Why i think ms is an infectious disease for the blog

Why I think MS is due to a virus

Gavin Giovannoni Blizard Institute, Barts and The London School of Medicine

December 2014

Disclosures

Over the last 15 years 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, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec for making available data slides on daclizumab for this presentation. He would also like to thank numerous colleagues for providing him with data and/or slides for this, and other, presentations.

Professor Giovannoni’s tour to Canada has been kindly sponsored by Biogen-Idec, therefore please interpret anything he says about Biogen-Idec’s products in this context.

This presentation has been designed and prepared by Professor Giovannoni with no input from any other parties.

We work on the hypothesis that MS is an autoimmune disease

Multiple

Sclerosis

Environ-ment

Genes

The autoimmune hypothesis

Multiple

Sclerosis

Environ-ment

Genes

Relapsing and Remitting Multiple Sclerosis: Pathology of the Newly Forming Lesion

Barnett & Prineas. Ann Neurol 2004;55:458–468

Magnetization Transfer Changes in the Normal Appearing White Matter Precede the Appearance of Enhancing Lesions in Patients with Multiple Sclerosis

Filippi et al. Ann Neurol 1998;43:809-814

Bermel et al. Ann Neuol 2012.

Predictors of long-term outcome in MSers treated with interferon beta-1a

REBOUND ACTIVITY AFTER NATALIZUMAB/FINGOLIMOD WITHDRAWAL

Rigau et al. Neurology 2012;79:2214-6. Alroughani et al. BMJ Case Rep. 2014 Oct 15;2014. pii: bcr2014206314.

REBOUND AFTER NATALIZUMAB WITHDRAWAL

Rigau et al. Neurology 2012;79:2214-6.

Highly-effective DMTs

Anti-CD20

Natalizumab

Alemtuzumab

Fingolimod Mitoxantrone

BMT

Cladribine

Daclizumab? Please note: daclizumab is not licensed in Canada

Daclizumab High-Yield Process (DAC HYP): First in Class IL-2 Immunomodulator

IL2Rβ (CD122) γcommon

(CD132)

α IL-2

β γ

IL-2

β γ

High Affinity

IL-2 Receptor IL2R (CD25)

CD, cluster of differentiation; IL, interleukin; NK, natural killer. 1. Depper JM et al. J Immunol. 1983;131:690-696; 2. McDyer JF et al. J Immunol. 2002;169:2736-2746; 3. Wuest SC et al. Nat Med. 2011;17:604-610; 4. Bielekova B. Proc Natl Acad Sci. 2006;103:5941-5946; 5. Martin JF et al. J Immunol. 2010;185:1311-1320; 6. Perry JSA et al. Sci Transl Med. 2012;4:145ra106.

Intermediate Affinity

IL-2 Receptor

• DAC HYP selectively blocks the high-affinity IL2R by binding the subunit (CD25)

• Promotes a shift of IL-2 signaling towards the intermediate-affinity IL-2R

Biological impact of DAC HYP • Inhibition of activated T cell responses1−3

• Expansion of CD56bright NK cells4,5

• Normalization of lymphoid tissue inducer cell numbers6

11

Please note: daclizumab is not licensed in Canada

DECIDE: daclizumab HYP vs. interferon β-1a in RRMS Annualized Relapse Rate (ARR)

0.393

0.216

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

IFN beta-1a 30 mcg DAC HYP 150 mg

45% Reduction (95% CI: 35.5%, 53.1%) p<0.0001

(n=922) (n=919)

AR

R

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.

Kappos et al. AECTRIMS 2014

Please note: daclizumab is not licensed in Canada

DECIDE: daclizumab HYP vs. interferon β-1a in RRMS Proportion Relapse Free

Pro

po

rtio

n o

f rel

ap

se-f

ree

pa

tien

ts

Percentage relapse free: Week 24: 88% vs. 83% Week 48: 81% vs. 71% Week 96: 73% vs. 59% Week 144: 67% vs 51% Risk reduction: 41%; p<0.0001*

BL 12 24 36 48 60 72 84 96 108 120 132 144

Time on study (weeks)

Source doc: 205ms301-efficacy-2014-08-04

Risk reduction Adobe p. 6/doc p. 1

Graph Adobe p. 78

Percentage relapse free Adobe p. 73/doc p. 68

Risk reduction estimated from a Cox proportional hazards model adjusted for baseline relapse rate, history of prior IFN beta use, baseline EDSS and baseline age. Analysis includes INEC confirmed relapses. * Not statistically significant per the sequential closed testing procedure. Kappos et al. AECTRIMS 2014

Please note: daclizumab is not licensed in Canada

• Reductions in lesions (T2, Gd+, and T1) were observed as early as 24 weeks for DAC HYP vs IFN beta-1a (p<0.001 for all comparisons)

DECIDE: daclizumab HYP vs. interferon β-1a in RRMS Effect on MRI-defined lesions at Week 96

*Adjusted mean for T2 and T1 lesions. †The number of new/newly enlarging T2 lesions at 96 weeks was a secondary endpoint. Data were adjusted for baseline lesion volume, history of prior IFN beta-1a use and baseline age (≤35 v >35). Missing data were not imputed and patients with no post baseline MRI were excluded from analysis of new/newly enlarging T2 lesions at 96 weeks. Missing data were imputed for all other analyses.

New T1 Hypointense Lesions ‘black holes’

4.4

2.1

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

52% Reduction p<0.0001

New Gd+ Lesions

1.0

0.4

0.0

0.2

0.4

0.6

0.8

1.0

1.2

65% Reduction p<0.0001

IFN beta-1a 30 mcg DAC HYP 150 mg

n=908 n=841 n=864 n=909 n=900 n=899

Me

an

* n

um

ber

of l

esio

ns

New/Newly Enlarging T2 Lesions†

9.4

4.3

0

1

2

3

4

5

6

7

8

9

10

54% Reduction p<0.0001

n=864 n=841

Kappos et al. AECTRIMS 2014

Please note: daclizumab is not licensed in Canada

DECIDE: daclizumab HYP vs. interferon β-1a in RRMS 3-Month and 6-Month Confirmed Disability Progression

Risk reduction: 16%; p=0.16

Proportion with progression Week 48: 6% vs. 8% Week 96: 12% vs. 14% Week 144: 16% vs. 20%

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

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

Risk reduction: 27%; p=0.0332

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

3-month* 6-month†

Pro

po

rtio

n o

f pa

tien

ts w

ith

co

nfi

rmed

pro

gre

ssio

n o

f dis

ab

ilit

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.

Kappos et al. AECTRIMS 2014

Please note: daclizumab is not licensed in Canada

Effect of Anti-CD25 Antibody Daclizumab in the Inhibition of Inflammation and

Stabilization of Disease Progression in MS

Bielikova et al. Arch Neurol. 2009;66(4):483-489

Please note: daclizumab is not licensed in Canada

Monoclonal antibody blockade of IL-2 receptor during lymphopenia selectively depletes regulatory T cells in mice and humans

Kappos et al. Blood 2011;118(11):3003-3012.

Autoimmune side effects: 1. Hypersensitivity dermatitis 2. Autoimmune hepatitis 3. Inflammatory bowel disease (IBD) 4. Glomerulonephritis

Please note: daclizumab is not licensed in Canada

.

Epidemics or clusters of MS

• No documented cases of MS on the Faroe Islands until after World War II

• 55 cases since 1940

• Occupied during World War II

• Authors concluded that this was evidence of an MS epidemic caused by an agent introduced by the troops

• However a number of concerns remain

The annual incidence of MS (per 100 000 inhabitants) in the Faroe Islands since 1940

Kurtze et al 1993

0

2

4

6

8

10

12

1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990

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

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)

Infectious agents in MS

. Ramagopalan et al 2009

. Handel et al, 2010

19390 MS patients and 16007 controls, p < 10-54

Infectious Mononucleosis and MS

MS IM

Ramagopalan et al, 2011

Pearson r = 0.70, p=0.000025

Infectious Mononucleosis and MS

Causation theory

Causation

early adopters

late adopters

Diffusion Curve

Causation - Koch’s Postulates

1. The specific organism should be shown to be present in all cases of animals suffering from a specific disease but should not be found in healthy animals.

2. The specific microorganism should be isolated from the diseased animal and grown in pure culture on artificial laboratory media.

3. This freshly isolated microorganism, when inoculated into a healthy laboratory animal, should cause the same disease seen in the original animal.

4. The microorganism should be reisolated in pure culture from the experimental infection.

1843-1910

Sir Bradford-Hill: Criteria for Causation

Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.

1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS

2. STRENGTH OF ASSOCIATION

3. TEMPORAL SEQUENCE

4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)

5. SPECIFICITY

6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE

7. BIOLOGICAL PLAUSABILITY

8. REASONING BY ANALOGY

9. EXPERIMENTAL EVIDENCE

Causation and Disease:

A Chronological Journey

Alfred S. Evans

Hardcover / Plenum Pub Corp

March 1993 / 0306442833

“Evidence” or “lack of evidence”

Infectious mononucleosis

Handel et al. 2010.

Small OR

Odds ratio of MS in subjects seronegative for EBV

Ascherio et al, 2007

EBV Seropositivity titres

99.2% vs 90.2%

. Ascherio et al, 2000

Primary infection with the EBV and risk of MS

• Nested case-control study including from over 8 million military personnel with serum stored in the Department of Defense Serum Repository.

Levin et al. Ann Neurol 2010.

MS

Controls N = 610

N = 305 10/305 (3.3%) EBV –ve

32/610 (5.2%) EBV –ve 10/28 (35.7%) EBV –ve

10/10 (100%) EBV –ve

• MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection.

. Levin et al. Ann Neurol 2010.

The ugly fact

“The great tragedy of Science; the slaying of a beautiful hypothesis by an ugly fact.” Thomas Henry Huxley

Viral serologies in children with MS

Banwell et al. Lancet Neurology, Sept. 2007

?

Coherence

Compston & Coles, Lancet 2008.

Epidemiology worldwide distribution & migration studies

Genetics of MS: the rate of MS in females is increasing

1Orton SM et al. Lancet Neurol 2006;5:932–936.

Smoking is a risk factor for multiple sclerosis

Handel et al. PLoS One. 2011 Jan 13;6(1):e16149.

Ramagopalan et al. Arch Neurol 2011; 68:469-72.

Biological plausability

EBV & Disease Activity

Farrell et al. Neurology 2009

EBNA-1 NOT VCA or EA

Dysregulated EBV infection in the MS brain

Serafini et al. J Exp Med. 2007 Nov 26;204(12):2899-912.

Negative follow-up studies

1. Torkildsen O, et al. Upregulation of Immunoglobulin-related Genes in Cortical

Sections from Multiple Sclerosis Patients. Brain Pathol. 2009 Oct 16. [Epub

ahead of print]

2. Willis SN, et al. Epstein-Barr virus infection is not a characteristic feature of

multiple sclerosis brain. Brain. 2009 Dec;132(Pt 12):3318-28.

3. Peferoen LA, et al. Epstein Barr virus is not a characteristic feature in the central

nervous system in established multiple sclerosis. Brain. 2010 May;133(Pt

5):e137. Epub 2009 Nov 16.

4. Hans Lassman et al, personal communication.

Innate immune activation is a hallmark of the active MS lesions

Tzartos et al., Neurology 2012.

Innate immune activation is a hallmark of the active MS lesions

Tzartos et al., Neurology 2012.

Intrathecal oligoclonal IgG bands (OCBs)

1. Rand KH, et al. (1998) Molecular approach to find target(s) for oligoclonal bands in multiple sclerosis. J Neurol Neurosurg Psychiatry 65:48-55.

2. Bray PF, et al. (1992) Antibodies against Epstein-Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein. Neurology 42:1798-804.

3. Cepok S, et al. (2005) Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 115:1352-60.

4. Rand KH, et al. (2000) Epstein-Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci 173:32-9.

C+ / S-

Analogy

Axthelm et al. Ann Neurol 2010

Japanese Macaque Encephalomyelitis: A Spontaneous Multiple Sclerosis–like Disease in a Nonhuman Primate

HTLV-1 myelopathy

Experimental evidence

N Engl J Med 2008;358:676-88.

Highly-effective DMTs

Anti-CD20

Natalizumab

Alemtuzumab

Fingolimod Mitoxantrone

BMT

Cladribine

Sir Bradford-Hill: Criteria for Causation

Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.

1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS - Yes (not 100%)

2. STRENGTH OF ASSOCIATION – ? / Yes (RR ~ 2 to 3)

3. TEMPORAL SEQUENCE - Yes

4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP) - ? (not relevant to infections)

5. SPECIFICITY – No (not 100% other putative autoimmune diseases also associated with

EBV)

6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE - No

7. BIOLOGICAL PLAUSABILITY - Yes

8. REASONING BY ANALOGY - Yes

9. EXPERIMENTAL EVIDENCE - No

Is EBV the cause of MS?

Is there a “Black Swan” flying in?

Charcot Project: viral aetiology

HIV and lower risk of MS: beginning to unravel a mystery using a record-linked database study

Nexø et al. Epidemiology 2013; 24:331-2

Treatment of HIV and Risk of Multiple Sclerosis

Gold et al. JNNP August 4, 2014 as 10.1136/jnnp-2014-307932.

Raltegravir → RRMS (INSPIRE STUDY) ClinicalTrials.gov ID: NCT01767701

Endogenous retroelements and autoimmune disease

Volkman & Stetson. Nat Immunol 2014

PREVENTION

DISEASE MODIFICATION

1. Epidemiologists 2. Virologists 3. Genomics 4. Bioinformatics 5. Immunologists 6. Neurologists 7. Pharmaceuticals

EBV

? mutations

EBV & HERVs

Early infection

Late infection

Asymptomatic seroconversion

Infectious mononucleosus

At risk MS

vD/Sunlight Smoking

Genetics

Vaccine

IM Rx

Anti-EBV

HAART

HERVs

Arthur Schopenhauer (1788 –1860)

All truth passes through three stages:

• It is ridiculed

• It is violently opposed

• It is accepted as self-evident

Acknowledgements • Ute Meier

• Monica Marta

• Sreeram Ramagopalan

• Ruth Dobson

• George Ebers

• Jo Topping

• Georgina Burrow

• Julian Gold

• Rachel Farrell

• Cosimo Maggiore

• Jaap Middeldorp

• Sandra Amor

• Dorothy Crawford

• Karen McCauley

• Adam Handel

• Giulio DeSanto

• Hadi Amir-Maghzi

• Chris Hawkes

• Klaus Schmierer

• David Baker