What would disease free status look like in MS and what is the evidence that we can achieve it?

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry

What would disease free status look like in MS and what is the

evidence that we can achieve it?

What would disease free status look like in MS and what is the

evidence that we can achieve it?

What is a disease?

What is a disease/what is MS?

A. Conventional definition

• E.g. “hepatitis is inflammation of the liver”

B. Pre-theoretical definition

• “SLE is characterised by the ARA criteria”

• Indirect definition

• Usually “polythetic”

• Inclusive definition using multiple characteristics

• According to Wittgenstein's model of a "long rope twisted together out of

many shorter fibres.“*

C. Theoretical definition

• E.g. “Down’s syndrome is trisomy 21”.

• Usually “monothetic”.

*Ludwig Wittgenstein a controversial 20th-century analytical philosopher (1889-1951).

Ludwig Wittgenstein

1889-1951

What is multiple sclerosis?

Multiple sclerosis definition

Pathological Definition: Inflammatory disease of the CNS

characterised by demyelination and variable degrees of

axonal loss and gliosis.

Clinical Definition: Objective CNS dysfunction, i.e.

involvement of two or more white matter structures

(space) separated by time, with no other aetiology.

What constitutes a useful set of diagnostic criteria?

TARGET DISORDER

PRESENT ABSENT

DIAGNOSTIC TEST RESULT

+ a b a + b

- c d c + d

a + c b + d a + b + c + d

From these we determine the sensitivity and specificity as follows: SENSITIVITY = a/(a+c) > 80% SPECIFICITY = d/(b+d) > 80%

Neurobiol Aging 1998; 19:109-116.

A clinico-pathoanatomical study of MS diagnosis

SPECIFICITY = True-ve /(True-ve + False+ve) ?

25% of cases diagnosed with MS on post-mortem are undiagnosed in life

– asymptomatic

– benign cases

Engell T. Acta Neurol Scand. 1989 May;79(5):428-30.

The evolving clinical definition of MS is changing the natural history of MS

1. Schumacker, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report

by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N

Y Acad Sci 1965;122:552-68.

2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.

Ann Neurol 1983;13:227-31.

3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from

the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.

4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald

Criteria". Ann Neurol 2005;58:840-6.

5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald

criteria. Ann Neurol. 2011;69:292-302.

Will Rogers phenomenon in MS

1879 - 1935

“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”

Inactive CIS Active CIS RRMS

MS diagnosed according the old Poser Criteria

MS diagnosed according the old Poser Criteria

Inactive CIS Active CIS RRMS

Inactive CIS

Less active RRMS

More Active RRMS

MS diagnosed according the New McDonald Criteria

Will Rogers Phenomenon in Multiple Sclerosis

Sormani et al. Ann Neurol 2008;64:428–433.

Poser

McDonald

Very low risk

age place of residence

outdoor activity / sun exposure / sun screen diet / vitamin D supplements

age of exposure to EBV smoking

At risk High Risk

Low risk

RIS CIS MS

family history genetics

sex month of birth place of birth

Unfavourable disease-modifying factors dynamic risk factors static risk factors

dynamic protective factors static protective factors

MRI / evoked potentials changes

Peripheral immunological changes T-regs (), NK cells, CD8 ()

Clinical disease

In utero childhood Adolescence / early adulthood adulthood

1. Declining Physiology – “peripheral immunological endophenotype” 2. Biological disease threshold – “CNS endophenotype”

3. Asymptomatic disease – RIS (abnormal MRI and/or evoked potentials) 4. Clinical disease

a. Clinically isolated syndrome (CIS) b. Relapsing MS

c. Relapsing secondary progressive MS d. Non-relapsing secondary progressive MS

Favourable disease-modifying factors

protective HLA haplotypes

CNS changes (OCBs and microscopic pathology)

2

3

2 4b 2 4c 2 4d

2 4a

1

“THE MS ENDOPHENOTYPE” - Giovannoni et al. Lancet Neurol. 2010 Jul;9(7):727-39.

The evolving clinical definition of MS

1. Schumacker, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report

by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N

Y Acad Sci 1965;122:552-68.

2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.

Ann Neurol 1983;13:227-31.

3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from

the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.

4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald

Criteria". Ann Neurol 2005;58:840-6.

5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald

criteria. Ann Neurol. 2011;69:292-302.

6. Polman, et al. ……………2016? RIS or asymptomatic/presymptomatic MS

What would disease free status look like in MS and what is the

evidence that we can achieve it?

What do you want to measure?

Current Dogma

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 - biology

- clinical outcomes

- biomarkers

Current Dogma

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

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Current Dogma

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

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Current Dogma

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

e.g. neurofilaments

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Current Dogma

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

e.g. neurofilaments

Clinical Attack

Disease Progression

Clinical Recovery - biology

- clinical outcomes

- biomarkers

Current Dogma

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

e.g. neurofilaments

Clinical Attack

Disease Progression

Clinical Recovery

? - biology

- clinical outcomes

- biomarkers

Current Dogma

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

e.g. neurofilaments

Clinical Attack

Disease Progression

Clinical Recovery

?

- biology

- clinical outcomes

- biomarkers

Gd

T2

CU

R

DP

Gd

T2

CU

R

DP

Effect of natalizumab on clinical and radiological disease activity in MS: a retrospective

analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study

Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.

35% vs. 64% Δ = 29%

14% vs. 58% Δ = 44%

Gd

T2

CU

R

DP

15% vs 47% Δ 32%

13% vs 68% Δ 55%

6% vs 37% Δ 31%

Effect of natalizumab on clinical and radiological disease activity in MS: a retrospective

analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study

Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.

A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

Gd

T2

CU

R

DP

Polman et al. N Engl J Med 2006;354:899-910.

Clinical implications

Breakthrough disease after treatment initiation

Patients with breakthrough disease can be identified with:

• Clinical measures

• Relapses

• EDSS progression

• MRI measures

• T2 and Gd+ lesions

• Biological markers

• IFNb neutralizing antibodies (NAbs)/lack of MxA induction

• Anti-natalizumab Abs

Relapse on IFNβ therapy increases risk of sustained disability progression

• Risk is not much greater for 2 relapses or more

• Sensitivity is only 50%

Bosca et al. Mult Scler 2008;14:636-39. 33

One new T2 lesion

2 or more new T2 lesions

Dobson et al. Submitted 2012.

MRI to monitor treatment response to IFN-beta: a systematic review

Measurement sensitivity?

MRI to monitor treatment response to IFN-beta: a systematic review

One new Gd+ lesion

2 or more Gd+ lesions

Dobson et al. Submitted 2012. 35

Strongest predictor of disability progression on IFNβ

therapy is progression itself

• Disease activity during 2 years of treatment and prediction of disability progression* at 6 years

Group Sensitivity (%)

(CI)

Specificity (%)

(CI)

A. An increase of at least one EDSS step confirmed at 6 months 85 (64-95) 93 (86-97)

B. Occurrence of any relapse 80 (58-92) 51 (41-61)

C. Occurrence of two or more relapses 45 (26-66) 81 (72-82)

D. A decrease in relapse rate less than 30% compared with 2 years before therapy 40 (22-61) 86 (77-91)

E. A decrease in relapse rate less than 50% compared with 2 years before therapy 40 (22-61) 81 (72-88)

F. No decrease or identical relapse rate compared with 2 years before therapy 35 (18-57) 88 (79-93)

G. Definition A or B 90 (70-97) 48 (38-58)

H. Definition A or E 85 (64-95) 76 (66-83)

I. Definition A and B 75 (53-89) 97 (91-99)

J. Definition A and E 40 (22-61) 99 (94-99)

* EDSS ≥6.0 or increase in at least 3 EDSS steps.

Rio et al. Ann Neurol. 2006;59:344.

Post-hoc analysis, disease-activity free: Patients with no relapse, no sustained disability

progression and no new MRI lesion activity

Placebo

(n=379*)

15.8

44.2 45.7

Weeks 0–96

3.5 mg/kg

(n=403*)

5.25 mg/kg

(n=411*)

56.1

23.9

54.2

Weeks 0–48

Placebo

(n=360*)

3.5 mg/kg

(n=384*)

5.25 mg/kg

(n=396*)

Placebo

(n=373*)

38.9

67.369.7

3.5 mg/kg

(n=395*)

80

60

40

20

0 5.25 mg/kg

(n=406*)

Weeks 0–24

Pati

en

ts d

isease a

cti

vit

y-f

ree (

%)

p<0.001 p<0.001 p<0.001

Cladribine tablets Cladribine tablets Cladribine tablets

OR = odds ratio *Based on observed data; no imputation used

Gd

CU

R

DP T2

OR (95% CI): 3.31 (2.46, 4.46)

OR (95% CI): 3.68 (2.73, 4.97)

OR (95% CI): 3.80 (2.77, 5.22)

OR (95% CI): 4.13 (3.02, 5.66)

OR (95% CI): 4.26 (3.03, 5.99)

OR (95% CI): 4.58 (3.26, 6.43)

Fingolimod treatment increases the proportion of patients who are free from disease

activity in multiple sclerosis; results from a phase 3, placebo-controlled study (FREEDOMS)

Kappos et al., AAN 2011

Gd

CU

R DP

T2

BG-12 Increases the Proportion of Patients Free of Clinical and Radiologic Disease Activity in Relapsing–Remitting Multiple Sclerosis: Findings from a DEFINE Post Hoc Analysis

Giovannoni et al., AAN 2012

Gd

CU

R

DP

T2

Fingolimod Treatment Increases the Proportion of Patients who are Free from Disease Activity in Multiple Sclerosis

Compared to Interferon beta-1a: Results from a Phase 3 Active-Controlled Study (TRANSFORMS)

Khatri et al. AAN 2012.

Gd

CU

R

DP T2

41

Disease Activity-Free Status in Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I (CARE-MS I) - Phase 3 Study

Odds of experiencing MS disease activity for SC IFNB-1a patients was 1.75 times higher than alemtuzumab patients; odds ratio=1.75 (95% CI: 1.17, 2.61), p=0.0064

CDA-Free MRI Activity–Free MS Disease

Activity-Free

p<0.0001

p=0.0388

p=0.0064

Giovannoni et al. ENS 2012

Gd

CU

R

DP T2

Power calculations from CLARITY study

Absolute difference 90% power

treatment rate - placebo rate

10% 20% 30%

Placebo rate

1 group 1 group 1 group

15% 354 108 54

+10% 389 118 59

30% 496 134 63

+10% 546 147 69

Giovannoni et al. Unpublished observations

Gd

CU

R DP

T2

Current Dogma

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

e.g. neurofilaments

Clinical Attack

Disease Progression

Clinical Recovery

?

? ?

? ?

- biology

- clinical outcomes

- biomarkers

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

Post-inflammatory neurodegeneration

Gunnarsson et al. Ann Neurol 2010.

Axonal Damage in Relapsing Multiple Sclerosis is Markedly Reduced by Natalizumab

Conclusions / Questions

• What would disease free-status look like?

• Absence of any clinical and biomarker evidence of disease activity

• Current definition = relapse, disease-progression, Gd-enhancing lesions and new T2 lesions

• What about brain atrophy and CSF neurofilament levels?

• Should the definition be stage specific?

• CIS/RRMS vs. R-SPMS vs. NR-SP/PPMS

• What do we do about post-inflammatory neurodegeneraton?

• What about the potential effects of superimposed accelerated or premature aging?

• How do we define an appropriate baseline for comparison?

• We need to optimise the time fore re-base lining MRI when looking for a change; this may need to be agent specific.

• How do we deal with the difference between maintenance and induction therapies?

• Maintenance - absence of DAF status indicated non-response

• Induction – absence of DAF status indicates a time to retreat.

• How do we standardise (or improve) on the metrics?

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

e.g. neurofilaments

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Do we need to challenge the dogma?

Do we need to challenge the dogma?

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

e.g. neurofilaments

Clinical Attack

Disease Progression

Clinical Recovery

Viral infection

What will a cure in MS look like?

www.ms-res.org