoms
of epilepsy (seizures) We now call drugs that only address seizure
symptoms Anti-seizure drugs (ASDs) Most current clinical trials are
for testing of ASDs. Almost every person with epilepsy takes at
least one ASD
Dont take any of these red pills, and if that doesnt work, dont
take any of the blue ones Sometimes, we feel Like this
Slide 10
DO WE NEED MORE NEW ANTISEIZURE DRUGS? Problem with current
ASDs: Seizure control Newly diagnosed well treated Still 40% with
therapy resistance New ASDs over last 20 years have not
substantially changed this equation! Safety/tolerability Some new
(and old) ASDs still have important safety and tolerability
problems
Slide 11
ASDs: 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
Slide 12
The evolution is coming: Compounds which are 2 nd or 3 rd
generation derivatives of ASDs introduced before 1970 1 st
Generation AED Carbamazepinee Tegretol TM Valproic Acid Depakote TM
2 nd Generation AED Oxcarbazepine Valrocemide (SPD493) Valnoctamide
3 rd Generation AED Eslicarbazepine Acetate (BIA 2-093)
Phenobarbital T2000 Perucca et al, Lancet Neurol, 2007
Slide 13
Compounds which are second generation derivatives of AEDs
introduced after 1990 GabapentinLevetiracetam Pregabalin
Brivaracetam (ucb 34714) Precursor CNS Drug Piracetam 1 st
Generation AED 2 nd Generation AED Perucca et al, Lancet Neurol,
2007
Slide 14
What s new in ASDs? (Approved or close to approval) One drug
approved Revolutionary: Perampanel Two drugs in late trials
Evolutionary Rikelta (brivaracetam) Stedesa (eslicarbazepine
acetate)
Slide 15
Perampanel First ASD to work on excitation rather than
inhibition or stabilization of membranes take away the kindling
rather than putting a blanket on the fire Inhibits excitatory
chemical in the brain (AMPA) Approved for add-on treatment in
partial onset seizures (adults) October 2012
Slide 16
Placebo (n=119) Perampanel 8 mg/day (n=132) Perampanel 12
mg/day (n=130) Perampanel : Percent reduction 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
Slide 17
Treatment-emergent side effects (add-on) TEAEs,
treatment-emergent adverse events PlaceboPerampanel Treatment
emergent Side effects % N (n=121) 8 mg (n=133) 12 mg (n=134) TEAEs
leading to study or study drug withdrawal 436.66.819.4 Most common
(10%) Dizziness 1139.937.638.1 Sleepiness 6313.218.017.2
Irritability 355.07.514.2 Headache 5413.215.013.4 Fall386.69.812.7
Ataxia2406.011.9
Slide 18
OLD MECHANISM-MORE POWERFUL/SAFER Brivaracetam
(Rikelta)Eslicarbazepine Acetate (Stedesa)
Slide 19
BRIVARACETAM (Rikelta) Works in a similar way in the brain as
Levetiracetam (Keppra TM ) but much stronger in animal models Also
other activity that Keppra does not have (sodium channel blocking)
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
Slide 20
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 1665 y
PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) 0 10 20 30 40 50
60 16.7% p = 0.047 32.0% p = 0.002 44.2% p = 0.001 55.8% %
Respondents PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) 0 10 %
Patients 1.9% 1/54 8.0% 4/50 7.7% 4/52 7.7% 4/52
Why do we need a better 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
Slide 23
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, and C-reactive
protein. Ann Neurol. 2009 Apr;65(4):448-56.
TegretolDilantinCONTROL
Slide 24
Eslicarbazepine Acetate A third generation Carbamazepine
(Tegretol TM ) Improves on second generation (Trileptal TM ) 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
marketed in US as Stedesa. FDA has accepted the submission
Slide 25
Other ASDs in development Revolutionary: YKP 5089 (mechanism
unknown) Ganaxolone (Neurosteroid-type positive allosteric
modulation at GABA A receptor sites) Huperzine (Naturally occurring
plant alkaloid also being explored for use in Alzheimers
disease)
Slide 26
Is That All There is a desperate need for Drugs that prevent
epilepsy Drugs that modify or treat underlying disease True
antiepileptic drug Drugs that address co-morbidities such as
cognitive disturbance, mood disorder, anxiety
Slide 27
Truly Anti-Epileptic Approaches Anti-Inflammatory Treatments
M-Tor Inhibitors Pre-treatment with an ASD or other therapy
Slide 28
Targeting Inflammation There is mounting evidence that
inflammation plays an active role epilepsy Inflammation is clearly
evident in brain tissue removed from patients with epilepsy. New
paradigm: If we can target inflammation, we may be able to impact a
key common mechanism and reverse the underlying cause of seizures.
28 Vezzani A, French J, Bartfai T, and Baram T. The Role of
Inflammation in Epilepsy. Nature Reviews Neurology 2011
Jan;7(1):31-40
Slide 29
What is the conclusion? If successful, this would be the first
anti-epilepsy therapy that would actually target the abnormality
rather than just masking seizures A trial of VX-765 is underway It
is likely that other anti- inflammatory treatments will follow
29
Slide 30
M-Tor Inhibitors Mammalian target of rapamycin (mTOR) signaling
pathway regulates how brain cells grow, differentiate and multiply.
Genetic defects in the pathway can cause diseases such as Tuberous
sclerosis, and cortical dysplasia (both causes of epilepsy) In
Animal models, M-Tor inhibitors can prevent or reverse epilepsy
caused by these illnesses Galanopoulou AS, Gorter JA, Cepeda C.
Finding a better drug for epilepsy: the mTOR pathway as an
antiepileptogenic target.
Slide 31
Clinical Trial of M-Tor Inhibitor Everolimus A clinical trial
of Everolimus (an M-Tor inhibitor) was performed in children with
TS and giant cell astrocytomas. It appeared that seizures were also
improved New trial in children/adults with TS and resistant
seizures Franz DN et al. Efficacy and safety of everolimus for
subependymal giant cell astrocytomas associated with tuberous
sclerosis complex (EXIST-1): a multicentre, randomised,
placebo-controlled phase 3 trial. Lancet. 2013 Jan
12;381(9861):125-32.
Slide 32
Pre-Treatment: Tuberous sclerosis-Treatment with vigabatrin
prior to development of epilepsy Jwiak et al Eur J Paediatr Neurol.
2011 Sep;15(5):424-31. Standard Care N=31 Patients with Epilepsy
N=22 (71%) Patients without Epilepsy N=9 (29%) Patients with
intellectual Disability N=15 (48%) Patients with Normal IQ N=7
(23%) Patients with intellectual Disability N=0 Patients with
Normal IQ N=7 (23%) Vigabatrin Rx N=14 Patients with Epileptiform
EEG N=10 (71%) Patients with Normal EEG N=4 (29%) Patients with
Epilepsy N=6 (42%) Patients without Epilepsy N=4 (29%) Patients
with Epilepsy N=0 Patients without Epilepsy N=4 (29%) Patients with
intellectual Disability N=2 (14%) Patients with intellectual
Disability N=0 Patients with Normal IQ N=4 (29%) Patients with
Normal IQ N=4 (29%) Patients with intellectual Disability N=0
Patients with Normal IQ N=4 (29%) 8 pts (58%) without epilepsy and
12 pts (87%) with nl IQ
Slide 33
Typical Randomized Controlled Trials vs Real Life Restricted
ages No other medical Problems No psychiatric disease No
pregnancy
Slide 34
What we dont know What we know What We Know after Regulatory
Trials
Slide 35
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
Slide 36
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
Slide 37
After Approval After approval we need comparative effectiveness
studies Determine which drugs will benefit which people Unlikely
that one size fits all This is where government trials are needed
National Institutes of Health Patient-Centered Outcome Research
Institute (PCORI)
Slide 38
The Epilepsy Study Consortium Sponsored by Epilepsy Therapy
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 commercial
concerns of pharmaceutical companies!
Slide 39
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 Need
patients to volunteer for clinical trials!
