Post on 07-May-2015
Multiple sclerosis: an unmet need
Biomarkers in MS
Gavin Giovannoni
Barts and The London
Disclosures
Professor Giovannoni 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, 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.
Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.
Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme, Merck-Serono and Novartis for making available data slides on natalizumab, alemtuzumab, oral cladribine and fingolimod for this presentation.
Why biomarkers?
• Diagnostic testing
• Positive & negative predictive testing
• Pathogenesis
• Immunology
• Aetiology
• Disease progression & recovery
• Disease heterogeneity
• Pharmacovigilance
• Monitor disease processes
• Prognosis (high vs. low risk patients)
• Monitoring effect of therapeutic interventions
Diagnostic markers
The evolving clinical definition of MS
1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by
the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y
Acad Sci 1965;122:552-68.
2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
Ann Neurol 1983;13:227-31.
3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the
International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.
4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald
Criteria". Ann Neurol 2005;58:840-6.
5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald
criteria. Ann Neurol. 2011;69:292-302.
Will Rogers Phenomenon in Multiple Sclerosis
1879 - 1935
“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”
Will Rogers Phenomenon in Multiple Sclerosis
Sormani et al. Ann Neurol 2008;64:428–433.
Poser
McDonald
Inactive CIS Active CIS RRMS
MS diagnosed according the old Poser Criteria
Inactive CIS
Less active RRMS
More Active RRMS
MS diagnosed according the New McDonald Criteria
Intrathecal synthesis of IgG
Images courtesy of Prof. Ed Thompson.
Isoelectric focusing with immunfixation
Diagnostic criteria for Primary Progressive MS
Polman et al. Ann Neurol 2005;58:840-6.
Accumulation of disability in PPMS: stratified by intrathecal IgG abnormalities
Proportion Progressing as Percent
Epoch CSF- CSF+
6 mo 7.3 9.8
12 mo 15.0 20.4
18 mo 22.8 28.1
24 mo 25.4 34.3
Years to Progression
2.43 2.26
Based on data from a second meeting of the DSMB and assume no therapeutic effect
Slide courtesy of Jerry Wolinsky
0 1 2 3 Years
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n P
rogr
essi
ng
Positive Negative
CSF
P =0.03
Not PPMS Not PPMS PPMS OCB+ve
PPMS MS diagnosed according the initial McDonald Criteria
Not PPMS
PPMS OCB-ve
PPMS OCB+ve
PPMS diagnosed according the New McDonald Criteria
Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.
Unmet need:
Evidence-based diagnostic criteria
What constitutes a useful diagnostic test or set of criteria?
TARGET DISORDER
PRESENT ABSENT
DIAGNOSTIC TEST RESULT
+ a b a + b
- c d c + d
a + c b + d a + b + c + d
From these we determine the sensitivity and specificity as follows: SENSITIVITY = a/(a+c) > 80% SPECIFICITY = d/(b+d) > 80%
Neurobiol Aging 1998; 19:109-116.
Pathological diagnosis
Dia
gno
stic
Cri
teri
a
A clinico-pathoanatomical study of multiple sclerosis diagnosis
SENSITIVITY = True+ve /(True+ve + False-ve)
Eye Department, Hvidovre Hospital, Denmark.
• Neuropathological examination of 518 consecutive patients with clinically definite MS revealed a correct diagnosis in 485 cases (94%).
• Clinical diagnosis had been established by a neurologist in all cases.
• Erroneous diagnosis included a variety of other neurological disorders.
• Also investigated was a randomly selected series of 33 patients with a clinical diagnosis of probable MS:
• post mortem confirmation of MS was obtained in circa 66%.
• The remainder the error pattern was similar to the above.
Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.
A clinico-pathoanatomical study of multiple sclerosis diagnosis.
SPECIFICITY = True-ve /(True-ve + False+ve)
~25% of cases of MS are undiagnosed in life (asymptomatic or benign cases)
Engell T. Acta Neurol Scand. 1989 May;79(5):428-30..
Potential consequences of a misdiagnosis
Potential consequences of a misdiagnosis
Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.
PML complicating treatment with natalizumab and IFNb-1a for MS
Potential fatal consequences of a misdiagnosis
TARGET DISORDER
PRESENT ABSENT
DIAGNOSTIC TEST RESULT
+ a b a + b
- c d c + d
a + c b + d a + b + c + d
What constitutes a useful diagnostic test or set of criteria?
From these we determine the sensitivity and specificity as follows: SENSITIVITY = a/(a+c) > 80% SPECIFICITY = d/(b+d) > 80% Neurobiol Aging 1998; 19:109-116.
Poser Criteria
McD
on
ald
Cri
teri
a
X Diagnostic tautology
McDonald MS
Poser MS
Response or non-response markers
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
24
Monitorin
g
Tre
atm
ent
Clin
ical
Occup &
socia
l
NAB
-ve
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
25
Monitorin
g
Tre
atm
ent
Clin
ical
Occup &
socia
l
NAB
-ve
Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis
Sorensen et al. Lancet 2003; 362: 1184–91.
Anti-natalizumab Antibodies
Number of Patients at Risk
Placebo
Antibody Negative
Transiently Positive
Persistently Positive
315
568
20
37
296
550
19
32
283
538
18
26
264
526
16
25
248
506
16
24
240
487
16
22
229
480
15
22
216
470
14
19
208
460
14
16
200
449
14
15
Weeks
0.0
0.1
0.2
0.3
0.4
0.5
0 12 24 36 48 60 72 84 96 108 120
29%
Placebo
17%
Antibody Negative
17%
Transiently Antibody Positive
34%Persistently Antibody Positive
Cu
mu
lati
ve
Pro
po
rtio
n o
f P
ati
en
ts
wit
h S
us
tain
ed
Dis
ab
ilit
y
Pro
gre
ss
ion
(E
DS
S) *,†
*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo
Number of Patients at Risk
Placebo
Antibody Negative
Transiently Positive
Persistently Positive
315
568
20
37
296
550
19
32
283
538
18
26
264
526
16
25
248
506
16
24
240
487
16
22
229
480
15
22
216
470
14
19
208
460
14
16
200
449
14
15
Weeks
0.0
0.1
0.2
0.3
0.4
0.5
0 12 24 36 48 60 72 84 96 108 120
29%
Placebo
17%
Antibody Negative
17%
Transiently Antibody Positive
34%Persistently Antibody Positive
Cu
mu
lati
ve
Pro
po
rtio
n o
f P
ati
en
ts
wit
h S
us
tain
ed
Dis
ab
ilit
y
Pro
gre
ss
ion
(E
DS
S) *,†
*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo
0.73
0.220.16
0.48*
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Ad
jus
ted
An
nu
ali
ze
d R
ela
pse
Ra
te (
95
% C
I)
Placebo
(n=315)
Antibody Negative
(n=568)
Transiently
Antibody Positive
( n=20)
Persistently
Antibody Positive
(n=37)
*p=0.009 vs. antibody-negative patients
0.73
0.220.16
0.48*
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Ad
jus
ted
An
nu
ali
ze
d R
ela
pse
Ra
te (
95
% C
I)
Placebo
(n=315)
Antibody Negative
(n=568)
Transiently
Antibody Positive
( n=20)
Persistently
Antibody Positive
(n=37)
*p=0.009 vs. antibody-negative patients
Calabresi et al, Neurol 2007
Impact of anti-natalizumab antibodies on . . . . .
Annualized relapse rate Progressive disability
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
28
Monitorin
g
Tre
atm
ent
Clin
ical
Occup &
socia
l
NAB
-ve
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 Highest Relative PML Risk
< 1 in 10,000 1 in 94 1 in 256 1 in 668 1 in 1887
Mitoxantrone
Azathioprine
Methotrexate
Cyclophosphamide
Mycophenolate
Cladribine
Rituximab
Etc.
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
30
Monitorin
g
Tre
atm
ent
Clin
ical
Occup &
socia
l
NAB
-ve
Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis
Plavina et al. ENS 2013
www.ms-res.org; >750,000 views
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
33
Monitorin
g
Tre
atm
ent
Clin
ical
Occup &
socia
l
NAB
-ve
Early Detection of PML improves clinical outcome
Dong-Si et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P04.271.
Months From PML Diagnosis
60,000
70,000
80,000
90,000
100,000
110,000
120,000
130,000
0
5
10
15
20
25A
pr-
10
Jun
-10
Au
g-10
Oct
-10
Dec
-10
Feb-
11
Ap
r-11
Jun
-11
Au
g-11
Oct
-11
Dec
-11
Feb
-12
Ap
r-12
Jun
-12
Au
g-12
Oct
-12
Dec
-12
Feb
-13
Ap
r-13
Jun
-13
Au
g-13
Oct
-13
Dec
-13
Feb
-14
Ap
r-14
Total n
um
be
r on
natalizu
mab
treatmen
t N
um
ber
of
PM
L ca
ses
pe
r m
on
th
Month
As of the 3rd April 2014 there are 454 confirmed
cases of PML
De-risking natalizumab treatment
Source: Data has been taken from Biogen-Idec’s monthly natalizumab risk/benefit and PML stratification update.
Biomarkers in the near future
Is NEDA good enough?
NEDA = no evident disease activity
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
Early or late?
37
Monitorin
g
Tre
atm
ent
Clin
ical
Occup &
socia
l
Dec 2007 Jul 2010 Jul 2013
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
The unmet need: treating-2-target
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
Rheumatoid arthritis End-stage joint disease
Control Multiple sclerosis
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy
Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions
and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials
(13,500 patients)
Sormani MP et al. Ann Neurol. 2014;75:43-49.
-1.0%
-0.8%
-0.6%
-0.4%
-0.2%
0.0% Years 0-2
-0.82%
-0.80%
P=0.822†
Placebo (N=315) Natalizumab (N=627)
Year 0-1* Year 1-2
-0.40%
-0.56%
-0.43%
-0.24%
P=0.004†
P=0.002†
†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.
AFFIRM Study: natalizumab and brain atrophy
Mea
n (
SE
) p
erc
en
tag
e c
ha
ng
e i
n B
PF
Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM
FREEDOMS, 2 years
Fingolimod 0.5 mg (n = 356)
Placebo (n = 329)
***
*
**
6 0 12 24
Time (months)
0
-0.4
-0.8
-1.2
-1.6
-2.0
−38%
vs placebo p<0.001
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
TRANSFORMS, 1 year
0 12
Time (months)
0.0
-0.4
-0.6
-1.0
IFNb-1a IM (n = 359)
Fingolimod 0.5 mg (n = 368)
−40%
vs IFNb-1a IM p<0.001
*** -0.2
-0.8
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
Reduction in brain atrophy on alemtuzumab
Alemtuzumab Improves Brain MRI Outcomes
in Patients With Active Relapsing-Remitting
Multiple Sclerosis: Three-Year Follow-up of the
CARE-MS Studies
Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5
Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8
AAN 2014
Blitz S65-008
1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal
Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering,
Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre,
Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a
Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA
CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)
Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF
For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%)
Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I)
Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II)
Med
ian
Ch
an
ge F
rom
Baselin
e,
% (
95%
CI)
Year No. of Patients 371 367 351 323
% Change from Previous Year – –0.59% –0.25% –0.19%
Med
ian
Ch
an
ge F
rom
Baselin
e,
% (
95%
CI)
Year 428 414 405 359
– –0.48% –0.22% –0.10%
No. of Patients
% Change from Previous Year
0 1 2 3
-1 .5 0
-1 .2 5
-1 .0 0
-0 .7 5
-0 .5 0
-0 .2 5
0 .0 0
0 1 2 3
-1 .5 0
-1 .2 5
-1 .0 0
-0 .7 5
-0 .5 0
-0 .2 5
0 .0 0
AAN 2014
Blitz S65-008
CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity
The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd-enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3
MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of
Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium;
MRI=magnetic resonance imaging; Y=year
No. of Patients 359 370 336 356 370 325 354 369 326
Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3
Pro
po
rtio
n o
f P
ati
en
ts,
% (
95
% C
I)
0
20
40
60
80
100
Gd-enhancing
lesion-free
New/enlarging
T2 lesion-free
MRI
activity-free
% MRI Activity Free in Treatment-Naive
Patients (CARE-MS I)
% MRI Activity Free in Patients Who
Relapsed on Prior Therapy (CARE-MS II)
No. of Patients 412 421 364 405 423 361
Gd-enhancing
lesion-free
New/enlarging MRI
activity-free
402 414 361
Pro
po
rtio
n o
f P
ati
en
ts,
% (
95
% C
I)
0
20
40
60
80
100
Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3
T2 lesion-free
Patients were treated with alemtuzumab 12 mg at baseline and 12 months later
Re-treatment in Year 3 was administered upon recurrence of disease activity
18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated
with alemtuzumab in Year 3; <3% were treated with another DMT in Year 3
AAN 2014
Blitz S65-008
CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)
Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF
For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%)
Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I)
Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II)
Med
ian
Ch
an
ge F
rom
Baselin
e,
% (
95%
CI)
Year No. of Patients 371 367 351 323
% Change from Previous Year – –0.59% –0.25% –0.19%
Med
ian
Ch
an
ge F
rom
Baselin
e,
% (
95%
CI)
Year 428 414 405 359
– –0.48% –0.22% –0.10%
No. of Patients
% Change from Previous Year
0 1 2 3
-1 .5 0
-1 .2 5
-1 .0 0
-0 .7 5
-0 .5 0
-0 .2 5
0 .0 0
0 1 2 3
-1 .5 0
-1 .2 5
-1 .0 0
-0 .7 5
-0 .5 0
-0 .2 5
0 .0 0
AAN 2014
Blitz S65-008
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
The unmet need: treating-2-target
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis
Lyke et al. J Neurol Neurosurg Psychiatry 1998;64:402–404.
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Axonal damage in R-MS is markedly reduced by Natalizumab
Gunnarsson et al. Ann Neurol 2010; Epub.
Natalizumab treatment of progressive MS reduces inflammation and tissue damage: CSF markers of axonal damage
Romme Christensen et al. ECTRIMS 2012.
Bas
elin
e
Follow-u
p
0
500
1000
1500
2000
2500
NfL
(p
g/m
l)
Cerebrospinal fluid NfL Fingolimod 0.5mg/1.25 mg versus placebo treated patients
p<0.001
Fingolimod, n=23 Placebo, n=12
p=0.470
Fingolimod 0.5 mg Fingolimod 1.25 mg
Baseline Follow-up Baseline Follow-up
Median (pg/ml)
644 321 (-50%) 886 738 (-17%)
*Non-parametric Wilcoxon matched pairs test; p value is calculated with inclusion of outliers Dr Jens Khule, ECTRIMS 2013
0
1000
2000
10000
NfL
(p
g/m
l)
Axonal damage in R-MS is markedly reduced by Natalizumab
Gunnarsson et al. Ann Neurol 2010; Epub.
Gunnarsson et al. Ann Neurol 2010; Epub.
CSF NFL
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
The unmet need: treating-2-target
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
NEDA
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 and CSF neurofilament levels be included in future definitions of NEDA?
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
Biomarkers are also needed to optimise the risks associated with the emerging therapies
Conclusions
• MS is a bad disease • Mortality, disability, unemployment, divorce, cognitive impairment, etc.
• Early highly-effective therapy is the only realistic option of preventing end-organ damage • Now an established treatment option in the EU
• NEDA (DAF) and T2T are entering the neurology lexicon
• Zero tolerance or ZeTo
• We need an acceptable working definition of an MS cure • NEDA x 15 years?
• We will need to include other biomarkers in the definition
If you want a copy of these slides you can download from www.ms-res.org
Back-up slides
Control Multiple sclerosis
Another infographic: end-organ damage
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in V
olu
me
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L)
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in V
olu
me
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L)
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MS Average
MS Upper limit
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L)
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L)
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early very
highly-effective
treatment
late very
highly-effective
treatment
-15%
Hypothetical treatment effects
Treatment-effect on atrophy correlates with treatment-effect on disability
Sormani et al. Ann Neurol 2014;75:43–49.
Coles et al. J Neurol. 2006 Jan;253(1):98-108.
Post-inflammatory neurodegeneration