New Antiepileptic drugs

Jacqueline A French MD NYU Comprehensive Epilepsy Center

20 15 10 5

ANTIEPILEPTIC DRUG DEVELOPMENT

eslicarbazepine Rufinamide Lacosamide Perampanel Retigabine Vigabatrin Pregabalin Zonisamide Levetiracetam Levetiracetam Tiagabine Oxcarbazepine Topiramate Fosphenytoin Lamotrigine Gabapentin Felbamate Sodium Valproate Ethosuximide Carbamazepine Benzodiazepines Phenobarbital Phenytoin Primidone Bromide 0 1840 1860 1880 1900 1920 1940 Calendar Year 1960 1980 2000

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 10,000 Compounds 250 Get to Animal Testing Reach Human Trials 10 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

Double-blind placebo-controlled trial for FDA approval

1-2 AEDs Dose 2 + AEDs Dose 1 + AEDs Placebo + AEDs Baseline Titration Treatment Taper (double-blind) + follow up

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)

LEVEL OF KNOWLEDGE AT TIME OF APPROVAL What we know What we don

’

t know

SERIOUS ISSUES IDENTIFIED BEFORE AND AFTER FDA APPROVAL

Drug FELBAMATE LAMOTRIGINE TOPIRAMATE TIAGABINE VIGABATRIN BEFORE APPROVAL Rash, Serious rash (Steven’s Johnson) Rash, Serious rash (Steven’s Johnson) Depression AFTER APPROVAL Fatal Aplastic Anemia Liver failure Risk < 16 y.o

Acute Glaucoma, heat stroke, Kidney Stones Status Epilepticus 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

O 1 st Generation AED O N C NH 2 Carbamazepinee Tegretol TM O NH NH O Phenobarbital CH 3 CH 2 CH 2 CHCOOH CH 3 CH 2 CH 2 Valproic Acid Depakote TM O 2 nd Generation AED N O C NH 2 Oxcarbazepine 3 rd Generation AED H 3 C O O

*

N O C NH 2 Eslicarbazepine Acetate (BIA 2-093) O O N CH 2 OCH 3 O N CH 2 OCH 3 T2000 CH 3 CH 2 CH 2 CHCO NHCH 2 CONH 2 CH 3 CH 2 CH 2 Valrocemide (SPD–493) CH 3 CH 2

*

CHCO NH 2 CH 3 CH 2 CH CH 3 Valnoctamide 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 82 % 18% 56 % 44 % Placebo 1200 RTG

2 French et al Neurology. 2011 May 3;76(18):1555-63

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

Perampanel : Percent change in seizure frequency during maintenance phase (Study 304)

74 % Placebo (n=119) 26 %

French et al Neurology® 2012;79:589–596

63 % 37 % Perampane l 8 mg/day (n=132) 64% 36 % Perampanel 12 mg/day (n=130)

Side effects (add-on)

1

Treatment emergent Side effects %

Side effectss leading to study or study drug withdrawal Most common ( ≥10%) Dizziness Sleepiness Irritability Headache Fall

N

43 113 63 35 54 38

Placebo (n=121)

6.6

9.9

13.2

5.0

13.2

6.6

Perampanel 8 mg (n=133) 12 mg (n=134)

6.8

37.6

18.0

7.5

15.0

9.8

• Unsteadiness TEAEs, treatment-emergent adverse events 24 0 6.0

Several cases of “severe aggression”/homicidal ideation

(Black box warning)

19.4

38.1

17.2

14.2

13.4

12.7

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).

OXCARBAZEPINE S Licarbaz R licarbaze pine epine

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

50 45 40 35 30 25 20 15 10 5 0 PL ESL 400 mg od ESL 800 mg od ESL 1200 mg od Study BIA-2093-301 Study BIA-2093-302 Study BIA-2093-303 800 mg and 1200 mg doses were statistically significant; 400 mg was not.

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

?

YES,

• 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

Immediate vs slow release

Cmax Risk of side effects

Cloyd, 1998 6 Time (hrs) 12 18

Risk of seizure breakthrough

2 4

Immediate vs slow release: Dose increase

Cmax Risk of side effects

Cloyd, 1998 6 Time (hrs) 12 18

Risk of seizure breakthrough

2 4

Immediate Release Oxcarbazepine

Higher plasma [MHD] were associated with larger decreases in seizures frequency p=0.0001

Seizure freedom

22% 10%* 3%* .6%*

Barcs, Epilepsia, 41(12):1597–1607, 2000

28%

OXC add on: Patients % Discontinued

73%* 45% 22%

*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 Scandinavica

Volume 129, Issue 3, pages 143-153, 21 DEC 2013 DOI: 10.1111/ane.12207

http://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 seizures study

Reduction in seizure frequency topiramate 200 mg sustained release (Qudexy) 50 Combined titration and maintenance phase 40 30 20 10 0 Chung et al. In preparation.

39.5% USL255 (N=124) 18.5% treatment effect on seizure reduction 21.65% Placebo (N=125)

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 (%) USL255 Placebo N=124 N=125

5 (4.0) Any neurocognitive TEAE 16 (12.9)

Neurocognitive TEAEs

Aphasia Dysarthria Disturbance in attention Memory impairment Psychomotor retardation Bradyphrenia Amnesia Cognitive disorder Confusional state Encephalopathy Mental impairment 3 (2.4%) 3 (2.4%) 3 (2.4%) 3 (2.4%) 3 (2.4%) 2 (1.6%) 1 (0.8%) 1 (0.8%) 1 (0.8%) 1 (0.8%) 1 (0.8%) Speech disorder Thinking abnormal 1 (0.8%) 1 (0.8%) Note: Preferred terms are in descending order of frequency as reported in the USL255 treatment group 0 1 (0.8%) 4 (3.2%) 1 (0.8%) 0 1 (0.8%) 0 0 0 0 0 0 0

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