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Why I think MS is an infectious disease was delivered at the grand round in London, Ontario, on 9th December 2014.
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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