ALEMTUZUMAB

SETTING NEW HORIZONS IN MULTIPLE SCLEROSIS TREATMENT

Professor Gavin Giovannoni

Blizard Institute, Barts and The London School of Medicine and Dentistry

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 Novartis for making available data slides on natalizumab,

alemtuzumab and fingolimod for this presentation.

www.ms-res.org

1.Early therapy

2.Effective therapy

3.Induction therapy

Objectives

1.Early therapy

2.Effective therapy

3.Induction therapy

Objectives

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

Window of therapeutic efficacy

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

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.

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

1.Early therapy

2.Effective therapy

3.Induction therapy

Objectives

Risks vs. Benefits

MS Infographic

www.ms-res.org

No evident 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

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

Treating-2-target

Choosing therapy

X Y Z

Define the

Individual’s MS

No

Treatment failure? Yes

• Patient’s preferences?

• Your choice?

Individual measures:

• Evidence of disease activity?

• Tolerability/safety?

• Adherence?

• Drug or inhibitory markers?

Monitoring

• MS prognosis

• Life style and goals

• Shared goals for therapy

Rebaseline

Rebaseline:

• IFNβ, natalizumab, fingolimod,

teriflunomide, DMF=3-6 months

• Glatiramer acetate=9 months

• Alemtuzumab=24 months

DMF=dimethyl fumarate.

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

MS Iceberg

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

Control Multiple sclerosis

Rheumatoid arthritis End-stage joint disease

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Treatment-effect on atrophy correlates with treatment-effect on disability

Sormani et al. Ann Neurol 2014;75:43–49.

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

Mean

(S

E)

perc

en

tag

e c

han

ge 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

No evident 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

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

Brain volume loss should be

included in our definition for NEDA

1.Early therapy

2.Effective therapy

3.Induction therapy

Objectives

Pros and cons of maintenance vs. induction therapies

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

Possible

cure

The Ideal MS Therapy

Reliable

long-term efficacy

Maintaining

QOL

Maintaining

independence

Maintaining the

ability to work

No issue for

pregnancy/fertility

Maximum reduction

of MS disease activity

Maximum

tolerability

Maximum

safety

Ease of

use

Minor impact on

everyday life

Role of T and B lymphocytes in MS

• Activation of autoreactive T cells1,2

• Genetic and environmental

factors involved3

• Increased migration across BBB1,2,4

• Inflammatory response to CNS

antigens1,2

• Release of proinflammatory cytokines

leading to recruitment and activation

of T and B lymphocytes, macrophages,

and microglial cells

• Local release of damaging mediators

by activated cells

• Demyelination, axonal loss1-4

BBB, blood–brain barrier.

1. Hemmer B, et al. Nat Clin Pract Neurol. 2006;2:201-211; 2. Piccio L, et al. In: Primer on Multiple Sclerosis. New York, NY: Oxford

University Press; 2011:47-59; 3. Sospedra M, Martin R. Annu Rev Immunol. 2005;23:683-747; 4. Compston A, Coles A. Lancet.

2008;372:1502-1517.

1.Early therapy

2.Effective therapy

3.Induction therapy

Alemtuzumab

Alemtuzumab for the treatment of RRMS

• Alemtuzumab is indicated for adult patients with

relapsing remitting multiple sclerosis (RRMS) with

active disease defined by clinical or imaging

features1.

• Alemtuzumab is a humanized monoclonal antibody

that selectively targets CD52, a protein abundant

on the surface of B and T lymphocytes2

• A phase 2 & 3 clinical trial program was

implemented to establish efficacy and safety in MS

patients

• Completed 3 head-to-head trials vs. high-dose

subcutaneous interferon beta-1a (SC IFNB-1a)

in patients with active relapsing-remitting

multiple sclerosis (RRMS) 3-6

1. SMPC – EMA label; 2. Hu Y et al. Immunology 2009;128:260-70; 3. Coles AJ et al. N Engl J Med 2008;359:1786-801; 4. Coles AJ et al. Lancet

2012;380:1819-1828; 5. Coles AJ et al. Lancet 2012;380(1829-1839); 6. Brinar V et al. Presented at 21st Meeting of the European Neurological

Society, 2011.

Overview of Alemtuzumab MoA

1. Selection

• In animal studies, innate immune cells that express lower levels of CD52 were affected minimally or transiently by Alemtuzumab2

2. Depletion

Decreases MS inflammation

• Alemtuzumab selectively depletes circulating T and B cells2,3

• Significant numbers of lymphocytes remain present in lymphoid organs after Alemtuzumab treatment2,3

3. Repopulation

Reduces MS disease activity

• CLP cells are presumed unaffected by Alemtuzumab2,4,5

• Distinctive pattern of T-, B-cell repopulation begins within weeks, potentially changing the balance of the immune system2,4,5

CD52 B

CD52 T B T

HSC

CLP

NK/T cell precursor

Pre/Pro B cell

B CD52

T CD52

Monocyte

Macrophage

Neutrophil

NKT

Targets T and B cells thought

to mediate MS inflammation1

The exact mechanism of action of alemtuzumab is not fully elucidated.

CLP, common lymphoid progenitor; HSC, hematopoietic stem cell; MOA, mechanism of action;

NK, natural killer.

1. Weber MS, Hemmer Bl. Results Probl Cell Differ. 2010;51:115-126; 2. Hu Y, et al. Immunology. 2009;128:260-270; 3.Turner MJ, et al. J

Neuroimmunol. 2013;261:29-36; 4. Cox AL, et al. Eur J Immunol. 2005;35:3332-3342; 5. Fox EJ. Exp Rev Neurotherapeutics. 2010;10:1789-1797.

Selective binding to CD52 • Little or no CD52 detected on

neutrophils, plasma cells, BM

stem cells1,2

• Limited, transient effect on innate

immunity3

• Greater effect on circulating cells; lesser

degree of depletion in lymphoid tissue3

CD52 Expression on

Immune Cell Populations2

©2009 Immunology. Used with permission. Placebo Alemtuzumab

To

tal Im

mu

ne

Ce

lls (

×10

8)

3

2

1

Blood

BM

Lymph nodes

Thymus

Spleen

BM, bone marrow; NTG, nontransgenic.

1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013. 2. Hu Y, et al. Immunology. 2009;128:260-270; 3. Turner MJ, et al. J

Neuroimmunol. 2013;15;261:29-36.

Post-Alemtuzumab: More Immune Cells Remain

in Lymphoid Tissue vs Peripheral Blood3

6

4

2

0 CD

52

Mo

lecu

les p

er

Ce

ll (×

10

5)

CD

4 s

ingle

pos.

CD

8 s

ing

le p

os.

Do

ub

le p

os.

Do

ub

le n

eg

.

Ma

cro

ph

ag

es

Ne

utr

op

hils

NK

ce

lls

Ste

m c

ells

CD

8 T

ce

lls

NT

G

B c

ells

CD

4 T

ce

lls

CD

4 T

reg

Spleen BM Thymus

Alemtuzumab depletes circulating T and B cells

• Alemtuzumab depleted lymphocytes rapidly and selectively after each treatment course1

• Occurred via antibody-dependent cellular cytolysis, complement-mediated lysis2,3

White Blood Cell Counts

Time After Alemtuzumab, mo

CARE-MS I: White Blood Cell Counts

Following Alemtuzumab1

0 1 2 3 4 5 6 7 8 9 10 11 12

0.0

0.5

1.0

1.5

2.0

4.0

4.5

5.0

Me

an

Ce

ll C

ou

nt (1

09/L

)

Basophils

NR, (0-0.2)4

Eosinophils

NR, (0-0.5)4

Monocytes

NR, (0-0.8)4

Lymphocytes

NR, 0.8-4.15

Neutrophils

NR, 1.8-7.74

NR, normal range.

1. Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341; 2. Minagar A, et al. Expert Opin Biol Ther. 2010;10:421-429; 3. Freedman MS, et

al. J Clin Cell Immunol. 2013;4:152; 4. Coles A, et al. Presented at: American Academy of Neurology; 2010; Toronto; PO6.172. 5. Data on file, Genzyme Therapeutics,

Ltd; Oxford, UK;

Repopulation changes the balance of the immune system

• After Alemtuzumab, distinctive pattern

of T-, B-cell repopulation emerged

within weeks1-3

— B cells return to baseline within 6 months

— T cells generally do not reach baseline by 12

months

• Relative increase in proportion

of Treg cells1,4

• Relative increase in proportion

of memory T, B lymphocytes1,4

• Effects similar after repeated courses4

LLN, lower limit of normal.

1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Cox AL, et al. Eur J Immunol. 2005;35:3332-3342. 3. Turner MJ,

et al. J Neuroimmunol. 2013;261:29-36; 4. Hartung HP, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2012; Lyon; P935; 5.

Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341.

May change balance of

immune system to reduce

MS disease activity1,3

CARE-MS I: Mean Treg Cells as Percentage of Total CD4+ Count4*

2

6

10

14

CD

4+ T

reg C

ell

Count, %

4

8

12

16 Alemtuzumab 12 mg

0.0

1

0.2

0.4

0.6

0.8

1.0

1.2

0 3 6 9 12 13 15 18 21 24

Time, mo

CARE-MS I: Mean Lymphocyte Counts After Alemtuzumab5*

CD4+ T cells

CD19+ B cells

CD19+ LLN

CD4+ LLN

IFNB-1a 44 μg

1 0 3 6 9 12 13 15 18 21 24

Time, mo

Cell

Count (1

09/L

)

Alemtuzumab pharmacokinetics in MS

Clinical effects persist after Alemtuzumab is cleared from circulation

• Alemtuzumab serum concentrations low or undetectable within ~30 days after treatment

Alemtuzumab 12 mg administered at time 0 and 12 months.

Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341.

CARE-MS I: Mean Serum Concentration Over Time

Time on Study, mo

4,000

0

2,000

3,000

1,000

0 1 3 6 9 12 24 15 18 21

Co

nce

ntr

ation

(n

g/m

L)

13

Alemtuzumab

12 mg

Alemtuzumab

12 mg

Efficacy of Alemtuzumab

Clinical development program

2017 2005 2013 2009 2003 2007 2011 2015

CAMMS2231

CARE-MS I3

CAMMS223 Extension2

CARE-MS II4

CARE-MS Extension5

• Included patients with active RRMS who

relapsed on prior therapy and those who

were naïve to treatment1-4

• Efficacy and safety established vs

high-dose IFNB-1a SC (no placebo

used) in 3 rater-blinded RCTs1-4

RCT, randomized controlled trial; SC, subcutaneous.

1. Coles, AJ et al. N Engl J Med. 2008;359:1786-1801; 2. Coles AJ, et al. Neurol. 2012;78:1069-1078; 3. Cohen JA, et al. Lancet. 2012;380:1819-

1828; 4. Coles AJ, et al. Lancet. 2012;380:1829-1839; 5. Data on file, Genzyme Therapeutics, Ltd; Oxford, UK.

Alemtuzumab vs high-dose IFNB-1a SC

MRI inclusion criteria:5

CARE-MS II: MS diagnosis per McDonald criteria; white matter lesions attributable to MS; ≥9 T2 lesions ≥3 mm, any axis;

Gd-enhancing lesion ≥3 mm, any axis, with ≥1 brain T2 lesions; spinal cord lesion with ≥1 brain T2 lesions; CARE–MS I:

MS diagnosis per McDonald criteria; cranial MRI demonstrating white matter lesions attributable to MS (within 5 y of screening);

CAMMS223: MS diagnosis per McDonald criteria, including cranial MRI; ≥1 enhancing lesion on any of ≤4 Gd-enhanced brain

scans during ≤3-mo run-in period (including baseline scan).

NA, not applicable; TIW, 3 times per week. aTreatment with beta interferon or glatiramer acetate for ≥6 months. bThrough month 13.

1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013. 2. Coles AJ, et al. Lancet. 2012;380:1829-1839; 3. Cohen JA, et al.

Lancet. 2012;380:1819-1828; 4. Coles AJ, et al. N Engl J Med. 2008;359:1786-1801; 5. Data on file. Genzyme Therapeutics, Ltd; Oxford, UK.

CARE-MS II1,2

Phase III

CARE-MS I1,3

Phase III

CAMMS2231,4

Phase II

Total patients, n

(% completed)

Alemtuzumab

12 mg/d 426 (94) 376 (96) 108 (85b)

IFNB-1a SC

44 μg TIW 202 (78) 187 (88) 107 (62b)

Patient population

Active RRMS,

relapse on prior

therapya

Active RRMS,

treatment-naïve

Active RRMS,

treatment-naïve

Eligibility

≥2 clinical episodes

in prior 2 y,

≥1 relapse in prior y

≥2 clinical episodes

in prior 2 y,

≥1 relapse in prior y

≥2 clinical episodes

in prior 2 y,

≥1 Gd-enhancing

lesion at baseline

Mean age, y 35 33 32

EDSS range (mean) 0.0-5.0 (2.7) 0.0-3.0 (2.0) 0.0-3.0 (1.9)

Mean disease duration, y (median) 4.5 (3.8) 2.0 (1.6) 1.3 (NA)

Phase II study design

CAMMS223

• Rater-blinded, comparator-

controlled trial1

— No placebo used

• 334 treatment-naïve patients

with early, active RRMS1

aReceived study drug.

Note: All treatment arms received 1 g methylprednisolone qd ×3 d at months 0, 12, and 24.

1. Coles AJ, et al. N Engl J Med. 2008;359:1786-1801; 2. Coles AJ, et al. Neurology. 2012;78:1069-1078.

• Co-primary endpoints:

ARR, time to 6-month SAD1

• Safety, efficacy assessments

continued in extension phase

beyond 36 months2

105 QD×3

0 12 24 36

Extension Phase2 Study Duration (mo)1

60

Alemtuzumab

12 mg/d IV 102 101 n=108a

QD×3 QD×5

24

77 92 67

Alemtuzumab

24 mg/d IV 104 n=108a

QD×5

22

82

92 74

IFNB-1a

44 µg TIW SC n=107a 95 80 42 66

Durable efficacy over 5 years

CAMMS223

aCo-primary endpoints.

Coles AJ, et al. Neurology. 2012;76:1069-1078.

0.35

0.12

0

0.1

0.2

0.3

0.4

0.5

38%

16%

0

10

20

30

40

50

0.46

-0.15

-0.4

-0.2

0

0.2

0.4

0.6

0.8

P<0.0001 P=0.0005 P=0.0056

Mean EDSS Score 6-Month SADa ARRa

Months 0-60 Months 0-60 Months 0-60

66% reduction 69% reduction

IFNB-1a 44 μg Alemtuzumab12 mg

Phase III study design

• Rater-blinded RCTs1,2

• Comparator-controlled (no placebo used)

• Scoring by blinded raters1,2

• Relapse, EDSS every 3 months

• MSFC every 6 months

• MRI annually

• Education, safety monitoring program

for patients, physicians1,2

— Surveys, urinalysis, CBC monthly

— Thyroid testing quarterly

• In CARE-MS II only, 24-mg arm included

but discontinued to accelerate recruitment

into other arms; thereafter deemed exploratory1

Both treatment arms received 1 g methylprednisolone qd ×3 d at months 0 and 12.

CBC, complete blood count; IV, intravenous.

1. Coles AJ, et al. Lancet. 2012;380:1829-1839; 2. Cohen JA, et al. Lancet. 2012;380:1819-1828 Image adapted from Hartung HP, Arnold DL.

Presented at: European Neurological Society; 2012; Prague.

Alemtuzumab

12 mg IV Daily

×5

Daily

×3

TIW

IFNB-1a

44 µg SC

Study Duration (mo)

0 12 24

Randomized

Alemtuzumab

24 mg IV Daily

×5

Daily

×3

Phase III efficacy endpoints

ARR, annualised relapse rate; MSFC, Multiple Sclerosis Functional Composite; SAD, sustained accumulation

of disability; SRD, sustained reduction in disability.

1. Cohen JA, et al. Lancet. 2012;380:1819-1828; 2. Coles AJ, et al. Lancet. 2012;380:1829-1839; 3. Data on file. Genzyme Therapeutics, Ltd; Oxford,

UK; 4. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013.

Co-Primary Endpoints1,2 Secondary Endpoints1,2 Select Tertiary Endpoints1-3

• ARR

• Time to 6-month SAD,

defined as increase of

≥1.0 point on EDSS from

baseline of ≥1.0 (or ≥1.5

point from baseline of 0),

confirmed twice during

6-month period

• Proportion of patients

relapse-free at study

completion

• Change in EDSS score

from baseline

• Percent change in T2

hyperintense lesion volume

from baseline to study

completion

• Change in MSFC

from baseline

• Time to first relapse

• Proportion of patients with

no MS disease activity

(MRI, relapse, SAD) at

years 1, 2

• Time to 6-month SRD

• Change in MSFC

components plus Sloan

charts from baseline

• MRI measures of MS-related

brain measures

• A priori efficacy objective met if statistically significant treatment effect demonstrated

for Alemtuzumab over IFNB-1a SC on either or both co-primary efficacy endpoint(s)4

Significant reduction in ARR

Lower rates of SAD in treatment-naïve patients

CARE-MS I

0.39 0.18

Risk reduction: 55%

P<0.0001

Ad

juste

d A

RR

(9

5%

CI)

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 Alem

(n=376)

IFNB-1a

(n=187)

187

376

185

376

181

372

177

368

170

368

164

357

162

352

158

345

149

336

25

15

10

5

0

20

Pa

tie

nts

With

SA

D (

%)

8%

11%

30% reduction

P=0.22 (NS)

IFNB-1a 44 μg Alemtuzumab12 mg

ARR: Years 0-21,2a Time to 6-Month SAD1a

Alem

IFNB-1a

0 3 6 9 12 15 18 21 24

Follow-Up Month

aCo-primary endpoints. Alem: alemtuzumab

1. Cohen JA, et al. Lancet. 2012;380:1819-1828; 2. Fox EJ, et al. Presented at: American Academy of Neurology; 2012; New Orleans, LA; PD5.004.

Reduced MRI activity across select markers

CARE-MS I

• Alemtuzumab reduced the proportion of patients with new MRI lesion activity

Endpoint1,2 Alemtuzumab INFB-1a SC P Value

Patients with no new or newly

enlarging T2 lesions, %a 52 42 0.035

Patients with no new

Gd-enhancing lesions, %a 85 73 0.001

Patients with no new T1-hypointense

lesions, %a 76 69 NS

Change from baseline in BPF, %a -0.867 -1.488 <0.0001

Change from baseline in T2

hyperintense lesion volume, %b -9.3 -6.5 NS

aTertiary endpoint.2

bSecondary endpoint.2

1. Alemtuzumab Summary of Product Characteristics; Oxford, UK: Genzyme Therapeutics, Ltd; 2013;

2. Cohen JA, et al. Lancet. 2012;380:1819-1828.

Alemtuzumab patients more likely free of MS disease activity

CARE-MS I

OR: 1.75

P=0.0064

P=0.0388 OR: 2.36

P<0.0001

42

56

27

51

74

39

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

(%

)

MRI

activity-freea

MS disease

activity-freec

Clinical disease

activity-freeb

IFNB-1a 44 μg

Alemtuzumab12 mg

aAbsence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesion. bAbsence of relapse or SAD. cAbsence of CDA or MRI activity.

CDA, clinical disease activity; OR, odds ratio

Giovanni G, et al. Presented at: European Neurological Society; 2012; Prague.

Alemtuzumab significantly reduced ARR & SAD

CARE-MS II

Time to 6-Month SADa

Alem

IFNB-1a 202

426

200

426

184

412

175

404

167

392

162

384

155

380

145

375

131

354

Pa

tie

nts

With

SA

D (

%)

0 3 6 9 12 15 18 21 24

25

15

10

5

0

20

Follow-Up Month

13%

21% 42% reduction

P=0.0084

aCo-primary endpoints. Alem: alemtuzumab

Coles AJ, et al. Lancet. 2012;380:1829-1839.

0.52 0.26 0.0

0.2

0.4

0.6

0.8

AR

R (

95

% C

I)

ARR: Years 0-2a

Alem

(n=426)

IFNB-1a

(n=202)

IFNB-1a 44 μg Alemtuzumab 12 mg

Alemtuzumab improved pre-existing disability

CARE-MS II

aSecondary endpoint; defined as decrease of ≥1 EDSS point lasting at least 6 months, assessed in patients

with baseline EDSS ≥2.0. bTertiary endpoint. cMeasured by SRD score in relapsing patients.

Coles AJ, et al. Lancet. 2012;380:1829-1839.

IFNB-1a 44 μg Alemtuzumab12 mg

‒0.17

P<0.0001

+0.24

ED

SS

Sco

re, m

ea

n

3.25

3.00

2.75

2.50

2.25

Follow-Up Month

0 3 6 9 12 15 18 21 24

40

30

20

10

0

Pa

tie

nts

With

6-M

on

th S

RD

(%

)

29%

13%

P=0.0002

Mean EDSS Change From Baselinea SRDb

Follow-Up Month

0 3 6 9 12 15 18 21 24

Alemtuzumab is the first and currently only MS therapy to demonstrate sustained improvement

in preexisting disability vs an active comparator (in 2 of 3 clinical trials)

Reduced MRI activity across select markers

CARE-MS II

• Alemtuzumab reduced the proportion of patients with new MRI lesion activity

aTertiary endpoint.2. bSecondary endpoint.2

BPF, brain parenchymal fraction; NS, non significant

1. Alemtuzumab Summary of Product Characteristics; Oxford, UK: Genzyme Therapeutics, Ltd; 2013;

2. Coles AJ, et al. Lancet. 2012;380:1829-1839.

Endpoints1,2 Alemtuzumab INFB-1a SC P Value

Patients with no new or newly

enlarging T2 lesions, %a 54 32 <0.001

Patients with no new

Gd-enhancing lesions, %a 82 66 <0.001

Patients with no new T1-hypointense

lesions, %a 80 62 <0.001

Change from baseline in BPF, %a -0.615 -0.810 0.012

Change from baseline in T2

hyperintense lesion volume, %b -1.3 -1.2 NS

Alemtuzumab patients more likely free of MS disease activity

CARE-MS II

aAbsence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesion. bAbsence of relapse or SAD. cAbsence of CDA or MRI activity.

CDA, clinical disease activity; OR, odds ratio

Hartung HP, et al. Presented at: American Academy of Neurology; 2013, San Diego, CA; P07.093.

32

41

14

53

60

32

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

(%

)

OR: 3.03

P<0.0001

OR: 2.14

P<0.0001

OR: 0.39

P<0.0001

MRI

activity-freea

MS disease

activity-freec

Clinical disease

activity-freeb

IFNB-1a 44 μg

Alemtuzumab12 mg

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)

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

CI)

Year No. of Patients 371 367 351 323

% Change from Previous Year – –0.59% –0.25% –0.19%

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

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

Safety of Alemtuzumab

Safety Issues

0 12 24 36

Observation Treatment Cycles Duration (mo)

60 Alemtuzumab

12 mg/d IV

QD×3 QD×5 ? QD×3

Short-term

Infusion reactions

Infections: viral and opportunistic

Travel

Baseline De-risking

VZV

Live vaccines

Latent TB

HPV

Pregnancy

Intermediate-term

2° autoimmunity

Pregnancy

Pulsed steroids

Travel

? Long-term

Immune senescence

2° malignancy

Risks

Monitoring & prophylaxis

Baseline bloods

VZV serology

CXR & quantiferon TB assay

Cervical smear

Pregnancy test

Monthly FBC & urinalysis

3-monthly TFTs

Annual MRI

Pretreatment with steroids, anti-

histamines and paracetamol

Herpes prophylaxis x 28 days

Listeriosis prevention diet Pre-planned rapid access to haematology,

nephrology, dermatology, etc.

Patient education

Baseline counselling Signed consent Engaged with self-monitoring Lifelong monitoring

Active public engagement programme

Overall AE rates in clinical trials

• Rate of AEs with Alemtuzumab 12 mg,

including those leading to treatment

discontinuation, generally similar to

those with IFNB-1a SC

aIncludes CAMMS223, CARE-MS I, and CARE-MS II.

AE, adverse event.

Data on file. Genzyme Therapeutics, Ltd; Oxford, UK.

2-year active-controlled experiencea

• AE profiles similar for treatment-naïve

patients and those who relapsed on

prior therapy

AEs IFNB-1a SC 44 μg

n=496 Alemtuzumab 12 mg

n=919

AEs, n (%) 469 (94.6) 896 (97.5)

Grade 1 (mild) 400 (80.6) 815 (88.7)

Grade 2 (moderate) 402 (81.0) 831 (90.4)

Grade 3 (severe) 106 (21.4) 227 (24.7)

Grade 4 (very severe) 10 (2.0) 27 (2.9)

AEs leading to treatment discontinuation, n (%) 39 (7.9) 21 (2.3)

Serious AEs, n (%) 91 (18.3) 168 (18.3)

Serious AEs leading to treatment discontinuation, n (%) 10 (2.0) 7 (0.8)

Deaths 0 3

Rate of AEs over time

• Rate of AEs was similar in IFNB-1a- and Alemtuzumab-treated patients,

except during month following Alemtuzumab administration, due to IARs1

— IAR rates lower with second vs first treatment course of Alemtuzumab1

• Similar pattern observed in CARE-MS II2 and CAMMS2233

Time, mo

Ra

te o

f A

Es

(to

tal e

ve

nts

/tota

l p

ers

on

-mo

nth

s)

CARE-MS I1

0

1

2

3

4

5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Both treatment arms received 1 g methylprednisolone qd ×3 d at months 0 and 12.

1. Coles AJ, et al. Presented at: American Academy of Neurology; 2012; New Orleans, LA; 2. LaGanke CC, et al. Presented at: American

Academy of Neurology; 2013; San Diego, CA. P01.174 3. Data on file, Genzyme Therapeutics, Ltd; Oxford, UK

Overview of IARs in clinical trials

CARE-MS I and II (Pooled)1

Avera

ge N

um

ber

of IA

R S

ym

pto

ms

Infusion Number

Course 1 Course 2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

1 2 3 4 5 1 2 3

• To manage IAR severity:

— Pretreat with corticosteroids,

(ie, methylprednisolone)

immediately before infusion

with Alemtuzumab for first 3 days

of any treatment course1

— Consider pretreatment with

antihistamines and/or antipyretics

• Observe patient for IARs

during and for 2 hours after

Alemtuzumab infusion

• Physician and patient education

Premedication and Monitoring2

• Predominantly mild to moderate;decreased with each treatment course3

• 3% serious: pyrexia, urticaria, atrial fibrillation, nausea, chest discomfort,

hypotension2

1. Data on file. Genzyme Therapeutics, Ltd; Oxford, UK; 2. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme

Therapeutics, Ltd; 2013; 3. Caon C. et al. Presented at: Consortium of Multiple Sclerosis Centers; 2012; San Diego, CA; DX41.

No increase in infection rate over 2 years

Time, mo

Incid

en

ce

of In

fection

s

0.0

0.1

0.2

0.3

0.4

0.5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

IFNB-1a

Alem12 mg

389

811

388

811

387

811

386

811

384

811

379

811

377

811

375

811

373

811

372

810

371

810

368

810

363

810

362

807

358

807

357

806

355

805

354

804

353

803

352

803

352

797

351

796

349

785

342

761

CARE-MS I and II (pooled data)

IFNB-1a 44g

Alemtuzumab12 mg

Alem: alemtuzumab

Havrdova E, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2013, Copenhagen; P603.

• Risk highest in first month after first

treatment; rates decreased over time

• No increase in infection risk that would

indicate cumulative immunosuppressive

effects

Overview of infections in clinical trials

• More frequent with Alemtuzumab

vs INFB-1a (71% vs 53%)1

• Predominately mild to moderate1

• Generally of typical

duration, resolved following

conventional treatment1

• Did not correlate with lymphocyte

counts3

• Total or subgroups CD4,

CD8, CD19

2-year active-controlled experience2a,b

IFNB-1a SC 44 μg

n=496

Alemtuzumab 12 mg n=919

Grade 1, 2 258 (52.0) 618 (67.2)

Grade 3 6 (1.2) 33 (3.6)

Grade 4 0 (0.0) 1 (0.1)

Serious AEs, n (%) 5 (1.0) 25 (2.7)

Nasopharyngitis 82 (16.5) 216 (23.5)

Urinary tract infection 40 (8.1) 162 (17.7)

Upper respiratory tract infection 57 (11.5) 141 (15.3)

Sinusitis 34 (6.9) 100 (10.9)

Oral herpes 6 (1.2) 79 (8.6)

Influenza 25 (5.0) 77 (8.4)

Bronchitis 16 (3.2) 64 (7.0)

Herpes zoster 4 (0.8) 38 (4.1)

Gastroenteritis 5 (1.0) 36 (3.9)

Pharyngitis 7 (1.4) 36 (3.9)

• Prophylaxis with oral

anti-herpes agent (acyclovir

200 mg twice a day used in

clinical trials) starting first day

of treatment, continuing for

1 mo after treatment course

Risk Mitigation (Monitoring)1

aInfections with incidence of ≥5.0% in any

treatment group shown. bIncludes CAMMS223, CARE-MS I, and CARE-MS II. cEvents occurring in ≥5% of Alemtuzumab-treated patients, based on all available follow-up.

1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Data on file. Oxford, UK: Genzyme Therapeutics, Ltd; 3. Havrdova

E, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2013; Copenhagen; P603.

ITP cases in detail (phase II and III studies)

aIndex case excluded. bCR: first recovery of platelet count ≥100 x 109/L after onset of ITP.

CR, complete response.

1. Cuker A, et al. Blood. 2011;118:6299-6305; 2. Data on file, Genzyme Corporation, Ltd; Oxford, UK;

3. Cohen JA, et al. Lancet. 2012;389:1819-1828; 4. Coles AJ, et al. Lancet. 2012;380:1829-1839.

Trial (ITP cases;

Alemtuzumab

patients)

Time from last dose

to ITP onset (mo)

Nadir platelet count

(109/L)

Time from ITP onset

to CRb (mo)

In CR at last follow-up

Yes/No (n)

CAMMS2231

(5; 216)a 1-15 1-41 1-8 Yes (5)

CARE-MS I2

(3; 376) 7-17 1-42 0.4-2.7 Yes (3)

CARE-MS II2

(8; 596) 3-13 1-37 0.2-1

Yes (7)

No (1)

CAMMS2231 CARE-MS I3 CARE-MS II4

Following implementation of mandatory

monitoring (after index case)3:

• 2 cases detected by visible ITP symptoms

• 3 patients diagnosed by monthly CBC

− 2 symptomatic; 1 presented with

cutaneous symptoms

• All in CR at last follow-up (response to

standard therapy or spontaneous

recovery)

• 1 case had initial platelet drop

that resolved spontaneously,

recurred 6 months later, and

responded to prednisolone

• All presented with visible signs

• All in CR at last follow-up

(response to standard

therapy)

• 3 cases initially presented

with visible signs

• 4 cases initially detected

by monthly CBC

• 6 of 7 in CR at last follow-up;

1 patient remained

on corticosteroids

Nephropathy cases in detail

aCreatinine normal range, 0.6-1.1 mg/dL.

CKD, chronic kidney disease; URTI, upper respiratory tract infection.

Wynn D, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2013; Copenhagen; P597.

Age/Sex/

Trial

Months

From

Last Dose

Dose (Courses;

Cumulative

Dose)

Serum Creatinine

at Diagnosis

mg/dL (mol/L) Prodrome

Treatment

Outcome

Anti-GBM cases

35 yr/female/

CAMMS223 39

12 mg

(2 courses;

96 mg)

1.8 (163) URTI, rash,

hematuria

Standard Rx

CKD3a

23 yr/female/

Extension 4

12 mg

(3 courses;

132 mg)

0.7 (63)

(Normal)a

Proteinuria;

hematuria

Standard Rx

CKD 1

Membranous nephropathy

26 yr/female/

CARE-MS II 5

12 mg

(2 courses;

96 mg)

0.6 (54)

(Normal)a

Proteinuria,

hematuria,

hypoalbuminemia,

peripheral edema

Furosemide

+ ACEI

Symptoms

improved

58 yr/female/

CAMMS3409

EXT

13

12 mg

(2 courses;

96 mg)

1.5 (135) Proteinuria,

hematuria, edema

Initial: diuretics +

albumin

Ongoing: diuretics

All cases (0.3% in clinical trials) detected by safety monitoring program; none resulted in renal failure

Monitoring, education essential for early detection, effective management

Autoimmune-related thyroid AE incidence Phase II through complete follow-up (6.7 years)

• Occurred in 34% of patients taking Alemtuzumab vs 6.5% of those taking INFB (P<0.0001)1

• Majority were hyperthyroidism1

• 4 events identified as serious (0.4 events per 100 person-years)2

• Delayed onset: peaked in third year after initial Alemtuzumab treatment, declined thereafter1,2

Phase III Studies3

CARE-MS I CARE-MS II

Rebif 44 µg

N=187

Alemtuzumab

12 mg

N=376

Rebif 44 µg

N=202

Alemtuzumab

12 mg

N=435

Any thyroid AEa (n,

%) 12 (6.4) 68 (18.1) 10 (5.0) 69 (15.9)

Hyperthyroidism 3 (1.6) 31 (8.2) 1 (0.5) 19 (4.4)

Hypothyroidism 6 (3.2) 29 (7.7) 3 (1.5) 29 (6.7)

Goiter 0 6 (1.6) 1 (0.5) 6 (1.4)

Thyroid mass 0 1 (0.3) 0 0

Lab investigations 5 (2.7) 21 (5.6) 6 (3.0) 22 (5.1)

Thyroid SAE (n, %) 0 4 (1.1) 0 2 (0.5)

Thyroid

carcinoma (n, %) 0 2 (1) 0 1 (<1)

aSome patients had >1 episode of thyroid dysfunction; for example, treatment of one hyperthyroidism case

in CARE-MS II resulted in development of hypothyroidism.

SAE, serious adverse event.

1. Daniels GH, et al. J Clin Endocrinol Metab. 2014;99:80-89; 2. Coles AJ, et al. Neurology. 2012;78:1069-1078; 3. Habek M, et al. Presented at: European Neurological

Society; 2012; Prague; P340.

Risks identified in clinical trials

aThrough 48 mo after first exposure.

ITP, immune thrombocytopenia; GBM, glomerular basement membrane; mAb, monoclonal antibody.

1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Wynn D, et al. Presented at: European

Committee for Treatment and Research in Multiple Sclerosis; 2013; Copenhagen; P597; 3. Coles AJ, et al. Neurology. 2012;78:1069-1078.

Identified Risk

Rate in Alemtuzumab-

Treated Patients Notes

ITP A

uto

imm

un

e E

ve

nts

~1% (1 fatality prior

to implementation of

monitoring program)1

• Onset generally occurred 14-36 mo after first exposure1

• Most cases responded to first-line medical therapy1

0.3%

(anti-GBM n=2)1

• Generally occurred within 39 mo after last administration1

• Responded to timely medical treatment and did not develop permanent

kidney failure2 Nephropathies

Thyroid

disorders

(Hypo-/hyper-)

~36%a

(serious, 1%)1

• Onset occurred 6-61 mo after first Alemtuzumab exposure;

peaked in year 3 and declined thereafter3

• Most mild to moderate, most managed with conventional medical

therapy, however, some patients required surgical intervention1

• Higher incidence in patients with history of thyroid disorders1

IARs >90%

(serious, 3%)1

• Occurred within 24 h of Alemtuzumab administration1

• Most mild to moderate; rarely led to treatment discontinuation1

• May be caused by cytokine release following mAb-mediated

cell lysis1

Infections 71%

(serious, 2.7%)1

• Incidence highest during first mo after infusion; rate decreased over time2

• More common with Alemtuzumab; mostly mild to moderate1

• Generally of typical duration; resolved following conventional medical

treatment1

Who should decide?

WWW.MS-RES.ORG

WWW.MS-RES.ORG

survival analysis

“hit hard and early ”

MS is an autoimmune disease hypothesis

15-20 year experiment

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

Questions?