GETTING TO ACCESS Innovative approaches to innovative medicines March 29, 2017

1. Sodium Channel Modulators &
Precision Medicine for Infant
Epilepsy
29th March 2017
Robin Sherrington, PhD

2. Forward Looking Statement/Safe Harbor
This presentation and the accompanying oral commentary contain forward-looking statements that involve risks,
uncertainties and assumptions. If the risks or uncertainties ever materialize or the assumptions prove incorrect, our
results may differ materially from those expressed or implied by such forward-looking statements. All statements other
than statements of historical fact could be deemed forward-looking, including, but not limited to, statements about
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payments; our ability to develop and commercialize product candidates for orphan and niche indications
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genes and drug targets; our expectations regarding federal, state and foreign regulatory requirements; the
therapeutic benefits, effectiveness and safety of our product candidates; the accuracy of our estimates of the size
and characteristics of the markets that may be addressed by our products and product candidates; our and our
collaborators’ ability to obtain and maintain regulatory approvals for our product candidates and the timing thereof;
the plans, strategies and objectives of management for future operations; and any statements of assumptions
underlying any of the items mentioned.
These statements are based on estimates and information available to us at the time of this presentation and are not
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2

3. Sodium Channels Gene Family
• Family of 9 highly homologues proteins (Nav1.1 to Nav1.9)
• Major role in electrical signaling e.g. nervous system action
potentials & neurotransmission
• Distinct roles & tissue expression for many
• To much & to little sodium current cause inherited
channelopathies
3
α-subunit β-subunit 1-4
Ahuja et al., 2015

4. 9 Sodium channels with very different roles
4
NaV Role
1.1
1.2
CNS e.g. convulsions,
dizziness, somnolence
1.4
Muscle e.g. periodic
paralysis, muscle weakness
1.5
Heart e.g. sinus rhythm &
arrhythmia
1.6
CNS e.g. ataxia, dizziness,
cognition
1.7 Peripheral e.g. pain
1.8/1.9 Peripheral e.g. pain
CNS Navs
Heart Navs
Sensory Navs (pain)

5. SCN8A Mutations & Epilepsy
• Infantile Epileptic Encephalopathy (IEE)
• Multiple heterozygous de novo missense mutations
in Nav1.6 causing too much sodium current
• Presents 1 day to 18 months after birth
• High seizure frequency
• Multiple seizure types, focal, spasms, tonic clonic,
myoclonic & absence
• Moderate to severe intellectual disability & autistic features
• Prominent motor deficits, hyptonia, dystonia, ataxia hypereflexia
• >10% risk of SUDEP before 5yrs
• Generally treatment resistant
5

6. Selective Nav1.6 inhibition why it makes
good sense
6
Nav1.6 Nav1.1
Excitatory
Pyramidal
Inhibitory
Interneuron
Nav1.6 GOF Epilepsy (IEE)
• Nav1.6 GOF in excitatory neurons
• Increased Nav1.6 mediated
excitation & seizures
• Non-selective inhibitors may limit
efficacy due to concomitant
Nav1.1 inhibition

7. NaV1.6 selective inhibitors are now possible
7
V
e
h
ic
le
X
P
C
(1
0
m
g
/k
g
)
X
P
C
(3
0
m
g
/k
g
)
0
5
1 0
1 5
2 0
Cumulative
RacineScore
* *
In Vitro In Vivo SCN8A GOF

8. Orphan Drug Act of 1983
• “A drug or biologic used to treat a rare
disease or condition”
• Affects <200,000 persons in the US
• Grant program to help certain companies with
cost
• Provides tax incentives
• Market exclusivity for 7 years
• Priority FDA reviews & protocol assistance
• FDA fees waived
• Orphan drugs are NOT the cause of
increasing healthcare costs
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9. Precision Medicine & Channelopathies
• Genetics provides molecular
insight
• Drug discovery can target the
right mechanism
• Gene testing to target the right
drug
• Drug development needs
support & collaboration
• Patient advocacy
• Patient registries (International Ion
Channel Patient Registry “IICPR”)
• KOL & clinical collaborators
• Regulators
• Industry
9
SCN8A
“The whole is greater than the sum of the parts” Aristotle 384-322 BC