Use of New Antiepileptic Agents, Esteem Pharma

Epilepsy

1. Use of the New Antiepileptic
Agents

Anthony Murro, M.D.

2. Research Support

* | currently received support for research
involving biravacetam from UCB

3. New Antiepileptic Agents

Lacosamide (Vimpat)
Rufinamide (Banzel)
Vigabatrin (Sabril)
Clobazam (Onfi)
Ezogabine (Potiga)

4. Lacosamide

* Adjunctive therapy in the treatment of
partial-onset seizures

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5. Lacosamide - Mechanism

* Lacosamide facilitates slow inactivation of
voltage gated sodium ion channels

II Ill IV

outside cell

inside cell

6. Lacosamide - Slow inactivation

Membrane depolarization occurs

A relatively slower & more sustained ion
channel conformation occurs at a intra-
membrane channel site

This conformation blocks sodium ion flow
Lacosamide enhances slow inactivation
(Goldin, 2011)

7. Sodium lon Channel Fast
Inactivation

« Voltage gated sodium ion channel
conformation occurs post-depolarization

* An intracellular protein segment
(inactivating particle) binds to a docking site
& blocks sodium ion flow

* Carbamazepine, felbamate, lamotrigine,
phenytoin, oxcarbazepine, topiramate
enhance fast inactivation

* (Goldin, 2011)

8. Slow inactivation

Intra-membrane sites S5 & S6 block ion
channel

Il TI IV

outside cell

inside cell

9. Fast Inactivation

Intracellular loop between domains III & IV
blocks ion channel

II TI IV

outside cell

inside cell

10. CRMP-2 Binding

« Lacosamide also binds to a collapsin
response mediator protein-2 (CRMP-2)

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11. CRMP-2 Binding

« This protein performs important roles that
include cytoskeletal, vesicle, and synaptic
functions in the developing brain.

* The significance of this binding is an area
of current research (Hensley et al., 2011)

12. Lacosamide Dosing

« Adult: 50 mg twice daily; may be increased
at weekly intervals by 100 mg/day

* Maintenance dose: 200-400 mg/day

13. Lacosamide Metabolism

* Linear kinetics 100-800 mg/d dose

+ Metabolism (CYP2C19) by de-methylation
to form O-desmethyl-lacosamide (inactive)

+ No significant induction/inhibition or P450
mediated interaction

(Chu et al, 2010)

14. Lacosamide Effectiveness
+ Multi-center randomized prospective
controlled trials
« > 400 patients per trial
* Age 16 years and older
« Adjunctive therapy with 1-3 anti-epileptic
medications

15. Lacosamide Median Sz Reduction
Group Ben-Menachem Halasz

Placebo 10% 20.5%
200 mg/d 26% 35.3%
400 mg/d 39% 36.4%

600 mg/d 40% ...

(Ben-Menachem et al, 2007, Halasz et al,
2009)

16. Lacosamide Effectiveness

« Dose of 600 mg/day not more effective but
did have increased side effect risk

« Events leading to discontinuation:
Dizziness, nausea, ataxia, vomiting,
nystagmus

« (Ben-Menachem et al, 2007)

17. Effect of Sodium Channel Blocker

Retrospective analysis suggests:

* Lacosamide will reduce seizure frequency
even when combined with a fast sodium
channel blocker (Sake et al., 2010,
Stephen et al., 2011)

18. Effect of Sodium Channel Blocker

Retrospective analysis suggests:

* Lacosamide with a sodium channel
blocker (e.g. phenytoin) will lead to less
seizure reduction & increased side effects

* Caution: Post-hoc analysis, small
samples, multiple comparisons, and
potential confounding factors.

(Sake et al., 2010, Stephen et al., 2011)

19. Lacosamide Pooled Analysis

Median Seizure Reduction

Group
Placebo

200 mg/d
400 mg/d
600 mg/d

Sodium Channel Blocker

Present Absent
18.9% 28%
33.3% 38%
39% 62.5%
42.7% 79%

20. Lacosamide Case Reports

+ Intravenous lacosamide has been used to
treat status epilepticus & seizure clusters.
Bolus of 200 mg IV at rate of 60 mg/min
(Hófler et al., 2011)

« Lacosamide has been used in primary
generalized epilepsy (Afra et al., 2012)

« Asingle report described worsening of
seizures in Lennox Gastaut syndrome with
lacosamide (Cuzzola et al., 2010)

21. Lacosamide Summary
Positive
* No significant drug interactions

« Common side effects are dose dependent
& easily managed with dose reduction

+ Infrequent need for serum drug levels
+ Low protein binding

Negative
* High cost

22. Role of Lacosamide

* The favorable profile makes lacosamide a
likely early choice for adjuvant drug
therapy of partial seizures

« Future research might confirm
effectiveness for primary generalized
epilepsy & status epilepticus.

* Future research might confirm greater
benefit among patients not using sodium
channel blockers

23. Rufinamide

« Adjunctive therapy in the treatment of
generalized seizures of Lennox-Gastaut
syndrome (LGS)

24. Rufinamide Mechanism

« Rufinamide slows sodium ion channel
recovery from the inactivated state & limits
repetitive neuronal firing

II III IV

outside cell

inside cell

25. Rufinamide Dosing

Children: Initial: 10 mg/kg/day in 2 equally
divided doses; increase dose by ~10
mg/kg every other day to a target dose of
45 mg/kg/day or 3200 mg/day (whichever
is lower) in 2 equally divided doses
Adults: Initial: 400-800 mg/day in 2 equally
divided doses; increase dose by 400-800
mg/day every other day to a maximum
dose of 3200 mg/day in 2 equally divided
doses.

26. Rufinamide Oral Absorption

* Oral absorption increases with food due to
increased solubility (33% increase overall
absorption & 50% increase in peak
concentration).

* Keep relationship with meals constant.

27. Rufinamide Metabolism

* Carboxylesterase metabolism to inactive
metabolite

« Rufinamide is a weak CYP3A4 inducer
* Non-linear drug kinetics

28. Rufinamide Drug Levels

« Drug levels correlate with effectiveness
and frequency of adverse effects

* Mean plasma level causing a 50%
decrease of seizure frequency was 30
mg/l; range in studies: 5-55 mg/l.

29. Rufinamide Drug Interactions

* Mild increased clearance of oral
contraceptives (CYP3A4 induction)

* Phenobarbital, primidone, phenytoin,
carbamazepine induce carboxyesterase &
significantly increase rufinamide clearance

« Valproate significantly increases
rufinamide levels by 60-70%

30. Rufinamide Lennox Gastaut
Median Seizure Reduction

Group All Seizures Tonic-atonic
Placebo 11.7% -1.4%
45 mg/kg-d 32.7% 42.5%

(Glauser et al., 2007)

31. Rufinamide Partial Seizures
Median Seizure Reduction

Group Seizure Reduction
Placebo -1.6%

Rufinamide* 20.4%

Dose: 1200-3200 mg/d (mean 2800 mg/d)
(Brodie et al, 2007)

32. Adverse Effects

Most common: Dizziness, fatigue,
somnolence, nausea, headache

AED hypersensitivity syndrome (rash &
fever) has occurred 1-4 weeks after
therapy & more likely in children

No significant effects on working memory,
psychomotor speed, or attention

(Wheles et al. 2010)

33. Rufinamide QT shortening

* > 20 msec reduction in QT can occur but
in in study population had < 300 msec

+ Rufinamide should not be given to those
with familial short QT syndrome potassium
channelopathy

* Do not administer in situations with
reduced QT interval: digoxin,
hpercalcemia, hyperkalemia, acidosis

34. Myoclonic-astatic epilepsy
(Doose syndrome)

Onset age 1-6 years of age
Myoclonic, astatic, & myoclonic-astatic Sz
Normal development prior to seizures
Prognosis variable: spontaneous resolution
in some; prolonged non-convulsive status
epilepticus, cognitive impairments &
evolution to Lennox-Gastaut in others
EEG: 2-3 Hz generalized spike wave
MRI normal

35. Myoclonic-astatic epilepsy
& Rufinamide

* In a case series, rufinamide adjunctive
therapy reduced seizure frequency by
>75% in 6 of 7 cases

« Seizure reduction decreased for patients
followed over longer time intervals of 6-18
months (von Stúlpnagela et al. 2012)

36. Rufinamide Summary

Positive

* Most side effects are dose dependent &
easily managed with dose reduction

* Infrequent need for serum drug levels

« Low protein binding

Negative

* Significant drug interactions are possible
* High cost

37. Role of Rufinamide

« Rufinamide has features similar to many of
the approved drugs for Lennox-Gastaut
(e.g. lamotrigine, topiramate).

« Future research might confirm the
beneficial effect of rufinamide for treatment
of myoclonic-astatic epilepsy.

38. Vigabatrin

« Adjunctive treatment for infantile spasms and
adult refractory complex partial seizure

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39. Vigabatrin Mechanism

* Irreversible & competitive binding to GABA
transaminase (Chu-Shore et al., 2010)

40. Vigabatrin Mechanism

* Possibly also might stimulate GABA
release

« Brain GABA increases by 40% at 2 hours
post-dose

« (Chu-Shore et al., 2010)

41. Vigabatrin

Linear dose relationship
Reduces phenytoin level by 20%

Dosage adjustment for decreased renal
clearance

(Chu-Shore et al., 2010)

42. Vigabatrin Dosing Complex Partial
Seizures

+ Adults: Initial: 500 mg twice daily; increase
daily dose by 500 mg at weekly intervals
based on response and tolerability.
Recommended dose: 3 g/day

+ Children: Oral: Initial: 40 mg/kg/day
divided twice daily; maintenance dosages
based on patient weight

43. Vigabatrin Dosing Infantile Soasm

* Initial dosing: 50 mg/kg/day divided twice
daily; may titrate upwards by 25-50
mg/kg/day every 3 days to a maximum of
150 mg/kg/day

44. Vigabatrin Effectiveness Complex
Partial Seizures

Table 4. Median Monthly Frequency of Complex Partial Seizures+

N Baseline Endstudy
Placebo 45 9.0 8.8
1 g/day SABRIL 45 8.5 u
B g/day SABRIL 41 8.5 a7
6 g/day SABRIL 43 8.5 4.5*
*P<0.05 compared to placebo=Including one patient with simple partial seizures with
secondary generalization only

(Dean et al., 1999)

45. Vigabatrin Effectiveness Complex
Partial Seizures

Table 5. Median Monthly Frequency of Complex

Partial Seizures
N Baseline Endstudy
Placebo | 90 9.0 7.5
3 g/day SABRIL 92 8.3 5.5*

*P<0.05 compared to placebo

(French et al., 1996)

46. Vigabatrin Treats Infantile Soasms
Tuberous Sclerosis Responds Best

Group % Spasm Free day 14
Vigabatrin low dose 11%
Vigabatrin high dose 36%
« Tuberous sclerosis 52%
+ Cryptogenic 27%
+ Symptomatic 10%

Low: 18-36 mg/kg-d; High: 100-148 mg/kg-d
(Elterman et al., 2001)

47. Hormonal Therapy Better Early
Response For Non-Tuberous
Sclerosis Cases
Percent Spasm Free
Group 2wks* 12-14 months
Hormonal 73% 75%
Vigabatrin 54% 76%

* Significant difference (Lux et al., 2005)
Tuberous sclerosis cases were excluded

48. Better Cognitive Outcome: Hormonal
Treatment Cryptogenic Cases

Outcome at 12-14 months Following Treatment
Symptomatic Vineland Adaptive Behavior Scale

Hormonal 70.8

Vigabatrin 75.9

Cryptogenic* Vineland Adaptive Behavior Scale
Hormonal 88.2**

Vigabatrin 78.9**

« Significant difference (Lux et al., 2005)
Tuberous sclerosis cases were excluded

49. Better Cognitive Outcome: Hormonal
Treatment Cryptogenic Cases

Outcome at 4 years Following Treatment
Symptomatic Vineland Adaptive Behavior Scale
Hormonal 45

Vigabatrin 50

Cryptogenic* Vineland Adaptive Behavior Scale
Hormonal 96

Vigabatrin 63

* Significant difference (Darke et al., 2005)
Tuberous sclerosis cases were excluded

50. Vigabatrin Effectively Treats
Tuberous Sclerosis

Practice Parameter: Medical Treatment of
Infantile Spasms:

“Overall cessation of spasms was seen in 41
of 45 (91%) of children treated with
vigabatrin, with a 100% response rate
seen in five studies.”

(Mackay et al. 2004)

51. Vigabatrin Visual Adverse Effects

* Bilateral irreversible concentric peripheral
field defects occur in 30-50% of cases

* Most with defects were treated for at least
6 months; often stable after 2 years

* Defects often asymptomatic but might
impair driving (Chu-Shore et al., 2010)

52. Vigabatrin Visual Adverse Effects

+ Adults: visual testing done at baseline &
each 6 months

* Infants: visual testing done at baseline €
test each 3 months for 18 months, then
each 6 months (sedate for
electroretinogram)

(Chu-Shore et al., 2010)

53. Vigabatrin Visual Effects

+ Common approach is treatment for a
duration under 3 months; consider
discontinuation after 6 months, if seizures
are effectively controlled (Kossoff EH,
2010).

« An experimental animal study found that
taurine prevented the visual adverse effect
(Firas et al, 2009)

54. Vigabatrin White Matter Changes

Lesions were asymptomatic & reversible
Age: 9 months - 18 years (median 5.4 yrs)
8 of 23 (34%) subjects were affected

T2/DWI scans show lesions in basal
ganglia, thalamus, brainstem, & dentate
nucleus (Pearl et al., 2009)

55. Vigabatrin White Matter Changes

Feature WithLesions Without Lesions

Number 8 subjects 15 subjects
Age 11 months 5 years
Duration 3 months 12 months

Dose 170 mg/kg-d 87 mg/kg-d

(Pearl et al., 2009)

56. Vigabatrin White Matter Changes

57. Vigabatrin Summary

Positive
« High effectiveness for infantile spasms

« Few significant drug interactions; exception is
phenytoin

* Infrequent need for serum drug levels
« Low protein binding

Negative

+ Irreversible visual field defects

« White matter lesions

« High cost

58. Role of Vigabatrin

+ Vigabatrin is likely to be among the last
choices for adjuvant treatment of partial
seizures

+ Vigabatrin is a good 15! choice for infantile
spasms from tuberous sclerosis (TS)

* Hormonal therapy might provide more
effective early control for non-TS cases &
better cognitive outcome for cryptogenic
infantile spasms

59. Clobazam

Adjunctive treatment of seizures associated
with Lennox-Gastaut syndrome

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60. Clobazam Mechanism
+ Allosteric activation of GABAa receptor

61. Clobazam Mechanism

« Allosteric activation of GABAa receptor

* Up-regulation GABA transporters 1 to 3
(GAT1 to GATS)

+ Clobazam has decreased affinity for
GABAa subunits that mediate sedative
effects

62. Clobazam Dosing

+ $30 kg: Initial: 5 mg once daily for 21
week, then increase to 5 mg twice daily for
21 week, then increase to 10 mg twice
daily thereafter

>30 kg: Initial: 5 mg twice daily for 21
week, then increase to 10 mg twice daily
for 21 week, then increase to 20 mg twice
daily thereafter

63. Clobazam Dosing

CYP2C19 poor metabolizers:

<30 kg: Initial: 5 mg once daily for 22
weeks, then increase to 5 mg twice daily;
after 21 week may increase to 10 mg twice
daily

>30 kg: Initial: 5 mg once daily for >1
week, then increase to 5 mg twice daily for
21 week, then increase to 10 mg twice
daily; after 21 week may increase to 20
mg twice daily

64. Clobazam Metabolism
Hepatic via CYP3A4 and to a lesser extent via
CYP2C19 and 2B6
N-demethylation to active metabolite [N-
desmethyl] with ~20% activity of clobazam.

CYP2C19 primarily mediates subsequent
hydroxylation of the N-desmethyl metabolite.
Carbamazepine reduces clobazam level, &
clobazam decreases valproate (Riss et al, 2008)
Many other potential drug interactions

65. Clobazam

* Placebo controlled trial in 238 cases
(age 2-60 years) with Lennox-Gastaut
syndrome (Ng YT et al, 2011)

* Treatment groups: placebo, 0.25
mg/kg-d, 0.5 mg/kg-d, 1.0 mg/kg-d.

« Weekly seizure rate reduction
showed a dose response effect

« Side effects: somnolence, pyrexia,
respiratory infections, lethargy,
behavioral problems.

66. Clobazam Treatment Response

Group Drop Attack Reduction
Placebo 12.1%
0.25 mg/kg-d (max 10 mg/d) 41.2%
0.5 mg/kg-d (max 20 mg/d) 49.4%
1.0 mg/kg-d (max 40 mg/d) 68.3%
(Ng YT et al, 2011)

67. Clobazam Side Effects

Somnolence
Fever
Lethargy
Drooling
Constipation

68. Clobazam Other Studies

« Retrospective studies involving refractory
partial seizures reported an early
improvement in seizure reduction.

« Many could not tolerate the drug due to
somnolence.

* Tolerance occurred; seizures re-occurred
in subjects that had improved initially
(Shimizu et al., 2003, da Silveira et al.,
2006)

69. Clobazam Summary

Positive

* High level of effectiveness for a difficult to
treat seizure disorder

* Common side effects are dose dependent
& easily managed with dose reduction

+ Parent compound & metabolite have long
half life

70. Clobazam Summary

Negative

* High cost

+ High protein binding

* Active metabolite 8 potentially significant
drug interactions

71. Role of Clobazam

* Clobazam is likely to be a useful drug for
adjuvant therapy of Lennox Gastaut

* Limiting factors are likely to be cost and
occurrence of drug related side effects

« Research might confirm the benefit of this
drug for refractory partial seizures.

72. Ezogabine (Retigabine)

Adjuvant treatment of partial-onset seizures

H
SON
Lye
F

73. « Binds to
KCNQ2/3
KCNQ3/5
potassium
channels

74. Ezogabine

« Ezogabine binds to KCNQ2/3 8 KCNQ3/5
potassium channels at a hydrophobic
pocket near channel gate

* This binding stabilizes the open KCNQ2/3
8 KCNQ3/5 potassium channels

« This causes membrane hyperpolarization
(Gunthorpe et al. 2012)

75. Ezogabine

« At high concentrations: blocks sodium
voltage gated sodium & calcium channels
and increases GABA synthesis (Czuczwar
et al., 2010)

76. Autosomal Dominant Neonatal

Epilepsy

Loss of function mutation KCNQ2/3

Focal or generalized tonic-clonic seizures

on day 3; seizures remit by 1 month

10-15% develop epilepsy

Therapy resistant epileptic

encephalopathy might occur (Kurahashi et

al., 2009)

77. Ezogabine Dosing

* Initial: 100 mg 3 times/day; may increase
at weekly intervals in increments of $150
mg/day to a maintenance dose of 200-400
mg 3 times/day (maximum: 1200 mg/day)

78. Ezogabine Metabolism

No P450 metabolism
Glucuronidation via UGT1A4, UGT1A1,
UGT1A3, and UGT1A9

Acetylation via NAT2 to an N-acetyl active
metabolite (NAMR) and other inactive
metabolites (eg, N-glucuronides, N-
glucoside)

Linear drug kinetics (Weisenberg et al,,
2011)

79. Ezogabine Drug Interactions

* No effect on oral contraceptive clearance

« Lamotrigine decreases ezogabine
clearance slightly; ezogabine increases
lamotrigine clearance slightly

80. Ezogabine Effectiveness
Group Seizure Reduction
Placebo 13.1%
600 mg/d 23.4%
900 mg/d 29.3%
1200 mg/d 35.2%

(Porter et al., 2007)

81. Ezogabine Effectiveness
Group Seizure Reduction
Placebo 15.9%
600 mg/d 27.9%
900 mg/d 39.9%

(Brodie et al., 2010)

82. Ezogabine Effectiveness

Group Seizure Reduction
Placebo 17.5%
1200 mg/d 44.3%

(French et al., 2011)

83. Ezogabine Side Effectts

Somnolence
Fatigue
Confusion
Dizziness
Headache
Dysarthria
Ataxia
Blurred vision

84. Ezogabine Summary

Positive

* Minimal drug interactions

« Common side effects are dose dependent
& easily managed with dose reduction

* Infrequent need for serum drug levels

* Unique drug mechanism

Negative
« High cost

85. Role of Ezogabine

« Ezogabine is likely to be a useful drug for
adjuvant therapy for refractory partial
seizures

* Limiting factors are likely to be cost and
occurrence of drug related side effects

86. Cumulative Summary

Lacosamide, & ezogabine are likely to be
considered early choices for adjuvant drug
therapy of partial seizure because:

« Minimal drug interactions

* Novel mechanisms of action

« Relatively safe side effect profile.

87. Cumulative Summary

Vigabatrin has a specialized role:

« First choice therapy for infantile spasms
among those with tuberous sclerosis

« Adjuvant therapy in otherwise refractory
infantile spasm cases.

« ACTH may be a better choice in select
infantile cases.

+ Vigabatrin is likely to be among the later
choices for refractory partial seizures due
to its risk of visual loss.

88. Cumulative Summary

Rufinamide and clobazam have a
specialized role as adjuvant therapy for
Lennox-Gastaut.

« Drug interactions are more complex with
these medications.

+ Side effects might limit the use of these
medications in some cases

89. Pharmacokinetic Properties
Drug Tmax T1/2 %PB
Lacosamide 1-2hr 13 hr <19%
Rufinamide 4-6 hr 6-10 hr 34%
Vigabatrin 2 hr 5-8 hr 0%
Clobazam 1-2hr 10-30 hr 82-90%
Clobazam** --- 36-46 hr ---
Ezogabine 1-2hr 810hr <80%
** desmethylclobazam active metabolite
(Chu et al, 2010)

90. References

Afra P, Adamolekun B. Lacosamide treatment of
juvenile myoclonic epilepsy. Seizure. 2012 Jan
24.

Appleton RE, Peters ACB, Mumford JP, Shaw
DE. Randomized, pao -controlled study of
vigabatrin as first-line treatment of infantile
spasms. Epilepsia. 1999;40:1627-1633.
Ben-Menachem E, Biton V, Jatuzis D, Abou-
Khalil B, Doty P, Rudd GD. Efficacy and safety
of oral lacosamide as adjunctive therapy in
adults with partial-onset seizures. Epilepsia.
2007 Jul;48(7):1308-17.

91. References

« Brodie M.J., W.E. Rosenfeld, B. Vazquez et al.
Rufinamide for the adjunctive treatment of partial
seizures in adults and adolescents: A randomized
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1909

« Brodie MJ, Lerche H, Gil-Nagel A, Elger C, Hall S, Shin
P, Nohria V, Mansbach H; RESTORE 2 Study Group.
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« Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N,
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92. References

Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N,
Mumford J. Therapeutic trial of vigabatrin in refractory
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Chu-Shore CJ, Thiele EA. New drugs for pediatric
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Czuczwar P, Wojtak A, Cioczek-Czuczwar A et al.
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93. References

« Darke K, Edwards SW, Hancock E, Johnson AL,

Kennedy CR, Lux AL, Newton RW, O'Callaghan Fu,
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* da Silveira MRM , Montenegro MA, Franzon RC,
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« Dean C, Mosier M, Penry K. Dose-response study of
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94. References

« Elger C.E. , H. Stefan, A. Mann et al. A 24-week
multicenter, randomized, double-blind, parallel-group,
dose-ranging study of Rufinamide in adults and
adolescents with inadequately controlled partial seizures.
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« Elterman RD, Shields WD, Mansfield KA, et al; US
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« French JA, M. Mosier, S. Walker et al. A double-blind,
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95. References

French JA, Abou-Khalil BW, Leroy RF, Yacubian EM,
Shin P, Hall S, Mansbach H, Nohria V; RESTORE
1/Study 301 Investigators. Randomized, double-blind,
placebo-controlled trial of ezogabine (retigabine) in
partial epilepsy.

Neurology. 2011 May 3;76(18):1555-63.

Firas Jammoul,, Qingping Wang, et al. Taurine deficiency
is a cause of vigabatrin-induced retinal phototoxicity.
Ann Neurol. 2009 January ; 65(1): 98-107

Glauser T, Kluger G, Sachdeo R et al. Rufinamide for
generalized seizures associated with Lennox-Gastaut
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96. References

Goldin AL. Mechanisms of sodium channel inactivation.
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Gunthorpe MJ, Large CH, Sankar R, The mechanism of
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Halasz P, Kälviäinen R, Mazurkiewicz-Beldzinska M,
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Hensley K, Venkova K, Christov A, Gunning W, Park J.
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97. References

Höfler J, Unterberger |, Dobesberger J,
Kuchukhidze G, Walser G, Trinka E.
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