presentación de powerpoint · 2017-06-28 · disclosure statement in the last year , giancarlo...
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Giancarlo Comi Dept. of Neurology & Institute of Experimental Neurology
Università Vita Salute S.Raffaele, Milano European Charcot Foundation
“MS Nowadays-new goals”
EAN 2017 Amsterdam June 23-27, 2017
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Disclosure statement
In the last year , Giancarlo Comi received personal compensation for activities such as consulting, scientific advisory boards or speaking from:
Bayer Schering Pharma, Biogen-Dompè, Biogen Idec, MerckSerono, Novartis, Roche, Sanofi-Aventis, Almirall, Teva, Actelion, Receptors.
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Early treatment Individualized treatment Induction strategy
Multiple Sclerosis Care Unit
NEW Goals: Outline
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Rationale for early therapy in multiple sclerosis
Comi, Lancet 2016
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Window of opportunity – earlier treatment modify the course of disease
Early treatment initiation and prompt intervention on break-through disease is critical to optimise disability outcomes
Incr
eas
ing
dis
abili
ty
Time
Intervention at diagnosis
Intervention later
No treatment
Later intervention
Intervention at diagnosis
Window of opportunity
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• Complexity and heterogeneity of MS • Polygenic inheritance • Multifaced gene-gene and gene-environment interaction
• Large intraindividual variability of MS courses
• Early long term prognostic factors • Short term prognostic factors
• Treatments with different mechanisms of action and different efficacy/safety profile
• Interindividual variability of the response to treatments
• Clinical and MRI predictors • Pharmacogenomics
• Multiple treatment algorithms
• Induction/Escalation • Combination
Bases for individualised treatment in MS
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•Clinical
•MR Imaging
•Neurophysiological
•Biological
Prognostic factors in MS
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Barcelona CIS cohort: Multivariate analysis at baseline
DMT =IFNβ/glatiramer acetate
HR=hazard ratio; OCB=oligoclonal bands. Tintoré M et al. Brain 2015
Risk of reaching EDSS ≥3.0 Risk of conversion to CDMS
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EPs and conversion to CDMS over 1 year 225 CIS (from consecutive pts undergoing CSF examination)
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Pelayo, Montalban et al. MSJ 2010
CIS: EPs & progression rate - time to EDSS 3.0
SEPs VEPs BAEPs no MEPs
n: 247 (out of /335)
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CSF Neurofilament light levels
G Arrambide et al Neurology 2016
NfL levels appear to be independent predictors for conversion to CDMS and correlate with MR inflammation variables and atrophy
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Predictivity of the response to DMTs
• Clinical and demographic
• MRI
• Eps
• Laboratory
• Pharmacogenomic
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Criterion
Age onset
< 28 years 0
> 28 years 2
Delay treatment after diagnosis
< 12 months 0
> 12 months 1
Relapse 1 year pre-DMT
< 2 relapse 0
> 2 relapses 1
Baseline EDSS
< 2 0
> 2 1
Baseline T2 lesions
< 9 0
>9 1
Baseline T1 Gd+ lesions
< 2 0
> 2 1
Baseline predictive score of disability worsening at 8 years in patients treated with injectables
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Log rank test, p: <0.0001
Score Tot pts
(561)
Disability
worsening
0 20 0%
1 70 7%
2 116 9%
3 135 13%
4 125 18%
> 5 95 26% Romeo 2015
*Worsening: 6 months confirmed EDSS > 2 points if entry EDSS < 3
6 months confirmed EDSS > 1 point if entry EDSS > 3
Patients free from disability worsening according to baseline score
Score 0
Score 1
Score 2
Score 3
Score 4
Score > 5
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Esposito et al, 2015 A pharmacogenetic study implicates SLC9A9 in multiple sclerosis disease activity
A genome-wide association study performed in Italian MS patients identified a genetic variant, the rs9828519G allele, associated with increased risk of non-response to IFNβ (Pdiscovery=4.43x10-8)
Replication studies performed in 3 independent cohorts confirmed the association (Preplication=7.78x10-4)
Study
USA
Italy
France
Combined analysis
OR
1.97
1.21
1.33
1.48
95%-CI
[1.33-2.92]
[0.80-1.83]
[0.91-1.96]
[1.18-1.86]
0.5 1.0 1.5 2.0 2.5 3.0
Odds Ratio
We investigated the genetic basis of inter-individual differences in response to IFNβ by studying ~1,000 MS patients classified in responders and non-responders
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MRI MRI Interferon
12 m MS
Predicts:
Disability progression
36 m
Assessing response to interferon beta A MAGNIMS study
Sormani 2016
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MAGNIMS score
Score=0, n=849, 66% Score=1, n=301, 24%
Score=2, n=130, 10%
Score 0 vs scores 1 or 2: PPV= 34%, NPV=81%, sensitivity=49%, specificity=73%, global accuracy=66%. Sormani 2016
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Treating to target: NEDA establishes a zero tolerance for ongoing measurable disease activity
Evolving Measures: NEDA (No Evidence of Disease Activity) in MS
NEDA
No Gd-enhancing T1 or new T2 lesions
on MRI
No relapses
No confirmed worsening of EDSS scores
No evidence of MRI disease activity
No evidence of clinical disease activity
1
NEDA Composite Measure NEDA may be influenced by:
• Baseline characteristics
• Study design
• Assessment timing or criteria (eg, 3-month vs 6-month)
• Timing for re-baseline of patients
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Proportion of patients achieving NEDA with DMDs
NEDA, no evidence of disease activity. CLARITY. Giovannoni G et al. Lancet Neurol 2011;10:329-37; FREEDOMS. Bevan CJ, Cree BAC. JAMA Neurol 2014;71:269-70; DEFINE. Giovannoni G et al. Neurology 2012;78 (PD5.005); TEMSO. Freedman M et al. Neurology 2012;78 (PD5.007); AFFIRM. Havrdova E et al. Lancet Neurol 2009;8:254-60; Coles et a, Lancet 2012
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Treatment Algorithms
ESCALATION
(safety first)
INDUCTION
(efficacy first)
COMBINATION
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Treatment algorithm: escalation
BMT
ATZ / OCR
ATZ / Cyclophosphamide / MTX
ATZ / CLA / DAC / FTY/ NTZ / OCR
DMF / GA / IFNβ / TER
More aggressive approach
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Treatment algorithm: induction
BMT
Combination?
DMF / FTY / GA / IFNβ / NTZ / TER
ATZ / CLA /Cyclophoshamide / DAC / MTX / OCR
4th line tx
3rd line tx
2nd line tx
1st line tx
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ORACLE: ARR during the open-label period
*Two sided 95% confidence interval. ARR has been normalised by duration in
the OLMP (total number of relapses/total time in the OLMP in days) x 365.25.
All patients started open-label treatment with IFN β-1a in the OLMP.
ARR, annualised relapse rate; IFN, interferon; OLMP, open-label maintenance period
Median time in OLMP:
64.4 weeks
Median time in OLMP: 48.1 weeks
Median time in OLMP: 57.3 weeks
0.42 (0.28, 0.56)
0.14 (0.00, 0.27)
0.24 (0.07, 0.40)
0,00
0,10
0,20
0,30
0,40
0,50
0,60
Placebo (n=60) Cladribine tablets 3.5 mg/kg (n=25)
Cladribine tablets 5.25 mg/kg (n=24)
An
nu
alis
ed
rela
pse
rate
(9
5%
CI*
)
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Cladribine in CLARITY/
placebo in CLARITY EXT
Cladribine throughout Placebo in CLARITY/
cladribine in CLARITY EXT
98 186 186 244 437 456 456 433 433 92 Annualiz
ed r
ela
pse r
ate
n= Total cumulative
dose
DB Extension
CLARITY EXT demonstrates the durable efficacy of cladribine and reconfirms the efficacy outcomes of the CLARITY study over 2 years
• The clinical benefits of cladribine 3.5 mg/kg in Years 1 and 2 may be
maintained for up to 4 years without further active treatment in Years 3 and
4; 72% of such patients remained relapse-free at the end of Year 4
2
8
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Induction with mitoxantrone followed by BETA IFN vs BETA IFN
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Algorithm for Treatment of Relapsing MS
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General recommendations The entire spectrum of disease modifying drugs should only be prescribed in centres
where there is an adequate infrastructure to provide: - proper monitoring of patients - comprehensive assessment - detection of side effects and ability to promptly address them.
ECTRIMS-EAN Clinical Practice Guideline on Pharmacological Management of
Multiple Sclerosis
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ECF has started an action to promote in Europe Multiple Sclerosis Care Unit
as the standard of treatment for MS
In collaboration with:
ECTRIMS – EAN – IFMS – MS Platform
&
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I. Sangion
M. Galdabini