Tracy Dixon-Salazar, PhD presents on emerging therapies in LGS

1. #LGSCONFERENCE17

2. Tracy Dixon-Salazar, PhD
Director of Research & Strategy
Emerging Therapies &
Clinical Trials in LGS

3. Overview
1. Introduction
2. New therapies
i. Novel targets
ii. Re-purposing
iii. Re-visiting
iv. Concept of precision
therapies

4. Many types of clinical Trails in
childhood epilepsy exist
0
2
4
6
8
10
12
14
16
Partial
epilepsy
No.ofRCTs
GTC LGS Infantile
spasms
JME Absence Neo-
natal
SMEI
Updated from NICE HTA newer AEDs 2005

5. 13 trails done in LGS
• Cochrane review 2013 Hancock & Cross
• 13 RCTs, 9 available
– Cinromide N=56 2-17 yrs (7.5)
– Felbamate N=73 4-36 yrs (13)
– TRH N=98 ?
– Lamotrigine N=169 3-25yrs (9)
– Lamotrigine N=20
– Topiramate N=98 2-42yrs (11.2)
– Rufinamide N=139 4-30 yrs
– Clobazam N=68
– Clobazam N=217 2-60 yrs

6. Conclusions: Cochrane review of LGS
Trials done
• Optimum treatment for Lennox-Gastaut syndrome
remains uncertain
• No study has shown any drug to be highly efficacious in
treatment of LGS
• Lamotrigine, topiramate, felbamate and rufinamide may
be helpful as add on therapy
• Evidence base for one therapy over another limited;
each patient needs to be considered individually, taking
into account potential benefit of each therapy vs risk of
adverse effects
Hancock E, Cross H. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev 2013;CD003277.

7. LGS first line therapy – expert opinion
Wheless et al, J Child Neurol 2005;20s1:s1-56

8. Cross, Auvin, Falip. Striano, Arzimanoglou 2017 submitted

9. Expectations of treatment and
treatment response in epilepsy
• Common disorder vs. rare disorder treatment
• Treatment aim is seizure freedom; >50%
reduction in seizures is considered successful
• Achieved with the first drug in 70%
• Achieved with the second drug in a further 10-
20%

10. New in treatment - Drugs
i. Novel targets
a. Neuronal synapse
b. Other sites
ii. Re-purposing drugs used in other
diseases
iii. Re-visiting drugs used for other
epilepsies or abandoned in the past

11. Site of action of
AEDs at the
neuronal
synapse
Bialer & White; Nature Reviews Drug Discovery
2010: 68-82
•Consider a new drug
which acts on a
different site
•Consider synergism

12. New sites of action
• Perampanel – post-synaptic AMPA receptors
• Cannabidiol – endocannabinoid system

13. Perampanel - highly selective, non-competitive, post-synaptic
AMPA receptor antagonist
Redrawn and adapted from [2] and [3].1Hanada et al. Epilepsia 2011;52:1331–1340;
2Rogawski MA, Löscher W. Nat Rev Neurosci 2004;5:553–564; 3Rogawski MA. Epilepsy Currents 2011;11:56–63. 13
Post-synaptic neuron
Pre-synaptic
neuron
Inhibitory interneuron
Post-synaptic excitability
AMPA receptor
Glutamate
NMDA receptor

14. % of patients achieving ≥50% reduction from baseline in seizure frequency/28
days
*P<0.05 vs placebo
**P<0.005 vs placeboN=45
N=21
N=13
N=44
N=20
ITT population: studies 304,305 &306, pooled. Double-blind phase
1Data on file, Eisai Inc; 2Rosenfeld et al. 2012 CNS; 3ISE Table 14.2. 2.2
Responder rate
14
Responderrate(%)
Overall
Population1
N=1478
Adolescents
(306)2
N=60
Adolescents
(304 & 305)2
N=83
Adolescents
(Pooled)3
N=143
N=441
N=180
N=172
N=431
N=254
N=14
N=21
N13
N=12
N=31
N=32
N=20
Adolescents
*
*
*
*
*
Krauss GL et al. Neurology 2012;78(18):1408--1415; French JA et al. Neurology 2012;79:589–596: French JA et al. Epilepsia. Epub 20
Aug 2012; 4Krauss GL et al. Epilepsia. Epub 20 Aug 2012.

15. Perampanel
• It works
• Even seizure freedom
• Even 2mg can be helpful
• Prevention of evolution to
bilateral convulsive
• Long half-life
• Introduce very slowly
Side effects
• Aggression can prevent
ongoing use
• Dizziness to be expected
• Can see overshoot
• Interaction with other drugs
– exacerbates lamotrigine
side-effects
Positive results

16. Cannabis
• One of the most widely used recreational and medicinal
drugs worldwide.
– ~150 million people smoking cannabis daily (WHO)
• Likely the first non-food plant cultivated by humans
(~8000 BC)
• Best known for its psychoactive constituent, Δ9-
tetrahydrocannabinol (‘THC’).

17. Two major cannabinoids
THC
• analgesic, anti-spasmodic,
anti-tremor, anti-
inflammatory, appetite
stimulant and anti-emetic
properties
CBD
• Anti-inflammatory, anti-
convulsant, anti-psychotic,
anti-oxidant, neuroprotective
and immunomodulatory
effects.
• Lacks the psychotomimetic
and psychotropic effects of
THC
• May alleviate some of the
potentially unwanted side-
effects of THC.

18. The endocannabinoid system
• First described in the late
1980s/early 1990s
• Endogenous ligands, receptors,
synthetic and degradation
enzymes
• Cannabinoid receptors:
– cell surface receptors
– present on a wide variety of cell
types.
– two CBR types:
• CB1:
• CB2:
• Endocannabinoids:
• anandamide
• 2-arachidonoyl glycerol
• Numerous synthetic ligands for
CB1Rs and CB2Rs have also
been developed
Anandamide 2-arachidonoyl glycerol (2-AG)
Courtesy of Dr Ben Whalley

19. Cannabidiol in childhood epilepsy
• 214 patients across 11
sites
• safety & tolerability 167
• Adverse events 79%
• 137 efficacy analysis
Dravet N=32
49% responders, 3% SF
LGS N=30
37% responders, 3% SF
Lancet Neurology e-pub ahead of print 15th December 2015

20. Conclusion: cannabidiol might reduce seizure frequency and might have an adequate
safety profile in children and young adults with highly treatment-resistant epilepsy.
Lancet Neurology 2016;15:270-
8
Safety analysis (N=162)
Somnolence 41 (25%)
Decreased appetite 31 (19%)
Diarrhoea 31 (19%)
Fatigue 21 (13%)
Convuslsion 18 (11%)
Increased appetite 14 (9%)
Status epilepticus 13 (8%)
Lethargy 12 (7%)
Weight increased 12 (7%)
Weight decreased 10 (6%)

21. AED interaction; clobazam
13/25 children CBD 2—
25mg/kg/day
Mass General Hospital,
Boston
Norclobazam increased in
12/13
Side effects 10/13
• Drowsiness 6
• Ataxia
2
• Irritability 2
• Restless sleep 1
• Urinary retention 1
• Tremor 1
• Loss of appetite 1
Geffrey et al, Epilepsia, 56(8):1246–1251, 2015

22. Cannabidiol in LGS; RCT

23. Where are we now with cannabinoids?
Efficacy
• 50% responders, 3%
seizure free
– Devinsky, Lancet
Neurology 2015
– Friedman, NEJM 2015
Emerging experience
• Side-effects
– Somnolence
– Decreased appetite
– Diarrhoea
– Tremor
• Interaction with clobazam
– Geffrey, Epilepsia 2015
• Abnormal liver function
• Up to 25-50 mg/kg/day
• Tolerance

24. Neonatal epileptic
encephalopathies
1
month
4
months0 1 year
6
months
Epilepsy limited to females with
mental retardation
PCDH19
Early onset epileptic
encephalopathy
STXBP1, CDKL5, ARX,
PLCB1, SLC25A22,
SPTN1, SLC19A3
Early myoclonic
encephalopathy
Infantile epileptic encephalopathies
KCNQ2
encephalopathy
Epilepsy in infancy with migrating
focal seizures
SCN1A, KCNT1, PLCB1
Dravet syndrome
SCN1A
West syndrome
CDKL5 in girls
ARX in boys
Copy Number Variants 8%
Genetic basis of the Early Infantile Epileptic Encephalopathies
Slide courtesy of Prof Helen Cross

25. Repurposing & precision therapies &
re-visiting
Loss of function mutations Gain of function mutations
• SCN2A and SCN8A
• Use sodium channel
blockers
– High dose phenytoin and
carbazepine
• SCN1A
– Avoid sodium channel
blockers
– CBD
– Revisting ‘old’ drugs

26. SCN1A and LGS - re-visiting
fenfluramine
• High doses used for obesity, heart valve thickening, taken off
market
• Effective for self-induced/photosensitive seizures
– Boel, Neuropediatrics 1996
• Effective in Dravet syndrome
– Ceulemans, Epilepsia 2012
• Mechanism uncertain: stimulates serotonin; 5HT2A agonist
• Randomised placebo control trial for LGS in Europe and US

27. SCN1A and LGS - re-visiting
fenfluramine

28. Summary
• Treatment options for LGS continue to expand
– Perampanel, Epidiolex (CBD), Fenfluramine trials
– Other drugs in earlier stages of development
– Using specific drugs to treat specific genetic forms of
epilepsy continues to progress

29. Thank you!

30. Fenfluramine (ZX008) LGS Phase 3 Study
L G S F a m i l y & P r o f e s s i o n a l
C o n f e r e n c e : E m e r g i n g T h e r a p i e s
& C l i n i c a l T r i a l s
D r . K e l l y K n u p p
N o v e m b e r 2 0 1 7

31. 31
Background: Fenfluramine in Epilepsy & LGS
• Timeline:
– Early 1980’s – initial case reports on potential utility for epilepsy
– 2012- Reported effectiveness in a cohort of DS patients in Belgium
– 2016 – Zogenix Initiates Phase III DS Program
– 2016 – AES poster presentation – Pilot LGS Open-Label Study
• Median 50% reduction in Major Motor Seizure Frequency
– 54% with > 50% reduction
• The most common treatment-emergent AEs reported:
– Decreased appetite (n=3; 23%)
– Decreased alertness/fatigue (n=3; 23%)
– Insomnia (n=2; 15%)
– 2017 – Zogenix to Initiate Phase III LGS Study

32. 32
ZX008 LGS Phase III: Study Design
• Part 1 – Placebo Controlled
• Part 2 – Open Label
Long-Term Safety
12 Months
All on Active Study Drug
Baseline
4 weeks
Titration
2 weeks
Maintenance
12 weeks
Transition to
Part 2 or Taper
2 weeks
Randomize
Placebo
ZX008
0.8 mg/kg/d
ZX008
0.2 mg/kg/d

33. 33
ZX008 LGS Phase III: Key Inclusion Criteria
• Male or female, age 2 to 35 years
• Diagnosis of Lennox-Gastaut syndrome, where seizures that result in
drops are not completely controlled by current antiepileptic
treatments (Add-on Treatment)
– If on Ketogenic Diet or VNS therapy, must be stable for 4 weeks prior to
screening
• Subjects must meet all of the following 4 criteria:
– Onset of seizures at 11 years of age or younger
– Multiple seizure types, including countable motor seizures that result in
drops
– Abnormal cognitive development
– Characteristic EEG Pattern consistent with LGS
• Seizure Frequency Prior to Screening
– must have had at least 8 drop seizures in the last 4 weeks prior to inclusion
• parent/guardian report to investigator or investigator medical notes

34. 34
ZX008 LGS Phase III: Key Exclusion Criteria
• Subject only has drop seizures in clusters, where individual
seizures cannot be counted reliably.
• Current or past history of cardiovascular or cerebrovascular
disease or pulmonary hypertension
• Positive result on urine tetrahydrocannabinol (THC) Panel or
whole blood cannabidiol (CBD) at the Screening Visit
• Subject does not have a reliable caregiver who can provide
seizure diary information throughout the study.

35. 35
Study Site Locations - 2017
Phillips
Tacoma, WA
Zupanc
Orange Co, CA
Perry
Fort Worth, TX
Laux
Chicago, IL
Thiele
Boston, MA
Marsh
Philadelphia, PA
Sullivan
San Francisco, CA
Devinsky
Livingston, NJ
Miller
Miami, FLTalwar
Tucson, AZ
Connolly
Vancouver, BC
Joshi
Aurora, CO
Sweney
Salt Lake City, UT
Smith
St. Paul, MN
Davis
Orlando, FL
Flamini
Atlanta, GA
Burdette
Grand Rapids, MI
Renfroe
Gulf Breeze, FL
Expected to be open by end of the year

36. 36
Additional Information
• If you are interested in participating or would like more
information:
–ClinicalTrials.gov – will be posted soon
–Contact Betty Quarles, Associate Director, Clinical
Operations
• 510-550-8308
• bquarles@Zogenix.com
• Medinfo@zogenix.com

37. Inside the LGS Brain
Brenda Porter MD, PhD

38. LEFT
RIGHT
NOT Seizure Background

39. Tonic Seizure

40. Atonic Seizure

41. Three Patients all LGS
• Etiology: All different, one had encephalitis at
3 months with prolonged status epilepticus.
One has a mutation in the SCN2A gene. One
has no known cause.
• They all have seizures that are called
generalized, that means both sides of the brain
seem to have simultaneous discharges.
• This is a key feature of LGS-generalize EEG
abnormalities.

42. Hemispheric synchrony

43. Corpus Callosotomy

44. Decrease in Drop Seizures Following CC
• Graham D
Graham D et al. 2017

45. Development
• Adults do not develop LGS.
• Infants and young children develop LGS.
– There often is a progression of seizure types with
age.
– Young infants will have focal or infantile spasms
then go on to develop the key generalized seizures
of LGS, Tonic and Atonic seizures.
– Why does the developing brain develop this
aberrant synchrony?

46. Multiple Etiologies
• Genetic-25-50%
• Lesion Genetic- 10-20%
• Lesion injury (early in life)-25%
• Somehow a change in the brain, often the
cortex that is present early in life and possibly
only on one side can cause the whole brain or
at least both sides to have a discharge
simultaneously.

47. Hemispheric synchrony

48. Conceptualizing Lennox–Gastaut syndrome as a secondary
network epilepsy
Archer et al 201

50. Take home points
• LGS is due to a usurping of the normal
networks that develop in childhood.
Abnormalities in the cortex in one or many
sites can drive the aberrant connections. The
network becomes “to linked” and that causes
seizures and cognitive problems.

51. So what to do?
• If there is a cortical driver take it out.
– Clear from TS and focal developmental disorders
and the first patient I showed with encephalitis you
can find cortical drivers in the network and
removing them can improve seizures and
(cognition?).
• Earlier you take it out the better (probably)
• What about manipulating the network? A
work in progress?

52. Network Modulation
• Electrical-Deep Brain Stimulation- Unclear still
what target though the thalamus is the most
often targeted site.
• Genetic- There are at least 40 companies
currently in phase 1-2 trials for gene
replacement. Though rare in brain disorders,
at least 2 are showing success.

53. Epilepsy Team
• Neurologists
• Nurses
Neurosurgeons
Dieticians
• Neurodiagnostic
Technologist
• Genetic Counselor
• Study
Coordinators