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Power presentation to MSers on emerging DMTs
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1
Disease-modifying drugs
Gavin GiovannoniBlizard Institute
Barts and The London, United Kingdom
Graeme WilsonMSer born 6th December 1973, died 4th December 2012
http://viaferria.blogspot.co.uk/
http://viaferria.blogspot.co.uk/
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
5
What is disease modification?
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
Who do we treat with DMTs?
Relapsing MS
Progressive
CIS Active RRMS
SPMS PPMS
Treat early
Natural course of disease
Laterintervention
Latertreatment
Treatmentat diagnosis Intervention
at diagnosis
Time
Disease Onset
Disability
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
100 MSers
Who are responders?
~20% - responders
~40% - partial-responders
-40% - non-responders
vs.
1
2
3
Clinical
MRI
NABs
What is the impact of more effective therapies?
Escalation therapies
Hartung et al. Lancet 2002:360:2018-25.
Natalizumab
Natalizumab (Tysabri) – mode of action
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
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
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.
20
Emerging DMTs
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
Progressive MS
www.ms-res.org
Disability
Time
12 months 24 months 36 months
Active
PlaceboProgressive MS
1. Reduce rate of disability progression
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
Delayed Progression1 Stabilised Progression2
Improved Function3 Recovered Function4
WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?
30
1
2
3
www.ms-res.org
Active tablet
Placebo tablet
Year 1 Year 2 Year 3560 MS’ers
280 MS’ers
280 MS’ers
Disability
Time
Year 1 Year 2 Year 3
Active
Placebo
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
New trial design
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
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
Axonal damage in relapsing MS is markedly reduced by natalizumab
Gunnarsson et al. Ann Neurol 2010; Epub.
=
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
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
Can we make LPs safer?
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
Ultrasound-guide lumbar punctures
54%
Neuroprotection & remyelination
Brain atrophy
or shrinkage
Kappos et al. N Engl J Med. 2010 Feb 4;362(5):387-401.
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
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
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
Graeme WilsonMSer born 6th December 1973, died 4th December 2012
http://viaferria.blogspot.co.uk/