The future: Presentation by Gavin Giovannoni

Disclosures
Professor Giovannoni has received personal compensation for
participating on Advisory Boards in relation to clinical trial design,
trial steering committees and data and safety monitoring
committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec,
Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW
Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche,
Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex
Pharmaceuticals.
Professor Giovannoni would like to acknowledge several
companies and colleagues for making available data slides for this
presentation.

4 December 1985
21 October 2015

4 December 1985
21 October 2015
?

Images courtesy of Professor Gavin Giovannoni

Epstein Bar Virus
Genetics
Vitamin D
Smoking
Risks
Adverse events
Differentia
l
Diagnosis
MRI
Evoked
Potentials
Lumbar
puncture
Blood
Tests
Diagnostic
Criteria
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual
dysfunction Tremor
Pain
Swallowing
SpasticityFalls
Balance
problems Insomnia
Restless
legsFertility
Clinical trials
Gait
Pressure
sores
Oscillopsia
Emotional
lability
Seizures
Gastrostomy
Rehab
Suprapubic
catheter Intrathecal
baclofen
Physio-
therapy
Speech
therapy
Occupational
Therapy
Functional
neurosurgery
Colostomy
Tendonotomy
Studying
Employment
Relationships
Travel
Vaccination
Anxiety
Driving
Nurse
specialists
Family
counselling
Relapse
s
1st line
2nd line
Maintenance Escalation Induction
Monitoring
Disease-free
Disease
progression
DMTs
Side Effects
Advanced
Directive
Exercise
Diet
Alternative
Medicine
Pregnancy
Breast
Feeding
Research
Insurance
Visual loss
Palliative
Care
Assisted
suicide
Social
service
s
Legal
aid
Genetic
counselling
Prevention
Diagnosis
DMT
Symptomatic
Therapist
Terminal
Counselling
Intrathecal
phenol
Fractures
Movement
disorders
Osteopaeni
a
Brain
atrophy
Hearing loss
Tinnitus
Photophobia
Hiccoughs
DVLA
Neuroprotection
Psychosis
Depersonaliation
Brain
Health
Cognitive
Reserve
Sudden
death
Suicide
OCD
Narcolepsy
Apnoea
Carers
Respite
Hospic
e
Respite
Dignita
s
Advanced
Directive
Rhiztomy
Wheelchair
Walking aids
Blood/Organ
donation
Brain
donation
Exercise therapy
NABs
Autoimmunit
y
Infections
Outcome measures
Web
Resources
Pathogenesis
Double
vision
What is
MS?
NEDA
T2T
OCT
Neurofilaments
JCV status
Pharma
Anaesthesia
www.ms-res.org
CIS
End-
organPPMS

Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
The therapeutic pyramid

Consequences of increasing EDSS scores: loss of employment
0
10
20
30
40
50
60
70
80
90
Work Capacity by Disability Level
0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0
EDSS Score
ProportionofMSers≤65YearsOld
Working(%)
The proportion of MSers employed or on long-term sick leave is calculated as a percentage of MSers aged 65 or younger.
1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;
2. Pfleger CC et al. Mult Scler. 2010;16:121-126.
Spain
Sweden
Switzerland
United Kingdom
Netherlands
Italy
Germany
Belgium
Austria
~10 yrs2

57%
7%
-20%
0%
20%
40%
60%
CISers
n = 40
Feuillet et al. Mult Scler. 2007.
Healthy Controls
n = 30
p < 0.0001
Deficits were found mainly in memory, speed of information
processing, attention and executive functioning.
MSers failing
≥ 2 cognitive
tests
Cognition in early multiple sclerosis

Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers

11,000 to 1
Trapp, et al. NEJM 1998;338:278-85

Juxtacortical gray matter lesion Intra-cortical gray matter lesions Subpial gray matter lesions
Cortex
White matter
Types of cortical lesions

Social functioning
Pfleger et al. Multiple Sclerosis 2010; 16(7) 878–882.

‘Rebranding’ MS a dementia - definition of
dementia
Dementia is a loss of mental ability severe enough to interfere
with normal activities of daily living, lasting more than six
months, not present since birth, and not associated with a loss
or alteration of consciousness.
• Interfere with normal activities of daily living
• Physical
• Mental
• Social
• Occupational
• Lasting more than six months
• Not present since birth
• Not associated with a loss or alteration of consciousness







“Multiple sclerosis is therefore a preventable
dementia.”
DSM IV

Remyelination
Nogo, MAG, OMgP
Lingo-1-NgR-
p75NTR
GAP-43
NCAM
Neuregulin
Slide courtesy of Klaus Schmierer.

Premyelinating oligodendrocytes
in chronic MS lesions1
Negative regulators of OPC
differentiation have been identified2,3
Investigating LINGO-1 as a target for
remyelination
and neuroprotection/neuroreparation
OPC=oligodendrocyte precursor cells; NCAM=neural cell adhesion molecule;
PSA=polysialic acid; RNAi=ribonucleic acid interference.
1. Chang A et al. N Engl J Med. 2002;346:165-173; 2. Adapted from Rudick RA et al. Expert Opin Biol Ther. 2008;8:1561-1570;
3. Mi S et al. Ann Neurol. 2009;65:304-315; 4. Mi S et al. Nat Neurosci. 2005;8:745-751; 5. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262.
In vivo effects of anti-LINGO-1 in
rat optic nerve crush model5
Reduced neurodegeneration and
increased axonal outgrowth (arrows) vs
control
Control RNAiLINGO-1 RNAi
In vitro effects of LINGO-1 blockade4
Mature
oligodendrocy
te
OPCs
Differentiatio
n
LINGO-1,
PSA-NCAM,
Notch
Anti-LINGO-
1
treatment
Proximal Distal
Control
treatment
Fluorescein isothiocyanate-conjugated
cholera toxin B–labeled axons after optic
nerve crush and vehicle injection

Premyelinating oligodendrocytes
in chronic MS lesions1
Negative regulators of OPC
differentiation have been identified2,3
Investigating LINGO-1 as a target for
remyelination
and neuroprotection/neuroreparation
OPC=oligodendrocyte precursor cells; NCAM=neural cell adhesion molecule;
PSA=polysialic acid; RNAi=ribonucleic acid interference.
1. Chang A et al. N Engl J Med. 2002;346:165-173; 2. Adapted from Rudick RA et al. Expert Opin Biol Ther. 2008;8:1561-1570;
3. Mi S et al. Ann Neurol. 2009;65:304-315; 4. Mi S et al. Nat Neurosci. 2005;8:745-751; 5. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262.
In vivo effects of anti-LINGO-1 in
rat optic nerve crush model5
Reduced neurodegeneration and
increased axonal outgrowth (arrows) vs
control
Control RNAiLINGO-1 RNAi
In vitro effects of LINGO-1 blockade4
Mature
oligodendrocy
te
OPCs
Differentiatio
n
LINGO-1,
PSA-NCAM,
Notch
Anti-LINGO-
1
treatment
Proximal Distal
Fluorescein isothiocyanate-conjugated
cholera toxin B–labeled axons after optic
nerve crush and vehicle injection

Anti-LINGO-1 results in remyelination in animal models of CNS
demyelination2
LPC=lysophosphatidylcholine/lysolecithin; mAb=monoclonal antibody.
Adapted from 1. Mi S et al. Nature Neurosci. 2004;7:221-228; 2. Mi S et al. Ann Neurol. 2009;65:304-315.
1 µm
Control mAb Anti-LINGO-1
1 µm
Cuprizone
LPC
*
*
*
*
Demyelinated axons
*Remyelinated axons
EAE

New phase 2 study designs: Acute optic neuritis
to assess neuroprotection and remyelination
1. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262
2. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.
RENEW1,2
Anti-LINGO-
1
(multi-
centre)
Anti-LINGO-1 (100 mg/kg IV Q4W
x 6)
Placebo (IV Q4W x 6)
Participants with
first episode of
unilateral AON
(n=82)
Randomised
within 4 weeks
of symptom
onset
Dosing period
20 weeks
Assessments at
24 and 32
weeks
3–5
days’
IV
steroid
s End of study
follow-up
32 weeks
Primary outcome: VEP

RENEW primary outcome: Anti-LINGO-1 and recovery of full-field VEP
latency in AON
*Adjusted mean change in optic nerve conduction latency of the affected eye compared with the unaffected fellow eye at baseline, Week 24
(ANCOVA), Week 32 (MMRM). ANCOVA=analysis of covariance; ITT=intent-to-treat; MMRM=mixed-effect model repeated measure; PP=per-
protocol.
Adapted from 1. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P008; 2. Cadavid D et al. Presented at AAN; Washington, USA;
2015:P7.202.
Placebo 100 mg/kg anti-LINGO-1
25
20
15
10
5
0
PP ITT
22.24
14.69
20.83
17.34
Week 24
34%
Latency
recovery
P=0.05
17%
Latency
recovery
P=0.33
Adjustedmeanchangein
Full-fieldVEPlatency*(ms)
n=36 n=33 n=41 n=41
PP=Subjects who completed the study, did not miss >1 dose of treatment
and did not receive MS modifying therapy
ITT=All randomised subjects who received ≥1 dose of study treatment
PP ITT
22.35
13.22
21.15
15.08
Week 32
41%
Latency
recovery
P=0.01
29%
Latency
recovery
P=0.07
n=36 n=33 n=41 n=41

Remyelination
Nogo, MAG, OMgP
Lingo-1-NgR-
p75NTR
GAP-43
NCAM
Neuregulin
Slide courtesy of Klaus Schmierer.
Agents in trial
1. GSK239512: histamine H(3)
receptor antagonist
2. BIIB033: anti-LINGO-1
3. Clemastine: anti-histamine
4. IRX4204 & Bexarotene: RXR-
agonist
5. Etc.

Acuteaxonal
transection
“Inflammatory scissors or shredder”
Acute neuroprotection
Axon
NO
Microglia
Na+
Na+/K+
ATPaseNaV1.6
Reverse
NCX
ATP
ATP
Ca2+
ATPase
Ca2+
Na+
NaV1.6
Na+
Figure courtesy of Dr Raju Kapoor
ATP=adenosine triphosphate; NaV1.6=Sodium channel, voltage gated, type VIII, alpha subunit; NCX=sodium-calcium exchanger.
1. BD Trapp et al. N Engl J Med. 1998;338:278-285; 2. Bittner S et al. Ther Adv Neurol Disord. 2013;6:322-336.
Acute neuroprotection: targeting axonal energy levels may
achieve acute neuroprotection1,2

Acute optic neuritis (AON) to assess phenytoin (neuroprotection)
Phenytoin
Participants with
AON N=86
Phenytoin (4 mg/kg OD)
Placebo
Randomised
within 2 wks
of symptom
onset
Treatment
period
3 months
Monitoring
period
3 months
Primary
outcome
measures
Primary outcome measure: RNFL thickness
RNFL thickness Macular volume
1. Kapoor R et al. Presented at AAN; Washington, USA; 2015; 2. https://clinicaltrials.gov/ct2/show/NCT01451593;

Primary outcome: RNFL
• Active-placebo
adjusted
difference 7.15 mm
(95% CI 1.08, 13.22
p=0.02)
• 30% reduction of
atrophy
in active group
• PP comparison:
Active-placebo
adjusted
difference 7.40 mm
(95% CI 0.76, 14.04
p=0.03)
50100150
RNFLaveragemm
Placebo Phenytoin
baseline UNaffected eye
Placebo Phenytoin
6m affected eye
Bars are standard errors around the unadjusted group means

Delayed/ongoing secondary
neurodegeneration1
“Post-inflammatory slow-burn”
Ongoing neuroprotection
TreatmentTargets
1. Inflammation2
a. Adaptive (B-cell follicles)3
b. Innate (activated microglia4 and
astrocytes5)
2. Axonal mechanisms6
a. Mitochondrial/energetics7
b. Axonal targets6
3. Remyelination8
4. Comorbidities/ageing (simvastatin)9
1. Trapp BD et al. N Engl J Med. 1998;338:278-285; 2. Loleit V et al. Curr Pharm Biotechnol. 2014;15:276–296; 3 Magliozzi R et al. Brain. 2007;130:1089-1104;
4. Rissanen E et al. J Nucl Med. 2014;55:939-944; 5. Mayo L et al. Nat Med. 2014;20:1147-1156; 6. Haines JD et al. Mt Sinai J Med. 2011;78:231-243;
7. Mahad D et al. Neuropathol Appl Neurobiol. 2008;34:577-589; 8. Münzel EJ et al. Drugs. 2013;73:2017-2029; 9. Chataway J et al. Lancet. 2014;383:2213-2221.
Targeting ongoing chronic neurodegeneration

Slide courtesy of Jeremy Chataway Chataway et al. Lancet 2014; 383: 2213–21.
BSI (Boundary Shift Integral)
Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive
multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial

www.ms-res.org
The off-patent
drug bill

Trial activity targeting progressive pathology
MRI Events
1st clinical
attack
Time (Years)
Subclinical
disease
Inflammation
Brain volume loss
Neuroaxonal loss
DiseaseSeverity
SPMSRRMS
1st MRI
lesion
Relapses
CISRIS R-SPMS
RIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing-remitting MS;
R-SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS
Late SPMS: SMART STUDY
fluoxetine, amiloride, riluzole
Early SPMS:
oxcarbazepine
CIS: PHENYTOIN RRMS:
? DE-FLAMES STUDY
PPMS
PPMS: Laquinimod
SP&PPMS: Ibudilast

Flipping the pyramid
IMS, immunosuppressant; TNF, tumour necrosis factor
Reproduced from Gut, Ordás I, Feagan BG and Sandborn WJ, 1754–63, 2011 with permission from BMJ Publishing Group Ltd.
Corticosteroids
+ IMS
Corticosteroids
TNF
antagonist
± IMS
Conventional
step care
Accelerated
step care
Moderate
Severe
Early top-down
Levelofdisease
Flipping the
pyramid

Fingolimod
Fingolimod
Dimethyl
fumarate
Alemtuzumab
Natalizumab
Laquinimod
Daclizumab HYP
Rituximab
Cladribine
Teriflunomid
e
Ocrelizumab
Ofatumumab
Targeting immune regulation has been successful previously in RRMS
Lymph node
APC=antigen-presenting cell; B=B cell; BBB=blood-brain barrier; CD=cluster of differentiation; CNS=central nervous system; IFN=interferon; IL=interleukin; MØ=macrophage; NK=natural killer cell;
NO=nitric oxide; PC=plasma cell; S1P-R=Sphingosine-1-phosphate receptor; T=T cell; Th=T-helper cell; TNF=tumour necrosis factor; VCAM=vascular cell adhesion molecule; VLA=Integrin alpha4beta1.
Adapted from 1. Barten LJ et al. Drug Des Devel Ther. 2010;4:343-366; 2. Loleit V et al. Curr Pharm Biotechnol. 2014;15:276-296.
BBB CNSPeriphery
Approved
therapies
Investigational
agents

Immunomodulatory Effect of Daclizumab Treatment
DAC treatment increases CD56bright NK cell proliferation via intermediate affinity IL-2
signaling1
Martin J et. al., J. Immunol, 2010.

53
Click to edit Master title styleDECIDE Study Design Overview
All patients had a minimum of 2 years and maximum of 3 years of treatment
The trial ended when the last patient randomized completed 2 years of treatment
96-144 week treatment period
RRMS Patients
(N=1841)
0 4 8 12 16 20 24 28 32 36 40 44 48 96 144
IM IFN beta-1a 30 mcg every 1 week (n=922)
SC DAC HYP 150 mg every 4 weeks (n=919)
Follow-up
Brain MRI
EDSS* EDSS* EDSS* EDSS* EDSS* EDSS*
*Also assessed at weeks 60, 72, 84, 108, 120, 132, 144. EDSS, Expanded Disability Status Scale; IFN, interferon; IM, intramuscular; mcg, micrograms;
MRI, magnetic resonance imagine; RRMS, relapsing remitting multiple sclerosis; SC, subcutaneous.
Inclusion Criteria:
• Age 18-55 years
• Confirmed RRMS1
• MRI consistent with MS
• Baseline EDSS 0-5
• ≥2 relapses within 3 years (≥1
in year prior to study)
• ≥1 relapse (or new MRI lesion)
within 2 years (≥1 in year prior
to study)
Time (weeks)
1:1 Randomization
53

54
Click to edit Master title styleAnnualized Relapse Rate (ARR)
(n=922) (n=919)
ARR
Estimated from a negative binomial regression model adjusted for baseline relapse rate, history of prior IFN beta use, baseline EDSS (≤2.5 vs > 2.5) and baseline age
(≤35 vs >35). Patients were censored at the earliest of the following events: 1) start of alternative MS medication, 2) 180 days post treatment discontinuation or 3)
end of treatment period. CI, confidence interval.
54

55
Click to edit Master title style
3-Month and 6-Month Confirmed Disability
Progression
Risk reduction: 16%; p=0.16
Proportion with progression
Week 48: 6% vs. 8%
Week 96: 12% vs. 14%
Week 144: 16% vs. 20%
BL 12 24 36 48 60 72 84 96 108 120 132 144
Time on study (weeks)
BL 12 24 36 48 60 72 84 96 108 120 132 144
Time on study (weeks)
Risk reduction: 27%; p=0.0332
Proportion with progression
Week 48: 4% vs. 7%
Week 96: 9% vs. 12%
Week 144: 13% vs. 18%
3-month* 6-month†
Proportionofpatientswith
confirmedprogressionofdisability
*3-month confirmed: Patients censored after tentative progression (n=67) analyzed per primary method in the statistical analysis plan: all imputed as non-progressors;
†6-month confirmed: Patients censored after tentative progression (n=108) imputed per observed rate in trial; tertiary endpoint. Estimated proportions are the average
over imputed datasets. For both endpoints risk reductions based on Cox proportional hazards model adjusted for baseline EDSS, history of prior IFN use, and age.

Ocrelizumab is a humanized mAb that depletes CD20+ B cells
via multiple mechanisms
57
mAb, monoclonal antibody.
1. Jaglowski SM, et al. Blood 2010;116:3705–14; 2. Winiarska M, et al. Front Biosci 2011;16277–306; 3. Klein C, et al. MAbs 2013;5:22–33.
COMPLEMENT-DEPENDENT
CYTOTOXICITY1-3
DIRECT
APOPTOSIS1-3
ANTIBODY-DEPENDENT
CELLULAR PHAGOCYTOSIS1-3
ANTIBODY-DEPENDENT
CELLULAR CYTOTOXICITY1-3

58
B cells are depleted to a greater extent in lymphoid
compartments compared with bone marrow
58
LN-ing, lymph node-inguinal; LN-man, LN-mandibular.
Gelzleichter T, et al. ACTRIMS-ECTRIMS 2014; Poster 64654.

Cladribine is an analog of deoxyadenosine
• Cladribine is an analog of deoxyadenosine, one of the building blocks of DNA, that
differs from the naturally occurring nucleoside, deoxyadenosine by a chlorine
substitution for hydrogen1,2
• Cladribine is resistant to deamination by the enzyme adenosine deaminase (ADA) by
virtue of its structural design1,2
1. Carson DA et al. Proc Natl Acad Sci USA 1980;77:6865-9. 2. Beutler E. Lancet 1992;340:952-6
OH
HO
O
N NCI
N
NH2
N
2-chlorodeoxyadenosine
(cladribine)
OH
HO
O
N NH
N
NH
2
N
Deoxyadenosine
Nitrogenou
s
base
Sugar
Phosphate
Backbone
Base pair
Adenine
Ribose

Cladribine Tablets lead to reductions in CD4+ T and CD8+
T cells
Placebo
(n=79)
Cladribine Tablets 3.5 mg/kg
(n=81)
Months
0
100
200
300
400
500
600
700
800
900
1000
1 2 3 4 5 6 7 8 9 101112131415161718192021222324LA*
Cells/µL
0
50
100
150
200
250
300
350
400
450
500
1 2 3 4 5 6 7 8 9 101112131415161718192021222324LA*
Cells/µL
BLBL
Normal range:
500-1500/µL
Normal range:
300-1000/µL
CD4+ T cells CD8+ T cells
Months
Arrows indicate administration of Cladribine Tablets. 1 treatment week = 1 or 2 tablets over 4-5 days
during a 28-day period.
*LA performed at 26 months. BL, baseline; LA, last assessment.
Soelberg-Sørensen S et al. ENS 2009 [P359]. Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28-35

Significant reduction in ARR vs
placebo over 2 years (primary endpoint)
0.33
0.14 0.15
Placebo
(n=437)
Cladribine
3.5 mg/kg
(n=433)
Annualizedrelapserate(95%CI)
Cladribine
5.25 mg/kg
(n=456)
(0.29, 0.38)
(0.12, 0.17)
(0.12, 0.17)
0.3
0
0.2
0
0.1
0
0.0
0
0.4
0
3.5 mg/kg vs placebo
57.6% relative
reduction
p<0.001
5.25 mg/kg vs
placebo
54.5% relative
reduction
p<0.001
ARR, annualized relapse rate.
Intent-to-treat population. Giovannoni G et al. N Engl J Med 2010;362:416-26

Significant delay in time to 3-month confirmed
disability progression (secondary endpoint)
Placebo
~30% reduction in
risk of developing
disability
progression at any
time point over 2
years
(96 weeks on
study)
Cladribine Tablets:
5.25 mg/kg and 3.5 mg/kg
10th percentile = 14.8 Study
months
Proportionof
patientswithprogression
0.0
0.1
0.2
0.3
0.4
0.5
0 4 14 16 24
Study months
2 6 8 10 12 18 20 22
Placebo:
10th percentile = 11.8 Study months
5.25 mg/kg vs
placebo
Hazard ratio: 0.69
95% CI: 0.49, 0.96
p=0.026a
Hazard ratio: 0.67
95% CI: 0.48, 0.93
p=0.018a
Prolongation of time to
sustained disability
progression by ~3
months
aThe hazard ratio, 95% CI, and p-values were estimated using Cox proportional hazards model with fixed effects for treatment
group and region.
Intent-to-treat population. Giovannoni G et al. N Engl J Med 2010;362:416-26. Data on file

Significantly more patients achieve
NEDAa over 2 years vs placebo
15.8
44.3
46
0
10
20
30
40
50
60
Placebo
(n=379)
Cladribine 3.5
mg/kg (n=402)
ProportionofpatientswithNEDA
(%)
Cladribine 5.25
mg/kg
(n=411)
Odds ratio: 4.28
95% CI: 3.05, 6.02
p<0.0001
5.25 mg/kg vs
placebo
Odds ratio: 4.62
95% CI: 3.29, 6.48
p<0.0001
NEDA, no evidence of disease activity.
Post hoc analysis. aNEDA was defined as having no relapses, no 3-month sustained change in EDSS score, no new T1 Gd+ lesions, and no
active T2 lesions. Giovannoni G et al. Lancet Neurol 2011;10:329-37

CLARITY EXT demonstrates the durable
efficacy of Cladribine Tablets on relapses and
reconfirms the efficacy outcomes of CLARITY
0.14 0.15 0.14 0.15
0.33
0.15 0.16
0.10 0.11 0.10
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
3.5 mg/kg CP 5.25 mg/kg CP 7 mg/kg CC 8.75 mg/kg CC 3.5 mg/kg PC
Cladribine Placebo
98 186 186 244437456456 433433 92
Annualizedrelapserate
n=
CLARITY
EXT
CLARITY CLARITY
EXT
CLARITY CLARITY
EXT
CLARITY CLARITY
EXT
CLARITY CLARITY
EXT
CLARITY
The similar ARRs seen in CLARITY and CLARITY EXT suggest that treatment with Cladribine Tablets leads to a
durable effect on ARR for up to 4 years. In addition, within-treatment group analysis of the 3.5 mg/kg PC group
(n=244)
demonstrated that switching to cladribine treatment in Years 3 and 4 led to a significant reduction in ARR in
patients previously treated with placebo in Years 1 and 2 (ARR fell from 0.25 to 0.10; p<0.001)a
CP=cladribine (3.5 mg/kg) in CLARITY, placebo in CLARITY EXT; PC=placebo in CLARITY, cladribine (3.5 mg/kg) in CLARITY EXT; CC=cladribine (3.5 or
5.25 mg/kg) in CLARITY, cladribine (3.5 mg/kg only) in CLARITY EXT. For each group, cladribine dose refers to cumulative dose over 4 years in
CLARITY EXT. ap-values for within-group comparisons were based on the two-sided Wilcoxon signed–rank test (see slide notes for more details).
Giovannoni G et al. N Engl J Med 2010;362:416-26. Giovannoni G et al. AAN 2013 [P07.119]

100
90
80
70
60
50
40
30
20
10
0
M3 M6 M9 M12 M15 M18 M21 M24
Time to McDonald MS conversion from randomization date (Months)
203 (0) 165 (37) 119 (82) 113 (87) 108 (88) 87 (95) 71 (96) 39 (98) 1 (99)Cladribine 5.25 mg/kg
204 (0) 167 (36) 114 (88) 108 (92) 92 (102) 82 (104) 71 (107) 39 (110) 3 (110)Cladribine 3.5 mg/kg
201 (0) 143 (58) 71 (128) 58 (141) 43 (154) 32 (162) 23 (165) 13 (169) 2 (169)Placebo
Patients at risk
(conversions):
87.1%
51.4%
56.1%
Hazard ratio vs placebob
5.25 mg/kg: 0.425, p<0.0001
3.5 mg/kg: 0.496, p<0.0001
Cumulativeincidence(%)
Risk reduction
5.25 mg/kg: 57.5%
3.5 mg/kg: 50.4%
Treatment with Cladribine Tablets reduces the risk of conversion
to McDonald 2005 MS in treatment-naïve patients with an FCDEa
– Cladribine 5.25 mg/kg
– Cladribine 3.5 mg/kg
– Placebo
M0
aPatients enrolled in ORACLE-MS were treatment-naïve with an FCDE at high risk of converting to MS. bCox proportional hazards model controlling for the
randomization stratification factor (region). FCDE, first clinical demyelinating event; M, Month. Leist TP et al. Lancet Neurol 2014;13:257-67

Rapid adoption of innovations is “biggest unmet need
of all”
Adapted from Everett M. Rogers, Diffusion of Innovations

Large disparities exist in access to disease-modifying
therapies
1. Hollingworth S et al. J Clin Neurosci 2014;21:2083–7; 2. World Bank, 2015. http://data.worldbank.org/indicator/SP.POP.TOTL;
3. MSIF, 2013. http://www.atlasofms.org; 4. Wilsdon T et al. 2013. http://crai.com/sites/default/files/publications/CRA-Biogen-
Access-to-MS-Treatment-Final-Report.pdf
Australia
Norway
Denmark
Sweden
Belgium
Austria
Germany
France
Finland
Spain
Italy
Slovenia
United Kingdom
Poland
0 20 40 60 80 100
Newer DMT
Established DMT
No DMT
All people with MS (%)
All data are from 2013
4
4
4
4
4
4
4
4
4
4
4
4
4
1–3
Established DMTs
DMTs approved for relapsing
forms of MS during the 1990s
and reformulations or generic
versions of these substances.
Newer DMTs
DMTs approved for relapsing
forms of MS that have a
different mechanism of action
from established DMTs.
1st line
2nd line
3rd line

www.msbrainhealth.org
Baseline Month 6
Month 12 Month 18
Baseline Month 6
Month 12 Month 18

Neuro-restoration
Remyelination
Neuroprotection
Anti-inflammatory
Therapeutic pyramid
Anti-ageing
BrainHealthInitiative
• Smoking
• Exercise
• Diet
• Alcohol
• Sleep
• Co-morbidities
• Infections
• Concomitant medications
• ? Menopause / HRT
MS-specific
MS non-specific
Brain Health

10%
60%
5%
15%
5%
DMTs Symptomatic Diagnostic Admin Blog
Neurologist’s ClinicTime – Prof G

10%
20%
10%
15%
45%
DMTs Symptomatic Counselling Admin Monitoring
Clinical Nurse Specialist (CNS) ClinicTime

Epstein Bar Virus
Genetics
Vitamin D
Smoking
Risks
Adverse events
Differential
Diagnosis
MRI
Evoked
Potentials
Lumbar
puncture
Blood
Tests
Diagnostic
Criteria
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual
dysfunction Tremor
Pain
Swallowing
SpasticityFalls
Balance
problems Insomnia
Restless
legsFertility
Clinical trials
Gait
Pressure
sores
Oscillopsia
Emotional
lability
Seizures
Gastrostomy
Rehab
Suprapubic
catheter Intrathecal
baclofen
Physio-
therapy
Speech
therapy
Occupational
Therapy
Functional
neurosurgery
Colostomy
Tendonotomy
Studying
Employment
Relationships
Travel
Vaccination
Anxiety
Driving
Nurse
specialists
Family
counselling
Relapses
1st line
2nd line
Maintenance Escalation Induction
Monitoring
Disease-free
Disease
progression
DMTs
Side Effects
Advanced
Directive
Exercise
Diet
Alternative
Medicine
Pregnancy
Breast
Feeding
Research
Insurance
Visual loss
Palliative
Care
Assisted
suicide
Social
services
Legal
aid
Genetic
counselling
Prevention
Diagnosis
DMT
Symptomatic
Therapist
Terminal
Counselling
Intrathecal
phenol
Fractures
Movement
disorders
Osteopaenia
Brain atrophy
Hearing loss
Tinnitus
Photophobia
Hiccoughs
DVLA
Neuroprotection
Psychosis
Depersonaliation
Brain
Health
Cognitive
Reserve
Sudden
death
Suicide
OCD
Narcolepsy
Apnoea
Carers
Respite
Hospice
Respite
Dignitas
Advanced
Directive
Rhiztomy
Wheelchair
Walking aids
Blood/Organ
donation
Brain donation
Exercise therapy
NABs
Autoimmunity
Infections
Outcome measures
Web
Resources
Pathogenesis
Double
vision
What is
MS?
NEDA
T2T
OCT
Neurofilaments
JCV status
Pharma
Anaesthesia
www.ms-res.org

Email
SMS
Private
ePortal
Letters
Clinic
Group
Clinics
Tele-
phone
Skype
Apps
Blog
Apps
Group
ePortal
SERVICEDEVELOPMENT

Is the MS dogma wrong?
immune activation
innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity
& remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
VIRUS
(EBV, HERVs)

Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
Prevention

Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
Prevention
EBV Vitamin D
SmokingGenes

Conclusions: the ‘future’ in MS
• MS service development – ‘uberization’ of MS care
• Better symptomatic therapies
• Need quicker adoption of innovations
• Brain Health Policy (www.msbrainhealth.org)
• UK move up the league tables
• Affordable DMTs , particularly in resource-poor settings
• New legislation for repurposing of off-patent drugs
• New therapeutic targets
• Therapeutic pyramid
• Neuroprotection / Remyelination
• New trial design
• Brain Health
• New anti-inflammatories
• Daclizumab
• Ocrelizumab
• Cladribine
• Black Swan
• Viral and other hypotheses
• Prevention of MS

Rheumatoid arthritis
End-stage joint disease

Acknowledgements
• Neurofilament
• Sharmilee Gnanapavan
• Axel Petzold
• Jens Kuhle
• Andrea Malaspina
• EAE
• David Baker
• Gareth Pryce
• Sarah Al-Izki
• Sam Jackson
• Katie Lidster
• Siddharthan Chandran
• David Hampton
• VSN16
• David Baker
• David Selwood
• Rachel Farrell, et al.
• Optic neuritis
• Raj Kapoor, et al.
• PROXIMUS
• Monica Marta, et al.
• MS Services
• AlisonThomson, et al.
• Affordable DMTs
• Klaus Schmierer, et al.
• Charcot Project (viruses in MS)
• JulianGold, et al.
• MS@UCLP
• Barts-MS, et al.
• UCL-UCLH
• RFH
• Queens Romford

The future: Presentation by Gavin Giovannoni

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