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Presentation from MS Day at Twickenham hosted by Imperial.
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Treating MS in 2014
Professor Gavin Giovannoni
Blizard Institute, Barts and The London School of Medicine and Dentistry
Disclosures 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-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.
Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.
www.ms-res.org
Questions: the MSers perspective
To make an informed decision you need to ask and understand the following questions:
1. Are you sure that you have MS?
2. What types of MS do you have?
3. What prognostic group do you fall into?
4. What is the risk of not having any treatment?
5. Do you have active MS?
6. Am I eligible for treatment with a DMT?
7. Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy?
8. What is the therapeutic target?
9. Can we cure MS?
Question: Are you sure that you have MS?
MS misdiagnosis rate of ~5%
Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988 Jul;78(1):39-44.
CDMS 485/518 (94%) - SENSITIVITY = True+ve /(True+ve + False-ve)
MS mimics
NMO
Shimizu et al. IFNβ-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology. 2010 Oct 19;75(16):1423-7.
Migraine
Kleinschmidt-DeMasters et al. PML complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005 Jul 28;353(4):369-74
Module Identifier
Question: What types of MS do you have?
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996 Apr;46(4):907-11.
RRMS R-SPMS/NR-SPMS PPMS RPMS
relapsing forms of MS vs. non-relapsing MS
Question: What prognostic group do you fall into?
Good prognosis Poor prognosis
Young
Female sex
Optic neuritis
Isolated sensory symptom
Full recovery from attack
Long interval to second
relapse
No disability after 5 years
Normal MRI / low lesion load
CSF negative for OCBs
Older age of onset
Male sex
“Multifocal“ onset
Efferent system affected (motor,
cerebellar, bladder)
High relapse rate in the first 2-5 years
Substantial disability after 5 years
Abnormal MRI with large lesion load
Genomic factors (e.g. ApoE4, KIF1B)
CSF positive for OCBs
Adapted from Miller et al., Lancet Neurology 2005: 4; 281-288
Question: What prognostic group do you fall into?
Favourable
Indeterminate
Poor
time Aim of
treatment
Relapsing-MS
Active Inactive Highly-active Rapidly-evolving severe
Active Inactive HA RES
A population of newly diagnosed CISers/MSers
Long-term outcomes under the current Rx paradigm
Long-term outcomes under the T2T-NEDA paradigm
Question: What is the risk of not having any treatment?
MS is one of the most common causes of neurological disability in young adults2
Natural history studies indicate that it takes a median time of 8, 20 and 30 years to reach the irreversible disability
levels of EDSS 4, 6 and 7, respectively3
Up to 75% increased annualized divorce rate4
Life expectancy is reduced by 5-10 years5
7.5x greater than suicide rate than the general population6
2 out of 3 patients with RRMS were unemployed due to the disease7
Utilit
y
EDSS Status
EDSS and utilitya show a significant inverse relationship1,b
aUtility measures are derived from EQ-5D using the EuroQoL instrument. bAdapted from Orme et al 2007. Error bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.
1.Orme M et al. Value In Health. 2007;10:54-60. 2.WHO. 2008.[TK] 3. Confavreaux, Compston. 2005.[TK] 4. Coles et al. 2001.[TK] 5. Confavreaux, Vukusic. 2006.[TK] 6. Sadovnick et al. Neurology 1991;41:1193-6.
7. Morales-Gonzales. Mult Scler. 2004;10:47-54.
Consequences of increasing EDSS scores: loss of employment1
0
10
20
30
40
50
60
70
80
90
Work Capacity by Disability Level
0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0
EDSS Score
Pro
po
rtio
n o
f P
ati
en
ts ≤
65
Ye
ars
Old
Wo
rkin
g (
%)
The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.
1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;
2. Pfleger CC et al. Mult Scler. 2010;16:121-126.
Spain
Sweden
Switzerland
United Kingdom
Netherlands
Italy
Germany
Belgium
Austria
~10 yrs2
www.ms-res.org
www.ms-res.org
Question: Do you have active MS?
vs.
1
2
3
Clinical
MRI
Biomarkers
Question: Am I eligible for treatment with a DMT?
MSer
Neurologist
Payers
Regulator
Question: Am I eligible for treatment with a DMT?
MS is an autoimmune disease hypothesis
15-20 year experiment
“hit hard and early ”
Question: Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy?
What is your treatment philosophy? maintenance-escalation vs. induction
survival analysis
Treatment Selection & treating-2-target
Choosing therapy
X Y Z
Define the Individual’s MS
No
Treatment failure? Yes
• Patient’s preferences?
• Your choice?
Individual measures:
• Evidence of disease activity?
• Tolerability/safety?
• Adherence?
• Drug or inhibitory markers?
Monitoring
• MS prognosis
• Life style and goals
• Shared goals for therapy
Rebaseline
Rebaseline:
• IFNβ, natalizumab, fingolimod,
teriflunomide, DMF=3-6 months
• Glatiramer acetate=9 months
• Alemtuzumab=24 months
DMF=dimethyl fumarate.
Treatment Ladder
1st-line A
1st-line B
1st-line C
1st-line D
1st-line E
2nd-line N
2nd-line M
3rd-line y
3rd-line X
Case studies
38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London Glatiramer acetate treatment for 3 years (good adherence and tolerance) Relapse with a mild left sensory loss Referred to me for a second opinion Switched to interferon β (intramuscular interferon β-1a; www.msdecisions.org.uk) Mild persistent flu-like side effects and lymphopenia 12/12’s neutralizing antibodies screen negative Volunteers for new research programme, which included a gadolinium-enhanced MRI protocol
Teacher
38-year-old teacher with relapsing–remitting MS As a result of fatigue and cognitive problems she is forced to take
early retirement Although fully functional she develops depression and anxiety In her spare time she spends a lot of time on the web and becomes
an expert patient Widely read
Net savvy; regular follower of www.ms-res.org
Teacher X
The relapsing MS DMT doughnut
CIS, clinically isolated syndrome; DMT, disease-modifying therapy; GA, glatiramer acetate; IFN, interferon; RIS, radiologically isolated syndrome; RRMS, relapsing–remitting MS.
Inactive RRMS
CIS
RIS or asymptomatic MS
Suboptimal responders?
Active
RRMS IFN β
or
GA
IFN β
Highly active RRMS Fingolimod Natalizumab
Teacher X
Teacher X
Ian Rogers. ACNR 2007: 7(3);14.
Case 2
Case 3
What is the therapeutic target?
No evident disease activity: 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
No evidence of disease activity defined as:1,2
× No relapses
× No sustained disability progression
× No MRI activity
× No new or enlarging T2 lesions
× No Gd-enhancing lesions
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
MS Iceberg
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
Control Multiple sclerosis
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy
Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions
and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials
(13,500 patients)
Sormani MP et al. Ann Neurol. 2014;75:43-49.
Which drugs slow the rate of brain atrophy in MSers?
1. Interferon beta a. Betaferon x b. Avonex ? c. Rebif x
2. Glatiramer acetate (Copaxone) x 3. Mitoxantrone (Novantrone) x 4. Natalizumab (Tysabri) 5. Fingolimod (Gilenya) 6. Teriflunomide (Aubagio) x 7. Alemtuzumab (Lemtrada) 8. Dimethyl-fumarate (Tecfidera) ?
Rheumatoid arthritis End-stage joint disease
Can you cure MS?
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
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
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
Neuro-restoration
Remyelination
Neuroprotection
Anti-inflammatory
Therapeutic pyramid
Anti-ageing
Brain
Health
Initiative
MRI Events
1st clinical attack
Time (Years)
Subclinical disease
Inflammation
Brain volume loss
Neuroaxonal loss
Dis
eas
e S
eve
rity
SPMS RRMS
1st MRI lesion
Relapses
CIS RIS R-SPMS
RIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing-remitting MS; R-SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS
SPMS: Natalizumab, Siponimod, DMF
Late SPMS: SMART STUDY fluoxetine, amiloride, riluzole
Early SPMS: PROXIMUS oxcarbazepine
CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY
PPMS
PPMS: Fingolimod, Ocrelizumab, Laquinimod
SP&PPMS: Ibudilast
Giovannoni & Cutter; Lancet Neurol 2006; 5: 887–94.
T2T-NEDA diffusion curve
• MSer
• Neurologist
• Payers
• Regulator
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.
Nogo, MAG, OMgP
Lingo-1-NgR-p75NTR
GAP-43
NCAM
Neuregulin
Agents in trial: • Benztropine: anticholinergic
• BIIB033: anti-LINGO-1
• Clemastine: anti-histamine
• GSK239512: histamine H(3)
receptor antagonist
• IRX4204 & Bexarotene:
RXR-agonist
• rHIgM22: oligodendrocyte
target
• VX15: anti-SEMA4D Courtesy of Sharmilee Gnanapavan, MBBS, BmedSci, PhD.
Remyelination
Markers of Remyelination
Image courtesy of Klaus Schmierer.
3 6 9 12 24
EDSS
0
TIME
Active (confirmed improvement)
Placebo (confirmed progression)
Exit EDSS showing improved function
Shadow plaque MRI - MTR
Schmierer et al. Ann Neurol 2004;56:407–415.
Conclusions
MS is a bad disease – Mortality, disability, unemployment, divorce, suicide cognitive impairment,
etc.
Era of individualised profiling – Prognosis, risk, treatment and monitoring
New treatment paradigm – Maintenance vs. induction therapy
– Therapeutic ladder vs. early highly-effective treatments as a 1st-line option
– Improved risk mitigation tools
– New treatment paradigm of treat-2-target of NEDA or no evidence of disease activity
– Future target to prevent organ damage
Is it fair to make MSers wait 20 years for the outcome of an ongoing experiment?
Watch out for a black swan?