Transcript Afternoon Keynote Address

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
10,000
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
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
Timeline: ASD approvals by FDA since 1990
20
Ezogabine(PotigaTM)
Number of AEDs
15
Brivaracetam (RikeltaTM)
Eslicarbazepine (ZebinixTM)
Perampanel (FycompaTM)
Clobazam (OnfiTM)
Vigabatrin (Sabril
Lacosamide (VimpatTM)
10
TM)
Rufinamide (BanzelTM)
Pregabalin (LyricaTM)
Oxcarbazepine (TrileptalTM)Zonisamide (ZonegranTM)
Levetiracetam (KeppraTM)
Not approved
Tiagabine (GabitrilTM)
5
Topiramate (TopamaxTM)
Felbamate
(FelbatolTM)
0
1990
Lamotrigine (Lamictal
TM)
Gabapentin (NeurontinTM)
1995
2000
2005
Year
2010
2015
http://www.accessdata.fda.gov
2020
Sometimes, we feel Like this…
“Don’t take any of these red pills,
and if that doesn’t work, don’t
take any of the blue ones”
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
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
Compounds which are second generation
derivatives of AEDs introduced after 1990
N
NH2
H
Piracetam
NH 2
COOH
N
*
1st Generation
AED
H
Gabapentin
NH 2
*
Generation
AED
O
H
Precursor CNS
Drug
2nd
O
COOH
CH3
H
O
O
NH2
Levetiracetam
*
N
*
CH3
H
Pregabalin
Perucca et al, Lancet Neurol, 2007
O
O
NH2
Brivaracetam
(ucb 34714)
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
Perampanel : Percent reduction in seizure
frequency during maintenance phase
-50
-32.13
(P=0.08)
-40
Median %
change in
seizure
frequency
-39.48
(P=0.03)
-30
-22.86
-20
-10
0
Placebo
(n=119)
Perampanel
8 mg/day
(n=132)
Perampanel
12 mg/day
(n=130)
Treatment-emergent side effects
(add-on)
Placebo
N
Treatment emergent Side effects %
Perampanel
8 mg
(n=133)
12 mg
(n=134)
(n=121)
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
Ataxia
24
0
6.0
11.9
TEAEs leading to study or study drug withdrawal
Most common (≥10%)
TEAEs, treatment-emergent adverse events
OLD MECHANISM-MORE
POWERFUL/SAFER
H3 C
O
O
*
N
O
Brivaracetam (Rikelta)
C
NH 2
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 patientsunknown 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
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)
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)
Tegretol
Dilantin
CONTROL
Mintzer S. et al Effects of antiepileptic drugs on lipids, homocysteine, and
C-reactive protein. Ann Neurol. 2009 Apr;65(4):448-56.
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
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
28
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 antiinflammatory treatments will
follow
29
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
Vigabatrin Rx
N=14
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
intellectual
Disability
N=0
Patients with
Normal IQ
N=7 (23%)
Patients with
Normal IQ
N=7 (23%)
Patients with
Normal EEG
N=4 (29%)
Patients with
Epileptiform
EEG
N=10 (71%)
Patients with
Epilepsy
N=6 (42%)
Patients without
Epilepsy
N=4 (29%)
Patients
with
Epilepsy
N=0
Patients without
Epilepsy
N=4 (29%)
8 pts (58%) without epilepsy
and 12 pts (87%) with nl IQ
Patients with
intellectual
Disability
N=2 (14%)
Patients with
Normal IQ
N=4 (29%)
Patients with
intellectual
Disability
N=0
Patients with
Normal IQ
N=4 (29%)
Jóźwiak et al Eur J Paediatr Neurol. 2011 Sep;15(5):424-31.
Patients with
intellectual
Disability
N=0
Patients with
Normal IQ
N=4 (29%)
Typical Randomized Controlled Trials
vs Real Life
Restricted ages
No other medical Problems
No psychiatric disease
No pregnancy
What We Know after Regulatory Trials
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
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)
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!
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!