ECTRIMS 2012: Alemtuzumab presentation at Genzyme Satellite Symposium

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MS Immunomodulation: Experiences with B and T Lymphocyte Targeting

Targeting Circulating Lymphocytes by Selective Depletion – Alemtuzumab

Professor Gavin GiovannoniBlizard Institute, Barts and The London School of

Medicine and Dentistry,London, UK

Alemtuzumab is not approved in the EU or US for treatment of MS, and should not be used for treatment of MS outside of a regulated formal clinical trial

Presenter Disclosure

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: Bayer-Schering Healthcare; Biogen-Idec; Canbex; Eisai; Elan; Fiveprime; Genzyme; Genentech; GSK; Ironwood; Merck-Serono; Novartis; Pfizer; Roche; Sanofi-Aventis; Synthon BV; Teva; UCB Pharma; and Vertex Pharmaceuticals

Multiple Approaches to Targeting Lymphocytes in MS:Therapies Specifically Targeting Lymphocytes

1. Barten LJ et al. Drug Design, Development and Therapy 2010:4 343–366; 2. Comabella M, Khoury SJ. Clin Immunol. 2012;142(1):2-8; 3. Gensicke H et al. CNS Drugs. 2012;26:11-37.

Therapy Target MOANatalizumab α-4 integrin Blocks entry of lymphocytes into the CNS1

Rituximab CD20 Depletes B cells expressing CD202

Ocrelizumab CD20 Depletes B cells mainly via antibody-dependent, cell-mediated toxicity3

Ofatumumab CD20 Depletes B cells mainly via complement-dependent cytotoxicity3

Daclizumab CD25 Inhibits activation and expansion of T cells2

Alemtuzumab CD52 Depletes T and B-cells from circulation2

These agents more directly target lymphocytes, but have different clinical profiles

Alemtuzumab: Introduction

Alemtuzumab is a humanized monoclonal antibody that selectively targets CD52, a protein abundant on the surface of B and T lymphocytes1,2

Completed a phase 2 (CAMMS223) and 2 pivotal phase 3 trials (CARE-MS I and CARE-MS II) in relapsing-remitting MS (RRMS)– Regulatory filing for approval in MS submitted

in EU and US in 2012

Intravenous infusion given as 2 courses – 12 mg on 5 consecutive days at Month 0 – 12 mg on 3 consecutive days at Month 12

1. Hu Y et al. Immunology 2009;128:260-70; 2. Fox EJ. Expert Rev Neurother 2010;10:1789-97.

Targeting Lymphocytes by Selective Depletion: Alemtuzumab

Alemtuzumab selectively depletes circulating T and B lymphocytes; other leukocytes are minimally affected2

A distinctive pattern of T and B cell repopulation begins within weeks after treatment with alemtuzumab, leading to a rebalancing of the immune system1-3

While the exact mechanism of action is unknown, pharmacodynamic changes following alemtuzumab may help explain its effect in MS2

aAlemtuzumab was administered at Months 0 and 12.LLN=lower limit of normal; NR=normal range1. Kovarova I et al. ENS 2012; 2. Fox EJ. Expert Rev Neurother 2010;10:1789-97; 3. Cox AL et al. Eur J Immunol 2005;35:3332-42;.

Innate Immune Cell Counts after Alemtuzumab (CARE-MS I)1,a

Lymphocyte Counts after Alemtuzumab (CARE-MS I)1,a

0.0

0.4

0.8

1.2

Cel

l Cou

nts

(109

/L)

0.2

0.6

1.0

CD4+ LLN

CD19+ LLN

CD4+ T cellsCD19+ (B cells)

0 1 3 6 9 12 13 15 18 21 24Months

Neutrophils NR=(1.8, 8.0)

Monocytes NR=(0.2, 1.1)

Eosinophils NR=(0.05, 0.55)Basophils NR=(0, 0.2)

Res

ults

(109

/L)

Months

Alemtuzumab Clinical Development Program:Head-to-head Studies vs. High-dose SC IFNB-1a

CAMMS223(completed)

CARE-MS I(completed)

CARE-MS II(completed)

Extension(ongoing)

Patients, n 334 581 840 ~1400

Study Duration, yrs 3 2 2 4

Patient Population

Active RRMS, treatment-naïve

EDSS ≤3Onset ≤3 yrs

Enhancing lesion

Active RRMS, treatment-naïve


Active RRMS, relapsing on prior drug


CAMMS223,CARE-MS I & II

patients

Treatment Arms

Alemtuzumab 12 mgAlemtuzumab 24 mgSC IFNB-1a 44 µg

Alemtuzumab 12 mg—

SC IFNB-1a 44 µg

Alemtuzumab 12 mgAlemtuzumab 24 mga

SC IFNB-1a 44 µg

Alemtuzumab 12 mg • 2 courses (former SC

IFNB-1a patients)• Re-treat as needed

(former alem patients)

Co-primary Outcomes

Relapse rateDisability progression

Relapse rateDisability progression

Relapse rateDisability progression Safety & efficacy

Phase 2 Phase 3

a Exploratory arm, discontinued enrollment early.IFNB-1a=subcutaneous interferon beta-1aBrinar V et al. ENS 2011.

Phase 3: CARE-MS I & II Studies Design

Co-primary endpoints: ARR and time to 6-month SADa

– Relapse assessed by blinded adjudication committee– Quarterly EDSS, semi-annual MSFC, and annual MRI assessed by blinded raters

Physician and patient education and monitoring program for safety

Alemtuzumab12 mg IV

Dailyx 5

Dailyx 3

3x/wk

IFNB-1a44 μg SC

Study duration (months)

0 12 24

Randomized 2:1

Note: Both treatment arms received 1 g methylprednisolone once daily x 3 days at Months 0 and 12.In CARE-MS II: Randomization into 3rd treatment arm (24 mg alemtuzumab) was discontinued early, and was deemed exploratory for statistical purposes (data not presented here)aDefined as increase of ≥1.0 EDSS point for ≥6 months (or ≥1.5 points if baseline EDSS=0).1. Coles AJ et al. ECTRIMS 2011; 2. Cohen JA et al. AAN 2012.

Active Comparator: SC interferon beta-1a (Rebif®)

Rebif 44 μg efficacy vs placebo in RMS patients over 2 years:1– 33% reduction of relapse rate– 78% reduction in active T2 lesions on MRI

SC IFNB-1a had superior short-term efficacy on relapse rate and some MRI parameters compared to IM IFNB-1a (Avonex®) in the EVIDENCE trial2,3

No other RMS disease modifying therapy has been shown superior to Rebif® in a blinded, randomized prospective study

1. PRISMS Study Group. Lancet 1998;352:1498-504. 2. Schwid SR, Panitch HS. Clin Ther 2007;29:2031-48;3. Panitch H et al. Neurology 2002;59:1496-506.

CARE-MS I & II: Baseline Characteristics

CARE-MS I1 CARE-MS II2

SC IFNB-1a(n=187)

Alem 12 mg(n=376)

SC IFNB-1a(n=202)

Alem 12 mg(n=426)

Age, yrs 33.2 (8.5) 33.0 (8.0) 35.8 (8.8) 34.8 (8.4)

Female, % 65.2 64.6 64.9 66.0

EDSS score 2.0 (0.8) 2.0 (0.8) 2.7 (1.2) 2.7 (1.3)Disease duration, yrs 2.0 (1.3) 2.1 (1.4) 4.7 (2.9) 4.5 (2.7)Relapses in past year, n 1.8 (0.8) 1.8 (0.8) 1.5 (0.75) 1.7 (0.9)

Prior therapy, % SC IFNB-1a (22 or 44 μg)IM IFNB-1aSC IFNB-1bGlatiramer acetateNatalizumab

– –

36.122.831.234.23.5

34.328.236.234.33.5

Duration of prior therapy, months – – 36 (23.7) 35 (25.0)

Alem=alemtuzumab1. Coles AJ et al. ECTRIMS 2011; 2. Cohen JA et al. AAN 2012.

All values shown are mean (SD) unless otherwise noted.

CARE-MS I and II: Annualized Relapse Rate (Co-primary Endpoint)

ARR=annualized relapse rate1. Coles AJ et al. ECTRIMS 2011; 2. Cohen JA et al. AAN 2012.

Years 0–2

0.39 0.18

Reduction: 54.9%p<0.0001

Adj

uste

d A

RR

(95%

CI)

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

CARE-MS I

Alem 12 mg(n=376)

SC IFNB-1a(n=187)

Years 0–2

0.52 0.26

Reduction: 49.4%p<0.0001

Adj

uste

d A

RR

(95%

CI)

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

CARE-MS II

Alem 12 mg (n=426)

SC IFNB-1a(n=202)

CARE-MS I and II: Time to 6-month Sustained Accumulation of Disability (Co-primary Endpoint)

EDSS=Expanded Disability Status ScaleSAD is defined as a ≥1 point increase in EDSS lasting ≥6 months (or ≥1.5 point increase if baseline EDSS=0).1. Coles AJ et al. ECTRIMS 2011; 2. Cohen JA et al. AAN 2012.

Hazard ratio: 0.58p=0.0084

Patie

nts

with

SA

D (%

)

25

15

10

5

0

20

CARE-MS II

0 3 6 9 12 15 18 21 24Follow-up Month

12.7%

21.1%Hazard ratio: 0.70p=0.22

CARE-MS I

Patie

nts

with

SA

D (%

)

25

15

10

5

0

20

0 3 6 9 12 15 18 21 24Follow-up Month

8.0%

11.1%SC IFNB-1a

Alemtuzumab 12 mg

SC IFNB-1a

Alemtuzumab 12 mg

187376

185376

181372

177368

170368

No. At RiskSC IFNB-1aAlem 12 mg

164357

162352

158345

149336

202426

200426

184412

175404

167392

162384

155380

145375

131354

CARE-MS II: Disability Improvement

*Defined as a decrease of at least 1 EDSS point lasting at least 6 months, assessed in patients with a baseline EDSS ≥2.0.1. Cohen J et al. AAN 2012; 2. Coles A et al. ECTRIMS 2011.

Sustained Reduction inDisability (SRD)*: CARE-MS II1

Mean EDSS Change fromBaseline: CARE-MS II1

Patie

nts

with

SR

D (%

)

40

30

20

10

00 3 6 9 12 15 18 21 24

Follow-up Month

Hazard ratio: 2.57p=0.0002

29%

13% ‒0.17 p=0.0044

p<0.0001

0.24 p=0.0064

Mea

n ED

SSSc

ore

3.25

3.00

2.75

2.50

2.25

Follow-up Month

Alemtuzumab 12 mg

SC IFNB-1a

0 3 6 9 12 15 18 21 24

SC IFNB-1a

Alemtuzumab 12 mg

In CARE-MS I, there was no significant difference between treatments on EDSS-based endpoints2

CARE-MS II disability improvement data (presenter: G Giovannoni) Immunomodulation, Friday October 12, 3.30 pm (poster #P922)

CARE-MS II: Disability – Highly Active Cohort

Highly active RRMS patients (n=143) defined as having ≥2 relapses in year prior to randomization and ≥1 Gd-enhancing lesion at baseline

While small patient numbers limit the power of this post hoc analysis, disability improvement was directionally consistent with the full cohort

‒0.17

0.24

Mea

n ED

SS S

core

3.3

3.1

2.7

2.3

2.1

2.9

2.5

Follow-up Month

Alemtuzumab 12 mg

SC IFNB-1a

0 3 6 9 12 15 18 21 24 Alem 12 mg(n=101)

17.62

% P

atie

nts

with

SA

D (9

5% C

I)

SC IFNB-1a (n=42)

8.95

51% reductionp=0.1516

Confavreux C et al. EFNS 2012.

CARE-MS II efficacy by prior DMT use (presenter: MS Freedman) Immunomodulation, Thursday, October 11, 3.30 pm (poster #P483)

CARE-MS II: Disability – by Prior Treatment

Alemtuzumab reduced risk of SAD vs. SC IFNβ-1a to a similar level as seen in total patient group (-42%), irrespective of prior treatment

-46-42

-44

-39-43

-41

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0SC IFNB-1a Any IFN Glatiramer Acetate

Ris

k R

educ

tion

in S

AD

with

A

lem

tuzu

mab

vs. S

C IF

NB

-1a

(%)

Prior UseNo Prior Use

SAD=sustained accumulation of disability, defined as Increase of ≥1.0 EDSS point for ≥6 months (or ≥1.5 points if baseline EDSS=0).Freedman MS et al. ECTRIMS 2012.

CARE-MS II efficacy by prior treatment (presenter: MS Freedman) Immunodulation, Thursday, October 11, 3.30 pm (poster #P483)

CARE-MS I & II Efficacy: MRI Summary

CARE-MS I1 CARE-MS II2,3

SC IFNB-1a (n=187)

Alem 12 mg (n=376)

SC IFNB-1a (n=202)

Alem 12 mg (n=426)

Pts with new/enlarging T2 lesions, %

57.6 48.5 (p=0.035)a

68 46 (p<0.0001)a

Change in T2 lesion volume, % ‒ median

-6.5 -9.3(p=0.31)a

-1.2 -1.3(p=0.14)

Pts with Gd- enhancinglesions, %

27.0 15.4 (p=0.0008)a

34 19(p<0.0001)a

Change in BPF, % ‒ median

-1.49 -0.87 (p<0.0001)a

-0.81 -0.62 (p=0.012)a

a An endpoint in the hierarchical analysis before this endpoint was not statistically significant.1. Coles AJ et al. ECTRIMS 2011; 2. Cohen JA et al. AAN 2012; 3. Data on file, Genzyme Corporation.

CARE-MS II MRI data (presenter: DL Arnold) Imaging, Friday October 12, 3.30 pm (poster #P877)

56.0

42.0

27.0

74.0

51.0

39.0

0

10

20

30

40

50

60

70

80

Clinical diseaseactivity-free

MRIactivity-free

MS diseaseactivity-free

CARE-MS I: Disease Activity Status –Proportion of Patients Free of MS Disease Activity

A significantly greater proportion of patients were disease-free with alemtuzumab vs. SC IFNB-1a in CARE-MS I

41.1

Patie

nts

(%)

Note: Clinical disease activity-free defined as absence of relapse or SAD; MRI activity-free defined as absence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesion; MS disease activity-free defined as absence of clinical disease activity or MRI activity.Giovannoni et al. ENS 2012.

p<0.0001

p=0.0388

p=0.0064

SC IFNB-1aAlem 12 mg

CARE-MS I & II Safety: Overview of AEs and SAEs

1. Coles AJ et al. ECTRIMS 2011; 2. Cohen JA et al. AAN 2012.

Adverse Events (AEs)


SC IFNB-1an=187n (%)

Alem 12 mgn=376n (%)




Patients with AEs 172 (92.0) 361 (96.0) 191 (94.6) 428 (98.4) 159 (98.8)

Patients with SAEs 27 (14.4) 69 (18.3) 44 (21.8) 85 (19.5) 30 (18.6)

AEs leading to treatment withdrawal 11 (5.9) 5 (1.3) 18 (8.9) 14 (3.2) 6 (3.7)

AEs leading to study discontinuation 5 (2.7) 0 6 (3.0) 1 (0.2) 0

Deaths 0 1 (0.3) 0 2 (0.5) 0

CARE-MS II safety (presenter: E Havrdova) Risk management for DMTs, Thursday October 11, 3.30 pm (poster #P545)

CARE-MS I & II Safety: Infusion-associated Reactions and Infections

Infusion-associated reactions were common in alemtuzumab-treated patients and were reduced with premedication1

– Symptoms commonly included headache, rash pyrexia, urticaria, flushing and chills– Few serious IARs; and only 1 patient discontinued treatment due to IAR

Infections were common in all treatment groups, but more frequent with alemtuzumab; most were mild to moderate and none were life-threatening or fatal2,3

1. Coles AJ et al. AAN 2012; 2. Coles AJ et al. ECTRIMS 2011; 3. Cohen JA et al. AAN 2012; 4. Data on file; Genzyme Corporation.








Infusion Reaction AEsSerious Infusion Reactions

NANA

338 (89.9)12 (3.2)

NANA

393 (90.3)12 (2.8)

156 (96.9)5 (3.1)

Infection AEsInfection SAEs

85 (45.5)2 (1.1)

253 (67.3)7(1.9)

134 (66.3)3 (1.5)

334 (76.8)16 (3.7)

134 (83.2)6 (3.7)

CARE-MS I: Rate of Adverse Events by Month

The rate of AE’s was similar in both arms except during the months with alemtuzumab administration, due to infusion-associated reactions (IARs)

Rat

e of

Adv

erse

Eve

nts

5

3

1 2 3 4 5 6 7 8 9

2

1

4

010 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Month

SC IFNB-1aAlem 12 mg/day

Coles AJ et al. AAN 2012.

CARE-MS I & II Safety: Secondary Autoimmunity

Most thyroid events managed by conventional oral medications; however, 3 patients underwent thyroidectomy (2 patients in CARE-MS I and 1 patient in CARE-MS II)

Most cases of immune thrombocytopenia purpura (ITP) responded to first-line treatment with prompt and durable responses; 1 CARE-MS II patient underwent splenectomy during the extension study

There were no cases of anti-GBM disease in the 2-year CARE-MS I and II studies

1. Selmaj K et al. AAN 2012; 2. Cohen JA et al. AAN 2012, 3. Habek M et al. ENS 2012








Thyroid AEsSerious thyroid AEs

12 (6.4)0

68 (18.1)4 (1.1)

10 (5.0)0

69 (15.9) 2 (0.5)

31 (19.3)2 (1.2)

ITP AEsSerious ITP AEs

1 (0.5)0

3 (0.8)3 (0.8)

00

4 (0.9) 3 (0.7)

3 (1.9)2 (1.2)

Phase 2 & 3 autoimmunity (presenter: E Fox) Risk management for DMTs, Friday October 12, 3.30 pm (poster #P1005)

Alemtuzumab Long-term Follow-up

1485 patients originally enrolled in the phase 2 and 3 alemtuzumabclinical trials in RRMS entered an extension study1

In the phase 2 extension (n=198):– Alemtuzumab treatment effects were maintained over 5 years, despite last

alemtuzumab treatment being 4 years prior for most patients2

– With safety follow-up up to 6.5 years:• AEs were consistent with the 3-year safety profile, with the exception of 1 case of

Goodpasture’s (anti-GBM) disease and a death due to Burkitt’s lymphoma2

• Incidence of thyroid disease peaked in the 3rd year

1. Fox E et al. ECTRIMS 2012; 2. Coles AJ et al. Neurology 2012;78:1069-78.

Alemtuzumab: Summary

Results of the extensive clinical program support the therapeutic approach of targeted circulating lymphocyte depletion and repopulation for MS – Significant benefits over established efficacy of SC IFNB-1a on ARR and

MRI measures in CARE-MS I and II– Significant benefits over established efficacy of SC IFNB-1a on disability in

CARE-MS II • Consistent across endpoints and cohorts

No new safety signals identified during phase 3 studies and long-term follow-up of phase 2– Proactive risk-minimization procedures enabled early detection and

management of autoimmune related AEs

Health & Medicine

ECTRIMS 2012: Alemtuzumab presentation at Genzyme Satellite Symposium