The charcot project - antivirals to treat MS
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Transcript of The charcot project - antivirals to treat MS
The Charcot Project: Antiviral Therapies for MS
Gavin Giovannoni
Version 2.0
Disclosures
Over the last 15 years I have received personal compensation for
participating in advisory boards in relation to clinical trial design, trial steering
committees, and data and safety monitoring committees from: Abbvie,
Almirall, Atara Bio, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Elan,
Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, MSD, Merck
Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and
Vertex Pharmaceuticals
The case for MS being due to a virus
To cure MS do we need to know the cause?
EBV, HERVs, etc.
Vitamin D, Obesity (? diet)
Smoking, organic solvents
Genes(HLA,....)
The MS 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
Clinical Attack
Disease Progression
Clinical Recovery
pathobiology
clinical outcomes
biomarkersPremature Ageing
Genetics Environment Chance
VIRUS(EBV, HERVs)
.
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
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.
Serafini et al. J Neuroimmunol. 2017 Jun 15;307:14-17.
Massive intracerebral Epstein-Barr virus reactivation in lethal
multiple sclerosis relapse after natalizumab withdrawal.
● Highly-active RRMS, severe
neurologic impairment (EDSS 7)
● Treated with natalizumab - EDSS 4.5
● Due to severe depression, stopped
Nz after 37 infusions.
● 3½ months later rapid disease
worsening
● Brain MRI showed >50 T2-lesions,
mostly Gd-enhancing
● JCV-PCR -ve in CSF
● Rapidly worsened, died d17
● PM active MS rebound
● JCV-PCR -ve in brain
Which virus?
Infectious agents in MS
. Ramagopalan et al 2009
MS IM
Ramagopalan et al, 2011
Pearson r = 0.70, p=0.000025
Infectious Mononucleosis and MS
Infectious mononucleosis
Handel et al. 2010.
Small OR19,390 MS patients and 16,007 controls, p < 10-54
EBV Seropositivity titres
99.2% vs 90.2%
. Ascherio et al, 2000
Odds ratio of MS in subjects seronegative for EBV
Ascherio et al, 2007
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 = 30510/305 (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.
“Evidence” or “lack of evidence”
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 with prior knowledge
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 MS
Handel et al. PLoS One. 2011 Jan 13;6(1):e16149.
Ramagopalan et al. Arch Neurol 2011; 68:469-72.
Biological plausibility
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.
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. Lassmann et al. Brain. 2011 Sep;134(Pt 9):2772-86. Tzartos et al. Neurology. 2012 Jan
3;78(1):15-23.
5. Tzartos et al. Neurology. 2012 Jan 3;78(1):15-23.
6. Serafini et al. J Neuropathol Exp Neurol. 2014 Jul;73(7):729-31.
7. Serafini et al. Brain. 2013 Jul;136 (Pt7):e233. doi: 10.1093/brain/aws315.
8. Han et al. Molecular signature of Epstein-Barr virus infection in multiple sclerosis brain
lesions. ECTRIMS Online Library. Oct 27, 2017; 200600.
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.
Please note rituximab is the only licensed anti-EBV drug!
Baker et al. EBioMedicine. 2017 Feb;16:41-50.
Saha & Robertson. DOI: 10.1158/1078-0432.CCR-10-2578 Published May 2011
EBV & B-cell
biology
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
EBV is the cause of MS, but we don’t know how it causes MS!
Dual-viral hypothesis
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
HERV-W-Env Protein Pathogenicity
HERV-W-Env protein
The envelope protein of HERV-W
Typically not expressed in healthy individuals.
Abnormal expression triggered by environmental factors (EBV…)
Appears to be involved in Multiple Sclerosis pathogenesis.
Activation of TLR4 pathway
by HERV-W-Env
Immune system
➢ Inflammation
➢ Autoimmunity
Non-immune cells
➢ Endothelial cells: inflammatory
responses
➢ Schwann cells: inflammatory
responses
➢ Oligodendrocytes precursor cells:
differentiation / remyelination blockade
GNbAC1A monoclonal humanized antibody
neutralizing HERV-W-Env
Successful Phase I and Phase IIa clinical trials in MS indication
Currently in Phase IIb efficacy clinical trial
HERV-W-Env
HERV-W-Env – TLR4 signaling pathway
Perron H et al. Virology. 2001;
Rolland A et al. J Immunol. 2006;
Kremer D, et al. Ann Neurol. 2013
Duperray A et al. Int Immunol. 2015;
Madeira et al. 2016, J Neuro Immunol;
Faucard et al. 2015, Ebiomedic;
Curtin et al. 2016, MS Relat DisordSlide courtesy : Hervé Perron
▪ Phase I Study completed in January 2012/validated July 2012
Excellent safety profile; No immunogenicity; PK is dose linear; Half-life compatible with
monthly administration
GNbAC1 a Humanized IgG4 antibody
neutralizing HER-W Env in Clinical trials
Curtin et al. Clin. Ther. 2012
▪ Phase IIa 1 year Study in MS patients with monthly infusions completed in March 2014:
promising data for GNbAC1.
▪ Excellent safety profile; No immunogenicity; MRI stability and no progression, notably
in PMS
▪ Safe mode of action validated in patients: No modification of any physiological
immune function in one-year treated patients (Normal profile of immune cell sub-
popuplations and responses to Immunity test panel in all patients…)
▪ Beyond expected simple effects of an “toxin-neutralizing” antibody.
Curtin et al. Mult. Scler. 2014
▪ Phase IIb efficacy Study Started in 2016: 10 European countries; 320 patients;
ascending doses (6, 12, 18 mg/Kg) and placebo; 1 year Monthly injections;
patients.
▪ Final 1-year results expected in March 2018.
Slide courtesy : Hervé Perron
HERV-W genomic structure as sequenced from MSRV virions
May antiretroviral drugs inhibit the expression of HERV-
W genome when activated ?
Slide courtesy : Hervé Perron
HERV-W endogenous retroviruses and MS
Dolei, MSJ 2018, Vol. 24(1) 42–47.
Targeting HERVs
BioEssaysVolume 35, Issue 9, pages 794-803, 17 JUL 2013 DOI: 10.1002/bies.201300049http://onlinelibrary.wiley.com/doi/10.1002/bies.201300049/full#bies201300049-fig-0001
INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS
change in gradient
change
(in means)
V1
V2
(screening
before
visit)V3 V4 V5 V6 V7
V8 after
Raltegravir
dispensed
A statistically significant
change in means is not in
this situation consistentwith a reduction inoutcome values due to
intervention.Raltegravir → RRMS (INSPIRE STUDY)ClinicalTrials.gov ID: NCT01767701
Slide courtesy : Julian Gold
PREVENTION
DISEASE
MODIFICATION
1. Epidemiologists
2. Virologists
3. Genomics
4. Bioinformatics
5. Immunologists
6. Neurologists
7. Pharmaceuticals
EBV
? mutations
Conclusion: ‘The Charcot Project’- EBV & HERVs
Early infection
Late infection
Asymptomatic
seroconversion
Infectious
mononucleosis
At risk MS
vD/Sunlight Obesity
Genetics
Vaccine
IM Rx
Anti-EBV
HAART
HERVs
GNbAC1
Smoking
Diet
Arthur Schopenhauer
(1788 –1860)
All truth passes through three stages:
• It is ridiculed
• It is violently opposed
• It is accepted as self-evident
Is there a “Black Swan” flying in?
AcknowledgementsQMUL:
Ute Meier
Monica Marta
Sreeram Ramagopalan
Ruth Dobson
Jo Topping
Georgina Burrow
Cosimo Maggiore
Hadi Amir-Maghzi
Chris Hawkes
Klaus Schmierer
David Baker
Jack Cuzick
Nick Wald
David Holden
Oxford:
George Ebers
Sreeram Ramagopalan
Adam Handel
Giulio DeSanto
Epidemiology, Oxford:
Raph Goldacre
Michael Goldacre
David Yeates
The Albion Centre, Sydney:
Julian Gold
Hubert Maruszak
UCL:
Robin Weiss
Rachel Farrell
Jeremy Garson
VU Amsterdam:
Jaap Middeldorp
Sandra Amor
Edinburgh:
Dorothy Crawford
Karen McCauley
Aarhus University:
Tove
Christiansen