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%

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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