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The staggered 2-step approach for treatments with profound
effect on immunity
Gavin Giovannoni Barts and The London
Disclosures
I 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, Almirall, 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.
The Multiple Sclerosis Spectrum
Subclinical inflammation, demyelination, and neurodegeneration may be present for months, or even years, before a patient experiences clinical symptoms1
MRI=magnetic resonance imaging; RIS =radiologicallty-isolated syndrome; CIS=clinically-isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS R-SPMS=relapsing SPMS; NR-SPMS=non-relapsing SPMS; PPMS=primary progressive MS 1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.
MRI Events
SPMS First clinical event
Time (Years)
RRMS Subclinical disease
Inflammation
Brain volume
Axonal loss
Dise
ase
Seve
rity
NR-SPMS RRMS CIS RIS R-SPMS
PPMS
Control Multiple sclerosis
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
57%
7%
-20%
0%
20%
40%
60%
CISers n = 40
Feuillet et al. Mult Scler. 2007.
Healthy Controls n = 30
p < 0.0001
Deficits were found mainly in memory, speed of information processing, attention and executive functioning.
MSers failing ≥ 2 cognitive
tests
Cognition in early multiple sclerosis
Coles et al. J Neurol. 2006 Jan;253(1):98-108.
Post-inflammatory neurodegeneration
21-year long-term follow-up of IFNb-1b study time 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
Goodin et al Neurology. 2012 Apr 24;78(17):1315-22.
At risk: IFNB-1b 250 µg Placebo
124 123
124 120
121 117
118 109
104 88
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
65%
70%
75%
80%
85%
90%
95%
100%
0 2 4 6 8 10 12 14 16 18 20 22
Prop
ortio
n of
pat
ient
s w
ho a
re s
till a
live
Time (Years)
Occupational functioning
Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.
At what level of physical disability does unemployment occur?
Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.
Quality of life of patients with MS in Europe
Kobelt et al. J Neurol Neurosurg Psychiatry 2006;77:918–926.
The Effect of MS on Quality of Life
• 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 scores 4.0, 6.0, and 7.0, respectively3
16
*Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% CIs. Half points on EDSS are not shown on graph axis, except at EDSS score 6.5. EDSS=Expanded Disability Status Scale; EQ-5D=European Quality of Life-5 Dimensions; QoL=quality of life. 1. Adapted from Orme M et al. Value In Health. 2007;10:54-60; 2. WHO and MS International Foundation (MSIF). http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed March 6, 2012; 3. Confavreaux C et al. Brain 2003; 176:770-782. 4. Compston A, Coles A. Lancet. 2008;372:1502-1517.
Util
ity
EDSS and Utility* Show a Significant Inverse Relationship1†
Util
ity
EDSS Status
0.0 1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0 9.0 –0.4 –0.3 –0.2 –0.1
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
Theoretical model: treat early and effectively
Natural course of disease
Later intervention
Later treatment
Treatment at diagnosis Intervention
at diagnosis
Time Disease Onset
Disa
bilit
y
Escalation to Natalizumab Is More Effective Than Switching Between IFN/GA
0
25
50
75
100
% P
atie
nts
Escalate to Natalizumab, n=106 Switch Between IFN/GA, n=161
Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed. After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161). *There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. Prosperini L et al. Mult Scler. 2012;18:64-71.
No EDSS Progression
No MRI Activity
Disease Activity Free
P<0.0001 P=0.0003 P<0.0001
51 36
51
21
83 67
77 59
No Relapses
P<0.0045
Over 24 months*
18
×
Should multiple sclerosis be redefined as a dementia?
Definition of dementia
Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.
• Normal activities of daily living • Physical • Mental • Social • Occupational
• Lasting more than six months • Not present since birth • Not associated with a loss or alteration of consciousness
www.multiple-sclerosis-research.org
What is the pathological substrate of MS dementia?
11,000 to 1
Trapp, et al. NEJM 1998;338:278-85
Defining the window of opportunity to treat MS?
“The window of opportunity”
MRI=magnetic resonance imaging; RIS =radiologicallty-isolated syndrome; CIS=clinically-isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS R-SPMS=relapsing SPMS; NR-SPMS=non-relapsing SPMS; PPMS=primary progressive MS 1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.
MRI Events
SPMS First clinical event
Time (Years)
RRMS Subclinical disease
Inflammation
Brain volume
Axonal loss
Dise
ase
Seve
rity
NR-SPMS RRMS CIS RIS R-SPMS
PPMS
“The window of opportunity”
MRI=magnetic resonance imaging; RIS =radiologicallty-isolated syndrome; CIS=clinically-isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS R-SPMS=relapsing SPMS; NR-SPMS=non-relapsing SPMS; PPMS=primary progressive MS 1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.
MRI Events
SPMS First clinical event
Time (Years)
RRMS Subclinical disease
Inflammation
Brain volume
Axonal loss
Dise
ase
Seve
rity
NR-SPMS RRMS CIS RIS R-SPMS
PPMS
Choosing a treatment strategy?
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
Ian Rogers. ACNR 2007: 7(3);14.
STRATA: Patients Had Stable EDSS Scores for Up to 5 Years
*P<0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.
2.36
2.69 2.54
3.13 3.07 3.22 3.24 3.21 3.15
2.38 2.36 2.39
2.90 2.69 2.72
2.84 2.85 2.79
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
FeederStudy
Baseline
FeederStudyEnd
SafetyStudyEnd
STRATABaseline
STRATA48 Weeks
STRATA96 Weeks
STRATA144 Weeks
STRATA192 Weeks
STRATA240 Weeks
1 Year 2 Years 3 Years 4 Years 5 Years
Cessation/ Treatment Gap*
Original Placebo Original Natalizumab Original Placebo – Now on Natalizumab
Mea
n ED
SS S
core
n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393
31
WWW.MS-RES.ORG
WWW.MS-RES.ORG
CARE-MS II: Risk of Sustained Disability over Intervals of up to 1 Year
Alemtuzumab reduced the risk of disability accumulation sustained for intervals of up to 1 year vs. SC IFNB-1a
21.1 18.8
15.2 12.7
11.1 9.5
0
5
10
15
20
25
30
35
40
6-month 9-month 12-month
Prop
ortio
n of
Pat
ient
s (%
)
42% reduction p=0.0084
39% reduction p=0.0446
43% reduction p=0.0127
SAD Timeframe
SC IFNB-1a 44 µg Alemtuzumab 12 mg
Includes events with onset during 2-year core study, and confirmation in the extension. Data on file, Genzyme Corporation.
CARE-MS II
(Primary Endpoint) (Post Hoc Analyses)
Definition of dementia
Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.
• Normal activities of daily living • Physical • Mental • Social • Occupational
• Lasting more than six months • Not present since birth • Not associated with a loss or alteration of consciousness
“Multiple sclerosis is possibly a preventable dementia.”