Treating MS in 2025

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.

Professor Giovannoni’s visit to Dublin has been kindly sponsored by Novartis, therefore please interpret anything he says about Novartis’ products in this context.

21 October 2015

4 December 1985

21 October 2015

4 December 1985

21 October 2015

?

The Future

Images courtesy of Professor Gavin Giovannoni /

ESRF end-stage renal failure

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

Spasticity Falls

Balance problems Insomnia

Restless legs Fertility

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

CIS End-

organ PPMS

The therapeutic pyramid

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory

The therapeutic pyramid

The Future

or

Futility?

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

Pro

port

ion o

f M

Sers

≤6

5 Y

ears

Old

W

ork

ing (

%)

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

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.

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 RNAi LINGO-1 RNAi

In vitro effects of LINGO-1 blockade4

Mature oligodendrocyt

e OPCs

Differentiation

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

Adju

ste

d m

ean c

hange in

Full-

field

VEP late

ncy* (

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.

Neuroprotection

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory

The therapeutic pyramid

Acute

axonal

tra

nsecti

on “Inflammatory scissors or

shredder”

Acute neuroprotection

Axon

NO

Microglia

Na+

Na+/K+

ATPase NaV1.6

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)

50

1

00

1

50

RN

FL a

vera

ge m

m

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 clinical attack

Time (Years)

Subclinical disease

Inflammation

Brain volume loss

Neuroaxonal loss

Dis

ease

Sev

erit

y

SPMS RRMS

1st MRI lesion

Relapses

CIS RIS 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

New antiinflammatories

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory

The therapeutic pyramid

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

Level of

dis

ease

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 CNS Periphery

Approved therapies

Investigational agents

Affordable DMTs

Unequal access to DMTs

www.ms-res.org

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

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

www.msbrainhealth.org

Baseline Month 6

Month 12 Month 18

Baseline Month 6

Month 12 Month 18

www.msbrainhealth.org

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

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

Spasticity Falls

Balance problems Insomnia

Restless legs Fertility

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

Services

NHS 1950

NHS 2000

Uberization of Healthcare

Email

SMS

Private ePortal

Letters

Clinic

Group Clinics

Tele- phone

Skype

Apps

Blog Apps

Group ePortal

SER

VIC

E D

EVEL

OP

MEN

T

Lateral thinking

Is there a “Black Swan”?

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

The therapeutic pyramid

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory

Prevention

The therapeutic pyramid

Neuroreparation

Remyelination

Neuroprotection

Anti-inflammatory

Prevention

The therapeutic pyramid

EBV Vitamin D

Smoking Genes

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