Drug Profiles Efficacy Safety and Tolerability Evolving Epilepsy Therapy Treatments Firstgeneration AEDs 19301980s Secondgeneration AEDs 19842006 Thirdgeneration AEDs 2006today Orphan AEDs ID: 758012
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Slide1
New Antiepileptic
Medications
Drug Profiles, Efficacy, Safety, and TolerabilitySlide2
Evolving Epilepsy Therapy
Treatments
First-generation AEDs
1930-1980s
Second-generation AEDs
1984-2006
Third-generation AEDs
2006-today
Orphan AEDs
Needs
Tolerability
Safety
Added efficacySlide3
Recent AEDs
Drug
Company
FDA
Approval
Indication
Clobazam
(
Onfi
®)
Lundbeck2011
Adjunctive therapy for LGS in patients ≥ 2 y
Eslicarbazepine
(
Aptiom
®)
Sunovion
(Sepracor + Dainippon)
2013
2015
Monotherapy or adjunctive therapy for POS
Lacosamide
(
Vimpat
®)
UCB Pharma
2008
2014
Monotherapy or adjunctive therapy for POS in patients ≥ 17 y
Perampanel
(
Fycompa
™)
Eisai
2012
2015
Adjunctive therapy for POS and PGTC seizures in patients ≥ 12 y
Retigabine/
Ezogabine (
Potiga
®)
GSK/Valeant
2011
Adjunctive therapy for POS in patients ≥ 18 y
Rufinamide (
Banzel
®)
Eisai
2008
2013
Adjunctive therapy for LGS in patients ≥ 1 y
Vigabatrin (
Sabril
®)
Lundbeck
2009
2013
Monotherapy for infantile spasms
Adjunctive therapy for CPS in patients ≥ 10 ySlide4
Clobazam
Summary: 1,5-benzodiazepine (N
ring position
)
GABAA receptor binding (Cl flux)
A
ffinity
for
ω
2 instead of ω1 subunitThus less sedation and tolerance than 1,4-benzodiazepines (eg, clonazepam)T1/2 = 18 hoursMetabolized by several CYP with an active metabolite norclobazamIndicated for adjunctive treatment of multiple seizure types in Canada, Japan; anxiety indication in
United Kingdom Slide5
Clobazam (cont)
Effective for drop seizures in LGSaAges 2 to 60; N = 238D
oses of 0.25 and 1 mg/kg/d
Weekly titration, initial 5 to 10 mg/d
Maximum dosage 40 mg/dFDA approved for LGS in 2011 (orphan drug approval
2008)
Approved in Europe
,
Canada
a. Ng YT, et al. Neurology. 2011;77:1473-1481.[1]Slide6
Clobazam (cont)
Mean Decrease in Seizure Rate, %
(95% CI, −3.6 to 27.8)
(95% CI, −7.6 to 26.3)
(95% CI, 17.2-52.5)
P
= .0414
(95% CI, 47.2-83.5)
P
< .0001
(95% CI, 33.4-65.4)
P
= .0015
Ng YT, et al.
Neurology.
2011;77:1473-1481.
[1]Slide7
Eslicarbazepine
Demonstrated efficacy up to 1200 mg with daily dosing in 3 pivotal trials (all conducted outside United States)
Effective in monotherapy trials with up to 1600 mg/day
Chemically related; MOA
same as with carbamazepine and oxcarbazepineForms S-
l
icarbazepine
(
OXC-MHD = S + R licarbazepine)Significant drug interactions with oral contraceptives and some other AEDs, including phenytoinMost common adverse events were dizziness, headache, diplopia, and somnolenceStephen LJ, et al. CNS Drugs. 2011;25:89-107.[2]; Elger C, et al. Epilepsia. 2007;48:497-504.[3]; Jacobson MP, et al. BMC Neurology
. 2015:15:46.[4]; Sperling MR, et al. Epilepsia. 2015;56:546-55.[5]Slide8
Shares dibenzazepine nucleus with CBZ and OXC, but with 5-carboxamide substitute
Primarily converted toS-licarbazepine
4% converted to
R-licarbazepine
via oxcarbazepine
Stephen LJ, et al.
CNS Drugs.
2011;25:89-107.
[2]; Elger C, et al. Epilepsia. 2007;48:497-504.[3]
5%
Oxcarbazepine
Eliscarbazepine acetate
R(-)-licarbazepine
S(+)-licarbazepine
Eslicarbazepine
Chemical StructureSlide9
Placebo
ESL 400 mg
ESL 800 mg
ESL 1200 mg
Study 301
Study 302
50
45
40
35
30
25
20
15
10
5
0
*
%
50
45
40
35
30
25
20
15
10
5
0
†
†
%
Median Relative Reduction in Seizure Frequency
Responder Rate
n = 402
n = 393
n = 252
n = 402
n = 393
n = 252
*
P
< .001; †
P
< .05.
Eslicarbazepine Pivotal Trial
Results
Percent
Reduction in Seizure Frequency and
50
% Responder Rate
*
* *
*
*
†
*
Study 303
Study 301
Study 302
Study 303
McCormack PL, et al.
CNS Drugs
. 2009;23:71-79
.
[6]Slide10
EslicarbazepinePhase 3 Treatment-Emergent Adverse Events
Treatment-Emergent Adverse Events With ≥ 10% Incidence Rates
BIA-2093-301
BIA-2093-302
Placebo
(n = 102)
ESL 400 mg/d
(n = 100)
ESL 800 mg/d
(n = 98)
Placebo
(n = 100)
ESL 400 mg/d
(n = 96)
ESL 800 mg/d
(n = 101)
Any TEAE
31.4
44.0
50.0
68.0
78.1
83.2
Dizziness
2.0
4.0
14.3
10.0
22.9
29.7
Headache
5.9
5.0
9.2
9.0
8.3
14.9
Diplopia
0
2.0
7.1
4.0
8.3
14.9
Somnolence
2.0
6.0
9.2
17.0
15.6
16.8
NR = not reported
.
Incidence
rates are for approved doses.
Other AEs (NR in 301
): nausea (range 4.0-11.9), abnormal coordination (5.0-12.9),
vomiting
(3.0-12.9)
Elger
C, et al.
Epilepsia
.
2009;50:454-63.
[7]
; Ben-Menachem
E, et al.
Epilepsy Res.
2010;89:278-85.
[8]Slide11
Eslicarbazepine Monotherapy Conversion TrialKaplan–Meier-Estimated 112-Day Exit Rate
Jacobson MP, et al. BMC Neurology. 2015:15:46
.
Cumulative Exit Rate at 112 Days (KM Estimate), %; 95% CI
65.3% lower confidence limit of historical controls
12.8
(7.5-21.5)
15.6
(8.1-28.7)
Jacobson MP, et al. BMC Neurology. 2015:15:46.[4]Slide12
Lacosamide
Lacosamide therapy:Indicated as monotherapy or adjunctive therapy in the management of POS in adult patients with epilepsyEnhancement of slow inactivation of sodium channels
Functionalized amino acid
with similarity to D-serine
(R)-
2-acetzamido-N-benzyl-3-methoxypropionamide
R(+) configuration is active
Molecular
weight
: 250.3Water solubility: 27 mg/mLSlide13
LacosamidePharmacokinetic Profile
Predictable and dose-proportional PK profile
Tmax
: 0.25 to 4 hours after oral administration
t½ ~
13 hours (twice-a-day
dosing)
Absolute bioavailability
~
100%Volume of distribution ~0.6 L/kgRenally excreted (95%)Low potential for drug-drug interactionsBioequivalence of oral and IV (30- and 60-minute infusions)Low protein binding (<15%)No food interaction has been observedLow inter- and intra-subject variability (~ 20%)No influence of gender or race observed
Vimpat® PI 2015.[9]Slide14
n = 359
n = 267
n = 466 n = 202
ITT – indirect comparison of results
between 3 studies
Median
Reduction, %
21
3738††
10
26
39
40
†
†
36
*
†
21
35
0
10
20
30
40
50
60
SP667
a
SP755
c
SP754
b
Placebo
LCM
200
mg/d
LCM
400 mg/d
LCM
600 mg/d
*
P
< .05;
†
P
< .01.
P
values
based on log-transformed data from pairwise treatment using ANCOVA models.
ITT = Intent to treat (randomized subjects receiving at least
1 dose
of trial medication with
≥ 1
post-baseline efficacy assessment).
The approved daily dose for
lacosamide
is up to 400 mg/day;
600
mg/d is above the FDA recommended dose
.
Lacosamide: Median
Percent Reduction in Seizure Frequency Per 28 Days:
Baseline
to Maintenance, Per Randomized Dose
a. Ben-Menachem E, et al.
Epilepsia
.
2007;48:1308-17.
[10]
;
b. Chung S, et al.
Epilepsia
.
2010;51:958-67.
[11]
;
c.
Halász
P, et al.
Epilepsia
.
2009;50:443-53.
[12]Slide15
Adverse Event (%)
MedDRA
Preferred Term
Placebo
n = 364
Lacosamide
200 mg/d
n = 270
400 mg/d
n = 471
600 mg/d
n = 203
Total
N = 944
Dizziness
8
16
30
53
31
Headache
9
11
14
12
13
Nausea
4
7
11
17
11
Diplopia
2
6
10
16
11
Vomiting
3
6
9
16
9
Fatigue
6
7
7
15
9
Vision blurred
3
2
9
16
8
Coordination abnormal
2
4
7
15
8
Safety population, N =
1308
; the approved
dosage
for
lacosamide
is
up to 400
mg/d.
Pooled safety data from 3 randomized, double-blind, placebo-controlled Phase 2/3 clinical trials, each trial included a 4- to 6-week titration phase followed by a 12-week maintenance phase. Safety population included adults (16-70 years of age) with POS, with or without secondary generalization, and taking 1-3 concomitant antiepileptic drugs.
Lacosamide Safety
and
Tolerability: Pooled
Pivotal Trial Data
Adverse
Events Occurring (≥ 10%) During the Treatment Phase
Chung S, et al.
CNS Drugs.
2010;24:1041-1054.
[
13]
Gil-Nagel A, et al. IEC 2009. Poster 508.
[
14]Slide16
Pooled Phase
2/3 Trial Data
≥ 50
%
Responder Rate, %
‡
n = 337
n = 244
n = 393
n = 142
Lacosamide Optimizing
Combination Therapy
≥ 50
%
Responder Rate
in
Patients Taking ≥ 1 Concomitant Sodium-channel Blocking
AEDs (
ITTm
Population*)
†
*The
modified ITT (
ITTm
) population (N =
1116)
included all randomized patients receiving ≥ 1 dose of trial medication with ≥ post-baseline efficacy assessment, excluding those who
discontinued
during the titration phase.
†
P
< .05; ‡
P
< .01 vs placebo
The approved daily dosage for
lacosamide
is ≤ 400 mg/day.
Sake J, et al.
CNS Drugs.
2010;24:1055-1068
[15]
;
Isojarvi
J, et al. ECE 2010. Poster 230.
[16]
‡Slide17
MedDRA
Preferred Term
Infusion duration 30 min, N = 40
n (%)
Headache
3 (8)
Dizziness
3 (8)
Diplopia
2 (5)
Nausea
2 (5)
Somnolence
4 (10)
Fatigue
0 (0)
Abdominal pain, upper
0 (0)
WBC urine positive
2 (5)
Infusion reactions
3 (8)
Krauss G, et al.
Epilepsia.
2010;51:951-957.
[17]
Lacosamide Infusion
AEsSlide18
Lacosamide Monotherapy Conversion TrialKaplan–Meier-Estimated 112-Day Exit Rate
Wechsler RT, et al. Epilepsia. 2014;55:1088-1098.
[18]
Kaplan-Meier Predicted Exit Percentage
Patients meeting
≥
1 exit criterion during the
Lacosamide
Maintenance Phase, FAS
Patients meeting
≥ 1 exit criterion, withdrawals due to a TEAE, and withdrawals due to lack of efficacy during the Lacosamide Maintenance Phase, FAS65.3% lower confidence limit of historical controlsSlide19
Perampanel
Selective
Antagonist for the AMPA
Subtype
of Ionotropic Glutamate Receptors
5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H)-one
Chemical StructureSlide20
Percentage of patients experiencing
≥ 50% reduction in seizure frequency (ITT) – maintenance (LOCF) period vs baseline
Median
percentage reductions in seizure frequency per 28 days (ITT)
– double-blind phase vs baseline
Placebo
Perampanel 2 mg
Perampanel 4 mg
Perampanel 8 mg
Krauss GL, et
al. Neurology. 2012;78:1408-15.[19]
Perampanel Study
306
Median
Percentage Reduction in Seizure Frequency and 50% Responder Rate
*
=
vs
placebo
n = 184
n = 180
n = 172
n = 169
Slide21
Perampanel Treatment-Emergent Adverse Events
Incidence of TEAEs (Safety Population)
Patients, n (%)
Placebo
n = 185
2 mg/d
n = 180
4 mg/d
n = 172
8 mg/d
n = 169
Any AE
101 (54.6)
111 (61.7)
111 (64.5)
121 (71.6)
Any TEAE
59 (31.9)
67 (37.2)
77 (44.8)
96 (56.8)
Any TEAE leading to study/treatment discontinuation
7 (3.8)
12 (6.7)
5 (2.9)
12 (7.1)
Any TEAE leading to dose reduction/interruption
6 (3.2)
3 (1.7)
12 (7.0)
29 (17.2)
Any serious TEAE
9 (4.9)
6 (3.3)
6 (3.5)
6 (3.6)
TEAEs in ≥ 5% (any treatment group)
Dizziness
18 (9.7)
18 (10.0)
28 (16.3)
45 (26.6)
Somnolence
12 (6.5)
22 (12.2)
16 (9.3)
27 (16.0)
Headache
16 (8.6)
16 (8.9)
19 (11.0)
18 (10.7)
Fatigue
5 (2.7)
8 (4.4)
13 (7.6)
9 (5.3)
Upper respiratory tract infection
5 (2.7)
11 (6.1)
6 (3.5)
3 (1.8)
Nasopharyngitis
3 (1.6)
7 (3.9)
9 (5.2)
3 (1.8)
Gait disturbance
2 (1.1)
1 (< 1)
2 (1.2)
9 (5.3)
Krauss GL, et
al.
Neurology.
2012;78:1408-15.
[19]Slide22
Perampanel for the Treatment of Refractory PGTC Seizures
French JA, et al. Neurology.
2015. [
Epub ahead of print].
[20]
P
< .0001
P
= .0019Slide23
Retigabine/Ezogabine
Novel MOA with activation of neuronal M-current mediated by KCNQ (Kv7) voltage-gated potassium channels
a
Half-life of 8 to 11 hours
a3x-per-day
dosing
(extended-release formulation in
development)
Limited potential for drug-drug interactions with other
AEDsbPhenytoin and carbamazepine may increase the clearance of retigabineSmooth muscle relaxant in rodents (bladder distention)ba. Luszczki JJ. Pharmacol Rep. 2009;61:197-216.[21]
; b. Bialer M, et al. Epilepsy Res. 2009;83:1-43.[22]Slide24
*P
< .047 for overall difference across retigabine 300, 600, and 1200 mg/d arms†
P < .001 for overall difference across all treatment arms
Intent-to-Treat
Population
Change in Total Monthly
Partial-seizure Frequency, %
Retigabine
*
Retigabine Dose-Ranging Trial for POS Primary Efficacy ResultsPorter RJ, et al.
Neurology. 2007;68:1197-1204.[23]Slide25
Retigabine Dose-ranging Trial for Partial-Onset SeizuresAdverse
EventsTable shows range of incidence in all 3 dosage groups (600, 900, 1200 mg/d). Only AEs with incidence ≥ 17% at the 1200 mg/day dose are shown.
*
P < .05
for placebo vs the combined retigabine groups for incidence of treatment-emergent
AEs.
Placebo, %
(n = 96)
Retigabine*, %
(n = 301)
CNS Related
Somnolence
6.3*
17.0-22.6
Confusion
5.2*
5.0-22.6
Dizziness
4.2*
8.0-17.9
Other
Headache
10.4*
11.0-17.0
Porter
RJ, et al.
Neurology
. 2007;68:1197-1204
.
[23]Slide26
Retigabine Safety Concerns
Retigabine carries a black box warning for retinal abnormalities and potential vision lossRetinal abnormalities reported >
4
yr of exposure
Seen in one-third of patientsRetigabine can cause blue skin discolorationReported in 10% of patients after ≥ 2
yr
of exposure
Appears as blue pigmentation on/around lips, finger/toe nail beds, scattered over body
Discoloration of the palate, sclera, and conjunctiva
also reportedUrinary retentionReported in 2% of patients exposed to retigabinePotiga® PI 2015.[24]Slide27
Rufinamide
Currently has orphan approval for the add-on treatment of seizures associated with LGSProlongs the inactive state of voltage-dependent sodium channels and limits sustained repetitive firing of sodium-dependent action potentialsUnsuccessful trials:
monotherapy
, pediatric POS, primary generalized epilepsy; indication for adjunctive POS not pursued Limited potential for drug-drug interactions
Valproic acid interaction in children (increases rufinamide
levels up to 70% in small children)
a
Krauss GL, et al.
Wyllie's Treatment of Epilepsy: Principles and Practice
. 2010:753-55.[25]Slide28
Rufinamide for Adjunctive Treatment in Lennox-
Gastaut
Syndrome
Efficacy
Reduction, %
≥ 50% Responders, %
Tonic-atonic seizures
Total seizures
Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.
[25]Slide29
Rufinamide Tolerability
Adverse events occurring in patients treated with rufinamide vs placebo
Adverse Event
Rufinamide
Placebo
Short-term Therapy, %
(N = 1875)
Long-term Therapy, %
(N = 1978)
Headache
22.9
29.5
18.9
Dizziness
15.5
22.5
9.4
Fatigue
13.6
17.7
9.0
Somnolence
11.8
n/a
9.1
Nausea
11.4
n/1
7.6
Serious AEs
6.3
13.2
3.9
Krauss GL, et al.
Wyllie's Treatment of Epilepsy: Principles and Practice
.
2010:753-55.
[25]Slide30
Rufinamide for Adjunctive Treatment of Partial Seizures50% Responder Rate
*P = .027; †P = .012; ‡P = .016.
14
‡
9
4.7
16*
12
†
0
10
20
30
40
Placebo
200 mg/d
400 mg/d
800 mg/d
1600 mg/d
Responder
Rate, %
Rufinamide
Krauss GL, et al.
Wyllie's Treatment of Epilepsy: Principles and Practice
.
2010:753-55.
[25]Slide31
RufinamideAdditional Studies
Monotherapy2 studies assessed monotherapy
; neither was positive on primary end point
Partial-onset pediatric
Greater reduction in seizure frequency for placebo than rufinamidePrimary g
eneralized tonic-clonic
Reduced frequency of generalized tonic-clonic seizures by 36.4%, compared to 25.6% for
placebo,
but results were not significant
As a result of these studies, an indication for POS was not pursuedKrauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25]Slide32
Rufinamide Dosing
Approved: rapid 1-week titration schedule
In pediatrics, an initial dosage
of 10 mg/kg/d with an
increase of 10 mg/kg/d every 2 days up to a target
dosage
of 45
mg/kg/d
(maximum 3200
mg/d)Adults are started at an initial dosage of 400 to 800 mg/d, with an increase of 400 to 800 mg every 2 days up to a maximum dosage of 3200 mg/dOpen-treatment series have shown that gradual rufinamide titration with increases every 5 to 7 days, along with reductions in ineffective concomitant AEDs, may reduce AEs seen during titration in clinical trials, such as somnolence and dizziness
Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25]Slide33
Vigabatrin
Currently approved as monotherapy for the treatment of infantile spasms and as adjunctive therapy for adult patients with refractory complex partial seizuresMOA believed to be irreversible inhibition of γ-aminobutyric acid transaminase (GABA-T)
Vigabatrin requires a Risk Evaluation and Mitigation Strategy (REMS) to help manage the risk of permanent vision loss associated with use of the drug
Sabril
® PI 2013.[26]
Krauss GL.
Epilepsy
Curr
. 2009;9:125-129.
[27]Slide34
Vigabatrin Carries a Boxed Warning for Vision Loss
Vigabatrin causes permanent bilateral concentric visual field constriction in 30% to 40% of patients
Visual field defects typically occur within the first 2 years of therapy
Mild to moderately severe and irreversible peripheral
field lossRisk mitigation: registration, severe epilepsy, monitoring of favorable treatment response to justify continued therapy,
perimetry
testing required every
3
months
Sabril® PI 2013.[16]Slide35
Vigabatrin REMS
Pellock JM, et al.
Epilepsy Behav
. 2011;22:710-717.
[28]
Refractory
Complex Partial Seizures
(n = 846)
Infantile
Spasms(n = 1500)Other(n = 120)Vigabatrin exposure
Exposed
308
390
53
Naive
493
992
57
Not reported
45
118
10
Dispensed
vigabatrin
810
1470
117
Total patients in registry: 2473
Total dispensed
vigabatrin
: 2397Slide36
AEDs in Clinical Trials
BrivaracetamBenzodiazepineNasal s
prays
Sublingual (acute treatment
) YKP3089Slide37
Summary
New AED therapies are emerging for treating drug-resistant epilepsyNovel AED mechanisms
modulate sodium and potassium ion channels and AMPA receptors
Individual patients may benefit from treatment with one of several new AEDs despite not tolerating or not responding to
previous AEDsSlide38
Abbreviations
AEs = adverse eventsAEDs = antiepileptic drugAMPA = α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidANCOVA = analysis of covarianceCI = confidence intervalCPS = complex partial seizuresCYP = cytochrome CBZ =
carbazepine
ESL = eslicarbazepineFAS = full analysis set
FDA = Food and Drug AdministrationGABA = gamma-aminobutyric acid ITT = intent to treatIV = intravenousKCNQ = potassium voltage-gated channel, KQT-like subfamily, member 1
KM =
kaplan-meierSlide39
LCM =
lacosamide
LGS
= Lennox-
Gastaut
syndrome
LOCF = last observation carried
forward
MedDRA
= Medical Dictionary for Regulatory ActivitiesmITT = modified intent to treatMOA = mechanism of actionOXC = oxcarbazepineOXC-MHD = oxcarbazepine monohydroxy derivativePK = pharmacokineticPGTC = primary generalized tonic-clonicPOS = partial-onset seizures REMS = risk evaluation and mitigation strategyTEAE = treatment-emergent adverse eventWBC = white blood cellAbbreviations (cont)Slide40
1. Ng YT, Conry JA, Drummond R, et al. Randomized, phase III study results of
clobazam in Lennox-Gastaut syndrome. Neurology. 2011;77:1473-1481. 2. Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents.
CNS Drugs. 2011;25:89-107.
3. Elger C, Bialer M, Cramer JA, et al. Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures.
Epilepsia. 2007;48:497-504.4.
Jacobson MP,
Pazdera
L,
Bhatia
P, et al; study 046 team. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study. BMC Neurology. 2015:15:46. 5. Sperling MR, Harvey J, Grinnell T, et al; 045 Study Team. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America. Epilepsia. 2015;56:546-555.6. McCormack PL, Robinson DM. Eslicarbazepine acetate. CNS Drugs. 2009;23:71-79.ReferencesSlide41
7. Elger C,
Halász P, Maia J, et al; BIA-2093-301 Investigators Study Group. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia. 2009;50:454-463.
8. Ben-Menachem E,
Gabbai AA, Hufnagel A, et al. Eslicarbazepine
acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89:278-285.9. Vimpat
®
[package insert]. Smyrna, GA; UCB,
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