Why haven’t we cured MS yet?

Gavin Giovannoni

Barts and The London

To cure MS do we need to know the cause?

EBV Vitamin D

Smoking Genes

We work on the hypothesis that MS is an autoimmune disease.

Multiple

Sclerosis

Environ-ment

Genes

The autoimmune hypothesis

Multiple

Sclerosis

Environ-ment

Genes

What does a cure mean?

Dis

abili

ty

Time

delayed worsening 1 stabilised 2

improved function 3 recovered function 4

What does a cure mean?

MRI Lesions

1st clinical attack

Time (Years)

Asymptomatic disease

Inflammation

Brain volume loss

Nerve cell loss

Dis

eas

e S

eve

rity

SPMS RRMS

1st MRI lesion

Relapses

CIS RIS R-SPMS

RIS = radiologically isolated syndrome (asymptomatic MS) CIS = clinically isolated syndrome RRMS = relapsing-remitting MS R-SPMS = relapsing secondary progressive MS SPMS = secondary progressive MS PPMS = primary progressive MS

PPMS

The therapeutic window for recovery

MRI Lesions

1st clinical attack

Time (Years)

Asymptomatic disease

Inflammation

Brain volume loss

Nerve cell loss

Dis

eas

e S

eve

rity

SPMS RRMS

1st MRI lesion

Relapses

CIS RIS R-SPMS

RIS = radiologically isolated syndrome (asymptomatic MS) CIS = clinically isolated syndrome RRMS = relapsing-remitting MS R-SPMS = relapsing secondary progressive MS SPMS = secondary progressive MS PPMS = primary progressive MS

PPMS

EDSS < 4.0 / ? Age < 40

The therapeutic window for recovery

Survival Curves

85%

50%

30%

0%

15yrs 25yrs 40yrs 50yrs

100% Benign MS

Proportioned of treated MSers are cured

Natural history

Unrealistic expectation

Delayed onset of SPMS

Defining a cure: a working definition

85%

50%

30%

0%

15yrs 25yrs 40yrs 50yrs

100%

Proportioned of treated MSers are cured

Natural history

NEDA = no evident disease activity

The autoimmune hypothesis

Multiple

Sclerosis

Environ-ment

Genes

Day 7

Limp tail

Impaired righting reflex

hindlimb paralysis

Moribund

partial paralysis

Normal

Remission

0

1

2

3

4

5

(1)

Clinical Score Professor Baker’s

Animal model of MS

Day 0

Slide courtesy David Baker

Curing animal MS

survival analysis

“highly effective treatments”

MS is an autoimmune disease hypothesis

15-20 year experiment

Can we repeat the animal experiment in MS?

Multiple

Sclerosis

Environ-ment

Genes

Relapses

Unreported relapses

Clinical disease worsening

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

Moving the target: the MS Iceberg

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

Control Multiple sclerosis

Moving the target: end-organ damage

NEDA

Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-target

Brain volume loss should be included in our definition for NEDA

No evidence of disease activity defined as:1,2

× No relapses

× No sustained worsening of disability

× No MRI activity

× No new or enlarging T2 lesions

× No Gd-enhancing lesions

Have we got it wrong?

EBV Vitamin D

Smoking Genes

Multiple

Sclerosis

Environ-ment

Genes

Is MS due to a virus?

Charcot Project

INSPIRE Trial (Raltegravir)

Etc. etc. etc.

Why haven’t we cured MS yet?

We may have, we need time to tell, or alternatively a black swan may fly in to the change the time-line.