ectrims 2015 hot topics therapeutic update unmet needs - gg2

Therapeutic Update: unmet needs in 2015

Gavin Giovannoni

Disclosures

Professor Giovannoni has received personal compensation for participatingon Advisory Boards in relation to clinical trial design, trial steeringcommittees 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 VertexPharmaceuticals.

Professor Giovannoni would like to acknowledge several companies andcolleagues for making available data slides for this presentation.

As ECTRIMS faculty my attendance at this meeting has been funded byECTRIMS.

Defining the unmet need depends on your worldview?

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

DifferentialDiagnosis

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 line

2nd 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

Prevention

Diagnosis

DMT

Symptomatic

Therapist

Terminal

Counselling

Intrathecalphenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

BrainHealth

CognitiveReserve

Sudden death

Suicide

OCD

Narcolepsy

Apnoea

Carers

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

Email

SMS

PrivateePortal

Letters

Clinic

GroupClinics

Tele-phone

Skype

Apps

BlogApps

GroupePortal

SER

VIC

E D

EVEL

OP

MEN

T

Symptomatic therapies

10%

60%

5%

15%

5%

DMTs Symptomatic Diagnostic Admin Blog

Clinic Time

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

DifferentialDiagnosis

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 line

2nd 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

Prevention

Diagnosis

DMT

Symptomatic

Therapist

Terminal

Counselling

Intrathecalphenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

BrainHealth

CognitiveReserve

Sudden death

Suicide

OCD

Narcolepsy

Apnoea

Carers

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

Time

Very NarrowTherapeutic Window

Minimal Therapeutic Level (μM)

}

Time

Baclofen/Cannabinoids

Dru

g L

ev

els

Time

(CNS) Side-Effects

Minimal Therapeutic Level

Time

Baclofen/Cannabinoids

Dru

g L

ev

els

Unmet need anti-spasticity

Dru

g L

ev

els

CNS-excluded CB1 agonist - slow release

Dru

g L

ev

els

CNS-excluded CB1 agonist

Time

DrugLevels

Therapeutic Window

(CNS) Side-Effects

Minimal Therapeutic Level

WideTherapeutic Window

Dru

g L

ev

els

(CNS) Side-Effects

Minimal Therapeutic Level(nM)

Time

CNS-excluded CB1 agonist

CNSSide-Effects

Dose 2Dose 1 Dose 3

NocturalSpasms

Baclofen/Cannabinoids

Dru

g L

ev

els

Time

Undertreatmentto reduceside effects

The Reality

Dose 2Dose 1 Dose 3

Dru

g L

ev

els

Time

SpasmsSpasms

Time

Ideal Drug

Dose 1 Dose 2

Leg movedto full

flexion forassessment

Spastic Leg

Chronic relapsing experimental allergic encephalomyelitis

Courtesy of Prof David Baker (aka the ‘Mouse Doctor’)

Mouse Movement in a Open Field Activity Monitor

Drug (same dose) Sedation(Side-Effects)

Inhibition of Spasticity

*P<0.05, ***P<0.001 Compared to baseline

VSN16 R

Water SolubleOrally-ActiveHigh Therapeutic WindowNo/Low Side Effects

CoI: UCL spin-Out Company

VSN16R -ve

Sativex x2 Dose +ve

Sativex +ve

Baclofen +ve

Vehicle -ve

Time Post-Administration (min)

0 30 60 90 120

Ch

an

ge

in H

ind

imb

Sti

ffn

ess

(%)

±S

EM

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

20

Vehicle

Baclofen

***

***

***

Sativex

**

***

Sativex x2

***

****** ***

VSN16R ***

***

VSN16

Adoption of innovations

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

DifferentialDiagnosis

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 line

2nd 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

Prevention

Diagnosis

DMT

Symptomatic

Therapist

Terminal

Counselling

Intrathecalphenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

BrainHealth

CognitiveReserve

Sudden death

Suicide

OCD

Narcolepsy

Apnoea

Carers

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

EDSS = 5.0

May 2015

Optic neuritis

MRI+ve

Spinal cordtriparesis

Case scenario: 25-year-old woman with RRMS

Unmet need for acute neuroprotection and remyelination

IV methylprednisolone

Natalizumabor

Alemtuzumab?

April 2015

Brain stemINO

IV methylprednisolone

2011

EDSS = 5.0

May 2015

Optic neuritis

MRI+ve

Spinal cordtriparesis

EDSS = 5.0

June 2015

JCV+ve(index = 1.6)

Case scenario: 25-year-old woman with RRMS

Unmet need for acute neuroprotection and remyelination

IV methylprednisolone

Natalizumabor

Alemtuzumab?

April 2015

Brain stemINO

IV methylprednisolone

2011

EDSS = 5.0 EDSS = 7.0 6.5

Optic neuritis

MRI+ve

June 2015

JCV+ve(index = 1.6)

Spinal cordparaparesis

IV methylprednisolone x2

Anti-AQ4 -ve

Sept 2015

Unmet need: Neuroprotectantand/or remyelination

May 2015

Spinal cordtriparesis

IV methylprednisolone

Natalizumab or

Alemtuzumab?

Natalizumabor

Alemtuzumab?

April 2015

Brain stemINO

IV methylprednisolone

2011

Case scenario: 25-year-old woman with RRMS

Unmet need for acute neuroprotection and remyelination

1 2 3

Time is brain or spinal cord

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 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

www.msbrainhealth.org

www.msbrainhealth.org

Baseline Month 6

Month 12 Month 18

Baseline Month 6

Month 12 Month 18

Affordable DMTs

Unequal access to DMTs

Neuroprotection & remyelination

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory Immunological5

Myelin repair / Axonal protection1,2

Membrane channel /Mitochondria3,4

The therapeutic pyramid

1. Haines JD et al. Mt Sinai J Med. 201;78:231-243; 2. Münzel EJ et al. Drugs. 2013;73:2017-2029; 3. Mahad D et al. Neuropathol Appl Neurobiol. 2008;34:577-589; 4. Schattling B et al. Exp Neurol. 2014;262:28-36;5. Loleit V et al. Curr Pharm Biotechnol. 2014;15:276-296.

Myelin repair / Axonal protection

Anti-LINGO-112,16

RXR (retinoid X receptor) agonists17

Muscarinic antagonists18

Biotin13

Neuroprotection / neuroreparation12,13,16-18

Immunological

Natalizumab1

Rituximab, ocrelizumab2

Daclizumab HYP (high-yield process)3

Laquinimod, minocycline4,5

Dimethyl fumarate6

Siponimod7

Reduced immune-mediated damage1-7

Relevant targets in RRMS and progressive MS: agents under clinical investigation

LINGO-1=leucine-rich repeat and Ig domain-containing 1.1. Börnsen L et al. PLoS One. 2012;7:e47578; 2. Lulu S et al. Neurotherapeutics. 2013;10:34-43; 3. Gold R et al. Lancet. 2013;381:2167-2175; 4. Mishra MK et al. Ann Clin Transl Neurol. 2014;1:409-422; 5. Chen X. J Neuroimmunol. 2011;235:1-8; 6. Linker RA et al. Brain. 2011;134:679-692; 7. Selmaj K et al. Lancet Neurol. 2013;12:756-767; 8. https://clinicaltrials.gov/ct2/show/NCT01451593; 9. Schattling B et al. Exp Neurol. 2014;262:28-36; 10. Al-Izki S et al. Brain. 2014; 137:92-108; 11. Waubant E et al. Ann Clin Transl Neurol. 2014;1:340-347; 12. Koch MW et al. Nat Rev Neurol. 2013;9:496-503; 13. Sedel F et al. Mult Scler Relat Disord. 2015;4:159-169; 14. https://clinicaltrials.gov/ct2/show/NCT01854359; 15. Mao P et al. Biochim Biophys Acta. 2013:1832:2322-2331; 16. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262; 17. Rodgers JM et al. Discov Med. 2013;16:53-63; 18. Deshmukh VA et al. Nature. 2013;502:327-332.

Membrane channel /Mitochondria

Phenytoin, Amiloride, CFM6104, oxcarbazepine8,9,10

Riluzole11

Glutamate receptors antagonists12

Biotin13

Idebenone14

Minocycline5

MitoQ15

Improve energy supply / inhibit neuronal injury5,8-15

Acu

te a

xon

al

tra

nse

ctio

n

“Inflammatory scissors or shredder”

Acute neuroprotection

Axon

NO

Microglia

Na+

Na+/K+

ATPaseNaV1.6

ReverseNCX

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

Ischaemic penumbra

* P<0.05, **P<0.01; CFM6104=[N-((5-(2-(2-(1h-imidazol-1-yl)ethyl)-2h-indazol-3-yl)-1,2,4-oxadiazol-3-yl)methyl)-3-methylbenzamide], a novel Na channel blocker; EAE=experimental autoimmune encephalitis.1. Adapted from Al-Izki S et al. Brain. 2014;137:92-108. 2. BD Trapp et al. N Engl J Med. 1998;338:278-285; 3. http://www.strokecenter.org/professionals/brain-anatomy/cellular-injury-during-ischemia/the-ischemic-penumbra; 4. Noval S et al. Mult Scler Int. 2011;472790

Acute optic neuritis

Immunological penumbra:selective targeting of a Na+ channel blocker to the acute CNS lesion1-4

Immunologic penumbra

CFM6104 in EAE

Ev

ide

nce

fo

r n

eu

rop

rote

ctio

nTime post-disease induction (days)

32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 480.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Vehicle CFM6104Day 33-48

No evident immunosuppression

Mea

n N

euro

log

ica

l Sco

re ±

SE

M

31

* * ***

** **

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;

Baseline characteristics

Placebo (SD)n=44

Phenytoin (SD)n=42

Age (yrs) 34.6 (9.1) 32.9 (8.2)

Gender (F:M) 32:12 31:11

Prior MS 3 1

Positive brain MRI (%) 73 76

Corticosteroids (%) 75 83

Duration of visual loss (dy) 8.0 (3.3) 8.2 (3.1)

LogMAR 1.07 (0.60) 1.11 (0.54)

2.5% Sloan acuity 0.77 (3.83) 0.21 (1.24)

FM 100-hue 1139 (775) 1066 (765)

RNFL affected eye (mm) 125.20 (43.42) 130.62 (46.43)

MV affected eye (mm3) 8.63 (0.43) 8.71 (0.46)

Primary outcome: RNFL

• Active-placebo adjusteddifference 7.15 mm(95% CI 1.08, 13.22p=0.02)

• 30% reduction of atrophyin active group

• PP comparison:Active-placebo adjusteddifference 7.40 mm(95% CI 0.76, 14.04p=0.03)

5010

015

0

RN

FL a

vera

ge

mm

Placebo Phenytoin

baseline UNaffected eye

Placebo Phenytoin

6m affected eye

Bars are standard errors around the unadjusted group means

Macular volume

• Active-placebo adjusteddifference 0.02 mm3

(95% CI 0.06, 0.34p=0.005)

• 34% reduction of atrophyin active group

• PP comparison:Active-placebo adjusteddifference 0.02 mm3

(95% CI 0.05, 0.36p=0.01)

77.

58

8.5

99.

510

Ma

cula

r vo

lum

e m

m3

Placebo Phenytoin

baseline UNaffected eye

Placebo Phenytoin

6m affected eye

Bars are standard errors around the unadjusted group means

Visual outcomes

010

2030

4050

Slo

an

2.5

%Placebo Phenytoin Placebo Phenytoin

6m UNaffected eye

Bars are standard errors around the unadjusted group means

-.5

0.5

11.

52

Log

MA

R

Placebo Phenytoin

6m affected eye

Placebo Phenytoin

6m UNaffected eye

Bars are standard errors around the unadjusted group means

6m affected eye

LogMAR 2.5% Sloan

Kapoor et al. Lancet Neurol 2010; 9: 681–88.

Latency in the execution of neuroprotection with Lamotrigine

Variable P value

Δ Serum NfH-SMI35

m0-m12 0.259

Δ Serum NfH-SMI35

m12-m24 0.043

Δ Serum NfH-SMI35

m0-m24 0.023

Gnanapavan et al., PLoS One 01/2013, 8(8):e70019

Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis

Kuhle et al. 2014

Fingolimod → PPMS Siponimod → SPMS (EXPAND STUDY)

Phase 2A study of natalizumab in progressive MS: CSF markers of axonal damage and demyelination (2° endpoint)

Slide courtesy of Romme Christensen, ECTRIMS 2012. Oral presentation 170.

NIND Mean +/- 95% CI

p=0.03

CS

F N

eu

rofi

lam

en

t ll

igh

t n

g/L

p=0.048

CS

F M

BP

ng

/ml

NIND Mean +/- 95% CI

Natalizumab → SPMS (ASCEND STUDY)ClinicalTrials.gov ID: NCT01416181

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

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory

The therapeutic pyramid

New trial design

Slow-burn neuroprotection: progressive MS

Petzold et al. J Neurol Neurosurg Psychiatry. 2005;76:206-11.

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory

The therapeutic pyramid

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-13. Clemastine: anti-histamine4. IRX4204 & Bexarotene: RXR-

agonist5. Etc.

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 oligodendrocyte

OPCs

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

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% Latencyrecovery

P=0.05

17%Latencyrecovery

P=0.33

Ad

just

ed m

ean

ch

an

ge

inFu

ll-f

ield

VE

P la

ten

cy*

(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% Latencyrecovery

P=0.01

29% Latencyrecovery

P=0.07

n=36 n=33 n=41 n=41

SD-OCT values at baselinea

Affected eye n=77 Fellow eye n=80 Difference n=77b

RGCL/IPL thickness, μm 64.8 (7.3) 69.5 (5.6) -4.76 (5.5)aValues are mean (SD); bSD-OCT was not available in the affected eye for 3 participants (missing data were not imputed).

Mean GCL/IPL thickness at each visit in the affected eye in the ITT population up to Week 32

No difference observed in RENEW secondary OCT efficacy endpoints at Week 32

RGCL=retinal ganglion cell layer; SD=standard deviation.1. Cadavid D et al. Presented at ACTRIMS-ECTRIMS; Boston, USA; 2014:P731; 2. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.

New anti-inflammatories

Fingolimod

Fingolimod

Dimethyl fumarate

Alemtuzumab

Natalizumab

Laquinimod

Daclizumab HYP

Rituximab

Cladribine

Teriflunomide

Ocrelizumab

Ofatumumab

Targeting immune regulation has been successful previously in RRMS1,2

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.

The investigational agents shown above are not registered or commercialised in Europe for RRMS

Las moléculas en investigación mostradas arriba no están registradas o comercializadas en España para la EMRR

BBB CNSPeriphery

Approved therapies

Investigational agents

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)

Conclusions: unmet needs in MS

• MS service development – ‘uberization’ of MS care

• Better symptomatic therapies

• Need quicker adoption of innovations

• Brain Health (www.msbrainhealth.org)

• 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

• New anti-inflammatories

• Daclizumab

• Ocrelizumab

• Cladribine

• Black Swan

• Viral and other hypotheses

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