The new treatment paradigm for MS: treat-2-target of NEDA

Zero Tolerance = ZeTo

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

Who should decide?

WWW.MS-RES.ORG

WWW.MS-RES.ORG

RRMS Active MS

Clinical or

MRI

What are the arguments for early treatment?

21-year long-term follow-up of IFNb-1b study time from study randomization to death

Early treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment

Goodin et al Neurology. 2012 Apr 24;78(17):1315-22.

At risk:

IFNB-1b 250 µg

Placebo

124

123

124

120

121

117

118

109

104

88

HR=0.532 (95% CI: 0.314–0.902)

46.8% reduction in hazard ratio

Log rank, P=0.0173

IFNB-1b 250 µg

Placebo

65%

70%

75%

80%

85%

90%

95%

100%

0 2 4 6 8 10 12 14 16 18 20 22

Pro

po

rtio

n o

f p

ati

en

ts w

ho

are

sti

ll a

live

Time (Years)

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

Post-inflammatory neurodegeneration

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

How bad is MS?

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

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.

*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.

QOL EDSS and utility* have shown a

significant inverse relationship9

Mortality Mortality ratio of patients with MS

exceeds CV disease,†,10 stroke,‡,11 and

early breast cancer12

Employment 50% of patients with MS are

unemployed as of EDSS 3.0 and/or

after 10 years from diagnosis13

Healthcare costs Bulk of cost attributed to services

(28.5%) and long-term sick leave and

early retirement (30%)§,14

Relationships Compared with general population, patients

with MS have a higher probability of

separating/divorcing and doing so sooner13

MS has a negative

impact on…

Consequences of Increasing EDSS Scores: Loss of Employment1

14

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

14

Uti

lity

EDSS Status

EDSS and utilitya show a significant inverse relationship

1,b

aUtility measures are derived from EQ-5D using the EuroQoL instrument. bError bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.

• 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

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 &codcol=15&codcch=747. Accessed October 6, 2010. 3. Confavreaux, Compston. 2005. 4. Compston A, Coles A. Lancet 2008

The effect of MS on quality of life

15

What about benign MS?

What prognostic group does the Mser fall Into?

Good Prognosis:

Younger age at onset1,2

Female sex1-3

Optic neuritis4

Isolated sensory symptoms4

Complete recovery from first attack5

Long interval to second relapse4

No disability after 5 years4

Normal MRI / low lesion load4

CSF negative for oligoclonal bands2,6

Poor Prognosis:

Older age of onset1,2

Male sex1-3

“Multifocal” onset4

Efferent systems affected (motor, cerebellar, bladder)4

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

17

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.

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

163 patients with “benign” MS

(disease duration >15 years and EDSS <3.5):

45% cognitive impairment

49% fatigue

54% depression

What is benign MS?

CIS Patients n = 40

Impact of MS: cognitive functioning in the CIS stage

Cognitive test performance in an exploratory study*

57%

7%

-20%

0%

20%

40%

60%

Feuillet et al. Mult Scler. 2007.

Healthy Controls n = 30

p < 0.0001

Deficits were found mainly in memory, speed of information

processing, attention and executive functioning

Patients failing ≥ 2 cognitive tests

20

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

Is there any other evidence?

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.

0

20

40

60

80

100

Any Negative EDSS=6 SPMS Wheelchair

% R

isk R

ela

tive t

o L

ow

Exp

osu

re

Long-term follow-up 16 years

IFN-beta exposure 80% vs. 20%

Goodin et al. PLoS One. 2011;6(11):e22444.

Establishing long-term efficacy: use of recursive partitioning and propensity score adjustment to estimate outcome in MS

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

25

TOP: Earlier Natalizumab Treatment Favors Annualized Relapse Rate Outcomes

26

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

TOP: Earlier Natalizumab Treatment Favors Annualized Relapse Rate Outcomes

27

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.

Baseline Relapse and Treatment History

Mean

An

nu

ali

zed

Rela

pse R

ate

P<0.0001

0.50

0.45

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0.00

0 DMT 1 DMT ≥2 DMTs 1 DMT 0 DMT ≥2 DMTs

0.16 0.18

0.23 0.24

0.28

0.40

1 Relapse ≥2 Relapses

P<0.0001

The current paradigm is safe and slow!

100 MSers

Who are the

responders?

~20% responders

~40% sub-optimal responders

~40% non-responders

vs.

1

2

3

Clinical

MRI

NABs

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-a

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

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.

Do highly-effective treatments stabilise MS?

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

47

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. 48

Demographics and Baseline Clinical Characteristics in Treatment-naïve Patients

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.

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

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

49

0.39

0.18

0

0.1

0.2

0.3

0.4

0.5

0.6

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 Reduced Annualized Relapse Rate vs. SC IFNB-1a in Treatment-naïve Patients

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

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

ps

e R

ate

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

ps

e R

ate

69% Risk reduction

vs. SC IFNB-1a

p<0.001

N=111 N=112

50

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 Reduced the Risk of 6-month Sustained Accumulation of Disability in Treatment-naïve Patients

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

Pa

tien

ts w

ith

SA

D (

%)

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

tien

ts w

ith

SA

D (

%)

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

51

Treatment-naïve Patients Were 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.

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

Treatment-naïve: CARE-MS I1,2

(Tertiary Endpoints)

52

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 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.

As expected, baseline EDSS and duration of disease were higher for patients who relapsed on prior compared with treatment-naïve patients

53

Alemtuzumab Significantly Reduced Clinical Disease Activity in Patients Who Relapsed on Prior Therapy

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

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)

54

Patients Who Relapsed on Prior Therapy Were More Likely to Be Disease Activity-free with Alemtuzumab vs. SC IFNB-1a

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 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

55

Alemtuzumab Improved Pre-existing Disability vs. SC IFNB-1a in Patients Who Relapsed on Prior Therapy

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

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)

56

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

57

CARE-MS Extension: Majority of Patients Treated with Alemtuzumab Remained 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

Relapse reduction with alemtuzumab treatment was durable; majority of patients remained relapse-free through Year 3

58

CARE-MS Extension: Majority of Patients Experienced 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

• 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

59

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. 60

What is your team’s treatment philosophy?

survival analysis

“hit hard and early ”

What is your treatment philosophy? maintenance-escalation vs. induction

survival analysis

“hit hard and early ”

MS is an autoimmune disease hypothesis

15-20 year experiment

What is your team’s treatment philosophy? maintenance-escalation vs. induction

Another example: treat early and effectively

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

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

Adjuvant (n = 50)

Salvage (n = 118)

p = 0.002

Su

rviv

al

Time since radiotherapy (years)

Biochemical relapse-free survival

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

Treatment objectives in relapsing MS

Freedom from

disease

activity/disease

activity free

Reduced ongoing

damage

Improved Quality of Life

Treat Early

68

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

69

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

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.

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