the importance of clinical trials: getting new therapies for epilepsy on the market

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%)


N=0


Vigabatrin Rx N=14

Patients with Epileptiform

EEG N=10 (71%)

Patients with Normal EEG N=4 (29%)

Patients with Epilepsy

N=6 (42%)


N=4 (29%)

Patients with

Epilepsy N=0


N=4 (29%)


N=2 (14%)


N=0




N=0


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!

the importance of clinical trials: getting new therapies for epilepsy on the market

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