dmt update ms life 2012
DESCRIPTION
Power presentation to MSers on emerging DMTsTRANSCRIPT
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1
Disease-modifying drugs
Gavin GiovannoniBlizard Institute
Barts and The London, United Kingdom
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Graeme WilsonMSer born 6th December 1973, died 4th December 2012
http://viaferria.blogspot.co.uk/
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http://viaferria.blogspot.co.uk/
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21-year long-term follow-up of IFNb-1b studytime from study randomization to death
Early treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment
Source: Poster Goodin et al AAN 2011
At risk:IFNB-1b 250 µgPlacebo
124123
124120
121117
118109
10488
HR=0.532 (95% CI: 0.314–0.902)46.8% reduction in hazard ratio Log rank, P=0.0173
IFNB-1b 250 µg
Placebo
0 2 4 6 8 10 12 14 16 18 20 2265%
70%
75%
80%
85%
90%
95%
100%
Time (Years)
Pro
po
rtio
n o
f p
ati
en
ts w
ho
are
sti
ll a
live
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5
What is disease modification?
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Disability
Time
6 months 12 months 24 months
Active
Placebo
6 months
Relapsing MS
1. Delay attacks / onset of MS2. Reduce number of attacks3. Reduce severity of attacks4. Reduce disability5. Delay onset of SPMS
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Who do we treat with DMTs?
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Relapsing MS
Progressive
CIS Active RRMS
SPMS PPMS
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Treat early
Natural course of disease
Laterintervention
Latertreatment
Treatmentat diagnosis Intervention
at diagnosis
Time
Disease Onset
Disability
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Any Negative EDSS=6 SPMS Wheelchair
% R
isk
Rel
ativ
e to
Lo
w E
xpo
sure
Long-term follow-up 16 yearsIFN-beta exposure 80% vs. 20%
Source: Poster Goodin et al AAN 2011
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100 MSers
Who are responders?
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~20% - responders
~40% - partial-responders
-40% - non-responders
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vs.
1
2
3
Clinical
MRI
NABs
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What is the impact of more effective therapies?
Escalation therapies
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Hartung et al. Lancet 2002:360:2018-25.
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Natalizumab
Natalizumab (Tysabri) – mode of action
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Natalizumab (Tysabri)
81%
64%
reduction in annualised relapse rate vs. placebo over 2 years (p < 0.001)
reduction in the risk of disability progression, sustained for 24 weeks, as assessed over 2 years (p =0.008)
1 in 3 Sustained improvement in disability
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Natalizumab (Tysabri)
Progressive multifocal leukoencephalopathy (PML)
Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.
207 cases -1st February 2012
44 (21%) died
163 (79%) alive
Mild disability – 10%Moderate disability – 50%Severe disability – 40%
5% NAbs – infusion reactions
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Natalizumab PML risk stratification tool
Anti-JC virus antibody status
Negative Positive
Prior immunosuppressant use
Natalizumab treatment>2 Years
Natalizumab treatment>2 Years
No Yes
No Yes No Yes
Lowest HighestRelative PML Risk
< 1 in 10,000 1 in 941 in 256 1 in 6681 in 1887
Mitoxantrone AzathioprineMethotrexate
CyclophosphamideMycophenolate
CladribineRituximab
Etc.
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20
Emerging DMTs
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Emerging DMTs for relapsing MSphase 3 & 4
Oral1. Fingolimod – 53% reduction in ARR relative to placebo
2. Cladribine – 55% reduction in ARR relative to placebo
3. BG12 – 53% reduction in ARR relative to placebo
4. Teriflunomide – 31% reduction in ARR relative to placebo
5. Laquinimod – 21% reduction in ARR relative to placebo
Parenteral6. Alemtuzumab (anti-CD52) – 55% reduction in ARR relative to IFNβ-1a
7. Ocrelizumab (anti-CD20) – 80% reduction in ARR relative to placebo8. Daclizumab (anti-CD25) – 54% reduction in ARR relative to placebo
?
Recruiting
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Progressive MS
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www.ms-res.org
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Disability
Time
12 months 24 months 36 months
Active
PlaceboProgressive MS
1. Reduce rate of disability progression
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Disability
Time
6 months 12 months 24 months
Active
Placebo
6 months
Compared to relapsing MS
1. Delay attacks / onset of MS2. Reduce number of attacks3. Reduce severity of attacks4. Reduce disability5. Delay onset of SPMS
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Delayed Progression1 Stabilised Progression2
Improved Function3 Recovered Function4
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WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?
30
1
2
3
www.ms-res.org
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Active tablet
Placebo tablet
Year 1 Year 2 Year 3560 MS’ers
280 MS’ers
280 MS’ers
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Disability
Time
Year 1 Year 2 Year 3
Active
Placebo
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Year 3 Year 4 Year 5~600 MS’ers
~300 MS’ers
300 MS’ers
Year 1 Year 2 Year 6 Year 7
Recruitment Trial Data analysis ? Registration
7 years
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New trial design
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Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Spinalfluid
neurofilament levels
Disability (EDSS) and 3 years
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Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Spinalfluid
neurofilament levels
Disability (EDSS) and 3 years
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Axonal damage in relapsing MS is markedly reduced by natalizumab
Gunnarsson et al. Ann Neurol 2010; Epub.
=
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Recruitment Trial Data analysis
6 months
6 months 60 MS’ers
6 months
LP1 LP2 LP3
30 MS’ers active tablet
30 MS’ers placebo tablet
2 years
6 months
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600 MS’ers for 7 years 60 MS’ers for 2 years
3 LPs = 10x as many trials in a ⅓ of the time
New paradigm
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Can we make LPs safer?
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Two types of spinal needle tips: the Quincke and Sprotte
Evans R W et al. Neurology 2000;55:909-914
Traumatic
or
cutting needle
Atraumatic
or
non-cutting needle
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Ultrasound-guide lumbar punctures
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54%
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Neuroprotection & remyelination
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Brain atrophy
or shrinkage
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Kappos et al. N Engl J Med. 2010 Feb 4;362(5):387-401.
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UK Clinical Trial Network (CTN): phase 3 adaptive designprimary outcome EDSS progression
Placebo
Drug A
Drug B
Drug C
Drug D
futility analysis
2yrs 3yrs
7yrs
EDSS1° outcome
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38 year old woman with left optic neuritissTE fFLAIR images
Baseline 52 weeks
Hickman et al. Neuroradiology 2001;43:123-8.
Trapp et al. N Engl J Med 1998.
Acute optic neuritis(focal lesion)
Romani et al. Clini Neurophys 2000;111:1602-6.
PhenytoinAmiloride
Anti-Lingo-1
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Conclusions• MS is a serious disease• Prognostic factors
– Disease course– Response markers
• Treatment – Effective DMTs for RRMS with an exciting and busy
pipeline– Definitive phase 3 PPMS & SPMS trials underway– New strategies for neuroprotection and
remyelination in progressive MS• MS prevention
www.ms-res.org
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Graeme WilsonMSer born 6th December 1973, died 4th December 2012
http://viaferria.blogspot.co.uk/