the state of dravet syndrome - elsevier cme...comprehensive epilepsy center assistant professor of...

The State of Dravet Syndrome in 2017 Linda C. Laux, MD

Medical Director

Comprehensive Epilepsy Center

Assistant Professor of Pediatrics

Northwestern University

Feinberg School of Medicine

Chicago, Illinois 2 2

The State of Dravet Syndrome in 1978

3

Les épilepsies graves de l'enfant

Dravet C. Vie Médicale. 1978;8:543-548.

Charlotte Dravet, MD. Pictured above in 1978.

The State of Dravet Syndrome Since 1978

Seizures

Gait

Cognition

EEG Treatment

4

SCN1A

5 Baulac S et al. Am J Hum Genet. 1999;65(4):1078-1085; Escayg A et al. Nat Genet. 2000;24(4):343-345; Claes L et al. Am J Hum Genet.

2001;68(6):1327-1332.

A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33.

Mutations of SCN1A, encoding a neuronal sodium channel, in 2 families with GEFS+2.

De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.

6

RESEARCH

Dravet Syndrome

7

Dravet Syndrome: Characteristics, Comorbidities, and Caregiver Concerns

A Dravet Syndrome Foundation (DSF) Survey NICOLE VILLAS, MEd BOARD PRESIDENT

DRAVET SYNDROME FOUNDATION CHERRY HILL, NEW JERSEY

8

Disclosures

Parent of a child with Dravet syndrome

Child is enrolled in clinical trial of fenfluramine: NCT02826863

No financial disclosures

9

Survey Design

Designed and distributed by Dravet Syndrome Foundation

Posted in Support Group (1600 members)

Link sent to ~4000 email addresses

Likert scales, lists, multiple choice, open response

10

Demographics – 256 responses

0

20

40

60

80

100

Re

spo

nd

en

ts (

n)

Patient Age

70% from United States

92% SCN1A+ 6% inherited

(CI = 5.4)

Villas N et al. Epilepsy Behav. 2017;74:81-86. 11

Patient Characteristics

Comorbidities

Characteristics, Comorbidities, and the Patient

• Gait • Cognitive

Impairment • Speech Delay

• Temperature Dysregulation

• Nocturnal Seizures • Autistic Traits

• Sleep Issues • Frequent

Infections • Behavior

• Blood Abnormalities

• Psychiatric Issues

12 Villas N et al. Epilepsy Behav. 2017;74:81-86.

Characteristics/Comorbidities by Age

0

20

40

60

80

100

% R

ep

ort

ed

Age

Osteopenia

Gait Disturbances

Severe DevelopmentalDelay

Nocturnal Seizures

Temp Dysregulation


Patient

14

0 20 40 60 80 100

Dental Issues

Frequent Infections & Immunity Issues

Hearing/Vision/Neurological Issues

Cardiac Issues

Psychiatric Issues

Urinary Tract, Bowel, & Digestive Issues

Developmental Slowing, Regression, or Stagnation

Autistic Characteristics

Communication Issues

Developmental Delays

Growth, Endocrine Function, & Metabolism Issues

Sleep Disorders

Orthopedic & Movement Issues

% of Caregivers Responding "Yes" to Any Issue in the Category

Frequency of Issues Reported


Caregiver Concerns

After seizure control:

1. Speech/Communication (43)

“We don’t know if he’s hurt.”

“…inability to communicate her feelings.” “I don’t know if he’s sick or in pain.”

16

Caregiver Concerns



2. Sibling Impacts (42)

“Time solely devoted to one child, the other siblings feel left out.”

“Concern for sibling’s quality of life.”

• 74% report having concerns about the emotional impact on siblings


Caregiver Concerns After seizure control:



3. Cognitive/Developmental Delay (39)

72% reported moderate developmental delay 57% reported severe developmental delay

80% reported global memory/executive function issues


Caregiver Concerns




3. Cognitive/Developmental Delay (39)

4. Behavior (34)

Behavior/Psychiatric Issues Reported as “Sometimes” or “Often”

0 50 100

% Reported

“BEHAVIOR”

Difficulty with impulse control

ADD or ADHD

Irritability

Aggression

Anxiety

Perseveration


Caregiver Concerns After seizure control:


2. Sibling Impacts

3. Cognitive/Developmental Delay

4. Behavior

5. Long-Term Care

“Where will he live when his mom and I are gone?”

“How will I manage to look after my son when I am older? (I am already 50 and exhausted)..”


Caregiver Concerns



2. Sibling Impacts

3. Cognitive/Developmental Delay

4. Behavior

5. Long-Term Care

6. SUDEP and Mortality

59% 24%

12%

6%

n=17 SUDEP

StatusEpilepticus

Drowning

Asphyxia

SUDEP=sudden unexpected death in epilepsy.

Villas N et al. Epilepsy Behav. 2017;74:81-86; Cooper M et al. Epilepsy Res. 2016;128:43-47.

Classification of Mortality

21

Impact on the Caregiver 97% reported sleep issues

82% sleep with the patient

46% use a pulse oximeter

66% of caregivers reported depression

“First marriage broke down due to pressures of caring, we are now divorced”


Impact on the Family

Logistical

0-3 years: Frequent status Outings difficult, cut short

11+ years: Can’t move patient after simple seizure, behavioral refusals Outings difficult, take longer than anticipated

Physical

Nocturnal seizures, fear of SUDEP, sleep issues Exhaustion

Transfers, equipment (wheelchairs, O2, emergency bag) Exhaustion

Constant care Exhaustion


Conclusion

Dravet syndrome is more than seizures, and significantly decreases the patient’s quality of life

Dravet syndrome impacts the patient and the family

24

Assessing the Impact of Caring for a

Child With Dravet Syndrome:

Results of a Single Center Survey

Kelly G. Knupp, MD, MSCS, FAES

Associate Professor of Pediatrics and Neurology

Neurology and Neurodiagnostics

Children’s Hospital Colorado,

University of Colorado Denver

Denver, Colorado

25

Themes I Hear in Clinic

• Constipation provokes seizures

• Poor sleep

• Long mealtimes

• Ambulation concerns

• No response to pain Leads to injuries

• Autonomic symptoms Flushing, not tolerating heat/cold

Racing HR

• Behavior Perseveration

Safety

Dravet syndrome

affects many body

systems; therefore,

family impact is large

26

Family Impact

• High stress in caregivers Deterioration of relationships

Fear

Uncertainty

Sleep problems

• Sleep deprivation

• Reduced mental health

• Deterioration of relationships

• Financial burden

• Depression

Nolan KJ et al. Dev Med Child Neurol. 2006;48(9):761-765; Skluzacek JV et al. Epilepsia. 2011;52 suppl 2:95-101;

Jensen MP et al. Epilepsy Behav. 2017;74:135-143. 27

Methods

• Survey emailed to caregivers of children with Dravet syndrome

at single institution

• Electronic survey administered through REDcap

• Assessed the following domains: Time spent

Difficulty performing caregiver tasks

Caregiver health-related quality of life (QoL)

Caregiver work-related productivity/activity impairment

28 Whittington MD et al. Epilepsy Behav. 2018;80:109-113.

Response Rate

• Sent to 60 caregivers 34 (57%) response rate

Of these, 30 (88%) had complete response

Patients aged 2 to 22 years

91% had known SCN1A mutation

73% of caregivers were employed

29 Whittington MD et al. Epilepsy Behav. 2018;80:109-113.

Moderate or Greater Time Burden

• Providing transportation (93%)

• Personal [DS patient] care (87%)

• Additional household tasks (83%)

• Communication (80%)

• Symptom observation (77%)

30 Campbell JD et al. Epilepsy Behav. 2018;80:152-156.

Moderate or Greater Difficulty

• Arranging for care (73%)

• Communication (70%)

• Coordinating resources (67%)

• Managing behavior problems (67%)

• Personal care (63%)

31 Campbell JD et al. Epilepsy Behav. 2018;80:152-156.

Time and Difficulty of Tasks

32

Reprinted from Epilepsy & Behavior, 80, Campbell JD, Whittington MD, Kim CH, VanderVeen GR, Knupp KG, Gammaitoni A. Assessing the impact of

caring for a child with Dravet syndrome: Results of a caregiver survey, 152-156, Copyright 2018, with permission from Elsevier.

Impact on Work Productivity and

Leisure Time EQ-5D VAS ≥65 (n=18) EQ-5D VAS <65 (n=12)

Mean (SD) Median (IQR) Mean (SD) Median (IQR)

Weekly time missed from work (hours) 7.4 (15.2) 0.5 (0.0, 2.8) 6.9 (12.3) 0 (0.0, 8.0)

Weekly time missed from leisure (hours) 31.0 (53.9) 7.0 (1.8, 23.0) 57.8 (59.2) 40.0 (7.3, 84.0)

Effect caregiving had on work

productivity 39.1 (25.6) 52.0 (13.8, 58.0) 76.9 (19.8) 75.0 (68.0, 90.0)

Effect caregiving had on leisure time 55.1 (24.0) 55.5 (39.5, 69.3) 82.6 (12.4) 81 (77.3, 91.8)

EQ-5D=EuroQol health-related quality-of-life survey; IQR=interquartile range; VAS=visual analog scale.

33

Reprinted from Epilepsy & Behavior, 80, Campbell JD, Whittington MD, Kim CH, VanderVeen GR, Knupp KG, Gammaitoni A. Assessing the impact of

caring for a child with Dravet syndrome: Results of a caregiver survey, 152-156, Copyright 2018, with permission from Elsevier.

Cost of Care Schematic

34

Reprinted from Epilepsy & Behavior, 80, Whittington MD, Knupp KG, VanderVeen G, Kim C, Gammaitoni A, Campbell JD. The direct and indirect

costs of Dravet Syndrome, 109-113, Copyright 2018, with permission from Elsevier.

Per-Person Direct Cost of Care

Cost Component Mean Unit

Cost

Caregiver-Reported

Annualized Rate

Mean (SD)

Annual Cost

Mean (SD)

Conventional Health Care Utilization

In-Home Visits $214 46.23 (137.64) $9,894 ($29,456)

Doctor Visits $245 11.13 (9.07) $2,728 ($2,221)

Emergency Department Visits $788 1.90 (2.27) $1,497 ($1,789)

Hospitalizations $10,204 1.13 (2.16) $11,565 ($22,001)

Ground Ambulance $1,111 0.67 (1.58) $741 ($1,753)

Air Ambulance $7,160 0.07 (0.25) $477 ($1,786)

Complementary and Alternative Health Care Utilization

Chiropractic Services $36 6.53 (16.80) $235 ($605)

Multivitamin Use $10 6.33 (9.07) $63 ($91)

Essential Oil Use $10 2.57 (5.90) $26 ($59)

Marijuana Prescription $150 0.33 (0.83) $50 ($125)

Total Annual Direct Cost

Mean (95% interval)

$27,276

($15,757, $41,904)

35



Indirect Cost Burden

Caregiver-Reported Time

Mean (SD)

Annual Cost

Mean (SD)

Lost Productivity (n=24, 73%)

Absenteeism 381 (704) hours $7,587 ($16,941)

Presenteeism 616 (719) hours $12,338 ($19,196)

Lost Leisure Time (n=33, 100%) 2,047 (2,929) hours $52,415 ($74,932)

Income Loss Due to Caregiving (n=21, 64%) $9,242 ($19,410)

Total Annual Indirect Cost

Mean (95% interval)

$81,582

($57,253, $110,151)

Total time commitment = 380 eight-hour work days/year

36



Conclusion

• Caregivers spend significant amount of time providing care

for children with Dravet syndrome

• Direct and indirect cost of care is great

• Total time commitment = 380 eight-hour work days per year!

37

SUDEP in Dravet Syndrome: What Do We Know

About Pathophysiology? Lieven G. Lagae, MD, PhD

Professor of Paediatric Neurology

Director of Paediatric Neurology

University Hospitals Leuven – Paediatric Neurology

Leuven, Flanders, Belgium

38

Presentation Outline

• SUDEP and epidemiology

• Pathophysiology and risk factors

• Mortality and SUDEP in Dravet syndrome

• Preventive measures?

39

Definition and Incidence of SUDEP

SUDEP is defined as sudden, unexpected, nontraumatic, nondrowning death in an individual with epilepsy, witnessed or unwitnessed, in which postmortem examination does not reveal an anatomical or toxicological cause of death. Documented status epilepticus is excluded.

Adapted from Shankar R et al. Epileptic Disord. 2017;19(1):1-9; Harden C et al. Neurology. 2017;88(17):1674-1680. 40

Practice Guidelines Summary* Incidence of SUDEP in Different Epilepsy Populations

*Complete guideline information available at Neurology.org † 95% CI (confidence interval)

0.22

1.2

0.58

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Childhood Adulthood Overall

In…

MODERATE Confidence

LOW Confidence

LOW Confidence

(0.64-2.32) †

(0.16-0.31)†

(0.31-1.08)†

Sudden Unexpected Death in Epilepsy

41 Reprinted from The Lancet, 378/9808, Shorvon S, Tomson T. Sudden unexpected death in epilepsy, 2028-2038, Copyright 2011, with permission

from Elsevier.

Reprinted from The Lancet Neurology, 7/11, Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions,

1021-1031, Copyright 2008, with permission from Elsevier.

Sudden Unexpected Death in Epilepsy: Current Knowledge and Future Directions

42

Typical Cardiovascular Events Peri-ictal

43 Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature. Nature Reviews Neurology. Mechanisms of sudden unexpected

death in epilepsy: the pathway to prevention. Massey CA, Sower LP, Dlouhy BJ, Richerson GB. 10(5);271-282. 2014.

Seizures Leading to SUDEP : The MORTEMUS Study

44

(Secondary) GTC Variable duration Generalized EEG suppression Night – Prone Early collapse 3 min, sometimes already fatal First respiratory suppression, then asystole

Reprinted from The Lancet Neurology, 12/10, Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy

monitoring units (MORTEMUS): a retrospective study, 966-977, Copyright 2013, with permission from Elsevier.

At end of fatal seizure = breathing >18 min At end of fatal seizure = heart rhythm very variable

Seizures Leading to SUDEP : The MORTEMUS Study

45 Reprinted from The Lancet Neurology, 12/10, Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy

monitoring units (MORTEMUS): a retrospective study, 966-977, Copyright 2013, with permission from Elsevier.

Role of Brainstem Serotonin?



4-aminopyridine in cortex

ECG=electrocardiogram; SD=spreading depolarization.

Spreading Depolarization in the Brainstem Mediates Sudden Cardiorespiratory Arrest in Mouse SUDEP Models

47 From Aiba I, Noebels JL. Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci Transl Med.

2015;7(282):282ra46. Reprinted with permission from American Association for the Advancement of Science.

Genetic Risk Factors



Klassen TL et al. Epilepsia. 2014;55(2):e6-e12. Reprinted with permission.

CNV=copy number variant.

High-Resolution Molecular Genomic Autopsy Reveals Complex Sudden Unexpected Death in Epilepsy Risk Profile

3-year-old boy with Dravet syndrome and SUDEP

De novo single nucleotide polymorphisms and CNVs in: SCN1A, KCNA1 and RYR3 and HTR2C

49

Adapted from Harden C et al. Neurology. 2017;88(17):1674-1680.

Practice guideline summary. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society

Risk Factors for SUDEP

50

10

5.07

15.46

4.7 6

0.4 0.1

0.02.04.06.08.0

10.012.014.016.0

Presence ofGTCS vs lack of

GTCS

Frequency ofGTCS

(1-2 GTCS/yr)

Frequency ofGTCS

(>3 GTSC/yr)

Not beingseizure-free

for 1-5 yr

Not adding anAED when

patients aremedicallyrefractory

Nocturnalsupervision

(riskreduction)

Use ofnocturnallistening

device (riskreduction)

Od

ds

Rat

io

(0.2-0.8)* (0-0.3)*

MODERATE Confidence

(7-14)*

(2.94-8.76)* (1.4-16)* (2-20)*

*CI

AED=antiepileptic drug; GTCS=generalized tonic-clonic seizure.

MODERATE Confidence

MODERATE Confidence

MODERATE Confidence

MODERATE Confidence

(9.92-24.10)*

HIGH Confidence

HIGH Confidence

Ranking the Leading Risk Factors in SUDEP

51

DeGiorgio CM, Markovic D, Mazumder R, Moseley BD. Ranking the leading risk factors for sudden unexpected death in epilepsy. Frontiers in Neurology.

2017;8:Article 473. https://www.frontiersin.org/articles/10.3389/fneur.2017.00473/full. This is an open-access article distributed under the terms of the

Creative Commons Attribution License (CC BY) and is available under Public License, https://creativecommons.org/licenses/by/4.0/legalcode.

Premature Mortality in Dravet Syndrome

Mean Age 8.7 ± 9.8 yrs 73% < 10 yrs age 93% < 20 yrs age

DS=Dravet syndrome; SE=status epilepticus.

52 Reprinted from Epilepsy & Behavior, 64/Pt A, Shmuely S, Sisodiya SM, Gunning WB, Sander JW, Thijs RD. Mortality in Dravet syndrome: A review, 69-74,

Copyright 2016, with permission from Elsevier.

Epilepsy-related deaths SUDEP 49% (n=87) + Status Epilepticus 32% (n=56) = 81% of all premature deaths compared with <3% new-onset epilepsies (non-DS)

Cause of Death in 177 Dravet Syndrome Cases

53 Reprinted from Epilepsy & Behavior, 64/Pt A, Shmuely S, Sisodiya SM, Gunning WB, Sander JW, Thijs RD. Mortality in Dravet syndrome: A review, 69-74,

Copyright 2016, with permission from Elsevier.

100 DS patients followed for a median of 17 years : 17 dead, 10/17 : SUDEP Dravet-specific SUDEP rate : 9.32/1000 person-years

Mortality in Dravet Syndrome

54 Reprinted from Epilepsy Research, 128, Cooper MS, Mcintosh A, Crompton DE, et al. Mortality in Dravet syndrome, 43-47, 2016,

with permission from Elsevier.

Dravet ?

Ranking the Leading Risk Factors in SUDEP

55

DeGiorgio CM, Markovic D, Mazumder R, Moseley BD. Ranking the leading risk factors for sudden unexpected death in epilepsy. Frontiers in Neurology.

2017;8:Article 473. https://www.frontiersin.org/articles/10.3389/fneur.2017.00473/full. This is an open-access article distributed under the terms of the

Creative Commons Attribution License (CC BY) and is available under Public License, https://creativecommons.org/licenses/by/4.0/legalcode.

Cardiac Abnormalities in Dravet Syndrome

DS patients had depressed Heart Rate Variability (HRV) variables compared with patients with epilepsy (ES) patients (ES/AED and ES/no-AED) and healthy control group.

ES=epileptic syndrome; RR=inter-beat; SDNN=standard deviation of normal-to-normal.

56 Reprinted with permission. Delogu AB, Spinelli A, Battaglia D, et al. Electrical and autonomic cardiac function in patients with Dravet syndrome. Epilepsia.

John Wiley and Sons. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Adapted from Auerbach DS et al. PLoS One. 2013;8(10):e77843.

EADs=early afterdepolarizations.

Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome

57

Increase Na influx Increased excitability

Heart rate decrease before SUDEP

Sudden Unexpected Death in Epilepsy: Basic Mechanisms and Clinical Implications for Prevention

58 Reproduced from Journal of Neurology, Neurosurgery & Psychiatry, Dlouhy BJ, Gehlbach BK, Richerson GB. vol. 87, 402-413, 2016,

with permission from BMJ Publishing Group Ltd.

59 Epilepsy Foundation of America. https://www.epilepsy.com/make-difference/public-awareness/aimforzero-striving-toward-future-free-sudden-

unexpected-death. Accessed February 12, 2018.

Non-EEG Seizure Detection Systems and Potential SUDEP Prevention: State of the Art: Review and Update

Monitoring Patients at Night?

Reprinted from Seizure, vol. 41, Van de Vel A, Cuppens K, Bonroy B, et al. Non-EEG seizure detection systems and potential SUDEP prevention:

State of the art: Review and update, 141-153, Copyright 2016, with permission from Elsevier. 60

We found very low-quality evidence of a preventative effect for nocturnal supervision against SUDEP. Further research is required to identify the effectiveness of other current interventions, for example, seizure detection devices, safety pillows, SSRIs, early surgical evaluation, educational program, and opiate and adenosine antagonists in preventing SUDEP in people with epilepsy.

Maguire MJ et al. Cochrane Database Syst Rev. 2016;7:CD011792.

Treatments for the Prevention of Sudden Unexpected Death in Epilepsy (SUDEP)

62

Summary: SUDEP in Dravet Syndrome

• Pathophysiology and risk factors:

refractory syndrome factors and (compound) genetic factors

• Mortality and SUDEP in Dravet syndrome

> 10 x higher than in other epilepsies

• Need for SUDEP preventive studies

63

Approaches to Treatment of Dravet Syndrome:

What's on the Horizon?

Joseph E. Sullivan, MD Associate Professor of Neurology & Pediatrics University of California, San Francisco (UCSF)

Director, UCSF Pediatric Epilepsy Center of Excellence San Francisco, California

64

Presentation Outline

• Dravet treatment landscape pre-2012

• Cannabidiol (CBD) Phase 3 Review

• Fenfluramine Phase 3 Review

• On the horizon

65

Treatments

• Valproate

• Topiramate

• Clobazam

• Stiripentol

• Levetiracetam

• Ketogenic diet

• Vagal nerve stimulation

• Bromides

• Verapamil

• Rescue plans with benzodiazepines

• Avoidance of carbamazepine, oxcarbazepine, phenytoin, lamotrigine

66

Sad, But Honest

67

The Pharmacologic Treatment of Dravet Syndrome • Valproate is used as a first-line agent to prevent the recurrence of

febrile seizures, and oral/nasal/rectal benzodiazepine is used for any long-lasting seizures, but these agents are most often insufficient

Chiron C, Dulac O. Epilepsia. 2011;52 suppl 2:72-75

Current therapeutic procedures in Dravet syndrome • Valproate and benzodiazepines are the first-line treatments, but are

usually insufficient therapeutic options Chiron C. Dev Med Child Neurol. 2011;53 suppl 2:16-18

The Data (or Lack Thereof!)

• Recent Cochrane Review 2013

• 14 studies – 11 excluded (9 uncontrolled, 2 abstract only, 1 metanalysis)

– Left with 2 studies, both of which evaluated stiripentol (STP)

Brigo F, Storti M. Cochrane Database Syst Rev. 2013;(11):CD010483. 68

Syndrome-specific Treatment? Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-

controlled syndrome-dedicated trial

69 Chiron C et al. Lancet. 2000;356(9242):1638-1642.

Methods

• After a baseline period of 1 month, placebo (n=20) or stiripentol (n=21)

Findings

• 15 (71%) patients were responders on stiripentol (including 9 free of clonic or tonic-clonic seizures),

• (-69%) than on placebo (+7%), P<·0001

Interpretation

• Results also provide good reason to focus studies on a specific epilepsy syndrome–a small sample of patients

is sufficient to show the efficacy that might have been missed in a heterogeneous population

70 Young S. Marijuana stops child’s severe seizures. CNN Health Web site. http://www.cnn.com/2013/08/07/health/charlotte-child-medical-

marijuana/index.html. Updated August 7, 2013. Accessed January 10, 2018.

Marijuana Stops Child’s Severe Seizures

Devinsky O et al; Cannabidiol in Dravet Syndrome Study Group. N Engl J Med. 2017;376(21):2011-2020.

Trial of Cannabidiol For Drug-resistant Seizures in the Dravet Syndrome

71

Study Overview

• Phase 3 double-blind, placebo-controlled trial

• 120 subjects randomized – 61 CBD (20mg/kg/d) vs 59 placebo

– Baseline seizure frequency (14 per month)

• 2-week dose escalation followed by 12-week maintenance

• 12 withdrew (9 CBD vs 3 placebo)

• Median of 3 concomitant AEDs (clobazam, valproates, levetiracetam, topiramate)

Devinsky O et al; Cannabidiol in Dravet Syndrome Study Group. N Engl J Med. 2017;376(21):2011-2020. 72

CBD 5% seizure free vs 0 in placebo

73

Cannabinoids for Epilepsy – Real Data, At Last

From The New England Journal of Medicine, Devinsky O, Cross JH, Laux L, et al; Cannabidiol in Dravet Syndrome Study Group, Trial of cannabidiol for

drug-resistant seizures in the Dravet syndrome, vol. 376, 2011-2020. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society; Berkovic SF. N Engl J Med. 2017;376(21):2075-2076.

Cross JH et al. Poster presented at: American Epilepsy Society Annual Meeting; December 2-6, 2016; Houston, TX.

Second Phase 3 Randomized Control Trial

• 12-week maintenance period

• Treatment effect increased for patients receiving cannabidiol

74

Adverse Events

Devinsky O et al; Cannabidiol in Dravet Syndrome Study Group. N Engl J Med. 2017;376(21):2011-2020.

93% Treatment vs 75% Placebo

• Diarrhea • Decreased appetite

• Vomiting • Lethargy

• Fatigue • Somnolence

• Pyrexia • Fatigue

• URI

75

CBD Conclusions

• Anecdotal experience led to well-designed placebo-controlled trials

• Appears to be safe, well tolerated, and effective in reducing seizures in Dravet syndrome

• Mechanism of action of cannabidiol remains poorly understood

• Role of other cannabinoids needs further study

76

Fenfluramine in Dravet Syndrome

Ceulemans B et al. Epilepsia. 2012;53(7):1131-1139. 77

Successful Use of Fenfluramine as an Add-on Treatment For Dravet Syndrome

78 Reprinted with permission. Ceulemans B, Boel M, Leyssens K, et al. Successful use of fenfluramine as an add‐on treatment for Dravet syndrome. Epilepsia.

John Wiley and Sons. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Fenfluramine Study

• Phase 3 double-blind, placebo-controlled trial

• 119 subjects randomized – 39 (0.8 mg/kg/d), 40 (0.2 mg/kg/d), 40 (placebo) – Baseline seizure frequency (40 per month)

• 6-week baseline, 2-week titration, 12-week maintenance

• 5 subjects withdrew (all in 0.8 mg/kg/d)

• Most on 2 to 3 concomitant AEDs (clobazam, valproates, topiramate, levetiracetam)

Lagae L et al. ZX008 (fenfluramine) in Dravet syndrome: results of a phase 3, randomized, double-blind, placebo-controlled trial. Poster presented at:

71st American Epilepsy Society Annual Meeting; December 1-5, 2017; Washington, DC. 79

ZX008 – Initial Phase 3 Clinical Trial Results

80 Lagae L et al. ZX008 (fenfluramine) in Dravet syndrome: results of a phase 3, randomized, double-blind, placebo-controlled trial. Poster presented at:

71st American Epilepsy Society Annual Meeting; December 1-5, 2017; Washington, DC.

• Phase 3 randomized, double-blind, placebo-controlled clinical trial of children and young adults with Dravet syndrome

• The study met its primary objective of demonstrating that ZX008 at 0.8 mg/kg/d was superior to placebo as adjunctive treatment according to the change in the frequency of convulsive seizures between the 6-week baseline period and the 14-week treatment period

– Patients treated with ZX008 0.8 mg/kg/d achieved a mean 63.9% reduction in monthly seizures compared with placebo (P<.001)

• Patients treated with ZX008 0.2 mg/kg/d also demonstrated statistically significant reductions in monthly convulsive seizures compared with placebo, with the results suggesting a dose-response relationship

ZX008 – Initial Phase 3 Clinical Trial Results (cont’d)

• 70% of patients treated with ZX008 0.8 mg/kg/d achieved a ≥50% reduction in monthly convulsive seizures compared with 7.5% of placebo-treated patients (P<.001)

• 45% of patients treated with ZX008 0.8 mg/kg/d achieved a ≥75% reduction in monthly convulsive seizures compared with 2.5% of placebo-treated patients (P=.001)

• ZX008 was generally well tolerated, with adverse events consistent with the known safety profile of fenfluramine

• 95% of patients treated with either dose of ZX008 experienced at least 1 treatment-emergent adverse event compared with 65% of placebo-treated patients

• Prospective safety monitoring throughout the study found no clinical or echocardiographic evidence of cardiac valvulopathy or pulmonary hypertension



Adverse Events

95% Treatment vs 65% Placebo

• Diarrhea • URI

• Vomiting • Decreased Appetite

• Pyrexia • Lethargy

• Nasopharyngitis • Somnolence



Cardiac Echo Findings

5 Placebo, 7 (0.2 mg/kg), 9 (0.8 mg/kg)

• No clinically significant abnormalities

• Trace mitral regurgitation or aortic regurgitation



Fenfluramine Conclusions

• Dramatic reduction in seizure frequency – Higher dose is superior to lower dose

• Clinically significant number of patients with “Near Seizure Freedom”

• Safe and well tolerated

• No clinically relevant cardiac echo findings

84

On the Horizon

85

Blinded Drug Screen

• Clinical observations led to studies

• 3500 FDA-approved compounds

• Screened in this SCN1 zebrafish model at 100 and 667 µM

• Observed for swim behavior – Electrophysiologic forebrain recordings

Courtesy of Baraban Lab 86

87 Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature. Nature Communications. Drug screening in Scn1a zebrafish mutant

identifies clemizole as a potential Dravet syndrome treatment, Baraban SC, Dinday MT, Hortopan GA. 2013.

Clemizole

• FDA approved with safe toxicology profile

• H1 antagonist

• NS4B RNA inhibiting properties

• What is the mechanism of action?

88

Mechanisms of Action • Clemizole hypothesized to act

independently of H1 antagonism

• 49 drugs with antihistaminergic properties – None inhibited mutant seizure

behavior – 3 were toxic

89

Dinday M, Baraban SC. Large-scale phenotype-based antiepileptic drug screening in a zebrafish model of Dravet syndrome. eNeuro. 2015;2(4):e0068-15.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596025/. This is an open-access article distributed under the terms of the Creative Commons Attribution

License (CC BY) and is available under Public License, https://creativecommons.org/licenses/by/4.0/legalcode.

• Huperzine A (Biscayne Pharmaceuticals)

• Fenfluramine (Zogenix)

90

Dinday M, Baraban SC. Large-scale phenotype-based antiepileptic drug screening in a zebrafish model of Dravet syndrome. eNeuro. 2015;2(4):e0068-15.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596025/. This is an open-access article distributed under the terms of the Creative Commons Attribution

License (CC BY) and is available under Public License, https://creativecommons.org/licenses/by/4.0/legalcode.

Adapted from Griffin A et al. Brain. 2017;140(3):669-683. 91

Disease Modifying?

• OPK-88001

• Phase 2 study-PK, safety and tolerability

– AntagoNAT (anti-Natural Antisense Transcript compound)

• Preliminary animal data increased SCN1A expression in mice

• Lumbar puncture on days 1, 14, 28, 56, 84

• Secondary end points – Seizure frequency

Hsiao J et al. EBioMedicine. 2016;9:257-277. 92

Conclusions

• 2 novel and effective drugs for the treatment of Dravet syndrome in just the past 3 years

• Open-label studies with both compounds are ongoing to determine durability of treatment effect

• Well-designed animal models are identifying novel compounds with novel pathways (serotonin)

• Disease-modifying therapies being explored

• Improved treatments at an earlier age may lead to improved outcomes

93

the state of dravet syndrome - elsevier cme...comprehensive epilepsy center assistant professor of...

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