what s new in antiepileptic drugs l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
What’s New In Antiepileptic Drugs PowerPoint Presentation
Download Presentation
What’s New In Antiepileptic Drugs

Loading in 2 Seconds...

play fullscreen
1 / 38

What’s New In Antiepileptic Drugs - PowerPoint PPT Presentation


  • 496 Views
  • Uploaded on

What’s New In Antiepileptic Drugs . Jacqueline A. French, M.D. NYU Comprehensive Epilepsy Center. ANTIEPILEPTIC DRUG DEVELOPMENT. Retigabine. Rufinamide Lacosamide Brivaracetam. ?. 20. Pregabalin. Zonisamide. Levetiracetam. Oxcarbazepine. Tiagabine. 15. Fosphenytoin. Topiramate.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'What’s New In Antiepileptic Drugs' - Albert_Lan


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
what s new in antiepileptic drugs

What’s New In Antiepileptic Drugs

Jacqueline A. French, M.D.

NYU Comprehensive Epilepsy Center

antiepileptic drug development
ANTIEPILEPTIC DRUG DEVELOPMENT

Retigabine

Rufinamide

Lacosamide

Brivaracetam

?

20

Pregabalin

Zonisamide

Levetiracetam

Oxcarbazepine

Tiagabine

15

Fosphenytoin

Topiramate

Lamotrigine

Gabapentin

Number of Licensed Antiepileptic Drugs

10

Felbamate

Sodium Valproate

Carbamazepine

Benzodiazepines

Ethosuximide

5

Phenytoin

Primidone

Phenobarbital

Bromide

0

2000

1840

1860

1880

1900

1920

1940

1960

1980

Calendar Year

since 1998
SINCE 1998

20

Pregabalin

10

Zonisamide

Levetiracetam

Number of Licensed Antiepileptic Drugs

Oxcarbazepine

Tiagabine

Topiramate

Fosphenytoin

5

Lamotrigine

Gabapentin

Felbamate

0

1990

2000

Calendar Year

do we need more new antiepileptic drugs
DO WE NEED MORE NEW ANTIEPILEPTIC 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
how do we make progress
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
slide6

Compounds which are second or third generation derivatives of AEDs introduced before 1970

CarbamazepineeTegretol TM

1st Generation

AED

Valproic Acid

Depakote TM

Phenobarbital

2nd Generation

AED

Valrocemide

(SPD–493)

Oxcarbazepine

T2000

Valnoctamide

3rd Generation

AED

Eslicarbazepine Acetate

(BIA 2-093)

Licarbazepine

(MHD)

Perucca et al, Lancet Neurol, 2007

slide7

Compounds which are second generation derivatives of AEDs introduced after 1990

Precursor CNS

Drug

Piracetam

1st Generation

AED

Gabapentin

Lamotrigine

Levetiracetam

2nd Generation

AED

XP-13512

JZP-4

Seletracetam

(ucb 44212)

Brivaracetam

(ucb 34714)

Pregabalin

Perucca et al, Lancet Neurol, 2007

what s new this year
What’s new this year?
  • Two new drugs to be approved
    • Revolutionary
      • Vimpat (lacosamide)
      • Inovelon (rufinamide)
  • Four drugs in late trials
    • Evolutionary
      • Rikelta (brivaracetam)
      • Eslicarbazepine
    • Revolutionary:
      • Carisbamate
      • Retigabine
what s new this year9
What’s new this year?
  • Many drugs off/going off patent (going generic)
    • Neurontin (gabapentin)
    • Lamictal (lamotrigine)
    • Topamax (topiramate)
    • Trileptal (oxcarbazepine)
    • Keppra (levetiracetam)
what s new this year10
What’s new this year?
  • Two new trial designs endorsed by FDA
    • “Withdrawal to monotherapy”: Speed approval for monotherapy
    • “Time to Nth seizure”: Create more “patient-friendly trials
drugs that work in new ways
DRUGS THAT WORK IN NEW WAYS

lacosamide

rufinamide

retigabine

lacosamide rikelta tm
Lacosamide (RIKELTATM)
  • Works on sodium channels, like Carbamazepine (Tegretol TM) and Phenytoin (DilantinTM)
  • However, It selectively enhances slow inactivation of sodium channels, whereas the older drugs work on fast inactivation
  • Approved in Europe, expected to be approved in US by December 2008
slide13

Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy:50%Responder Rates (n=418)

41%*

38%*

33%

(* P<0.05

vs PL)

% Patients

22%

Placebo LCS 200mg LCS 400mg LCS 600mg

Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

slide14
Lacosamide Treatment-emergent adverse events (%) leading to discontinuation in at least 5% of patients in any treatment group

Percentages are based on the number of patients in the randomized dose group who received at least one dose of trial medication.

Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

rufinamide inovelon tm
RUFINAMIDE (INOVELONTM)
  • Also works on sodium channels with new mechanism
  • Approved in Europe for treatment of a severe form of epilepsy (Lennox-Gastaut syndrome)
    • “Orphan drug”
  • In Front of FDA for Lennox-Gastaut and Partial seizures
rufinamide lennox gastaut responder rate tonic atonic seizure frequency
Rufinamide Lennox-Gastaut Responder Rate: Tonic-Atonic Seizure Frequency

P=0.0003

P=0.002

P=0.006

% of Subjects

≥75%

≥50%

≥25%

Seizure Reduction

rufinamide aes with incidence 3 vs placebo all treated subjects with epilepsy double blind only
Rufinamide AEs With Incidence ≥3% vs Placebo: All Treated Subjects With Epilepsy (Double-blind Only)
slide18

What we don’t know

LEVEL OF KNOWLEDGE AT TIME OF APPROVAL

What we

know

what do we know about aeds at time of approval
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
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
retigabine
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)
  • Trials completed, ready to submit to FDA for approval
patients with 50 seizure reduction in overall treatment period titration maintenance
Patients with >50% Seizure Reduction in Overall Treatment Period(Titration + Maintenance)

Study 302

Study 301

% Patients

179

181

178

152

153

600

900

Placebo

1200 RTG

Placebo

RTG

Intent-to-treat

*p<0.005 **p<0.001

old mechanism more powerful safer
OLD MECHANISM-MORE POWERFUL/SAFER

Brivaracetam

Eslicarbazepine Acetate

brivaracetam
BRIVARACETAM
  • Similar mechanism to Levetiracetam (KeppraTM) but much stronger in animal models
  • Also has sodium channel blocking activity
  • FDA trials underway
slide27

Genetic Absence Epilepsy Rats from Strasbourg

Levetiracetam

Values given are means ± S.D. (n=8)

slide28

Genetic Absence Epilepsy Rats from Strasbourg

seletracetam

Values given are means ± S.D. (n=8)

efficacy of brivaracetam 5 20 and 50 mg day add on treatment in refractory partial onset epilepsy
Efficacy of Brivaracetam (5, 20 and 50 mg/day) Add-on Treatment in Refractory Partial-Onset Epilepsy

RESPONDER RATES

SEIZURE-FREEDOM RATES

p = 0.001

55.8%

60

10

8.0%

4/50

7.7%

4/52

7.7%

4/52

p = 0.002

44.2%

50

p = 0.047

32.0%

40

% Patients

% Respondents

30

16.7%

20

1.9%

1/54

10

0

0

PBO

(n=54)

BRV5

(n=50)

BRV20

(n=52)

BRV50

(n=52)

PBO

(n=54)

BRV5

(n=50)

BRV20

(n=52)

BRV50

(n=52)

ITT population: n=208; 110M, 98F; age range 16–65 y

eslicarbazepine
Eslicarbazepine
  • A “third generation” Carbamazepine (TegretolTM)
  • Improves on second generation (TrileptalTM)
    • Less effect on sodium
    • Smoother release may produce less side effects
  • Hopefully will work equally as well
  • Ready to submit to FDA
many drugs going off patent
Many Drugs going off Patent
  • This allows multiple (generic) companies to make the drug, in addition to the brand manufacturer
  • At same dose, two formulations must be within (80%-125%) of amount in brand, with 90% assurance.
  • Different generic brands could be either high or low
  • If a physician does not check the “do not substitute” box, insurance companies are at liberty to switch patients to generic
slide33

Brand TRx as Percent of Total Molecule

Generic Erosion

Prescription

Source: WKH PHAST TRX and Sales data factored by Verispan PDDA

Note: Celexa included as a reference of typical generic erosion

many drugs going off patent34
Many Drugs going off Patent
  • Generics may be very good and close to the brand; The problem is that EACH TIME a new prescription is filled, it can be filled with a different company’s generic, which could be high or low.
slide35
No well performed blinded studies to assess risk from switching between generics
  • Excipients and colorants may be different, leading to potential for allergic reactions
  • Dissolution properties may vary
  • Risks of generics should be weighed against cost benefits1

1Epilepsy Foundation. Statement on substitution of generic antiepileptic drugs.

changing to generic or to brand
Changing to Generic (or to Brand)
  • Baseline levels
  • Check level again when stable on new preparation
  • Ideally limit changes between different generic manufacturers
  • Report suspected problems (preferably with documentation) to FDA MedWatch (http://www.fda.gov/medwatch/)!
the epilepsy study consortium
The Epilepsy Study Consortium
  • Sponsored by Epilepsy Therapy

Development 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 comercial concerns of pharmaceutical companies!

the future
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
  • Acceptance by FDA of 2 new trial designs will speed good therapies