the future: presentation by gavin giovannoni

The future

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.

Musings

21 October 2015

4 December 1985

21 October 2015

4 December 1985

21 October 2015

?

The Future

Images courtesy of Professor Gavin Giovannoni /

ESRFend-stage renal failure

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

DifferentialDiagnosis

At risk

RIS CIS

Minimal impairment

Moderateimpairment

Severeimpairment

Terminal

Phase

MRI

EvokedPotentials

Lumbar puncture

BloodTests

DiagnosticCriteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

PainSwallowing

SpasticityFalls

Balance problems Insomnia

Restless legsFertility

Clinical trials

Gait

Pressuresores

Oscillopsia

Emotionallability

Seizures

Gastrostomy

Rehab

Suprapubiccatheter Intrathecal

baclofen

Physio-therapy

Speech therapy

OccupationalTherapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

EmploymentRelationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Family counselling

Relapses

1st line2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

AlternativeMedicine

PregnancyBreastFeeding

Research

Insurance

Visual loss

PalliativeCare

Assistedsuicide

Socialservices

Legalaid

Genetic counselling

PreventionDiagnosis

DMTSymptomatic

Therapist

Terminal

Counselling

Intrathecalphenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

BrainHealth

CognitiveReserve

Sudden death

SuicideOCD

Narcolepsy

ApnoeaCarers

Respite

Hospice

Respite

Dignitas

Advanced Directive

Rhiztomy

Wheelchair

Walking aids

Blood/Organdonation

Brain donation

Exercise therapy

NABs

Autoimmunity

Infections

Outcome measures

WebResources

Pathogenesis

Doublevision

What isMS?

NEDA

T2TOCT

Neurofilaments

JCV statusPharma

Anaesthesia

www.ms-res.org

CISEnd-

organPPMS

The therapeutic pyramid

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory


The Future

or

Futility?

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory


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 8.0/9.0EDSS Score

Prop

ortio

n of

MSe

rs ≤

65 Y

ears

Old

Wor

king

(%)

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%

CISersn = 40

Feuillet et al. Mult Scler. 2007.

Healthy Controlsn = 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

CortexWhite 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

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory


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 remyelinationand 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 oligodendrocyteOPCs

Differentiation

LINGO-1,PSA-NCAM,

Notch

Anti-LINGO-1treatment

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 remyelinationand 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 oligodendrocyteOPCs

Differentiation

LINGO-1,PSA-NCAM,

Notch

Anti-LINGO-1treatment

Proximal DistalFluorescein 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:P2.2622. 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 period20 weeks

Assessments at24 and 32 weeks

3–5 days’ IV steroids

End of studyfollow-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

0PP ITT

22.24

14.69

20.83

17.34

Week 24

34% LatencyrecoveryP=0.05


Adju

sted

mea

n ch

ange

inFu

ll-fie

ld V

EP la

tenc

y* (m

s)

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



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-histamine4. IRX4204 & Bexarotene: RXR-

agonist 5. Etc.

Neuroprotection

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory


Acut

e ax

onal

tran

sect

ion

“Inflammatory scissors or shredder”

Acute neuroprotection

AxonNO

Microglia

Na+

Na+/K+

ATPaseNaV1.6Reverse

NCX

ATPATP

Ca2+ ATPase

Ca2+

Na+

NaV1.6

Na+

Figure courtesy of Dr Raju KapoorATP=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 period3 months

Monitoring period3 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)

5010

015

0

RNFL

ave

rage

mm

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

Treatment Targets

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 clinicalattack

Time (Years)

Subclinical disease

Inflammation

Brain volume loss

Neuroaxonal loss

Dise

ase

Seve

rity

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 STUDYfluoxetine, amiloride, riluzole

Early SPMS:oxcarbazepine

CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY

PPMS

PPMS: Laquinimod

SP&PPMS: Ibudilast

New antiinflammatories

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory


Flipping the pyramid

IMS, immunosuppressant; TNF, tumour necrosis factorReproduced from Gut, Ordás I, Feagan BG and Sandborn WJ, 1754–63, 2011 with permission from BMJ Publishing Group Ltd.

Corticosteroids+ IMS

Corticosteroids

TNFantagonist

± IMS

Conventionalstep care

Acceleratedstep care

Moderate

SevereEarly top-down

Leve

l of d

isea

se

Flipping the pyramid

Fingolimod

Fingolimod

Dimethyl fumarate

Alemtuzumab

Natalizumab

Laquinimod

Daclizumab HYP

Rituximab

Cladribine

Teriflunomide

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

Daclizumab

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 treatmentThe 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 style3-Month and 6-Month Confirmed DisabilityProgression

Risk reduction: 16%; p=0.16

Proportion with progressionWeek 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 144Time on study (weeks)

BL 12 24 36 48 60 72 84 96 108 120 132 144Time on study (weeks)

Risk reduction: 27%; p=0.0332

Proportion with progressionWeek 48: 4% vs. 7% Week 96: 9% vs. 12% Week 144: 13% vs. 18%

3-month* 6-month†

Prop

ortio

n of

pati

ents

with

co

nfirm

ed p

rogr

essio

n of

disa

bilit

y

*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

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-DEPENDENTCYTOTOXICITY1-3

DIRECTAPOPTOSIS1-3

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

58LN-ing, lymph node-inguinal; LN-man, LN-mandibular.Gelzleichter T, et al. ACTRIMS-ECTRIMS 2014; Poster 64654.

Cladribine

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

G

G

T

TG

T

G

CC

AA

C

A

C

OH

HO O

N NCI

N

NH2

N

2-chlorodeoxyadenosine(cladribine)

OH

HO O

N NH

N

NH2

N

Deoxyadenosine

Nitrogenousbase

SugarPhosphateBackbone

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

0100200300400500600700800900

1000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 LA*

Cells

/µL

050

100150200250300350400450500

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 LA*

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)

Annu

aliz

ed re

laps

e ra

te (9

5% C

I)

Cladribine5.25 mg/kg

(n=456)

(0.29, 0.38)

(0.12, 0.17) (0.12, 0.17)

0.30

0.20

0.10

0.00

0.403.5 mg/kg vs placebo

57.6% relative reductionp<0.001

5.25 mg/kg vs placebo54.5% 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)

PlaceboCladribine Tablets 5.25 mg/kgCladribine Tablets 3.5 mg/kg

~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

Prop

ortio

n of

pa

tient

s with

pro

gres

sion

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 placeboHazard ratio: 0.69 95% CI: 0.49, 0.96

p=0.026a

3.5 mg/kg vs placeboHazard 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

0

10

20

30

40

50

60

15.8

44.3 46

Placebo(n=379)

Cladribine 3.5 mg/kg (n=402)

Prop

ortio

n of

pat

ient

s with

NED

A (%

)

Cladribine 5.25 mg/kg(n=411)

3.5 mg/kg vs placeboOdds ratio: 4.28

95% CI: 3.05, 6.02p<0.0001

5.25 mg/kg vs placeboOdds ratio: 4.62

95% CI: 3.29, 6.48p<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

3.5 mg/kg CP 5.25 mg/kg CP 7 mg/kg CC 8.75 mg/kg CC 3.5 mg/kg PC0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.14 0.15 0.14 0.15

0.33

0.15 0.16

0.10 0.11 0.10

Cladribine Placebo

98 186 186 244437456456 433433 92

Annu

aliz

ed re

laps

e ra

te

n=CLARITY

EXTCLARITY CLARITY

EXTCLARITY CLARITY

EXTCLARITY CLARITY

EXTCLARITY CLARITY

EXTCLARITY

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

0M3 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/kg204 (0) 167 (36) 114 (88) 108 (92) 92 (102) 82 (104) 71 (107) 39 (110) 3 (110)Cladribine 3.5 mg/kg201 (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<0.00013.5 mg/kg: 0.496, p<0.0001

Cum

ulati

ve in

cide

nce

(%)

Risk reduction5.25 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

Affordable DMTs

Unequal access to DMTs

www.ms-res.org

Vetoing NICE

www.ms-res.org

Adoption of innovations

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

Denmark

Belgium

Germany

Finland

Italy

United Kingdom

0 20 40 60 80 100

Newer DMTEstablished DMTNo 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 DMTsDMTs approved for relapsing forms of MS during the 1990s and reformulations or generic versions of these substances.

Newer DMTsDMTs 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

Brain Health Initiative• Smoking• Exercise• Diet• Alcohol• Sleep• Co-morbidities• Infections• Concomitant medications

• ? Menopause / HRT

MS-specific

MS non-specific

Brain Health

Symptomatic therapies

10%

60%

5%

15%

5%

DMTs Symptomatic Diagnostic Admin Blog

Neurologist’s Clinic Time – Prof G

10%

20%

10%

15%

45%

DMTs Symptomatic Counselling Admin Monitoring

Clinical Nurse Specialist (CNS) Clinic Time

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

DifferentialDiagnosis

At risk

RIS CIS

Minimal impairment

Moderateimpairment

Severeimpairment

Terminal

Phase

MRI

EvokedPotentials

Lumbar puncture

BloodTests

DiagnosticCriteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

PainSwallowing

SpasticityFalls

Balance problems Insomnia

Restless legsFertility

Clinical trials

Gait

Pressuresores

Oscillopsia

Emotionallability

Seizures

Gastrostomy

Rehab

Suprapubiccatheter Intrathecal

baclofen

Physio-therapy

Speech therapy

OccupationalTherapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

EmploymentRelationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Family counselling

Relapses

1st line2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

AlternativeMedicine

PregnancyBreastFeeding

Research

Insurance

Visual loss

PalliativeCare

Assistedsuicide

Socialservices

Legalaid

Genetic counselling

PreventionDiagnosis

DMTSymptomatic

Therapist

Terminal

Counselling

Intrathecalphenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

BrainHealth

CognitiveReserve

Sudden death

SuicideOCD

Narcolepsy

ApnoeaCarers

Respite

Hospice

Respite

Dignitas

Advanced Directive

Rhiztomy

Wheelchair

Walking aids

Blood/Organdonation

Brain donation

Exercise therapy

NABs

Autoimmunity

Infections

Outcome measures

WebResources

Pathogenesis

Doublevision

What isMS?

NEDA

T2TOCT

Neurofilaments

JCV statusPharma

Anaesthesia

www.ms-res.org

Services

NHS 1950

NHS 2000

Uberization of Healthcare

Email

SMS

PrivateePortal

Letters

Clinic

GroupClinics

Tele-phone

Skype

Apps

BlogApps

GroupePortal

SERV

ICE

DEVE

LOPM

ENT

Lateral thinking

Is there a “Black Swan”?

Is the MS dogma wrong?

immune activationinnate 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


Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory

Prevention


Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory

Prevention


EBV Vitamin D

SmokingGenes

www.digestingscience.co.uk

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

http://www.msbrainhealth.org/

Rheumatoid arthritisEnd-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• Alison Thomson, et al.

• Affordable DMTs• Klaus Schmierer, et al.

• Charcot Project (viruses in MS)• Julian Gold, et al.

• MS@UCLP• Barts-MS, et al.• UCL-UCLH• RFH• Queens Romford

Questions