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The Importance of Clinical Trials: Getting New Therapies for Epilepsy on the Market. Jacqueline A. French, M.D. NYU Comprehensive Epilepsy Center. The first randomized controlled trial: Lind ’ s treatise on scurvey. Six groups (2 patients/group): 2pts : a quart of cider a day - PowerPoint PPT Presentation
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The Importance of Clinical Trials: Getting New Therapies for Epilepsy on the Market
Jacqueline A. French, M.D.NYU Comprehensive Epilepsy Center
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
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!
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
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
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
Anti-seizure drugs
• All available therapies only treat symptoms of epilepsy (seizures)
• We now call drugs that only address seizure symptoms “Anti-seizure drugs” (ASD’s)
• Most current clinical trials are for testing of ASD’s. – Almost every person with epilepsy takes at least
one ASD
Ezogabine(PotigaTM)Eslicarbazepine (ZebinixTM)
1990 1995 2000 2005 2010 2015 20200
5
10
15
20
Felbamate
Vigabatrin (Sabril TM)
Zonisamide (ZonegranTM)
Lamotrigine (Lamictal TM)
Perampanel (FycompaTM)
Gabapentin (NeurontinTM)
Topiramate (TopamaxTM)
Oxcarbazepine (TrileptalTM)
Tiagabine (GabitrilTM)
Pregabalin (LyricaTM)
Clobazam (OnfiTM)
Rufinamide (BanzelTM)
Year
Num
ber o
f AED
sTimeline: ASD approvals by FDA since 1990
Brivaracetam (RikeltaTM)
Levetiracetam (KeppraTM)
Lacosamide (VimpatTM)
http://www.accessdata.fda.gov
Not approved
(FelbatolTM)
“Don’t take any of these red pills, and if that doesn’t work, don’t
take any of the blue ones”
Sometimes, we feel Like this…
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
ASD’s: 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
The evolution is coming: Compounds which are 2nd or 3rd generation derivatives of ASDs introduced before 1970
1st Generation AED
CarbamazepineeTegretol TM
Valproic AcidDepakote TM
2nd Generation AED
Oxcarbazepine Valrocemide(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
CH3CH2CH2CHCONHCH2CONH2
Perucca et al, Lancet Neurol, 2007
Compounds which are second generation derivatives of AEDs introduced after 1990
Gabapentin Levetiracetam
Pregabalin Brivaracetam(ucb 34714)
Precursor CNS Drug Piracetam
COOHNH2
COOHNH2
*
HCH3
CH3
NO
H
H
O
NH2
N O
H
O
NH2
*
NO
H
O
NH2
*
*
1st Generation AED
2nd Generation AED
Perucca et al, Lancet Neurol, 2007
What’s “new” in ASD’s? (Approved or close to approval)
• One drug approved– Revolutionary:
• Perampanel• Two drugs in late trials
– Evolutionary• Rikelta (brivaracetam)• Stedesa (eslicarbazepine acetate)
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
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
Treatment-emergent side effects (add-on)
TEAEs, treatment-emergent adverse events
Placebo Perampanel
Treatment emergent Side effects %N
(n=121)
8 mg(n=133)
12 mg (n=134)
TEAEs 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
Ataxia 24 0 6.0 11.9
OLD MECHANISM-MORE POWERFUL/SAFER
N
CNH2O
*
O
H3CO
Brivaracetam (Rikelta) Eslicarbazepine Acetate (Stedesa)
BRIVARACETAM (Rikelta)• Works in a similar way in the brain as Levetiracetam
(KeppraTM) 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
Efficacy of Brivaracetam (5, 20 and 50 mg/day) Add-on Treatment in Refractory Partial-Onset Epilepsy
SEIZURE-FREEDOM RATESRESPONDER RATES
ITT 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
espo
nden
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 EventsPBO 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)
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
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, andC-reactive protein. Ann Neurol. 2009 Apr;65(4):448-56.
Tegretol Dilantin CONTROL
Eslicarbazepine Acetate• A “third generation” Carbamazepine (TegretolTM)• Improves on second generation (TrileptalTM)
– 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
Other ASD’s in development• Revolutionary:
– YKP 5089 (mechanism unknown)
– Ganaxolone (Neurosteroid-type positive allosteric modulation at GABAA receptor sites)
– Huperzine (Naturally occurring plant alkaloid also being explored for use in Alzheimer’s disease)
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
Truly Anti-Epileptic Approaches
• Anti-Inflammatory Treatments• M-Tor Inhibitors• Pre-treatment with an ASD or other therapy
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.
Vezzani A, French J, Bartfai T, and Baram T. The Role of Inflammation in Epilepsy. Nature Reviews Neurology 2011 Jan;7(1):31-40
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
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.
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.
Pre-Treatment: Tuberous sclerosis-Treatment with vigabatrin prior to development of epilepsy
Jóźwiak 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 withNormal IQN=7 (23%)
Patients with intellectual Disability
N=0
Patients withNormal IQN=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 withNormal IQN=4 (29%)
Patients withNormal IQN=4 (29%)
Patients with intellectual Disability
N=0
Patients withNormal IQN=4 (29%)
8 pts (58%) without epilepsy and 12 pts (87%) with nl IQ
Typical Randomized Controlled Trials vs Real Life
Restricted agesNo other medical ProblemsNo psychiatric diseaseNo pregnancy
Clinical Trial
Clinical Practice
What we don’t know
What we know
What We Know after Regulatory Trials
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
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 OutcomeResearch Institute (PCORI)
The Epilepsy Study Consortium
• Sponsored by Epilepsy TherapyProject 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!
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!