Disease Activity-Free Status in CARE-MS I Phase 3 Study

G Giovannoni, DL Arnold, JA Cohen, AJ Coles, C Confavreux, EJ Fox, HP Hartung, E Havrdova, K Selmaj, H Weiner, V Brinar, M Stojanovic, SL Lake,

DH Margolin, M Panzara, M Rizzo, and DAS Compston

for the CARE-MS I investigators

2

Disclosures

Dr Gavin Giovannoni reports receiving 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, GlaxoSmithKline, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva Pharmaceuticals, UCB Pharma, and Vertex Pharmaceuticals.

Dr Douglas L. Arnold reports receiving personal compensation or research support form Bayer Healthcare, Biogen Idec, Genentech, Genzyme, Roche, and Teva Pharmaceuticals.

Dr Jeffrey Cohen reports receiving personal compensation as a consultant or speaker from Biogen Idec, Eli Lilly, Novartis, Teva Pharmaceuticals, Receptos, and Vaccinex.

Dr Alasdair J. Coles reports receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck-Serono, and UCB-Celltech.

Prof Christian Confavreux reports receiving research support from Bayer-Schering, Biogen Idec, Genzyme, Merck-Serono, Novartis, Sanofi-Aventis and Teva Pharmaceuticals.

Dr Edward Fox reports receiving consultancy fees, honoraria, travel, and research support from Bayer Healthcare, Novartis, Ono, Sanofi-Aventis, Biogen Idec, EMD Serono, Genzyme, Opexa Therapeutics, Pfizer, Teva Pharmaceuticals, and Eli Lilly.

Dr Hans-Peter Hartung reports receiving the approval of the Rector of HHU fees for consulting, lectures, and activities in Steering Committees of the following companies: Bayer Schering, Biogen Idec, BioMS, Genzyme, Merck-Serono, Novartis, Teva Pharmaceuticals, and Sanofi-Aventis.

Prof Eva Havrdova reports receiving honoraria and grant support from Bayer-Schering, Biogen Idec, Genentech, Genzyme, GlaxoSmithKline, Merck-Serono, Octapharma, Pfizer, Roche, Sanofi-Aventis, and Teva Pharmaceuticals.

CARE-MS I

Dr Krzysztof Selmaj reports receiving consulting fees from Genzyme, Novartis, Biogen Idec, and Roche; lecture fees from Novartis, Merck-Serono, Biogen Idec, and Bayer Healthcare; and financial compensation, including travel, from Genzyme for scientific presentations.

Dr Howard Weiner reports receiving consulting/honoraria from Biogen Idec, EMD Serono, Genzyme, Teva Pharmaceuticals, Novartis, Nasvax, and GlaxoSmithKline and research support from EMD Serono and GlaxoSmithKline.

Dr Gavin Giovannoni reports receiving 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, GlaxoSmithKline, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva Pharmaceuticals, UCB Pharma, and Vertex Pharmaceuticals.

Prof Alastair Compston reports receiving consulting fees, lecture fees, and grant support from Genzyme and lecture fees from Bayer Schering Pharma on behalf of the University of Cambridge.

Drs Vesna Brinar and Miroslav Stojanovic report no conflicts of interest.

Drs David H. Margolin, Stephen L. Lake, and Michael Panzara report receiving personal compensation as employees of Genzyme, a Sanofi company.

Funding was provided by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals.

3

Anti CD52 mAb: humanized monoclonal antibody

Targets CD52 causing depletion of circulating B and T lymphocytes

The acute anti-inflammatory effect is immediately followed by a distinctive pattern of repopulation that occurs over time

This repopulation creates a rebalanced immune system; this mechanism may explain how anti CD52 mAb reduces MS disease activity

Anti CD52 mAb has minimal impact on other immune cells

White Blood Counts after Anti CD52 mAb in CARE-MS I

Neutrophils

MonocytesEosinophilsBasophils

Lymphocytes

0.0

0.5

1.0

1.5

2.0

4.0

4.5

5.0

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

ell

Co

un

ts (

109

/L)

Months after Anti CD52 mAb

CARE-MS I

4

Background and Objective

Two successful phase 3 clinical trials for relapsing-remitting MS (RRMS) vs. subcutaneous interferon beta-1a (SC IFNB-1a)

– CARE-MS I (treatment-naïve patients):• Relapse rate reduced by 55% (p<0.0001)• No significant reduction in sustained accumulation of disability (SAD) (p=0.22)

– CARE-MS II (patients active on prior treatment):• Relapse rate reduced by 49% (p<0.0001) • Risk of SAD reduced by 42% (p=0.0084)

Objective: compare the effects of anti CD52 mAb and SC IFNB-1a on the proportion of patients free of MS disease activity in CARE-MS I (tertiary endpoint)

CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple SclerosisCARE-MS I

55

CARE-MS I: Study Design

Two-year, randomized, rater-blinded, global, multicenter trial

Key inclusion criteria:– Treatment-naïve RRMS– ≥ 2 relapses in last 2 years; ≥1 relapse in last year– EDSS 0–3 – Disease onset <5 years

CARE-MS I

n=173

n=367n=367

3x/week

Anti CD52 mAb12 mg IV(n=376)

IFNB-1a44 mcg SC(n=187)

Daily x 5

Daily x 3

Study duration (months)

0 12 24

Randomized 2:1 (N=581)

Randomized 2:1 (N=581)

6

Measurements of Disease Activity in MS

Relapse– Symptoms must be attributable to MS, last at least 48 hours, be present at

normal body temperature, and be preceded by at least 1 month (30 days) of clinical stability

– Assessed by blinded raters; Relapse Adjudication Panel

6-Month Sustained Accumulation of Disability (SAD)– Increase of ≥1.0 points for ≥6 months, or 1.5 points if baseline EDSS = 0– Blinded raters assessed EDSS at baseline and every 3 months

MRI– New or enlarging T2 lesions or new gadolinium-enhancing lesions– Cranial MRI performed at baseline and annually; scans read by blinded

neuro-radiologists at independent center

CARE-MS I

7

Disease-Free Composite Endpoints

Clinical Disease Activity (CDA)-free: absence of relapse or SAD

MRI Activity-free: absence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesion

MS Disease Activity-free: absence of CDA or MRI activity

CARE-MS I

8

Relapse-free

78%

59%55% Risk Reductionp<0.0001

Follow-up Month

Pat

ien

ts w

ith

ou

t R

elap

se (

%) 100

85

75

65

500 3 6 9 12 15 18 21 24

187 175 156 137 127 118 116 109 101376 366 358 340 321 313 306 299 287

SC IFNB-1aAnti CD52 mAb

No. of Observations

95

80

70

60

90

55

CARE-MS I

9

6-month SAD-free

Unexpectedly low rate of SAD events in the SC IFNB-1a armUnexpectedly low rate of SAD events in the SC IFNB-1a arm

CARE-MS I

100

94

86

80

90

88

96

84

92

98

82

89%89%

92%92%

Follow-up Month

Pat

ien

ts w

ith

ou

t S

AD

(%

)

0 3 6 9 12 15 18 21 24

187 185 181 177 170 164 162 158 149376 376 372 368 363 357 352 345 336

SC IFNB-1aAnti CD52 mAb

No. of Observations

p=0.22

SC IFNB-1aAnti CD52 mAb

10

Clinical Disease Activity-free at Year 2

Odds of experiencing CDA 2.4 times higher with SC IFNB‑1a vs. Anti CD52 mAb; odds ratio = 2.36 (95% confidence interval [CI]: 1.62, 3.43),

CARE-MS I

p<0.0001

p=0.2173

p<0.0001

SC IFNB-1aAnti CD52 mAb

11

MRI Activity-free at Year 2

CARE-MS I

No New/Enlarging T2

LesionsNo Gd-Enhancing

LesionsMRI Activity-Free

p=0.0352

p=0.0008

p=0.0388

SC IFNB-1aAnti CD52 mAb

12

MS Disease Activity-free at Year 2

• Odds of experiencing MS disease activity 1.75 times higher with SC IFNB-1a vs. Anti CD52 mAb; odds ratio=1.75 (95% CI: 1.17, 2.61)

CARE-MS I

CDA-Free MRI Activity–Free MS Disease Activity-Free

p<0.0001

p=0.0388

p=0.0064

SC IFNB-1aAnti CD52 mAb

13

Number of Measures of Disease Activity over 2 Years

CARE-MS I

• Measures of disease activity: relapse, SAD, T2 new/enlarging and Gd+T1 lesions

SC IFNB-1aAnti CD52 mAb

14

Safety Summary

Infusion-associated reactions (IARs)– 90% of anti CD52 mAb patients– Commonly included headache, rash, pyrexia, urticaria, flushing and chills– Responsive to premedication– Few serious IARs; and only 1 patient discontinued treatment due to IAR

Infections – 67% anti CD52 mAb vs. 46% SC IFNB-1a; mostly mild to moderate severity, none

life-threatening or fatal – Most common infections included upper respiratory, UTI, herpes, and localized

fungal– Few serious infections (1.9% anti CD52 mAb vs. 1.1% SC IFNB-1a)

Autoimmune events– Thyroid disorders (18% anti CD52 mAb vs. 6.4% SC IFNB-1a), few serious (1% anti

CD52 mAb vs. 0% SC IFNB-1a), detected through regular monitoring; most events managed by conventional oral medications

– Immune Thrombocytopenic Purpura (0.8% Anti CD52 mAb vs. 0.5% SC IFNB-1a)– Risk minimization plan (patient and physician education, monthly questionnaires,

and monthly labs) allowed early detection and intervention

CARE-MS I

15

Conclusions

CARE-MS I

Freedom from disease activity is an important treatment goal in active relapsing-remitting MS

In an active, early, treatment-naïve population, anti CD52 mAb-treated patients were more likely to be free of clinical disease activity, MRI activity, and overall disease activity than SC IFNB-1a-treated patients

These results reinforce and extend previously reported superior efficacy of anti CD52 mAb over SC IFNB-1a

Safety profile for anti CD52 mAb was consistent with prior studies

The benefit-risk profile of anti CD52 mAb suggests that it may be an effective treatment option in active, early, treatment-naive RRMS patients

16

CARE-MS I Study Group and Acknowledgments

ArgentinaDeri

AustraliaBroadleyBoundyDreyerKingMacdonellMcCombePaineReddelVucic

Brazil CallegaroMartins

CanadaFreedmanGrand’MaisonJacquesTraboulseeYeung

CroatiaAntonelliBrinarHabekKidemet-PiskaćTrkanjecVladic

Czech RepublicKovarovaVachova

SerbiaDinčićDrulovićNadjStojanovićVojinović

SwedenLycke

UkraineKobysMartsynkevychNehrychOrzheshkovskyiVoloshyna

United KingdomColesCompston GiovannoniRobertsonSharrack

United StatesBassBomprezziBosterBraleyCarterCascioneEdwardsFoxGazda GoodmanGudesblattGupta

United States (cont)HerbertHunterHuttonIoneteJonesKaufman KhanLaGanke LallanaLynchMillerMinagarPardoRoweSheppardSteingoTwymanVaishnavVincentWendtWrayWynn

GenzymeBachtellHollensteinJurgensenLakeMargolinMercerOyuelaPalmerPanzaraRizzoSaltonstallSmith

Neurology Steering CommitteeCompston (UK)Arnold (CA)Cohen (US)Coles (UK)Confavreux (FR)Fox (US)Hartung (DE)Havrdova (CZ)Selmaj (PL)Weiner (US)

Data Monitoring CommitteeClifford (US)Barkhof (ND)Snydman (US)DeGroot (US)Cines (US)D’Agostino (US)Antel (CA)Panitch (US) (in memoriam)

Relapse Adjudication PanelGreenberg (US)Kraus (AT)Limmroth (DE)Markowitz (US)Naismith (US)Tabby (US)

MRI AnalysesArnold; NeuroRX (CA)Fisher; CCF (US)

FranceClanet

GermanyBaumHaasStangelZiemannZiemssen

MexicoSantosViolante

PolandKozubskiSelmajStelmasiakSzczudlik

Russia BarantsevichBelovaBoykoGusevMishinMagzhanovMalkovaPoverennovaSkorometsStolyarovYakupovZavalishin

CARE-MS I