Why treat MS early with highly effective induction therapies?
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.
early therapy
highly-effective therapy
induction therapy
Getting your ducks in a row!
+ +
Why early?
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.
STRATA: subjects 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.
1 Year 2 Years 3 Years 4 Years 5 Years
Cessation/
Treatment Gap* Original Placebo
Original Natalizumab
Original Placebo – Now on Natalizumab
Mean
ED
SS
Sco
re
n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393
6
TOP: earlier natalizumab treatment favors annualized relapse rate outcomes
7
P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior
year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor
of interest. Error bars represent 95% CIs.
DMT=disease-modifying therapy; CI=confidence interval.
Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372.
Baseline EDSS Score
<3.0 ≥3.0
Prior DMTs Used
0 1 ≥2
P<0.0001 P<0.0001
Theoretical model: treat early and effectively
Natural course of disease
Later intervention
Later treatment
Treatment at diagnosis Intervention
at diagnosis
Time Disease Onset
Dis
abili
ty
Time is brain
Does the biology of MS change with time?
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Post-inflammatory neurodegeneration
The current dogma
Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.
MRI Events
Time (Years)
Inflammation
Brain volume
Axonal loss
Dis
eas
e S
eve
rity
SPMS RRMS CIS RIS
The current paradigm: S&S
safe & slow
S&S treatment paradigm
A
B
C
D
E
N M
Y X Moderate
Efficacy
Intermediate
Efficacy
High
Efficacy
1st-line
2nd-line
3rd-line
The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study.
The exact relationship between MRI findings and the clinical status of the patient is unknown.
Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503;
Brex PA et al. N Engl J Med. 2002;346:158-164.
Baseline number of brain lesions predicts progression to EDSS Score ≥3.0
Queen Square Study
100 MSers
Who are the
responders?
~20% responders
~40% sub-optimal responders
~40% non-responders
vs.
1
2
3
Clinical
MRI
NABs
How bad is MS?
Consequences of increasing EDSS scores: loss of employment1
0
10
20
30
40
50
60
70
80
90
Work Capacity by Disability Level
0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0
EDSS Score
Pro
po
rtio
n o
f P
ati
en
ts ≤
65
Ye
ars
Old
Wo
rkin
g (
%)
The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.
1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;
2. Pfleger CC et al. Mult Scler. 2010;16:121-126.
Spain
Sweden
Switzerland
United Kingdom
Netherlands
Italy
Germany
Belgium
Austria
~10 yrs2
What about benign MS?
163 patients with “benign” MS
(disease duration >15 years and EDSS <3.5):
45% cognitive impairment
49% fatigue
54% depression
What is benign MS?
Impact of MS: cognitive functioning in the CIS stage
Feuillet et al. MSJ 2007
CIS Patients n = 40
57%
7%
-20%
0%
20%
40%
60%
Healthy Controls n = 30
p < 0.0001
Deficits were found mainly in memory, speed of information
processing, attention and executive functioning Patients failing
≥ 2 cognitive tests
Relapses don’t count!
Weinshenker et al. Brain. 1989 Dec;112 ( Pt 6):1419-28.
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.
Bermel et al. Ann Neuol 2012.
Predictors of long-term outcome in
MSers treated with interferon beta-1a
Treatment vs. Natural History
MRI activity doesn’t count!
Bermel et al. Ann Neuol 2012.
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 2013.
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 2013.
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
Including brain atrophy!
Control Multiple sclerosis
RIP
TREATMENT EFFECT ON BRAIN ATROPHY CORRELATES WITH
TREATMENT EFFECT ON DISABILITY IN MULTIPLE SCLEROSIS
Sormani et al. Ann Neurol 2013, In Press.
TREATMENT EFFECT ON BRAIN ATROPHY CORRELATES WITH
TREATMENT EFFECT ON DISABILITY IN MULTIPLE SCLEROSIS
Sormani et al. Ann Neurol 2013, In Press.
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-beta-1b trial
Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
Why highly-effective treatments?
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.
1 Year 2 Years 3 Years 4 Years 5 Years
Cessation/
Treatment Gap* Original Placebo
Original Natalizumab
Original Placebo – Now on Natalizumab
Mean
ED
SS
Sco
re
n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393
50
CAMMS2231
(completed)
CARE-MS I2
(completed)
CARE-MS II3
(completed)
Extension4,5,a
(ongoing)
Phase 2 3 3 3
Patient
population
Active RRMS,
treatment-naïve
Active RRMS,
treatment-naïve
Active RRMS,
relapsed on prior therapy
RRMS patients enrolled
into phase 2 and 3
studies
Patients, n 334 581 840 1322
Study
duration, yrs 3 2 2 4
Inclusion
criteria
EDSS ≤3
Onset ≤3 yrs
Enhancing lesion
EDSS ≤3
Onset ≤5 yrs
EDSS ≤5
Onset ≤10 yrs
CAMMS223,
CARE-MS I & II
patients
Treatment
arms
Alemtuzumab 12 mg
Alemtuzumab 24 mg
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
—
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
Alemtuzumab 24 mgb
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
(Re-treatment as needed
after 2 fixed courses)
Co-primary
outcomes
Relapse rate
Sustained accumulation of disability (SAD)
Relapse rate
SAD
Long-term safety and
efficacy outcomes
Alemtuzumab clinical development program vs. high-dose sc IFNB-1a
a Enrolling patients from all 3 studies; b Exploratory arm, discontinued enrollment early
CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; EDSS=Expanded Disability Status Scale; SC IFNB=subcutaneous
interferon beta
1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-39; 4.
Brinar V et al. ENS 2011. P912; 5. Fox E et al. AAN 2013. S41.001.
Rebif® is a registered trademark of EMD Serono, Inc.
Demographics and baseline clinical characteristics in treatment-naïve subjects
Gd=gadolinium; SD=standard deviation a Inclusion criteria included EDSS ≤3, onset of symptoms within 3 years, ≥2 relapses in the previous 2 years, and ≥1 Gd-enhancing lesion. b Inclusion criteria included EDSS ≤3, disease duration ≤ 5 years, ≥2 relapses in the previous 2 years and ≥1 relapse in the previous year;
1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Data on file, Genzyme Corporation; 3. Cohen JA et al. Lancet 2012;380:1819-28.
CAMMS2231-2,a CARE-MS I3,b Pooled CAMMS223 and
CARE-MS I1-3
SC IFNB-1a
44 μg
N=111
Alemtuzumab
12 mg
N=112
SC IFNB-1a
44 μg
N=187
Alemtuzumab
12 mg
N=376
SC IFNB-1a
44 μg
N=294
Alemtuzumab
12 mg
N=483
Age, years mean (SD) 32.8 (8.8) 31.9 (8.0) 33.2 (8.5) 33.0 (8.0) 33.1 (8.6) 32.9 (8.0)
Gender, % female 64 64 65 65 65 65
Time since first relapse,
years, mean (SD) 1.6 (1.0) 1.4 (0.84) 2.0 (1.3) 2.1 (1.4) 1.8 (1.2) 1.9 (1.3)
EDSS, mean (SD) 1.9 (0.8) 1.9 (0.7) 2.0 (0.8) 2.0 (0.8) 1.9 (0.8) 2.0 (0.8)
No. of relapses in prior year,
mean (SD) 1.6 (0.8) 1.7 (0.9) 1.8 (0.8) 1.8 (0.8) 1.8 (0.8) 1.8 (0.8)
Patients with Gd-enhancing
lesions,% 100 100 51 46 69.7 58.6
1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28.
Alemtuzumab significantly reduces annualized relapse rate vs. SC IFNB-1a in treatment-naïve subjects
0.39
0.18
0
0.1
0.2
0.3
0.4
0.5
0.6
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
54.9% Risk reduction vs.
SC IFNB-1a
p<0.0001
An
nu
ali
ze
d R
ela
pse
Rate
N=187 N=376
CARE-MS I
(Co-primary endpoint)2
0.36
0.11
0
0.1
0.2
0.3
0.4
0.5
0.6
CAMMS223
(Co-primary endpoint)1
An
nu
ali
ze
d R
ela
pse
Rate
69% Risk reduction
vs. SC IFNB-1a
p<0.001
N=111 N=112
53
a CARE-MS I and CAMMS223 pooled data; b Sustained accumulation of disability (SAD) is defined as a ≥1 point increase in Expanded Disability
Status Scale (EDSS) lasting ≥6 months (or ≥1.5 point increase if baseline EDSS=0).
1. Cohen JA et al. Lancet 2012;380:1819-28; 2. Data on file, Genzyme Corporation.
Alemtuzumab reduces the risk of 6-month sustained accumulation of disability in treatment-naïve subjects
Pa
tie
nts
wit
h S
AD
(%
)
50% Risk reduction
vs. SC IFNB-1a
p=0.0029 13.9%
7.1%
30% Risk reduction
vs. SC IFNB-1a
p=0.22
Pa
tie
nts
wit
h S
AD
(%
)
25
15
10
5
0
20
0 3 6 9 12 15 18 21 24
8.0%
11.1%
SC IFNB-1a 44 μg
Alemtuzumab 12 mg
SC IFNB-1a 44 μg
Alemtuzumab 12 mg
Treatment-naïve: CARE-MS I1
(Co-primary Endpoint)
Pooled Treatment-naïve2,a
(Post Hoc Analysis)
Follow-up Month Follow-up Month
25
15
10
5
0
20
0 3 6 9 12 15 18 21 24
54
Treatment-naïve subjects are more Likely to be disease activity-free with alemtuzumab vs. sc IFNB-1a
CDA-freea MRI Activity-freeb MS Disease Activity-
freec
p<0.0001
p=0.0388
OR=1.75 p=0.0064
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
aClinical disease activity (CDA)-free: Absence of relapse or SAD; bMRI activity-free: absence of new Gd-enhancing lesion or new or enlarging T2
hyperintense lesion; cMS disease activity-free: Absence of CDA or MRI activity.
OR=odds ratio;
1. Giovannoni G et al. ENS 2012; 2. Cohen JA et al. Lancet 2012;380:1819-28.
Treatment-naïve: CARE-MS I1,2
(Tertiary Endpoints)
Pooled treatment-naïve
(CAMMS223 and CARE-MS I)
N=4831-3
Patients Who Relapsed on Prior
Therapy (CARE-MS II)
N=4264
Age, years
Mean (SD) 32.9 (8.03)
34.8 (8.4)
Gender
Female, %
64.6
66.0
Years since initial episode
Mean (SD)
1.9 (1.30)
4.5 (2.7)
EDSS
Mean (SD)
2.0 (0.80)
2.7 (1.3)
No. of relapses in prior year
Mean (SD)
1.8 (0.80)
1.7 (0.86)
Prior therapy, %
SC IFNB-1a (22 or 44 μg)
IM IFNB-1a
SC IFNB-1b
Glatiramer acetate
Natalizumab
34
28
36
34
4
Patients with Gd-enhancing
lesions, % 58.6 42.4
Baseline demographics and clinical characteristics of alemtuzumab-treated subjects
1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Data on file, Genzyme Corporation; 3. Cohen JA et al. Lancet 2012;380:1819-28; 4. Coles AJ
et al. Lancet 2012;380(9856):1829-39.
Alemtuzumab significantly reduced clinical disease activity in subjects who relapsed on prior therapy
aSix-month SAD defined as EDSS score increase ≥1.0 point for ≥6 months (or ≥1.5 points when baseline EDSS = 0); bNumber of events among
patients who received prior natalizumab is too small to draw meaningful conclusions.
CI=confidence interval; HR=hazard ratio
1. Coles AJ et al. Lancet 2012;380:1829-39; 2. Freedman MS et al. AAN 2013, P07.111.
ARR Years 0–2: CARE-MS II1
(Co-primary Endpoint)
Alemtuzumab 12
mg
(n=426)
SC IFNB-1a
44 µg
(n=202)
Risk reduction: 49.4%
p<0.0001 21.1%
12.7%
HR: 0.58
42% Risk reduction
p=0.0084
6-Month Sustained Accumulation of
Disability: CARE-MS II
(Co-primary Endpoint)
57
Subjects who relapsed on prior therapy were more likely to be disease activity-free with alemtuzumab vs. sc IFNB-1a
Clinical disease activity-free: absence of relapse or SAD; MRI activity-free: absence of new Gd-enhancing lesion or new or enlarging T2 hyperintense
lesions; MS disease activity-free: absence of clinical disease activity and MRI activity; SAD: Increase of ≥1.0 EDSS point for ≥6 months (or ≥1.5 points if
baseline EDSS = 0).
SC IFNB-1a=subcutaneous interferon beta-1a
1. Hartung HP et al AAN 2013; P07.093; 2. Coles AJ et al. Lancet 2012;380:1829-39.
OR=3.03
p<0.0001
p<0.0001 p<0.0001
Relapsed on Prior Therapy: CARE-MS II
(Tertiary Endpoints)1,2
Alemtuzumab improved pre-existing disability vs. sc IFNB-1a in subjects who relapsed on prior therapy
HR: 2.57
p=0.0002
HR: 3.02
p=0.0003
HR: 3.00
p=0.0001
SRD Timeframeb
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
a SRD defined as a reduction from baselilne of ≥1 EDSS point for ≥6, 9, OR 12 months; assessed in patients with baseline EDSS score ≥ 2. b Includes events that initiated in the core studies and continued into the extension.
1. Coles AJ et al. Lancet 2012;380:1829-39 ; 2. Data on file, Genzyme Corporation.
Sustained Reduction of Disabilitya
Relapsed on Prior Therapy: CARE-MS II1,2
(Tertiary Endpoint) (Post Hoc Analyses)
CARE-MS extension study designed to evaluate long-term outcomes with alemtuzumab
Received SC IFNB-1a
Extension Study (Safety & Efficacy Follow-up)
May receive optional re-treatment course(s)
not sooner than 12 months after the
previous course
No
Yes
Administer 2 annual
alemtuzumab treatment courses
Relapse or 2 active
MRI lesions?
Monitor for MS activity through extension trial
Month 48
Received alemtuzumab
(Month 0 and 12)
CARE-MS I or II
Pivotal Studies
Fox E et al. AAN 2013, S41.001.
Extension study treatments used alemtuzumab 12 mg IV
~80% of patients did not receive re-treatment or other DMT during Year 3
<2% of patients received another DMT during Year 3
CARE-MS extension: majority of subjects treated with alemtuzumab remain relapse-free at year 3
Fox E et al. AAN 2013, S41.001.
Treatment-naïve
(CARE-MS I)
Relapsed on Prior Therapy
(CARE-MS II)
Relapse-free Patients
%P
ati
en
ts
N=376 N=349 N=425 N=387
CARE-MS extension: majority of subjects experience further benefits on disability through year 3
Relapsed on Prior Treatment
(CARE-MS II)
EDSS change (baseline to Year 2)
Data shown are for alemtuzumab 12-mg groups.
Hartung HP et al. ECTRIMS 2013, P592.
Remained stable Years 2-3
Improved Years 2-3
Yr-1 Yr-2 Yr-3 Yr-1 Yr-2 Yr-3
Summary of safety in clinical study population 2-year controlled experience
Treatment-naïve Patients1,a Relapsed on Prior Therapy2
SC IFNB-1a
(N=294)
(%)
Alemtuzumab
12 mg
(N=483)
(%)
SC IFNB-1a
(N=202)
(%)
Alemtuzumab
12 mg
(N=435)
(%)
AEs 94.6 96.7 94.6 98.4
SAEs 16.0 17.1 21.8 19.5
Identified risks
IARs — 91.7 — 90.3
Thyroid disorders 5.4 17.4 5.0 15.9
ITP3,4 0 1.0 0 0.9
Glomerulonephritis 0 0 0 0.2
Serious infections 0.7 1.9 1.5 3.7
aData pooled for CAMMS223 and CARE-MS I studies.
1. Data on File. Genzyme Corporation; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3.Coles AJ et al. Lancet 2012;380:1829-39; 4. Fox E et al. AAN
2013, S41.001.
Alemtuzumab summary of safety
Well-characterized safety and tolerability profile across alemtuzumab
clinical development program1-3
– Most common adverse events were mild/moderate infusion reactions,
which were manageable with appropriate pre-medication and/or treatment,
and patient education1-3
– Low rates of serious infection, consistent with relative sparing of both
innate immune cells and specific lymphocyte subpopulations1,2
– Autoimmune adverse events, including thyroid-related events, ITP, and
nephropathies, were detected with safety monitoring program and
generally responded to conventional therapy1-3
Incorporation of proactive risk-minimization procedures into clinical
trials allowed for early detection and management of identified risks1-3
– Clinical trial experience has informed the Risk Mitigation Plan for
alemtuzumab in the EU
1. Cohen JA et al. Lancet 2012;380:1819-28; 2. Coles AJ et al. Lancet 2012;380:1829-39; 3. Fox E et al. AAN 2013, S41.001.
Summary of recommended risk mitigation strategies for alemtuzumab in the EU
Identified Risks Mitigation Strategies Timing
Infusion-associated
reactions (IARs)
Corticosteroids Immediately prior to
alemtuzumab administration
On each of the first 3 days of
any treatment course
Antihistamines and/or
antipyretics (optional)
Prior to alemtuzumab
administration
Serious infections Oral prophylaxis for herpes
infection
Starting on the first day of
each treatment course
Continuing for a minimum of
1 month following treatment
with alemtuzumab
HPV screening Annually for female patients
Active or inactive (“latent”)
tuberculosis infection
evaluation
Before initiation of therapy
Immune
thrombocytopenia
(ITP) and other
cytopenias
Complete blood count with
differential
Prior to initiating
alemtuzumab treatment
Monthly until 48 months after
last infusion.a
Nephropathies,
including anti-GBM
disease
Serum creatinine Prior to initiating
alemtuzumab treatment Monthly until 48 months after
last infusiona
Urinalysis with microscopy Prior to initiating
alemtuzumab treatment Monthly until 48 months after
last infusiona
Thyroid disorders Thyroid function tests (such as
TSH) Prior to initiating
alemtuzumab treatment Every 3 months until 48
months after last infusiona
aAfter 48 months, testing should be performed based on clinical findings suggestive of the adverse event.
LEMTRADA EU Summary of Product Characteristics, September 2013.
What is your treatment philosophy?
survival analysis
“hard and early ”
What is your treatment philosophy? maintenance-escalation vs. induction
survival analysis
“hard and early ”
MS is an autoimmune disease hypothesis
15-20 year experiment
What is your treatment philosophy? maintenance-escalation vs. induction
Another example: treat early and effectively
Emerging concepts in MS
Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340.
NEDD – no evidence of detectable disease (oncology)
NEDA - no evidence of disease activity (msologoy)
DAF – disease activity free
T2T; treat-2-target (rheumatology)
10 9 7 6 5 4 3 2 1 0 8
0.8
0.6
0.4
0.2
0.0
1.0
Adjuvant (n = 50)
Salvage (n = 118)
p = 0.002
Su
rviv
al
Time since radiotherapy (years)
Biochemical relapse-free survival
ZeTo; zero tolerance
No evidence of disease activity: 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 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
T2T - NEDA
Zero Tolerance
Functional
Improvement
Maintain reserve
capacity
Treatment objectives in relapsing MS
Freedom from
disease
activity/disease
activity free
Reduced ongoing
damage
CNS Repair
Healthy
ageing
Improved Quality of Life
Treat Early
73
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?
74
Mo
nito
rin
g
Tre
atm
en
t C
linic
al
Occu
p &
so
cia
l
What does the future hold?
75
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
2001 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
mo
nit
ori
ng
trea
tmen
t cl
inic
al
Occ
up
. & s
oci
al
JCV
high positive
Final
year of
school
University
Pregnancy Old
Age
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?
Mo
nito
rin
g
Tre
atm
en
t C
linic
al
Occu
p &
so
cia
l
Dec 2007 Jul 2010 Jul 2013
Maintenance vs. Induction
Maintenance therapies
• Continuous treatment
• Low to very high efficacy
• Reversible
• Perceived to be lower risk
• Examples • Laquinimod, GA, IFN-beta, teriflunomide, BG12,
fingolimod, natalizumab, daclizumab
• Breakthrough disease • Suboptimal or failure to respond
• NEDA reliable metric for efficacy
• Rebound activity • Highly likely
• Can be life threatening
• Pregnancy • Contra-indicated
• No potential for a cure • Rebound
• SPMS & progressive brain atrophy
Induction therapies
• Short-courses or pulsed therapy
• Very high efficacy
• Irreversible
• Perceived to be higher risk
• Examples • Mitoxantrone, cladribine, alemtuzumab, anti-
CD20 (?), BMT
• Breakthrough disease • Marker for retreatment
• NEDA unreliable to assess efficacy
• Rebound activity • Less likely
• Unlikely to be life-threatening
• Pregnancy • Strategy of choice
• Potentially curative • 15-20 year experiment
• BMT, alemtuzumab, cladribine
Who should decide?
WWW.MS-RES.ORG
WWW.MS-RES.ORG
Case studies
Ian Rogers. ACNR 2007: 7(3);14.
Conclusions • MS is a bad disease
• Mortality, disability, unemployment, divorce, cognitive impairment, etc.
• Early highly-effective treatment is the only realistic option of offering a cure
• Now an established treatment option, which has become safer
• NEDA, T2T and DAF are entering the neurology lexicon
• Zero tolerance or ZeTo
• We need an acceptable working definition of an MS cure
• NEDA x 15 years?
• Induction therapies (alemtuzumab, cladribine)
• Improved risk mitigation tools
• Is it fair to make MSers wait 20 years for the outcome of an ongoing experiment?
• Alemtuzumab, BMT, natalizumab, cladribine extension studies
early therapy
highly-effective therapy
induction therapy
Any questions?
+ +
ZeTo – zero tolerance
Treat-2-Target proposed NEDA treatment algorithm for relapsing MS
NEDA=no evidence of disease activity.
A
B
C
D
E N
M
Y X Moderate
Efficacy
Intermediate
Efficacy
High
Efficacy
FTY Efficacy
Ris
ks
+
+ -
-
IFNb
GA
BMT
Mx
Nz
Alemz
? CD20
Lq
BG12
? Dac
Teri
Nz
Clad