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Background to why early aggressive treatment is an important emerging treatment strategy!
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Hit hard and early!
Gavin Giovannoni
Barts and The London School of Medicine and Dentistry XVIIIth European Charcot Foundation Symposium
Marbella , Spain 29th Nov to 1st Dec 2012
Disclosures
I have received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: 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.
Emerging concepts in MS
NEDD; no evidence of detectable disease
TTT; treat-to-target
Emerging concepts in MS
NEDD; no evidence of detectable disease
TTT; treat-to-target
How would you define a MS cure?
"To claim that someone has been cured of MS one would have to show that the person who had the disease had no disease activity for at least 15 years. The latter would be a composite of no MRI activity (new gadolinium-enhancing lesions, new T2 or enlarging T2 lesions and a lack of progressive whole brain atrophy) and no clinical activity (relapses or disease progression).“
GIOVANNONI; WWW.MS-RES.ORG: FRIDAY, 6 APRIL 2012.
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Post-inflammatory neurodegeneration
Hartung et al. Lancet 2002:360:2018-25.
We don’t want to throw the baby out with the bathwater!
Treat early
Natural course of disease
Later intervention
Later treatment
Treatment at diagnosis Intervention
at diagnosis
Time Disease Onset
Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial
Goodin et al. Neurology 2012;78:1315-1322.
Any Negative EDSS=6 SPMS Wheelchair
% R
isk R
ela
tive t
o L
ow
Exp
osu
re
Long-term follow-up 16 years
IFN-beta exposure 80% vs. 20%
Goodin et al. PLoS One. 2011;6(11):e22444. Epub 2011 Nov 30.
Establishing long-term efficacy: use of recursive partitioning and propensity score adjustment to estimate outcome in MS
Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon b-1b trial
Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
Association between use of interferon beta and progression of disability in MSers with relapsing-remitting multiple sclerosis
Tremlett et al. JAMA. 2012;308(3):247-256.
Association between use of interferon beta and progression of disability in MSers with relapsing-remitting multiple sclerosis
Tremlett et al. JAMA. 2012;308(3):247-256.
100 MSers
Who are the responders?
~20% responders
~40% sub-optimal responders
~40% non-responders
vs.
1
2
3
Clinical
MRI
NABs
Relapses don’t count!
Relapse on IFNβ Therapy Increases Risk of Sustained Disability Progression
Bosca et al. Mult Scler. 2008;14:636-639.
HR SE P Value 95% CI
No relapses (reference=1) 1
One relapse 3.41 1.47 0.005 1.46–7.98
Two or more relapses 4.37 1.74 0.000 1.90–9.57
HR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 or More Relapses During the First 2 Years of IFN Treatment
0 20 40 60 80
0
0.25
0.50
0.75
Analysis Time (Months)
No Relapses One Relapse Two or More Relapses
1.00
EDSS
Pro
gres
sio
n
Surv
ival
Pro
bab
ility
HR=hazard ratio; SE=standard error
Relapses and residual deficits
Lublin FD et al. Neurology. 2003;61:1528-1532.
Predictors of long-term outcome in MSers treated with interferon beta-1a
Bermel et al. Ann Neuol 2012; In Press.
Bermel et al. Ann Neuol 2012; In Press.
Predictors of long-term outcome in MSers treated with interferon beta-a
Bermel et al. Ann Neuol 2012; In Press.
Predictors of long-term outcome in MSers treated with interferon beta-1a
MRI activity doesn’t count!
Bermel et al. Ann Neuol 2012; In Press.
Predictors of long-term outcome in MSers treated with interferon beta-1a
MRI to monitor treatment response to IFNβ: a meta-analysis
Dobson et al. Submitted 2012.
Study or Subgroup Odds Ratio
IV, Random, 95% CI
Kinkel 2008
Prosperini 2009
Total (95% CI) 9.86 (2.33, 41.70)
Study or Subgroup Odds Ratio
IV, Random, 95% CI
Kinkel 2008
Pozzilli 2005
Prosperini 2009
Sormani 2011
Total (95% CI) 2.69 (0.72, 10.04)
0.01 0.1 1 10 100 Disease Less Likely Disease More Likely
One New T2 Lesion
Favors Experimental Favors Control
100 10 1 0.1 0.01
Two or More New T2 Lesions
Study or Subgroup Odds Ratio
IV, Random, 95% CI
Kinkel 2008
Rio 2008
Total (95% CI) 5.46 (2.48, 12.04)
MRI to monitor treatment response to IFNβ: a meta-analysis
Dobson et al. Submitted 2012.
Study or Subgroup Odds Ratio
IV, Random, 95% CI
Kinkel 2008
Pozzilli 2005
Tomassini 2006
Total (95% CI) 3.34 (1.36, 8.22)
0.01 0.1 1 10 100 Disease Less Likely Disease More Likely
One New Gd+ Lesion
0.01 0.1 1 10 100
Disease Less Likely Disease More Likely
Two or More New Gd+ Lesions
Disease progression doesn’t count!
Strongest predictor of disability progression on IFNβ therapy is progression itself
Disease activity during 2 years of treatment and prediction of disability progression* at 6 years
Group Sensitivity (%)
(CI) Specificity (%)
(CI)
A. An increase of at least one EDSS step confirmed at 6 months 85 (64–95) 93 (86–97)
B. Occurrence of any relapse 80 (58–92) 51 (41–61)
C. Occurrence of two or more relapses 45 (26–66) 81 (72–82)
D. A decrease in relapse rate less than 30% compared with 2 years before therapy
40 (22–61) 86 (77–91)
E. A decrease in relapse rate less than 50% compared with 2 years before therapy
40 (–61) 81 (72–88)
F. No decrease or identical relapse rate compared with 2 years before therapy
35 (18–57) 88 (79–93)
G. Definition A or B 90 (70–97) 48 (38–58)
H. Definition A or E 85 (64–95) 76 (66–83)
I. Definition A and B 75 (53–89) 97 (91–99)
J. Definition A and E 40 (22–61) 99 (94–99)
*EDSS score ≥6.0 or increase in at least 3 EDSS steps.
Río J et al. Ann Neurol. 2006;59:344-352.
Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon b-1b trial
Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
Curved Ball
0 3 6 X
Survival analysis and disability progression
0 3 6 X
Survival analysis and disability progression
0 3 6 X
Survival analysis and disability progression
X
X
X
X
X
X
3
X
X
X
X
X
X
3
survival analysis
X
X
X
X
X
X
3
survival analysis
median or mean EDSS
Impact of early interferon beta-1b on disease evolution over 5-years in MSers with CIS
Freedman et al. WCTRIMS 2008.
survival analysis median or
mean EDSS
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial
Coles et al. Lancet 2012: November 1, http://dx.doi.org/10.1016/
survival analysis
median or mean EDSS
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial
Coles et al. Lancet 2012: November 1, http://dx.doi.org/10.1016/
56.0
42.0
27.0
74.0
51.0
39.0
0
10
20
30
40
50
60
70
80
Clinical disease
activity-free
MRI
activity-free
MS disease
activity-free
CARE-MS I: Disease Activity Status – Proportion of Patients Free of MS Disease Activity
41.1
Pati
en
ts (
%)
Note: Clinical disease activity-free defined as absence of relapse or SAD; MRI activity-free defined as absence of new Gd-enhancing lesion or new or
enlarging T2 hyperintense lesion; MS disease activity-free defined as absence of clinical disease activity or MRI activity.
Giovannoni et al. ENS 2012.
p<0.0001
p=0.0388
p=0.0064
SC IFNB-1a
Alem 12 mg
“Every clinical trial is an experiment. In fact every time you treat a patient you should view it as an experiment and use it as an opportunity to learn something about the disease!”
survival analysis
What is your treatment philosophy? maintenance-escalation vs. induction
survival analysis
“hit hard and early ”
What is your treatment philosophy? maintenance-escalation vs. induction
survival analysis
“hit hard and early ”
MS is an autoimmune disease hypothesis
15-20 year experiment
What is your treatment philosophy? maintenance-escalation vs. induction
Who should decide?
WWW.MS-RES.ORG
WWW.MS-RES.ORG
WWW.MS-RES.ORG
Are you prepared to walk where others fear to tread?
Conclusions • NEDD, TTT and DAF are entering the neurology lexicon
• We need an acceptable working definition of an MS cure • DAF x 15 years?
• Should the definition be disease-stage specific?
• How do we deal with maintenance and induction therapies? • Maintenance - absence of DAF status indicates non-response
• Induction – absence of DAF status indicates a time to retreat
• Improve risk mitigation tool
• Who should make the decision re early aggressive treatment? • Regulators
• Payers
• Neurologists
• MSers
• Is it fair to make MSers wait 20 years for the outcome of an experiment? • Alemtuzumab extension study
• What do we do about post-inflammatory neurodegeneration? • We need better outcomes, e.g. regional brain atrophy and CSF neurofilament levels
• Neuroprotective treatments
Conclusions • NEDD, TTT and DAF are entering the neurology lexicon
• We need an acceptable working definition of an MS cure • DAF x 15 years?
• Should the definition be disease-stage specific?
• How do we deal with maintenance and induction therapies? • Maintenance - absence of DAF status indicates non-response
• Induction – absence of DAF status indicates a time to retreat
• Improve risk mitigation tool
• Who should make the decision re early aggressive treatment? • Regulators
• Payers
• Neurologists
• MSers
• Is it fair to make MSers wait 20 years for the outcome of an experiment? • Alemtuzumab extension study
• What do we do about post-inflammatory neurodegeneration? • We need better outcomes, e.g. regional brain atrophy and CSF neurofilament levels
• Neuroprotective treatments
? ?
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