This presentation by Gavin Giovannoni looks at the new treatment paradigm for MS. It includes: arguments for early treatment in multiple sclerosis, the effect of MS on quality of life and whether highly-effective treatments stabilise MS. It was presented at the MS Trust Annual Conference in November 2013.

1. The new treatment paradigm for MS:
treat-2-target of NEDA
Zero Tolerance = ZeTo
Gavin Giovannoni
Barts and The London

2. 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 and Merck-Serono for making available data slides on natalizumab,
alemtuzumab and oral cladribine for this presentation.

3. Who should decide?

4. WWW.MS-RES.ORG

5. WWW.MS-RES.ORG

6. RRMS
Active MS
Clinical
or
MRI

7. What are the arguments for early
treatment?

8. 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
IFNB-1b 250 µg
Placebo
HR=0.532 (95% CI: 0.314–0.902)
46.8% reduction in hazard ratio
Log rank, P=0.0173
At risk:
IFNB-1b 250 µg
Placebo
124
123
124
120
121
117
118
109
104
88
Goodin et al Neurology. 2012 Apr 24;78(17):1315-22.

9. Post-inflammatory neurodegeneration
Coles et al. J Neurol. 2006 Jan;253(1):98-108..

10. Theoretical model: treat early and effectively
Time is brain
Natural course
of disease
Disability
Later
treatment
Treatment
at diagnosis
Disease
Onset
Later
intervention
Intervention
at diagnosis
Time

11. How bad is MS?

13. Untreated MS is a devastating disease
Cognitive Dysfunction
•Prevalence: 43% to 65%1,2
•Affects employment, activities
of daily living,
and social functioning2
Life Shortening
•5- to 11-year decrease in
life expectancy3-7
•2- to 7-fold increase in suicide
risk5,8
•∼50% MS patients die of
disease-related causes5,6,8
QOL
QOL
EDSS and utility* have shown a
EDSS and utility* have shown a
significant inverse relationship99
significant inverse relationship
MS has a negative
MS has a negative
impact on…
impact on…
Healthcare costs
Healthcare costs
Bulk of cost attributed to services
Bulk of cost attributed to services
(28.5%) and long-term sick leave and
(28.5%) and long-term sick leave and
early retirement (30%)§,14
early retirement (30%)§,14
Mortality
Mortality
Mortality ratio of patients with MS
Mortality ratio of patients with MS
exceeds CV disease,†,10 stroke,‡,11 and
exceeds CV disease,†,10 stroke,‡,11 and
early breast cancer12
early breast cancer12
Employment
Employment
∼50% of patients with MS are
∼50% of patients with MS are
unemployed as of EDSS 3.0 and/or
unemployed as of EDSS 3.0 and/or
after 10 years from diagnosis13
after 10 years from diagnosis13
Relationships
Relationships
Compared with general population, patients
Compared with general population, patients
with MS have a higher probability of
with MS have a higher probability of
separating/divorcing and doing so sooner13
separating/divorcing and doing so sooner13
*In this study, utility measures were derived from EQ-5D using the EuroQoL instrument;
†
in patients with type 2 diabetes; ‡in patients with valvular heart disease in Olmsted County,
Minnesota; §MS patients with EDSS ≥6.
EDSS=Expanded Disability Status Scale; QOL=quality of life; CV=cardiovascular;
EQ-5D=European Quality of Life-5 Dimensions.
1. Rao SM et al. Neurology. 1991;41:685-691; 2. Rao SM et al. Neurology. 1991;41:692-696; 3. Sadovnick AD et al. Neurology. 1992;42:991-994;
4. Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71:16-19; 5. Torkildsen G et al. Mult Scler. 2008;14:1191-1198; 6. Smestad C et al. Mult Scler.
2009;15:1263-1270; 7. Kingwell E et al. J Neurol Neurosurg Psychiatry. 2012;83:61-66; 8. Sadovnick AD et al. Neurology. 1991;41:1193-1196;
9. Orme M et al. Value Heath. 2007;10:54-60; 10. De Marco R et al. Diabetes Care. 1999;22:756-761; 11. Petty DW et al. Mayo Clin Proc.
2005;80:1001-1008; 12. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 13. Pfleger CC et al. Mult Scler. 2010;16:121-126;
14. Beg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.

14. Consequences of Increasing EDSS Scores:
Loss of Employment1
Proportion of Patients ≤65 Years Old
Working (%)
Work Capacity by Disability Level
Austria
Belgium
Germany
Italy
Netherlands
Spain
Sweden
Switzerland
United Kingdom
90
80
70
60
50
40
30
~10 yrs2
20
10
0
0.0/1.0 2.0
3.0
4.0
5.0
6.0
6.5
7.0 8.0/9.0
EDSS Score
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.
14
14

15. The effect of MS on quality of life
a
EDSS and utility show a significant inverse relationship
1,b
Utility
• 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 4, 6, and 7, respectively3
EDSS Status
Utility measures are derived from EQ-5D using the EuroQoL instrument.
Error bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis,
except at EDSS 6.5.
a
b
1. Adapted from Orme M et al. Value In Health. 2007;10:54-60. 2. WHO and MSIF. http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1
15
&codcol=15&codcch=747. Accessed October 6, 2010. 3. Confavreaux, Compston. 2005. 4. Compston A, Coles A. Lancet 2008

16. What about benign MS?

17. What prognostic group does the Mser fall Into?
Good Prognosis:
Poor Prognosis:
•Younger age at onset1,2
•Older age of onset1,2
•Female sex1-3
•Male sex1-3
•Optic neuritis4
•“Multifocal” onset4
•Isolated sensory symptoms4
•Efferent systems affected (motor,
cerebellar, bladder)4
•Complete recovery from first attack5
•Long interval to second relapse
4
•No disability after 5 years4
•Normal MRI / low lesion load4
•CSF negative for oligoclonal bands2,6
•Incomplete recovery from first
attack5
•High relapse rate in the first 2–5
years4
•Substantial disability after 5 years4
•Abnormal MRI with large lesion
load4
•CSF positive for oligoclonal bands2,6
CSF=cerebrospinal fluid
1. Scalfari A et al. J Neurol Neurosurg Pschiatry 2013;00:1-9; 2. Fernandez O. J Neurol Sci 2013;331:10-3; 3. Damasceno A et al. J Neurol Sci
2013;324:29-33; 4. Miller D et al. Lancet Neurol 2005:4;281-8; 5. Confavreux C et al. Brain 2003;126:770-82; 6. Villar LM et al. J Clin Invest
2005;115:187-94.
17

18. Baseline Number of Brain Lesions
Predicts Progression to EDSS Score ≥3.0
Queen Square Study
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.

19. What is benign MS?
163 patients with “benign” MS
(disease duration >15 years and EDSS <3.5):
45% cognitive impairment
49% fatigue
54% depression

20. Impact of MS: cognitive functioning in the
CIS stage
Cognitive test performance in an exploratory study*
60%
Patients
failing ≥ 2
cognitive
tests
40%
57%
20%
Deficits were found mainly in
memory, speed of information
processing, attention and
executive functioning
7%
0%
p < 0.0001
-20%
CIS Patients
n = 40
20
Healthy Controls
n = 30
Feuillet et al. Mult Scler. 2007.

21. Theoretical model: treat early and effectively
Time is brain
Natural course
of disease
Disability
Later
treatment
Treatment
at diagnosis
Disease
Onset
Later
intervention
Intervention
at diagnosis
Time

22. Is there any other evidence?

23. 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.

24. % Risk Relative to Low Exposure
Establishing long-term efficacy: use of recursive partitioning
and propensity score adjustment to estimate outcome in MS
100
Long-term follow-up 16 years
IFN-beta exposure 80% vs. 20%
80
60
40
20
0
Any Negative
EDSS=6
SPMS
Wheelchair
Goodin et al. PLoS One. 2011;6(11):e22444.

25. STRATA: Patients Had Stable EDSS Scores for up to 5 years
Cessation/
Treatment Gap*
Original Placebo
Original Natalizumab
Mean EDSS Score
Original Placebo – Now on Natalizumab
n = 380 707
381 707
280 552
385 709
274 569
1 Year
*P<0.0001
Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.
25
230 479
205 462
194 427
2 Years
3 Years
4 Years
174 393
5 Years

26. TOP: Earlier Natalizumab Treatment Favors
Annualized Relapse Rate Outcomes
P<0.0001
P<0.0001
<3.0
≥3.0
0
Baseline EDSS Score
1
≥2
Prior DMTs Used
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.
26

27. Mean Annualized Relapse Rate
TOP: Earlier Natalizumab Treatment Favors
Annualized Relapse Rate Outcomes
0.50
P<0.0001
0.40
0.45
0.40
0.35
P<0.0001
0.30
0.25
0.24
0.23
0.16
0.28
0.18
0.20
0.15
0.10
0.05
0.00
0 DMT
1 DMT
0 DMT
≥2 DMTs
1 DMT
≥2 DMTs
≥2 Relapses
1 Relapse
Baseline Relapse and Treatment History
P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0vs ≥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 are 95% CIs.
Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain. P372.
27

28. The current paradigm is safe and slow!

29. 100 MSers
Who are the
responders?

30. ~20% responders
~40% sub-optimal responders
~40% non-responders

31. 1
Clinical
vs.
2
MRI
3
NABs

32. Relapses don’t count!

33. Weinshenker et al. Brain. 1989 Dec;112 ( Pt 6):1419-28.

34. Relapse on IFNβ Therapy Increases Risk of
Sustained Disability Progression
HR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 or
More Relapses During the First 2 Years of IFN Treatment
HR
No relapses (reference=1)
SE
P Value
95% CI
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
EDSS Progression
Survival Probability
1.00
No Relapses
One Relapse
Two or More Relapses
0.75
0.50
0.25
HR=hazard ratio; SE=standard error
0
0
20
40
60
Analysis Time (Months)
80
Bosca et al. Mult Scler. 2008;14:636-639.

35. Relapses and residual deficits
Lublin FD et al. Neurology. 2003;61:1528-1532.

36. Predictors of long-term outcome in
MSers treated with interferon beta-1a
Bermel et al. Ann Neuol 2012.

37. Predictors of long-term outcome in
MSers treated with interferon beta-a
Bermel et al. Ann Neuol 2012.

38. Predictors of long-term outcome in
MSers treated with interferon beta-1a
Treatment vs. Natural History
Bermel et al. Ann Neuol 2012.

39. MRI activity doesn’t count!

40. Predictors of long-term outcome in
MSers treated with interferon beta-1a
Bermel et al. Ann Neuol 2012.

41. MRI to monitor treatment response to IFNβ: a meta-analysis
One New T2 Lesion
Study or Subgroup
Kinkel 2008
Pozzilli 2005
Prosperini 2009
Sormani 2011
Total (95% CI) 2.69 (0.72, 10.04)
0.01
Odds Ratio
IV, Random, 95% CI
0.1
1
10
Disease Less Likely Disease More Likely
100
Two or More New T2 Lesions
Study or Subgroup
Kinkel 2008
Prosperini 2009
Total (95% CI) 9.86 (2.33, 41.70)
Odds Ratio
IV, Random, 95% CI
0.01
0.1
1
10
100
Favors Experimental Favors Control
Dobson et al. Submitted 2013.

42. MRI to monitor treatment response to IFNβ: a meta-analysis
One New Gd+ Lesion
Odds Ratio
IV, Random, 95% CI
Study or Subgroup
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
Two or More New Gd+ Lesions
Odds Ratio
IV, Random, 95% CI
Study or Subgroup
Kinkel 2008
Rio 2008
Total (95% CI) 5.46 (2.48, 12.04)
0.01
0.1
Disease Less Likely
1
10
100
Disease More Likely
Dobson et al. Submitted 2013.

43. Disease progression doesn’t count!

44. 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
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)
Group
*EDSS score ≥6.0 or increase in at least 3 EDSS steps.
Río J et al. Ann Neurol. 2006;59:344-352.

45. 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.

46. Do highly-effective treatments stabilise
MS?

47. STRATA: Patients Had Stable EDSS Scores for up to 5 years
Cessation/
Treatment Gap*
Original Placebo
Original Natalizumab
Mean EDSS Score
Original Placebo – Now on Natalizumab
n = 380 707
381 707
280 552
385 709
274 569
1 Year
*P<0.0001
Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.
47
230 479
205 462
194 427
2 Years
3 Years
4 Years
174 393
5 Years

48. Alemtuzumab Clinical Development Program vs. High-dose SC IFNB-1a
CAMMS2231
(completed)
CARE-MS I2
(completed)
CARE-MS II3
(completed)
Extension4,5,a
(ongoing)
2
3
3
3
Active RRMS,
treatment-naïve
Active RRMS,
treatment-naïve
Active RRMS,
relapsed on prior therapy
RRMS patients enrolled
into phase 2 and 3
studies
334
581
840
1322
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)
Relapse rate
SAD
Long-term safety and
efficacy outcomes
Phase
Patient
population
Patients, n
Study
duration, yrs
Co-primary
outcomes
Relapse rate
Sustained accumulation of disability (SAD)
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.
a
48

49. Demographics and Baseline Clinical Characteristics in
Treatment-naïve Patients
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
32.8 (8.8)
31.9 (8.0)
33.2 (8.5)
33.0 (8.0)
33.1 (8.6)
32.9 (8.0)
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
Age, years mean (SD)
Gender, % female
• CARE-MS I and CAMMS223 were pooled to increase the sample size for
subpopulation analyses
−
Similar study designs, eligibility rules, baseline demographic characteristics, assessment
schedules, and definitions of the co-primary efficacy endpoints
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.
49

50. Alemtuzumab Significantly Reduced Annualized Relapse Rate vs.
SC IFNB-1a in Treatment-naïve Patients
Annualized Relapse Rate
0.6
69% Risk reduction
vs. SC IFNB-1a
p<0.001
0.5
0.4
0.3
0.36
0.2
0.1
0
0.11
N=111
N=112
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
Annualized Relapse Rate
CAMMS223
(Co-primary endpoint)1
0.6
CARE-MS I
(Co-primary endpoint)2
54.9% Risk reduction
vs. SC IFNB-1a
p<0.0001
0.5
0.4
0.39
0.3
0.2
0.18
0.1
0
N=187
N=376
• Alemtuzumab provided superior reduction in annualized relapse rate:
– 69% reduction beyond SC IFNB-1a at 3 years in CAMMS2231
– ~55% reduction beyond SC IFNB-1a at 2 years in CARE-MS I2
1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28.
50

51. Alemtuzumab Reduced the Risk of 6-month Sustained
Accumulation of Disability in Treatment-naïve Patients
Treatment-naïve: CARE-MS I1
(Co-primary Endpoint)
25
20
30% Risk reduction
vs. SC IFNB-1a
p=0.22
15
11.1%
SC IFNB-1a 44 μg
10
8.0%
5
Alemtuzumab 12 mg
Patients with SAD (%)
Patients with SAD (%)
25
Pooled Treatment-naïve2,a
(Post Hoc Analysis)
20
50% Risk reduction
vs. SC IFNB-1a
p=0.0029
15
13.9%
SC IFNB-1a 44 μg
10
7.1%
5
Alemtuzumab 12 mg
0
0
0
3
6
9
12
15
18
Follow-up Month
21
24
0
3
6
9
12 15 18
Follow-up Month
21
24
• In CARE-MS I, fewer SC IFNB-1a patients accumulated disability than expected, which
may have reduced the ability to detect a significant treatment effect1
• In a pooled analysis of treatment-naïve patients, alemtuzumab reduced risk of 6-month
SADb by 50% vs. SC IFNB-1a2
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.
a
51

52. Treatment-naïve Patients Were More Likely to be Disease ActivityFree with Alemtuzumab vs. SC IFNB-1a
Treatment-naïve: CARE-MS I1,2
(Tertiary Endpoints)
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
p<0.0001
p=0.0388
OR=1.75
p=0.0064
CDA-freea
MRI Activity-freeb
MS Disease Activityfreec
• Alemtuzumab-treated patients were ~2 times more likely to be free of overall MS
disease activity compared with SC IFNB-1a–treated patients over 2 years1,2
Clinical disease activity (CDA)-free: Absence of relapse or SAD; bMRI activity-free: absence of new Gd-enhancing lesion or new or enlarging T 2
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.
a
52

53. Baseline Demographics and Clinical Characteristics of
Alemtuzumab-treated Patients
Pooled treatment-naïve
(CAMMS223 and CARE-MS I)
N=4831-3
Age, years
Mean (SD)
Gender
Female, %
32.9 (8.03)
Patients Who Relapsed on Prior
Therapy (CARE-MS II)
N=4264
34.8 (8.4)
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)
−
34
28
36
34
4
58.6
42.4
Prior therapy, %
SC IFNB-1a (22 or 44 μg)
IM IFNB-1a
SC IFNB-1b
Glatiramer acetate
Natalizumab
Patients with Gd-enhancing lesions,
%
• As expected, baseline EDSS and duration of disease were higher for patients who
relapsed on prior compared with treatment-naïve patients
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.
53

54. Alemtuzumab Significantly Reduced Clinical Disease Activity in
Patients Who Relapsed on Prior Therapy
ARR Years 0–2: CARE-MS II1
(Co-primary Endpoint)
Risk reduction: 49.4%
p<0.0001
6-Month Sustained Accumulation of
Disability: CARE-MS II
(Co-primary Endpoint)
HR: 0.58
42% Risk reduction
p=0.0084
21.1%
12.7%
SC IFNB-1a Alemtuzumab
44 µg
12 mg
(n=202)
(n=426)
• Alemtuzumab significantly reduced relapse rate and risk of 6-month SADa by an additional
49.4% and 42% beyond SC IFNB-1a, respectively, in patients who relapsed on prior
therapy1
• Benefits on clinical disease activity were similar regardless of type, duration, or number of
prior treatments2,b
Six-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.
a
54

55. Patients Who Relapsed on Prior Therapy Were More Likely to Be
Disease Activity-free with Alemtuzumab vs. SC IFNB-1a
Relapsed on Prior Therapy: CARE-MS II
(Tertiary Endpoints)1,2
p<0.0001
p<0.0001
OR=3.03
p<0.0001
• Alemtuzumab-treated patients were 3 times more likely to be free of overall
MS disease activity compared with SC IFNB-1a–treated patients over 2 years
Clinical disease activity-free: absence of relapse or SAD; MRI activity-free: absence of new Gd-enhancing lesion or new or enlarging T 2 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.
55

56. Alemtuzumab Improved Pre-existing Disability vs.
SC IFNB-1a in Patients Who Relapsed on Prior Therapy
Sustained Reduction of Disabilitya
Relapsed on Prior Therapy: CARE-MS II1,2
HR: 2.57
p=0.0002
HR: 3.00
p=0.0001
HR: 3.02
p=0.0003
SC IFNB-1a 44 µg
Alemtuzumab 12 mg
SRD Timeframeb
(Tertiary Endpoint)
(Post Hoc Analyses)
• Alemtuzumab-treated patients were 2.5–3 times more likely to have disability
improvement sustained over intervals of up to 1 year vs. SC IFNB-1a
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.
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.
a
b
56

57. CARE-MS Extension Study Designed to Evaluate Long-term
Outcomes with Alemtuzumab
CARE-MS I or II
Pivotal Studies
Extension Study (Safety & Efficacy Follow-up)
Received
alemtuzumab
(Month 0 and 12)
Monitor for MS
activity through
extension trial
Month 48
Received
SC IFNB-1a
Administer
2 annual
alemtuzumab
treatment
courses
Relapse
or 2 active MRI
lesions?
Yes
May receive optional
retreatment course(s)
not sooner than
12 months after the
previous course
No
• 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
Fox E et al. AAN 2013, S41.001.
57

58. CARE-MS Extension: Majority of Patients Treated with Alemtuzumab
Remained Relapse-free at Year 3
Relapse-free Patients
Relapsed on Prior Therapy
(CARE-MS II)
%Patients
Treatment-naïve
(CARE-MS I)
N=376
N=349
N=425
N=387
• Relapse reduction with alemtuzumab treatment was durable; majority of
patients remained relapse-free through Year 3
Fox E et al. AAN 2013, S41.001.
58

59. CARE-MS Extension: Majority of Patients Experienced Further
Benefits on Disability Through Year 3
Relapsed on Prior Treatment
(CARE-MS II)
Remained stable Years 2-3
Improved Years 2-3
EDSS change (baseline to Year 2)
•
The majority of patients who relapsed on prior therapy and whose EDSS score
improved or remained stable in the core studies (Years 0–2) remained stable or
improved further through Year 3
•
Results were consistent with observations in treatment-naïve patients in CARE-MS I
Data shown are for alemtuzumab 12-mg groups.
Hartung HP et al. ECTRIMS 2013, P592.
59

60. Summary of Recommended Risk Mitigation Strategies for
Alemtuzumab in the EU
Identified Risks
Infusion-associated
reactions (IARs)
Mitigation Strategies
Timing
Corticosteroids
Immediately prior to
alemtuzumab administration
Antihistamines and/or
antipyretics (optional)
Prior to alemtuzumab
administration
Oral prophylaxis for herpes
infection
Starting on the first day of
each treatment course
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
Serious infections
After 48 months, testing should be performed based on clinical findings suggestive of the adverse event.
LEMTRADA EU Summary of Product Characteristics, September 2013.
a
On each of the first 3 days of
any treatment course
Continuing for a minimum of
1 month following treatment
with alemtuzumab
60

61. What is your team’s treatment
philosophy?

62. What is your treatment philosophy?
maintenance-escalation vs. induction
survival analysis
an
safe
rt
“sta
t h”
moo
ds
“hit hard and early ”

63. What is your team’s treatment philosophy?
maintenance-escalation vs. induction
survival analysis
r
“sta
an
safe
t
t h”
moo
ds
“hit hard and early ”
e r at
ge n i s
s
rode
neu ypothe
a
is
h
MS isease
d
ive
MS is an autoimmune
disease hypothesis
15-20 year
experiment

64. Another example: treat early and effectively

65. Treat-2-Target Proposed NEDA Treatment Algorithm for
Relapsing MS
High
Efficacy
Intermediate
Efficacy
Moderate
Efficacy
X
M
NEDA=no evidence of disease activity.
N
Y

66. Emerging concepts in MS
NEDA - no evidence of disease activity
Biochemical relapse-free survival
1.0
Adjuvant (n = 50)
Survival
0.8
0.6
0.4
Salvage (n = 118)
p = 0.002
0.2
0.0
0
1
2
3
4
5
6
7
Time since radiotherapy (years)
T2T; treat-2-target
Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340.
8
9
10

67. No evidence of disease activity: NEDA
Treat-2-target
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
Should brain volume loss and CSF neurofilament levels be
included in our definition for ‘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.

68. Treatment objectives in relapsing MS
Treat Early
Freedom from
disease
activity/disease
activity free
Reduced ongoing
damage
68
T2T - NEDA
Zero Tolerance

69. Treatment objectives in relapsing MS
Treat Early
Freedom from
disease
activity/disease
activity free
CNS Repair
Reduced ongoing
damage
69
Functional
T2T - NEDA
Improvement
Maintain reserve
Zero Tolerance
capacity
Healthy
ageing

70. Ian Rogers. ACNR 2007: 7(3);14.

72. Conclusions
• MS is a bad disease
• Mortality, disability, unemployment, divorce, cognitive impairment, etc.
• Early aggressive 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, natalizumab, cladribine extension studies.

73. WWW.MS-RES.ORG