TIME MATTERS Monday, 10 June 2013, 11:45–13:15 Plenary Hall, Fira Barcelona, Convention Centre Gran Via, Barcelona, Spain
Treatment decisions debate: motion for
switching to a high-efficacy therapy early
Gavin Giovannoni
London, UK
38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London
• Glatiramer acetate treatment for 3 years (good adherence and tolerance)
• Relapse with a mild left sensory loss
• Referred for a second opinion
• Switched to IFN β-1a IM; (www.msdecisions.org.uk)
• Mild persistent flu-like side effects and lymphopenia
• 12/12’s neutralizing antibodies screen negative
• Volunteers for new research programme, which included a gadolinium-enhanced MRI protocol
Teacher
38-year-old teacher with relapsing–remitting MS
• As a result of fatigue and cognitive problems she is forced to take
early retirement
• Although fully functional she develops depression and anxiety
• In her spare time she spends a lot of time on the web and becomes
an expert patient
– Widely read
– Net savvy; regular follower of www.ms-res.org
Teacher X
Unemployment
Probability of remaining actively employed after onset of MS (N = 2,538)
Time (years)
Pro
babili
ty
0.8
0.6
0.4
0.2
0.0
1.0
5 10 15 20 25 0
Control persons
MS patients
Pfleger CC, et al. Mult Scler 2010; 16:121–126.
Costs and quality of life of patients with MS in Europe
Kobelt G, et al. J Neurol Neurosurg Psychiatry 2006; 77:918–926.
Expanded Disability Status Scale score
Pro
port
ion o
f patients
≤ 6
5 y
ea
rs o
f a
ge
wo
rkin
g
80
70
60
50
40
30
20
10
0
90
2 3 4 5 6 6.5 7 8/9 0/1
Austria
Belgium
Germany
Italy
The Netherlands
Spain
Sweden
Switzerland
UK
Proportion of patients employed or on long-term sick leave (N = 13,186)
Predictors of long-term outcome in MS patients treated with IFN β-1a
IFN, interferon; IM, intramuscular; LOCF, last observation carried forward; MSCRG, Multiple Sclerosis Collaborative Research Group. Bermel RA, et al. Ann Neurol 2013; 73:95–103.
2-year participation MSCRG study: 172
Patients located: 149 (87%)
Consented and enrolled in ASSURANCE: 136 (79%)
Alive: 122 (90%)
Originally
randomized
to IM IFN β-1a:
63 (52%)
Originally
randomized
to placebo:
59 (48%)
Died (LOCF): 14 (10%)
Originally
randomized
to IM IFN β-1a:
6 (43%)
Originally
randomized
to placebo:
8 (57%)
Predictors of long-term outcome in MS patients treated with IFN β-1a
Gd+, gadolinium enhancing; IM, intramuscular. a ≥ 2 gadolinium-enhancing lesions (cumulative) ≥ 3 new T2 lesions on Year 2 MRI compared with baseline; and ≥ 2 relapses over 2 years. Bermel RA, et al. Ann Neurol 2013; 73:95–103.
IM in
terf
ero
n β
-1a
40 30 20 10 1
Pla
ce
bo
Odds ratio of advancing into the
worst quartile of EDSS change after 15 years
Disease activity
during the
2-year triala
New T2
Relapse
Gd+
New T2
Relapse
Gd+
Odds ratio
(confidence interval)
2.62 (0.93, 7.43)
1.53 (0.56, 4.19)
1.79 (0.65, 5.16)
2.89 (0.88, 9.54)
4.44 (1.43, 13.85)
8.96 (2.53, 31.65)
p value
0.069
0.408
0.284
0.080
0.010
< 0.001
Study or subgroup
Odds ratio
IV, random, 95% CI
Kinkel 2008
Prosperini 2009
Total (95% CI) 9.86 (2.33, 41.70)
MRI to monitor treatment response to IFN β: a meta-analysis
CI, confidence interval. Dobson et al. Submitted 2013.
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
Two or more new T2 lesions
100 10 1 0.1 0.01
Disease less likely Disease more likely
0.01 0.1 1 10 100
Disease less likely Disease more likely
0.01 0.1 1 10 100
Disease less likely Disease more likely
Study or subgroup
Odds ratio
IV, random, 95% CI
Kinkel 2008
Pozzilli 2005
Tomassini 2006
Total (95% CI) 3.34 (1.36, 8.22)
Study or subgroup Odds ratio
IV, random, 95% CI
Kinkel 2008
Rio 2008
Total (95% CI) 5.46 (2.48, 12.04)
One new Gd-enhancing lesion
Two or more new Gd-enhancing lesions
MRI to monitor treatment response to interferon β: a meta-analysis
CI, confidence interval; Gd, gadolinium. Dobson et al. Submitted 2013.
The relapsing MS DMT doughnut
CIS, clinically isolated syndrome; DMT, disease-modifying therapy; GA, glatiramer acetate; IFN, interferon; RIS, radiologically isolated syndrome; RRMS, relapsing–remitting MS.
Inactive RRMS
CIS
RIS or asymptomatic MS
Suboptimal responders?
Active
RRMS IFN β
or
GA
IFN β
Highly active RRMS Fingolimod Natalizumab
Predictors of long-term outcome in MS patients treated with IFN β-1a
Gd+, gadolinium enhancing; IM, intramuscular. a ≥ 2 gadolinium-enhancing lesions (cumulative) ≥ 3 new T2 lesions on Year 2 MRI compared with baseline; and ≥ 2 relapses over 2 years. Bermel RA, et al. Ann Neurol 2013; 73:95–103.
IM in
terf
ero
n β
-1a
40 30 20 10 1
Pla
ce
bo
Odds ratio of advancing into the
worst quartile of EDSS change after 15 years
Disease activity
during the
2-year triala
New T2
Relapse
Gd+
New T2
Relapse
Gd+
Odds ratio
(confidence interval)
2.62 (0.93, 7.43)
1.53 (0.56, 4.19)
1.79 (0.65, 5.16)
2.89 (0.88, 9.54)
4.44 (1.43, 13.85)
8.96 (2.53, 31.65)
p value
0.069
0.408
0.284
0.080
0.010
< 0.001
Consultant Neurologist
84%
Academic/Honorary Consultant Neurologist
14%
Associate specialist 2%
What is your position? (N = 50)
8%
26%
26%
24%
16%
Yes – routinely
Yes – frequently
Yes – occasionally
Yes – rarely
No – never
0% 5% 10% 15% 20% 25% 30%
MRI – Do you use conventional MRI to monitor for a response or non-response to DMTs? (N = 50)
Only 8% of HCPs ‘regularly’ use
conventional MRI to monitor for a
response/non-response to DMTs
Is conventional MRI used to monitor response or non-response to DMTs?
DMT, disease modifying therapy; HCP, healthcare professional.
Teacher X
Teacher X
fingolimod
natalizumab
Summary of natalizumab data vs. placebo
Polman CH, et al. N Engl J Med 2006; 354:899–910.
Study Treatment arms 2-year outcomes
AFFIRM
• N = 942
• Relapsing MS
• 18–50 years of age
• EDSS score 0–5.0
• 2-year study
1. Natalizumab 300 mg
2. Placebo
Outcome, reduction vs. placebo Natalizumab 300 mg
Annualized relapse rate 68% (p < 0.001)
New/enlarging T2 lesions 83% (p < 0.001)
Gadolinium-enhancing lesions 92% (p < 0.001)
42% relative reduction in risk
of progression (p < 0.001)
Pro
po
rtio
n o
f p
atie
nts
with
3-m
on
th
su
sta
ine
d p
rogre
ssio
n o
f d
isab
ility
29%
17%
Time (weeks)
Placebo
(n = 315)
Natalizumab
(n = 627)
120 108 96 84 72 60 48 36 24 12 0
0.4
0.3
0.2
0.1
0.0
AFFIRM: 2-year results
Summary of fingolimod data vs. placebo
ITT, intention-to-treat. a Includes patients who received both 0.5 mg and 1.25 mg fingolimod. 1. Kappos L, et al. N Engl J Med 2010; 362:387–401; 2. Kappos L, et al. AAN 2012. S41.004.
Study Treatment arms 2-year outcomes
FREEDOMS1
• N = 1,272
• RRMS
• 18–55 years of age
• EDSS score 0–5.5
• 2-year study
1. Fingolimod 0.5 mg
2. Fingolimod 1.25 mg
3. Placebo
Outcome, reduction vs. placebo Fingolimod 0.5 mg/day
Annualized relapse rate 54% (p < 0.001)
New/enlarging T2 lesions 74% (p < 0.001)
Gadolinium-enhancing lesions 82% (p < 0.001)
0 1 2 3 4 5
100
90
80
70
60 0
Time (years)
FREEDOMS extension: > 4-year results (core ITT population)2
74%
66%
Fingolimod 0.5 mg
(n = 425 core/n = 331 extension)
Placebo
(Month 0–24, n = 418)
Placebo–fingolimod switcha
(n = 300)
27% relative reduction in risk
of progression (p = 0.017)
Pa
tie
nts
fre
e o
f 3
-mo
nth
co
nfirm
ed
ED
SS
dis
ab
ility
pro
gre
ssio
n (
%)
TRANSFORMS extension study: fingolimod vs. interferon β-1a
a EOS (end of study) is the last available visit for the randomized patients between initiation and completion of the study; b Includes patients who received both 0.5 mg and 1.25 mg fingolimod; c Occurring during Year 1 on treatment; d Positive status defined as a 1-point increase on the EDSS; e Positive status if the sum of the number of new or newly enlarged T2 lesions at Month 12 compared with baseline and the number of Gd-enhanced T1 lesions at Month 12 was > 2. 1. Khatri B. et al. ENS 2012. O218; 2. Hartung HP, et al. ENS 2013. P380.
Between-group comparison of aggregate ARR
(up to 4.5 years)1
Disease activity status at end of Year 2 in patients
switched from interferon β-1a to fingolimod2
0.4
0.2
0
0.1
0.2
0.3
0.4
0.5
44.3
66
0
25
50
75
Disease activity free*(n = 296)
Year 1: IFN β-1a
Year 2: IFN β-1a–fingolimodb
*Disease activity variables: ● confirmed relapsec ● 3-month confirmed disability progressiond ● MRI activitye
AR
R
Month 0-12: IFN β-1a
Month 12-EOSa: IFN β-1a–fingolimodb
n = 341 n = 431
Pro
po
rtio
n o
f p
atie
nts
–0.6
–0.2
–1.0
–0.9
–0.8
–0.7
–0.6
–0.5
–0.4
–0.3
–0.2
–0.1
0.0
PRIMUS activities
–0.3
0
–0.5
–0.4
–0.3
–0.2
–0.1
0.0
FSS
–3.2
–0.8
–4.0
–3.5
–3.0
–2.5
–2.0
–1.5
–1.0
–0.5
0.0
BDI-II
Beneficial effect of fingolimod on fatigue and depressive symptoms
BDI-II, Beck Depression Inventory-II; CI, confidence interval; FSS, Fatigue Severity Scale; LOCF, last observation carried forward; PRIMUS, Patient-Reported Indices for Multiple Sclerosis. Higher scores indicate worse functioning, fatigue or depressive symptoms. Crayton H, et al. CMSC 2013. DX20.
Difference, 0.3
(95% CI, 0.18 to 0.51)
p < 0.001
Difference, 2.5
(95% CI, 1.50 to 3.44)
p < 0.001
Ch
an
ge
fro
m b
ase
line to
Mo
nth
6 (
LO
CF
),
lea
st squ
are
s m
ea
n
Fingolimod 0.5 mg Standard of care disease-modifying therapy
Difference, 0.4
(95% CI, –0.26 to 0.96)
p = 0.258
Activities of daily living Fatigue Depressive symptom score
Beneficial effect of fingolimod on physical and mental aspects of HRQoL
CI, confidence interval; DMT, disease-modifying therapy; HRQoL, health-related quality of life; LOCF, last observation carried forward; SF-36 Short Form (36) Health Survey v2 standard. Lower scores indicate worse quality of life. Crayton H, et al. CMSC 2013. DX20.
SF-36 summary score changes
1.7
2.2
0.4 0.4
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Physical Component Summary Mental Component Summary
Ch
an
ge
fro
m b
ase
line
to
Mo
nth
6 (
LO
CF
),
lea
st sq
ua
res m
ea
n
Difference, 1.3
(95% CI, 0.30 to 2.31)
p = 0.011
Difference, 1.7
(95% CI, 0.41 to 3.07)
p = 0.011
Fingolimod 0.5 mg Standard of care DMT
Adjuvant (n = 50)
Salvage (n = 118)
p = 0.002
Emerging concepts in MS
Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340.
NEDA; no evidence of disease activity
T2T; treat-2-target
10 9 7 6 5 4 3 2 1 0 8
0.8
0.6
0.4
0.2
0.0
1.0
Su
rviv
al
Time since radiotherapy (years)
Biochemical relapse-free survival
No evidence of disease activity
Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Treat-2-target
Should brain volume loss be included in our definition for
‘no evidence of disease activity’?
No evidence of disease activity defined as:1,2
No relapses
No sustained disability progression
No MRI activity
• No new or enlarging T2 lesions
• No Gd-enhancing lesions
Effect of natalizumab on brain paraenchymal fraction
Miller D, et al. Neurology 2007; 68:1390−1401.
0 12 24
0
0.2
0.4
0.6
0.8
1.0
Time (months)
AFFIRM: 2-year results2 M
ean r
eduction in b
rain
pare
nchym
al fr
action (
%)
P = 0.822
Natalizumab
Placebo
P = 0.002 P = 0.004
*
*
Effect of fingolimod on brain volume loss
IFN, interferon; IM, intramuscular; PBVC, percentage brain volume change. TRANSFORMS *** p < 0.001 versus interferon -1a. p value calculated using Wilcoxon rank sum test. FREEDOMS/FREEDOMS II * p < 0.05; ** p < 0.01; *** p < 0.001 versus placebo. p values calculated using rank analysis of covariance adjusted for treatment, region and baseline normalized brain volume. Cohen J, et al. AAN 2013. S51.006.
0 6 12 24
Fingolimod 0.5 mg (n = 358)
Placebo (n = 355)
0 6 12 24
Fingolimod 0.5 mg (n = 425)
Placebo (n = 418)
TRANSFORMS
–1.4
–1.2
–1.0
–0.8
–0.6
–0.4
–0.2
0.0
0 12
Fingolimod 0.5 mg (n = 429)
IFN beta-1a IM (n = 431)
FREEDOMS FREEDOMS II
**
*** *
*** *
***
***
33%
reduction
32% reduction
35% reduction
Me
an
PB
VC
fro
m b
ase
line
Months
Is it time for a paradigm shift? Early treatment with a high-efficacy therapy
Figure: http://multiple-sclerosis-research.blogspot.co.uk/2012/06/research-dmt-slow-onset-of-progression.html; Accessed 4 June 2013. Based on a review of Bergamaschi R, et al. Mult Scler 2012; Epub ahead of print.
Disability
Disease
onset
Time
Later
treatment
Treatment
at diagnosis
Intervention
at diagnosis
Later
intervention
Natural course
of disease
Treatment ladder
1st-line A
1st-line B
1st-line C
1st-line D
1st-line E
2nd-line N
2nd-line M
3rd-line Y
3rd-line X
Conclusions
MS is a bad disease
Disability (physical and cognitive)
High societal costs (unemployment,
healthcare costs, divorce)
Survival compromised
Treat early and aggressively
(TIME MATTERS)
Prognostic factors
Clinical findings, MRI activity and
other emerging biomarkers
Treatment response markers
Clinical (relapses and disability
progression)
MRI (T2 and Gd-enhancing lesions)
Neutralizing antibodies (efficacy
and safety)
Treat-2-Target
No evidence of disease activity
Concerns about using a treatment
ladder (TIME MATTERS)
No fixed treatment algorithms;
no 1st-, 2nd- or 3rd-line therapies
(TIME MATTERS)