1 Abatacept Brian Daniels, M.D. Senior Vice-President Global Clinical Development Bristol-Myers Squibb

1

AbataceptAbataceptBrian Daniels, M.D.Brian Daniels, M.D.Senior Vice-PresidentSenior Vice-President

Global Clinical DevelopmentGlobal Clinical DevelopmentBristol-Myers SquibbBristol-Myers Squibb

2

Abatacept:Abatacept:IntroductionIntroduction

Anthony Waclawski, Ph.D.Anthony Waclawski, Ph.D.Executive DirectorExecutive Director

Global Regulatory SciencesGlobal Regulatory Sciences Bristol-Myers SquibbBristol-Myers Squibb

3

AbataceptAbatacept

4

Proposed IndicationProposed Indication

ORENCIA is indicated for: ORENCIA is indicated for:

Reducing signs and symptoms, inducing major Reducing signs and symptoms, inducing major clinical responseclinical response

Inhibiting the progression of structural damage, andInhibiting the progression of structural damage, and

Improving physical function Improving physical function

Adult patients with moderately to severely active Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate rheumatoid arthritis who have had an inadequate response to one or more DMARDs, such as response to one or more DMARDs, such as methotrexate, or TNF blocking agents methotrexate, or TNF blocking agents

May be used in combination with methotrexate or May be used in combination with methotrexate or other non-biologic DMARD therapyother non-biologic DMARD therapy

5

Regulatory BackgroundRegulatory Background

IND for Rheumatoid ArthritisIND for Rheumatoid Arthritis …………………… October 2000October 2000

Special Protocol AssessmentSpecial Protocol Assessment ............ ............ November November

20022002

Fast Track Program Fast Track Program .......................................................... August 2003August 2003

Pre-BLA meetingPre-BLA meeting .................................. .................................. October 2004October 2004

Continuous Marketing Application Continuous Marketing Application ........ March 2005March 2005

6

Overview of Clinical Development ProgramOverview of Clinical Development Programin Rheumatoid Arthritisin Rheumatoid Arthritis

Phase II Dose finding

monotherapy study (IM103002)

Dose ranging in methotrexate inadequate responders (IM101100)

Combination with etanercept (IM101101)

Phase III Methotrexate

inadequate responder (IM101102)

TNF inadequate responder (IM101029)

Safety Trial (IM101031)

IM101100LT

IM101101LT

IM101102LT

IM101029LT

IM101031LT

Ongoing Open-Label

Extension Studies

7










IM101100LT

IM101101LT

IM101102LT

IM101029LT

IM101031LT

Ongoing Open-Label

Extension Studies

8










IM101100LT

IM101101LT

IM101102LT

IM101029LT

IM101031LT

Ongoing Open-Label

Extension Studies

9

Abatacept: Safety DatabaseAbatacept: Safety Database

Placebo-controlled studiesPlacebo-controlled studies

– 1,955 patients representing 1,688 person-years1,955 patients representing 1,688 person-yearsof exposureof exposure

– 1,330 for 1 year or more1,330 for 1 year or more

Open-label uncontrolled experience: 2,339 patients Open-label uncontrolled experience: 2,339 patients

Combined double-blind and open-label: 2,688 patients Combined double-blind and open-label: 2,688 patients representing 3,827 person-years of exposurerepresenting 3,827 person-years of exposure

Pharmacovigilance Plan Pharmacovigilance Plan

10

Presentation OutlinePresentation Outline

EfficacyEfficacy .................................. George Vratsanos, M.D.George Vratsanos, M.D.

SafetySafety ........................................ Dan MacNeil, M.D.Dan MacNeil, M.D.

SummarySummary …............…............ Brian Daniels, M.D.Brian Daniels, M.D.

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Abatacept:Abatacept:Summary of EfficacySummary of Efficacy

George Vratsanos, M.D.George Vratsanos, M.D.Medical DirectorMedical Director

ImmunologyImmunologyBristol-Myers SquibbBristol-Myers Squibb

12

Outline of PresentationOutline of Presentation

Mechanism of ActionMechanism of Action

Dose selection from Phase II TrialsDose selection from Phase II Trials

Results from Pivotal Phase III Efficacy Trials in: Results from Pivotal Phase III Efficacy Trials in:

– Methotrexate Inadequate RespondersMethotrexate Inadequate Responders

– Anti-TNF Inadequate RespondersAnti-TNF Inadequate Responders

13

Abatacept Selectively Modulates Abatacept Selectively Modulates Co-Stimulation via CD80/86:CD28 PathwayCo-Stimulation via CD80/86:CD28 Pathway

APC

Abatacept

MHC TCR

CD80/86

CD28

T-cell

14

FibroblastFibroblast

Role of Activated T-Cells in RARole of Activated T-Cells in RA

ActivatedActivatedMacrophageMacrophage

ActivatedActivatedB-cellB-cell

IL-6IL-6TNF-TNF- MMPsMMPs Autoantibodies, Autoantibodies, e.g. RFe.g. RF

ActivatedActivatedT-cellT-cell

Inflammation & Joint Destruction

ActivationActivation

15

Proposed Mechanism of Action of AbataceptProposed Mechanism of Action of Abatacept

Decrease T-cell activation and proliferationDecrease T-cell activation and proliferation

Decrease pro-inflammatory cytokine secretion Decrease pro-inflammatory cytokine secretion from activated synovial macrophagesfrom activated synovial macrophages

Decrease autoantibody production (e.g. RF)Decrease autoantibody production (e.g. RF)

No depletion of T-cells or other leukocytesNo depletion of T-cells or other leukocytes

16

Dose SelectionDose Selection

17

Dose Finding StudyDose Finding Study

IM103-002IM103-002

Patient PopulationPatient Population DMARD DMARD Inadequate RespondersInadequate Responders

Background Background MedicationMedication

NoneNone(Monotherapy)(Monotherapy)

Abatacept Doses Abatacept Doses 10 mg/kg10 mg/kg2 mg/kg2 mg/kg

0.5 mg/kg0.5 mg/kg

Primary EndpointPrimary Endpoint (ACR 20)(ACR 20)

3 months3 months

Dose Finding StudyDose Finding Study

IM103-002IM103-002Dose Ranging StudyDose Ranging Study

IM101-100IM101-100

Patient PopulationPatient Population DMARD DMARD Inadequate RespondersInadequate Responders

Methotrexate Methotrexate InadequateInadequate RespondersResponders

Background Background MedicationMedication

NoneNone(Monotherapy)(Monotherapy)

MethotrexateMethotrexate

Abatacept Doses Abatacept Doses 10 mg/kg10 mg/kg2 mg/kg2 mg/kg

0.5 mg/kg0.5 mg/kg

10 mg/kg10 mg/kg2 mg/kg2 mg/kg

Primary EndpointPrimary Endpoint (ACR 20)(ACR 20)

3 months3 months 6 months6 months

Phase II Dose Response StudiesPhase II Dose Response StudiesDouble-Blind, Randomized, Placebo ControlledDouble-Blind, Randomized, Placebo Controlled

18

0

10

20

30

40

50

60

70

80

0 30 60 90 120 150 180 210 240 270 300 330 360

Visit Days

% R

es

po

nd

ers

Abatacept 10mg/kg (N=115)

Abatacept 2 mg/kg (N=105)

Placebo (N=119)

15 1

** p < 0.001 vs placebo^ p < 0.01 vs placebo

IM101-100

ACR 20 Response Rates Over TimeACR 20 Response Rates Over TimeDose Ranging StudyDose Ranging Study

^** ** ** ** ** **

**

Primary Endpoint

19

Rationale for Phase III DesignRationale for Phase III Design

20

Phase III Pivotal StudyPhase III Pivotal StudyPatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

Methotrexate continued

Other DMARDs washout

ScreeningScreening

6 Months

Co-primary eCo-primary endpointndpoint ACR 20ACR 20

Placebo (N = 219)

Abatacept (N = 433)

RandomizationRandomization

1 Year

IM101-102

Day 1

Co-primaryCo-primary endpointendpoint Physical FunctionPhysical Function Structural damageStructural damage

Double-blind Open-label

Treated (N = 652) 10mg/kg

Changes in DMARDs allowed

21

Demographic and Patient CharacteristicsDemographic and Patient CharacteristicsPatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

IM101-102

AbataceptAbataceptN = 433N = 433

PlaceboPlaceboN = 219N = 219

Age in years, meanAge in years, mean 5252 5050

Female (%)Female (%) 78 78 8282

Caucasian (%)Caucasian (%) 8888 8888

Disease duration in years, meanDisease duration in years, mean 99 99

RF+ (%)RF+ (%) 8282 7979

Steroids (%)Steroids (%) 7272 6868

Methotrexate dose, mean mg/wkMethotrexate dose, mean mg/wk 1616 1616

22

Clinical CharacteristicsClinical CharacteristicsPatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

MeanMeanAbataceptAbatacept

N = 433N = 433PlaceboPlaceboN = 219N = 219

Number of tNumber of tender jointsender joints 3131 3232

Number of swollen jointsNumber of swollen joints 2121 2222

Physical function, HAQ scorePhysical function, HAQ score 1.71.7 1.71.7

CRP, mg/dLCRP, mg/dL 3.33.3 2.82.8

DAS-28 (ESR)DAS-28 (ESR) 6.86.8 6.86.8

Percent Patients with ErosionsPercent Patients with Erosions > 99> 99 100100

IM101-102

23IM101-102

Abatacept Abatacept PlaceboPlaceboN = 433N = 433 N = 219N = 219

Completed Double Blind PeriodCompleted Double Blind Period 385 (89)385 (89) 162 (74)162 (74)

DiscontinuedDiscontinued 48 (11)48 (11) 57 (26)57 (26)

Adverse EventsAdverse Events 18 (4.2)18 (4.2) 4 (1.8)4 (1.8)

DeathDeath 1 (0.2)1 (0.2) 1 (0.5)1 (0.5)

Lack of EfficacyLack of Efficacy 13 (3.0)13 (3.0) 40 (18)40 (18)

Lost to Follow-upLost to Follow-up 1 (0.2)1 (0.2) 1 (0.5)1 (0.5)

Withdrawal of ConsentWithdrawal of Consent 10 (2.3)10 (2.3) 5 (2.3)5 (2.3)

OtherOther 5 (1.2)5 (1.2) 6 (2.7)6 (2.7)

Patient Disposition at 1 YearPatient Disposition at 1 YearPatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

Number (%) of PatientsNumber (%) of Patients

24

0

10

20

30

40

50

60

70

80

1 29 57 85 113 141 169 197 225 253 281 309 337 365

Visit Days

% R

es

po

nd

ers

Abatacept (N = 424)

Placebo (N = 214)

ACR 20 Response Over TimeACR 20 Response Over TimePatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

IM101-102

**** ** **

** ** **

*

^

**

15

** p < 0.001^ p < 0.01* p < 0.05

ITT analysis; All patients who D/C are considered non-responders

Primary Endpoint

25

** p < 0.001^ p < 0.01


0

5

10

15

20

25

30

35

1 29 57 85 113 141 169 197 225 253 281 309 337 365

Visit Days

% R

es

po

nd

ers

Abatacept (N = 424)

Placebo (N = 214)

IM101-102

ACR 70 Response Over TimeACR 70 Response Over TimePatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

** ^

****

**

**

**

15

26

14

1.90

5

10

15

20

25

% R

es

po

nd

ers

Abatacept (N = 424)

Placebo (N = 214)

Substantial Clinical Responses at 1 Year Substantial Clinical Responses at 1 Year Patients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

**

** p < 0.001

Major Clinical Response

IM101-102

18

16

4.2 3.8

0

5

10

15

20

25

No Swollen Joints No Tender Joints

% o

f P

ati

en

ts

Abatacept (N = 424)

Placebo (N = 212)

% of Patients with Joint Counts of Zero

****

LOCF Analysis

27

Summary of ACR 20 Subgroup Analyses at 6 MonthsSummary of ACR 20 Subgroup Analyses at 6 MonthsPatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

All PatientsAll Patients

IM101-102

-20 0 20 40 60 80

All (N=638)

< 65 years (N = 547)

≥ 65 years (N = 91)

Female (N = 507)

Male (N = 131)

< 60 kg (N = 164)

60-100 kg (N = 433)

> 100 kg (N = 41)

Negative (N = 75)

Positive (N = 520)

≤ 2 years (N = 136)

> 2 to ≤ 5 years (N =137)

> 5 to ≤ 10 years (N = 159)

> 10 years (N = 206)

AgeAge

GenderGender

RF + or –RF + or –

Body weightBody weight

Duration of RADuration of RA

Treatment Difference with 95% CI

Abatacept Better

Placebo Better

28

Evaluation of Structural Damage ProgressionEvaluation of Structural Damage ProgressionPatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

Assessed using Genant Modified Sharp Assessed using Genant Modified Sharp scoringscoring systemsystem

Paired radiographs obtained in over 90% of all Paired radiographs obtained in over 90% of all randomized patientsrandomized patients

Radiographs scored in blinded fashion using Radiographs scored in blinded fashion using validated methodvalidated method

Data analyzed using comparison of distribution Data analyzed using comparison of distribution of changes from baseline, mean and median of changes from baseline, mean and median changeschanges

29

Genant Modified Sharp Scoring SystemGenant Modified Sharp Scoring SystemPatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

Erosions (Maximum score: 145)Erosions (Maximum score: 145)

– 14 joints in each hand / wrist14 joints in each hand / wrist

– 6 joints in each foot6 joints in each foot

Joint Space Narrowing (Maximum score: 145)Joint Space Narrowing (Maximum score: 145)

– 13 joints in each hand / wrist13 joints in each hand / wrist

– 6 joints in each foot6 joints in each foot

30

0.58

1.211.18

2.32

0.63

1.14

0

1

2

3

Erosion JSN Total

Mea

n C

han

ge

fro

m B

asel

ine Abatacept (N = 391)

Placebo (N = 195)

**^

**

IM101-102

Mean Change in Radiographic Scores at 1 Year Mean Change in Radiographic Scores at 1 Year Patients With Inadequate Response to MethotrexatePatients With Inadequate Response to Methotrexate

** p < 0.001 ^ p < 0.01

JSN = Joint Space Narrowing

31

0.00 0.00

0.53

0.25

0.00

0.27

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Erosion JSN Total

Med

ian

Ch

ang

e fr

om

Bas

elin

e Abatacept (N = 391)

Placebo (N = 195)

IM101-102

Median Change in Radiographic Scores at 1 Year Median Change in Radiographic Scores at 1 Year Patients With Inadequate Response to MethotrexatePatients With Inadequate Response to Methotrexate

JSN = Joint Space Narrowing

32

Distribution of Radiographic Changes in Total Score at 1 YearDistribution of Radiographic Changes in Total Score at 1 Year Patients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

-10

0

10

20

30

40

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Cumulative Probability

Ch

an

ge

fro

m B

as

eli

ne

Placebo (N = 195)

Increasing score

Unchanged

Lower Score

IM101-102

33

-10

0

10

20

30

40

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Cumulative Probability

Ch

an

ge

fro

m B

as

eli

ne

Abatacept (N = 391)Placebo (N = 195)

IM101-102

Comparison of Distribution of Comparison of Distribution of Radiographic Changes in Total Score at 1 YearRadiographic Changes in Total Score at 1 Year

Patients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

pp = 0.012 for Total Score = 0.012 for Total Score

pp = 0.029 for Erosion Score = 0.029 for Erosion Score

pp = 0.009 for JSN Score = 0.009 for JSN Score

34

Physical Function Responder Analysis (HAQ) at 1 YearPhysical Function Responder Analysis (HAQ) at 1 YearPatients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

IM101-102

6458

393933

21

69

44

0

10

20

30

40

50

60

70

80

≥ 0.22Improvement

≥ 0.3Improvement

≥ 0.5Improvement

≥ 0.8Improvement

% R

es

po

nd

ers

Abatacept (N = 424)

Placebo (N = 214)

** p < 0.001

****

**

**

Primary Analysis

35

0

10

20

30

40

50

60

70

80

1 29 57 85 113 141 169 197 225 253 281 309 337 365

Visit Days

% R

es

po

nd

ers

(d

ec

rea

se

≥ 0

.3)

Abatacept (N = 424)

Placebo (N = 214)

15

Clinically Important Improvement in Physical Function Clinically Important Improvement in Physical Function (Decrease in HAQ (Decrease in HAQ ≥ 0.3≥ 0.3))

Patients with Inadequate Response to MethotrexatePatients with Inadequate Response to Methotrexate

IM101-102

*** ** ^ ** ** ** **

** p < 0.001^ p < 0.01* p < 0.05


36

Clinically Important Improvement in Physical Function Clinically Important Improvement in Physical Function (Decrease in mHAQ ≥ 0.3) Over 3 Years(Decrease in mHAQ ≥ 0.3) Over 3 Years

Dose-Ranging StudyDose-Ranging Study

Patient PopulationPatient Population

(Randomized 10mg/kg; (Randomized 10mg/kg; Entered open-label)Entered open-label) 1 Yr1 Yr 2 Yr2 Yr 3 Yr3 Yr

As ObservedAs Observed All PatientsAll Patients Number of Patients Number of Patients % Response% Response

848455%55%

737353%53%

646453%53%

IM101-100

Patients Who Discontinue Considered Non-respondersPatients Who Discontinue Considered Non-responders

All Patients (N = 84)All Patients (N = 84) % Response% Response 55%55% 46%46% 42%42%

mHAQ Responders at 1 year (N = 46)mHAQ Responders at 1 year (N = 46) % Response% Response —— 67%67% 57%57%

37

Improvement in Quality of Life (SF-36) at 1 Year Improvement in Quality of Life (SF-36) at 1 Year Patients with Inadequate Response to Methotrexate Patients with Inadequate Response to Methotrexate

IM101-102

9.1

5.0

0

2

4

6

8

10

12

Me

an

Ch

an

ge

fro

m B

as

elin

e

Abatacept (N = 417)Placebo (N = 207)

**

Physical Component SummaryPhysical Component Summary

6.9

4.7

0

2

4

6

8

10

12

Me

an

Ch

an

ge

fro

m B

as

elin

e

Abatacept (N = 417)

Placebo (N = 207)

*

** p < 0.001* p < 0.05

LOCF Analysis

Mental Component SummaryMental Component Summary

38

8.0

9.4

11.6

6.5

8.1 8.4 8.8

6.3

4.55.7 5.9

4.24.7

5.3 5.5

4.2

0

5

10

15

PhysicalFunction

Role-Physical

Bodily Pain

GeneralHealth

Vitality SocialFunction

Role-Emotional

MentalHealth

Me

an

Ch

an

ge

fro

m B

as

elin

e

Abatacept Placebo

Improvement in Quality of Life (SF-36) at 1 YearImprovement in Quality of Life (SF-36) at 1 Year Patients with Inadequate Response to Methotrexate Patients with Inadequate Response to Methotrexate

IM101-102

****

**

**** ** ^

^

** p < 0.001^ p < 0.01

LOCF Analysis

39

Phase III Pivotal StudyPhase III Pivotal Study

Patients with Inadequate Response Patients with Inadequate Response to Anti-TNF Therapyto Anti-TNF Therapy

40

Placebo (N = 133)

Abatacept (N = 258)

RandomizationRandomization

Day 1

Double-blind Open-label

6 Months

Co-primaryCo-primary endpointendpoint ACR 20ACR 20 Physical FunctionPhysical Function

IM101-029

Treated (N = 391)

Stratified Recent vs PriorStratified Recent vs Prior

DMARDs continued

AntiTNF washout period

(28–60 days)

10mg/kg

Phase III Pivotal StudyPhase III Pivotal StudyPatients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy

41

Key Requirements for EntryKey Requirements for EntryPatients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy

Only patients with lack of efficacy on Anti-TNF eligibleOnly patients with lack of efficacy on Anti-TNF eligible

Minimum of 10 swollen and 12 tender joints with Minimum of 10 swollen and 12 tender joints with elevated CRP despite at least 3 months of Anti-TNF elevated CRP despite at least 3 months of Anti-TNF therapy required therapy required

Lack of efficacy occurred immediately before Lack of efficacy occurred immediately before enrollment (‘recent user’) or more distantly (‘prior user’)enrollment (‘recent user’) or more distantly (‘prior user’)

Lack of efficacy directly observed in recent usersLack of efficacy directly observed in recent users

Source Documentation of inadequate response Source Documentation of inadequate response required for prior usersrequired for prior users

IM101-029

42

Demographic and Patient CharacteristicsDemographic and Patient CharacteristicsPatients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy

IM101-029



Age in years, mean 53 53

Female (%) 77 80

Caucasian (%) 96 93

RA duration in years, mean 12 11

RF+ (%) 73 73

43

Anti-TNF Use Before StudyAnti-TNF Use Before StudyPatients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy

IM101-029

% of Patients% of Patients



History of Anti-TNF UseHistory of Anti-TNF Use

Recent UsersRecent Users 38 38 4141

Prior UsersPrior Users 6262 5959

Type of Anti-TNF UseType of Anti-TNF Use

Infliximab UsersInfliximab Users

Etanercept UsersEtanercept Users

6868

3232

6060

4040

Both Infliximab & Etanercept Both Infliximab & Etanercept 2121 1717

44

Clinical CharacteristicsClinical CharacteristicsPatients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy

IM101-029

MeanMean



Number of tender jointsNumber of tender joints 3131 3333

Number of swollen joints Number of swollen joints 2222 2222

Physical function, HAQ scorePhysical function, HAQ score 1.81.8 1.81.8

CRP, mg/dLCRP, mg/dL 4.64.6 4.04.0

DAS-28 (ESR)DAS-28 (ESR) 6.96.9 6.96.9

45

Patient Disposition at Six MonthsPatient Disposition at Six Months Patients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy




Completed Double Blind periodCompleted Double Blind period 223 (86)223 (86) 99 (74)99 (74)

Discontinued Discontinued 35 (14)35 (14) 34 (26)34 (26)

Adverse eventsAdverse events 9 (3.5)9 (3.5) 5 (3.8)5 (3.8)

DeathDeath 00 00

Lack of EfficacyLack of Efficacy 14 (5.4)14 (5.4) 27 (20)27 (20)

Lost to Follow-upLost to Follow-up

Withdrawal of consentWithdrawal of consent

OtherOther

5 (1.9)5 (1.9)

5 (1.9)5 (1.9)

2 (0.8)2 (0.8)

00

2 (1.5)2 (1.5)

00

IM101-029

46

0

10

20

30

40

50

60

70

80

1 29 57 85 113 141 169

Visit Days

% R

es

po

nd

ers

Abatacept (N = 256)

Placebo (N = 133)

ACR 20 Responses Over TimeACR 20 Responses Over TimePatients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy

IM101-029

** ****

**

^

^

**

** p < 0.001^ p < 0.01


15

Primary Endpoint

47

Substantial Clinical ResponsesSubstantial Clinical ResponsesPatients with Patients with Inadequate Response to Anti-TNF Therapy

0

2

4

6

8

10

12

14

1 29 57 85 113 141 169

Visit Days

% R

es

po

nd

ers

Abatacept (N = 256)

Placebo (N = 133)

15

*

^

** ^

*

** p < 0.001^ p < 0.01* p < 0.05

IM101-029

ACR 70

1

7.97.5

1.50.8

0

2

4

6

8

10

No Swollen Joints No Tender Joints

% o

f P

ati

en

ts

Abatacept (N = 254)

Placebo (N = 130)

% of Patients with Joint Counts of Zero

**

LOCF AnalysisITT analysis; All patients who D/C are considered non-responders

48

Summary of ACR 20 Subgroup Analyses at 6 MonthsSummary of ACR 20 Subgroup Analyses at 6 MonthsPatients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy

IM101-029

-20 0 20 40 60 80

All (N = 389)

< 65 years (N = 318)

≥ 65 years (N = 71)

Female (N = 304)

Male (N = 85)

< 60 kg (N = 68)

60-100 kg (N = 266)

> 100 kg (N = 53)

Recent (N = 152)

Prior (N = 237)

Etanercept (N = 104)

Infliximab (N = 208)

Etanercept and Infliximab (N = 77)

All PatientsAll Patients

AgeAge

GenderGender

Anti-TNF HistoryAnti-TNF History

Body weightBody weight

Type of Anti-TNFType of Anti-TNF

Abatacept Better

Placebo Better

Treatment Difference with 95% CI

49

Physical Function Responder Analysis (HAQ) at 6 MonthsPhysical Function Responder Analysis (HAQ) at 6 MonthsPatients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy

IM101-029

47

41

2023

14

59

4.5

33

0

10

20

30

40

50

60

70

80

≥ 0.22Improvement

≥ 0.3Improvement

≥ 0.5Improvement

≥ 0.8Improvement

% R

es

po

nd

ers

Abatacept (N = 256)

Placebo (N = 133)

** p < 0.001

**

****

**

Primary Analysis

50

Improvement in Quality of Life (SF-36) at 6 Months Improvement in Quality of Life (SF-36) at 6 Months Patients with Inadequate Response to Patients with Inadequate Response to Anti-TNF Therapy

IM101-029

6.6

1.10

2

4

6

8

10

Me

an

Ch

an

ge

fro

m B

as

elin

e

Abatacept (N = 242)

Placebo (N = 129)

**

Physical Component SummaryPhysical Component Summary

5.2

2.1

0

2

4

6

8

10

Me

an

Ch

an

ge

fro

m B

as

elin

e

Abatacept (N = 242)

Placebo (N = 129)

^

Mental Component SummaryMental Component Summary

** p < 0.001^ p < 0.01

LOCF Analysis

51

Improvement in Quality of Life (SF-36) After 6 Months Improvement in Quality of Life (SF-36) After 6 Months Patients with Inadequate Response to Patients with Inadequate Response to Anti-TNF Therapy

5.3

6.5

8.7

4.0

6.67.3

6.0

4.3

1.3 1.32.5

0.7 1.82.4 2.5

1.60

5

10

15

PhysicalFunction

Role-Physical

Bodily Pain

GeneralHealth

Vitality SocialFunction

Role-Emotional

MentalHealth

Me

an

Ch

an

ge

fro

m B

as

elin

e

Abatacept Placebo

IM101-029

** p < 0.001^ p < 0.01* p < 0.05

LOCF Analysis

****

**

**

****

*

^

52

Clinical Biomarker DataClinical Biomarker Data

53

0

10

20

30

40

50

Abatacept Placebo

pg

/mL

Mean Values of Biomarkers at 6 MonthsMean Values of Biomarkers at 6 MonthsPatients with Inadequate Response to Anti-TNF TherapyPatients with Inadequate Response to Anti-TNF Therapy

IM101-029

TNF-α

0

10

20

30

40

50

Abatacept Placebo

pg

/mL

IL-6

MMP-3

Rheumatoid Factor

Pro-inflammatory Cytokines Proteolytic Enzyme

Autoantibody

0

20

40

60

80

100

Abatacept Placebo

ng

/mL

0

50

100

150

200

250

300

Abatacept Placebo

U/m

L

Abatacept Placebo

B/L 6 Mo B/L 6 Mo

B/L 6 Mo B/L 6 Mo

B/L 6 Mo B/L 6 Mo

B/L 6 Mo B/L 6 Mo

Normal Range Normal

Range

Normal RangeNormal

Range

B/L = baseline value

54

ConclusionsConclusions

All primary and key secondary outcomes achieved:All primary and key secondary outcomes achieved:– Consistent effect on ACR 20, 50 and 70Consistent effect on ACR 20, 50 and 70– Inhibition of structural damage Inhibition of structural damage – Improvement in physical function and Improvement in physical function and

quality of lifequality of life

Major reductions in disease activity:Major reductions in disease activity:– ACR 70 responseACR 70 response– Major clinical responseMajor clinical response– Proportion of patients with no swollen or Proportion of patients with no swollen or

tendertender jointsjoints

55

Daniel J. MacNeil, M.D.Daniel J. MacNeil, M.D.Executive DirectorExecutive Director

Global PharmacovigilanceGlobal Pharmacovigilance Bristol-Myers Squibb Bristol-Myers Squibb

Abatacept:Abatacept:Summary of SafetySummary of Safety

56

Abatacept Safety Presentation TopicsAbatacept Safety Presentation Topics

Description of patient population and overview Description of patient population and overview

of general safety and tolerabilityof general safety and tolerability

Clinical findings on infection and malignancyClinical findings on infection and malignancy

Plans for further assessment of safety profile Plans for further assessment of safety profile post-approvalpost-approval

57

Safety Assessment Methods Safety Assessment Methods

Based on safety data provided to and reviewed by Based on safety data provided to and reviewed by FDA in BLA and 4 Month Safety Update FDA in BLA and 4 Month Safety Update

Tables include events occurring up to 56 days Tables include events occurring up to 56 days post last dose of study drug (5 half-lives) post last dose of study drug (5 half-lives)

Adverse events classified using standard coding Adverse events classified using standard coding dictionary, MedDRA dictionary, MedDRA

Severity classified by investigator according to Severity classified by investigator according to regulatory and functional criteria regulatory and functional criteria

58

RA Safety PopulationRA Safety Population

Cumulative Cumulative (Double-Blind and Open-Label)(Double-Blind and Open-Label)

Open-Label, UncontrolledOpen-Label, UncontrolledN = 2,339

N = 2,688

PlaceboPlaceboAbataceptAbatacept

N = 1,955(204)

Double-Blind, ControlledDouble-Blind, Controlled(Biologic Background)(Biologic Background)

N = 989(134)

BLA/4M

59

Extent of Exposure to AbataceptExtent of Exposure to Abatacept

Population: Treated patients in 5 Core RA studiesPopulation: Treated patients in 5 Core RA studies

66 1567 1567 (80) (80) 2467 2467 (92)(92)

1212 1330 1330 (68) (68) 1792 1792 (67)(67)

1818 –– 1471 1471 (55)(55)

2424 –– 278 278 (10)(10)

3636 –– 162 162 (6) (6)

Exposure Exposure in Monthsin Months Number (%) of PatientsNumber (%) of Patients

Cumulative Cumulative N = 2688N = 2688

Double-BlindDouble-Blind N = 1955 N = 1955

Person-YearsPerson-YearsExposure Exposure 16881688 3827 3827

Median MonthsMedian MonthsExposure (Range)Exposure (Range) 12 (2, 14)12 (2, 14) 20 (2, 48) 20 (2, 48)

60

Age in years, meanAge in years, mean

% Female% Female

% Caucasian% Caucasian

Disease duration in yearsDisease duration in years

5252

8080

8787

1010


5353

7979

8888

1010

Patient CharacteristicsPatient Characteristics Double-Blind, Controlled Study Periods Double-Blind, Controlled Study Periods


Double-Blind Concomitant Double-Blind Concomitant Medication Use: Medication Use:

MethotrexateMethotrexate

Systemic SteroidSystemic Steroid

BiologicBiologic

83% 83%

75%75%

14%14%

82% 82%

74%74%

10%10%

BLA

61

Overview of Patients with Adverse EventsOverview of Patients with Adverse EventsDouble-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods

AEsAEs

SAEsSAEs

Discontinuation due to AEsDiscontinuation due to AEs

DeathsDeaths


1736 (88.8)1736 (88.8)

266 (13.6)266 (13.6)

107 (5.5) 107 (5.5)

10 (0.5)10 (0.5)


840 (84.9)840 (84.9)

122 (12.3)122 (12.3)

39 (3.9)39 (3.9)

6 (0.6)6 (0.6)


62

Adverse Events with Difference Adverse Events with Difference Between Abatacept vs Placebo (Between Abatacept vs Placebo (≥≥2%) 2%)

Double-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods

Total Patients with AE Total Patients with AE

HeadacheHeadache

NasopharyngitisNasopharyngitis

DizzinessDizziness

HypertensionHypertension

DyspepsiaDyspepsia

1736 (88.8) 1736 (88.8)

356 (18.2)356 (18.2)

225 (11.5)225 (11.5)

183 (9.4)183 (9.4)

129 (6.6)129 (6.6)

126 (6.4) 126 (6.4)

840 (84.9) 840 (84.9)

125 (12.6) 125 (12.6)

90 (9.1) 90 (9.1)

69 (7.0) 69 (7.0)

43 (4.3) 43 (4.3)

42 (4.2)42 (4.2)

Preferred TermPreferred TermAbataceptAbataceptN = 1955N = 1955


BLA


63

Total Patients with SAEs Total Patients with SAEs

Musculoskeletal and Musculoskeletal and Connective Tissue DisordersConnective Tissue Disorders

Infections and InfestationsInfections and Infestations

Injury, Poisoning, and Procedural ComplicationsInjury, Poisoning, and Procedural Complications

Neoplasms Benign, Malignant and Unspecified Neoplasms Benign, Malignant and Unspecified

Gastrointestinal Disorders Gastrointestinal Disorders

Nervous System DisordersNervous System Disorders

Cardiac DisordersCardiac Disorders

Serious Adverse Events (≥ 1.0%) Serious Adverse Events (≥ 1.0%) Double-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods

266 (13.6)266 (13.6)

59 (3.0)59 (3.0)

58 (3.0)58 (3.0)

29 (1.5)29 (1.5)

28 (1.4)28 (1.4)

23 (1.2)23 (1.2)

19 (1.0)19 (1.0)

18 (0.9)18 (0.9)

System Organ ClassSystem Organ ClassAbataceptAbataceptN = 1955N = 1955


122 (12.3)122 (12.3)

37 (3.7)37 (3.7)

19 (1.9)19 (1.9)

7 (0.7)7 (0.7)

11 (1.1)11 (1.1)

13 (1.3)13 (1.3)

14 (1.4)14 (1.4)

17 (1.7)17 (1.7)


64

Total Patient DeathsTotal Patient Deaths

Cardiac DisordersCardiac Disorders

General DisordersGeneral Disorders

Neoplasms Benign, Malignant & Neoplasms Benign, Malignant & UnspecifiedUnspecified

Infections and InfestationsInfections and Infestations

Injury, Poisoning & Procedural Injury, Poisoning & Procedural ComplicationsComplications

Nervous System DisordersNervous System Disorders

Investigations (Diagnostic Procedures Investigations (Diagnostic Procedures or Findings)or Findings)

DeathsDeathsDouble-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods

10 (0.5)10 (0.5)

4 (0.2)4 (0.2)

3 (0.2)3 (0.2)

2 (0.1)2 (0.1)

1 (< 0.1)1 (< 0.1)

1 (< 0.1)1 (< 0.1)

00

00

6 (0.6)6 (0.6)

2 (0.2)2 (0.2)

2 (0.2)2 (0.2)

1 (1 (00.1).1)

2 (0.2)2 (0.2)

00

1 (0.1)1 (0.1)

1 (0.1)1 (0.1)

System Organ ClassSystem Organ ClassAbataceptAbatacept

N = 1955N = 1955PlaceboPlacebo

N = 989N = 989


4M

65

Safety in Combination with Safety in Combination with Other Biologic TherapiesOther Biologic Therapies

66



Overview of Safety in Patients Treated with Overview of Safety in Patients Treated with Biologic Background TherapyBiologic Background Therapy Double-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods

AEs 192 (94.1) 113 (84.3)

All infections 130 (63.7) 58 (43.3)

SAEs 40 (19.6) 12 (9.0)

Serious Infections 9 (4.4) 2 (1.5)

Malignancies 3 (1.5) 0

Deaths 0 0

Biologic RA TherapyBiologic RA Therapy

BLA


67

Special Topics:Special Topics:Infections and MalignanciesInfections and Malignancies

68

InfectionsInfections

Frequency and Type of Infection Frequency and Type of Infection – Overall Overall – Most Common Most Common – Serious Serious

Severity of InfectionSeverity of Infection– % serious, % severe or very severe in intensity% serious, % severe or very severe in intensity– % IV antibiotic therapy% IV antibiotic therapy– % resulting in discontinuation of therapy% resulting in discontinuation of therapy– % resulting in death % resulting in death

Incidence Rate of Infection over time Incidence Rate of Infection over time Infections of Particular Interest Infections of Particular Interest

– Pneumonia Pneumonia – HerpesHerpes– Tuberculosis Tuberculosis

69

Total Patients with InfectionsTotal Patients with Infections

Upper Respiratory Tract InfectionUpper Respiratory Tract Infection

NasopharyngitisNasopharyngitis

SinusitisSinusitis

Urinary Tract Infection Urinary Tract Infection

InfluenzaInfluenza

BronchitisBronchitis

1051 (53.8)1051 (53.8)

248 (12.7)248 (12.7)

225 (11.5)225 (11.5)

125 (6.4)125 (6.4)

113 (5.8)113 (5.8)

111 (5.7)111 (5.7)

101 (5.2)101 (5.2)

478 (48.3)478 (48.3)

119 (12.0)119 (12.0)

90 (9.1) 90 (9.1)

68 (6.9) 68 (6.9)

45 (4.6) 45 (4.6)

52 (5.3) 52 (5.3)

45 (4.6) 45 (4.6)

Most Common Infections (≥ 5%) Most Common Infections (≥ 5%) Double-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods




BLA

70

Total Patients with Serious InfectionsTotal Patients with Serious Infections

PneumoniaPneumonia

CellulitisCellulitis

Urinary Tract Infection Urinary Tract Infection

Bronchitis Bronchitis

DiverticulitisDiverticulitis

Pyelonephritis AcutePyelonephritis Acute

SepsisSepsis

Serious Infections (≥ 0.2%) Serious Infections (≥ 0.2%) Double-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods

58 (3.0)58 (3.0)

9 (0.5)9 (0.5)

5 (0.3)5 (0.3)

4 (0.2)4 (0.2)

4 (0.2)4 (0.2)

3 (0.2)3 (0.2)

3 (0.2)3 (0.2)

1 (<0.1)1 (<0.1)

19 (1.9)19 (1.9)

5 (0.5) 5 (0.5)

2 (0.2) 2 (0.2)

1 (0.1) 1 (0.1)

0 0

0 0

0 0

3 (0.3)3 (0.3)




BLA

71

Intensity of InfectionsIntensity of Infections Double-Blind, Controlled Study Periods Double-Blind, Controlled Study Periods



24 (2.4)24 (2.4)58 (3.0)58 (3.0)SevereSevere

4 (0.4)4 (0.4)4 (0.2)4 (0.2)Very SevereVery Severe

227 (23.0)227 (23.0)537 (27.5)537 (27.5)ModerateModerate

319 (32.3)319 (32.3)699 (35.8)699 (35.8)MildMild


BLA

478 (48.3)478 (48.3)1051 (53.8)1051 (53.8)Total Patients with InfectionsTotal Patients with Infections

72

IV Antibiotics UseIV Antibiotics Use

StudyStudy# Months on # Months on Study DrugStudy Drug AbataceptAbatacept PlaceboPlacebo

IM101-102IM101-102(MTX-IR)(MTX-IR)

0 – 60 – 6 9/433 (2.1)9/433 (2.1) 5/219 (2.3)5/219 (2.3)

6 – 126 – 12 15/401 (3.7) 15/401 (3.7) 7/174 (4.0)7/174 (4.0)

IM101-029IM101-029(Anti-TNF IR)(Anti-TNF IR) 0 – 60 – 6 3/258 (1.2)3/258 (1.2) 4/133 (3.0)4/133 (3.0)

IM101-031IM101-031(Safety)(Safety) 0 – 120 – 12 38/959 (4.0) 38/959 (4.0) 18/482 (3.7) 18/482 (3.7)

BLA

n/N (%) of Patientsn/N (%) of Patients

73

Total Discontinued Due to InfectionsTotal Discontinued Due to Infections

PneumoniaPneumonia

24 (1.2)24 (1.2)

4 4 (0.2)(0.2)

10 (1.0)10 (1.0)

1 (0.1)1 (0.1)

Localized infectionsLocalized infections 33 (0.2)(0.2) 00

BronchitisBronchitis 22 (0.1)(0.1) 2 (0.2)2 (0.2)

SepsisSepsis 11 (<0.1) (<0.1) 2 (0.2)2 (0.2)

Discontinuation Due to Infections*Discontinuation Due to Infections*Double Blind, Controlled Study PeriodsDouble Blind, Controlled Study Periods

* AEs that led to discontinuation in 2 or more patients




74

Deaths Due to Infectious Adverse EventsDeaths Due to Infectious Adverse EventsDouble-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods

Total Infectious DeathsTotal Infectious Deaths

AspergillosisAspergillosis

PneumocystisPneumocystis

SepsisSepsis


1 (<0.1)1 (<0.1)

1 (<0.1)1 (<0.1)

0 0

00


2 (0.2)2 (0.2)

0 0

1 (0.1)1 (0.1)

1 (0.1)1 (0.1)


BLA

75

Time Intervals (Months)Time Intervals (Months)

0-6 0-6 6-126-12 12-1812-18 18-2418-24 24-30 24-30 >30 >30

n/p-y*n/p-y* 50/128550/1285 39/103239/1032 22/79522/795 9/3999/399 4/1174/117 3/1983/198

IR/100 p-y**IR/100 p-y** 3.923.92 3.813.81 2.782.78 2.262.26 3.453.45 1.531.53

(95% CI)(95% CI) (2.91, 5.17)(2.91, 5.17) (2.71, 5.20)(2.71, 5.20) (1.74, 4.21)(1.74, 4.21) (1.03, 4.29)(1.03, 4.29) (0.94, 8.83)(0.94, 8.83) (0.31, 4.46)(0.31, 4.46)

Serious Infection Incidence Rates by Time IntervalsSerious Infection Incidence Rates by Time IntervalsCumulative Study Periods – Through 4 Month UpdateCumulative Study Periods – Through 4 Month Update

* n/p-y = Number of patients / person-years** IR/100 p-y = Incidence rates per 100 person-years

4M

76




Total Patients with PneumoniaTotal Patients with Pneumonia 4242 (2.1)(2.1) 1010 (1.0)(1.0)

Median Onset in Days (Range) *Median Onset in Days (Range) * 161 161 (9, 358)(9, 358) 223223 (53, 359)(53, 359)

Median Duration in Days (Range) *Median Duration in Days (Range) * 1212 (2, 50)(2, 50) 14 14 (1, 51)(1, 51)

SeriousSerious 1414 (0.7)(0.7) 66 (0.6)(0.6)

SevereSevereVery SevereVery Severe

111111

(0.6)(0.6)(<0.1)(<0.1)

1122

(0.1)(0.1)(0.2)(0.2)

DiscontinuedDiscontinued 55 (0.3)(0.3) 11 (0.1)(0.1)

Overview of PneumoniaOverview of PneumoniaDouble-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods

BLA* Onset and duration calculated using specific PT of “Pneumonia” only.

77

Incidence of Infections in Herpes FamilyIncidence of Infections in Herpes FamilyDouble-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods




Herpes SimplexHerpes Simplex 37 37 (1.9)(1.9) 1010 (1.0)(1.0)

Herpes ZosterHerpes Zoster 3030 (1.5)(1.5) 1616 (1.6)(1.6)

Herpes Viral InfectionHerpes Viral Infection 55 (0.3)(0.3) 22 (0.2)(0.2)

VaricellaVaricella 33 (0.2)(0.2) 00

Epstein-Barr VirusEpstein-Barr Virus 00 00

CytomegalovirusCytomegalovirus 00 00

BLA

78

TuberculosisTuberculosisCumulative Study PeriodsCumulative Study Periods

2 cases of presumed tuberculosis with abatacept2 cases of presumed tuberculosis with abatacept Tuberculous Infection (Double-Blind): Tuberculous Infection (Double-Blind):

– Presented with cervical lymphadenitis; diagnosis Presented with cervical lymphadenitis; diagnosis based on histologybased on histology

Pulmonary Tuberculosis Suspected (Open-Label)Pulmonary Tuberculosis Suspected (Open-Label)

– Presented with dry cough, fever, diaphoresis and Presented with dry cough, fever, diaphoresis and crepitus; diagnosis based on clinical presentation crepitus; diagnosis based on clinical presentation and chest radiographand chest radiograph

1 case of presumed tuberculosis with placebo1 case of presumed tuberculosis with placebo Tuberculosis - Suspect (Double-Blind): Tuberculosis - Suspect (Double-Blind):

– Unknown presentation; no definitive diagnosisUnknown presentation; no definitive diagnosis

79

Infections: ConclusionsInfections: Conclusions

Abatacept treatment associated with an increase Abatacept treatment associated with an increase in frequency of infections, including 1% increase in frequency of infections, including 1% increase in serious infectionsin serious infections

Infections occurring with abatacept were similar to Infections occurring with abatacept were similar to those occurring on placebo in type, severity, those occurring on placebo in type, severity, treatment, duration, and outcometreatment, duration, and outcome

80

MalignancyMalignancy

PresentationPresentation

– Non-clinical findingsNon-clinical findings

– Overall clinical experienceOverall clinical experience

– Malignancies of particular interestMalignancies of particular interest Evaluation based onEvaluation based on

– Frequency versus placebo in Double-BlindFrequency versus placebo in Double-Blind

– Incidence over time in Cumulative PeriodIncidence over time in Cumulative Period

– Incidence relative to reference databases Incidence relative to reference databases (both general population and RA specific)(both general population and RA specific)

– Clinical characteristicsClinical characteristics

81

Carcinogenicity Study in MiceCarcinogenicity Study in Mice

Duration: up to 88 weeksDuration: up to 88 weeks

Exposures: 0.8-, 1.9- and 3.0-fold human exposureExposures: 0.8-, 1.9- and 3.0-fold human exposure

Sustained immunomodulation at all dose levelsSustained immunomodulation at all dose levels

Increased incidence of virally mediated tumorsIncreased incidence of virally mediated tumors

– Lymphoma at all doses Lymphoma at all doses Murine leukemia virus detected in Murine leukemia virus detected in

genome of micegenome of mice

– Mammary gland tumors in females at top two Mammary gland tumors in females at top two dosesdoses Mouse mammary tumor virus detected Mouse mammary tumor virus detected

in tumorsin tumors

82

Primate Toxicology StudyPrimate Toxicology Study

Conventional toxicology study enhanced to Conventional toxicology study enhanced to evaluate lymphoid neoplasiaevaluate lymphoid neoplasia

Duration: One year study – cynomolgus monkeysDuration: One year study – cynomolgus monkeys

Exposure multiples up to 9-fold human exposureExposure multiples up to 9-fold human exposure

Oncogenic virus in genome of 38/40 monkeysOncogenic virus in genome of 38/40 monkeys

No lymphoma or pre-lymphomatous changesNo lymphoma or pre-lymphomatous changes

83

Total 26 (1.3) 11 (1.1)

Non-melanoma Skin 15 (0.8) 6 (0.6) Basal Cell Carcinoma 10 (0.5) 4 (0.4) Squamous Cell Carcinoma 6 (0.3) 2 (0.2)Solid 9 (0.5) 5 (0.5) Lung 4 (0.2) 0 Thyroid 2 (0.1) 0 Breast 1 (<0.1) 2 (0.2) Prostate 1 (<0.1) 0 Bladder 1 (<0.1) 0 Renal 1 (<0.1) 0 Endometrial / Uterine 0 2 (0.2) Melanoma 0 1 (0.1)Hematologic 2 (0.1) 0 Lymphoma 1 (<0.1) 0 Myelodysplastic Syndrome 1 (<0.1) 0

MalignanciesMalignanciesDouble-Blind, Controlled Study PeriodsDouble-Blind, Controlled Study Periods


Placebo Placebo N = 989N = 989Type of MalignancyType of Malignancy

4M


84

Non-melanoma Skin Non-melanoma Skin 15 (0.89)15 (0.89) 24 (0.63)24 (0.63)SolidSolid 9 (0.53)9 (0.53) 21 (0.55)21 (0.55) Lung Lung 4 (0.24)4 (0.24) 8 (0.21)8 (0.21) ThyroidThyroid 2 (0.12)2 (0.12) 2 (0.05)2 (0.05) BreastBreast 1 (0.06)1 (0.06) 2 (0.05)2 (0.05) ProstateProstate 1 (0.06)1 (0.06) 2 (0.05)2 (0.05) BladderBladder 1 (0.06)1 (0.06) 1 (0.03)1 (0.03) RenalRenal 1 (0.06)1 (0.06) 1 (0.03)1 (0.03) OvarianOvarian 00 2 (0.05)2 (0.05) MelanomaMelanoma 00 1 (0.03)1 (0.03) Endometrial / UterineEndometrial / Uterine 00 2 (0.05)2 (0.05) CervixCervix 00 1 (0.03)1 (0.03)HematologicHematologic 2 (0.12)2 (0.12) 5 (0.13)5 (0.13) LymphomaLymphoma 1 (0.06)1 (0.06) 4 (0.10)4 (0.10) Myelodysplastic SyndromeMyelodysplastic Syndrome 1 (0.06)1 (0.06) 1 (0.03)1 (0.03)

Malignancies – AbataceptMalignancies – AbataceptDouble-Blind and Cumulative Study PeriodsDouble-Blind and Cumulative Study Periods

Type of MalignancyType of Malignancy

Double-BlindDouble-BlindN = 1955 (p-y = 1688)N = 1955 (p-y = 1688)

n (per 100 p-y)n (per 100 p-y)

CumulativeCumulativeN = 2688 (p-y = 3827)N = 2688 (p-y = 3827)


4M

85

0.01 0.1 1 10 100

Malignancies – Standardized Incidence RatiosMalignancies – Standardized Incidence RatiosCompared to U.S. General Population*Compared to U.S. General Population*

Cumulative Study PeriodsCumulative Study Periods

Standardized Incidence Ratios***

Overall**Overall**

Lung Lung

Colon and RectumColon and Rectum

BreastBreast

ProstateProstate

LymphomaLymphoma

Melanoma of SkinMelanoma of Skin

BladderBladder

RenalRenal

Endometrial / UterineEndometrial / Uterine

ThyroidThyroid

OvarianOvarian

CervixCervix

* SEER Cancer Statistics Review 1997-2002 ** Excludes non-melanoma skin malignancies*** Age and gender adjusted. Bars depict 95% confidence intervals

86

Comparison of RA Cohorts to General PopulationsComparison of RA Cohorts to General PopulationsPublished LiteraturePublished Literature

11.50.55

1.09 12.4

0.5 1.2

0.4 1.68

0.1 1 10 100

Published Standardized Incidence Ratios

LymphomaLymphoma

LungLung

Colon and Colon and RectalRectal

BreastBreast

87

RA Cohorts – DMARD SpecificRA Cohorts – DMARD Specific

Patients treated with DMARDS in the following Patients treated with DMARDS in the following RA cohortsRA cohorts

– British Columbia RA Registry (Canada)British Columbia RA Registry (Canada)

– National Data Bank for Rheumatic Diseases National Data Bank for Rheumatic Diseases (U.S.)(U.S.)

– Norfolk Arthritis Registry (U.K.)Norfolk Arthritis Registry (U.K.)

88

0 1 2 3 4 5 6 7 8 9 10

Lymphoma – Abatacept Observed and Expected Cumulative Study Periods and Observational Cohorts

Expected events are age-adjusted (10-year age groups) and gender-adjusted and account for exposure. Confidence intervals are based on exponential survival function.

Number of Events

4M

Expected

Observed

US General

BC

NOAR

NDB

89

0 2 4 6 8 10 12 14 16 18 20

Lung Cancer – Abatacept Observed and ExpectedCumulative Study Periods and RA Observational Cohorts

4M

Number of Events

Expected events are age-adjusted (10-year age groups) and gender-adjusted and account for exposure. Confidence intervals are based on exponential survival function.

Expected

Observed

US General

BC

NOAR

NDB

90

Patient No.Patient No.Age/Race/GenderAge/Race/Gender Adverse EventAdverse Event DoseDose

Latency Latency (Days)(Days) Con Meds*Con Meds*

IM101-102-39-9IM101-102-39-981 / W / F81 / W / F

B-cell Lymphoma / B-cell Lymphoma / Hashimoto’s ThyroiditisHashimoto’s Thyroiditis

750 mg750 mg 241 D241 D MTXMTX[Infliximab][Infliximab]

IM101-102-136-15IM101-102-136-1546 / W / M46 / W / M

Diffuse Large Diffuse Large B-cell Lymphoma B-cell Lymphoma (CD20 + Stage Ia)(CD20 + Stage Ia)

750 mg750 mg 203 D203 D MTXMTX

IM101-101-14-2IM101-101-14-261 / W / F61 / W / F

Diffuse Large Diffuse Large B-Cell Lymphoma B-Cell Lymphoma (Stage IVb)(Stage IVb)

750 mg750 mg 1086 D1086 D EtanerceptEtanercept

IM101-029-26-9IM101-029-26-958 / W / M58 / W / M

Large T-cell Lymphoma Large T-cell Lymphoma (Stage IIb)(Stage IIb)

750 mg750 mg 505 D505 D MTXMTXLFNLFN[Infliximab][Infliximab]

LymphomasLymphomasCumulative Study Periods

4M

*[ ] = Previous medication

91

Lung CancerLung Cancer

Typical clinical presentationTypical clinical presentation

– Older patients (all over 60 years of age)Older patients (all over 60 years of age)

– Highly associated with smoking (7/8)Highly associated with smoking (7/8)

– No predominant tumor typeNo predominant tumor type

Short latency in two cases (29 and 100 days of Short latency in two cases (29 and 100 days of treatment) making causal relationship to therapy treatment) making causal relationship to therapy unlikelyunlikely

Pre-existing radiographic abnormalities indicative Pre-existing radiographic abnormalities indicative of malignancy identified in two other casesof malignancy identified in two other cases

92

Lung Cancer Incidence Rates by Time IntervalsLung Cancer Incidence Rates by Time IntervalsCumulative Study Periods – Through 4 Month UpdateCumulative Study Periods – Through 4 Month Update

* n/p-y = Number of patients / person-years** IR/100 p-y = Incidence rates per 100 person-years

Time Intervals (Months)Time Intervals (Months)

0-6 0-6 6-126-12 12-1812-18 18-2418-24 24-30 24-30 >30 >30

n/p-y*n/p-y* 2/12852/1285 2/10322/1032 4/7954/795 0/3990/399 0/1170/117 0/1980/198

IR/100 p-y**IR/100 p-y** 0.16 0.16 0.19 0.19 0.500.50 0 0 00 0 0

(95% CI)(95% CI) (0.02, 0.56)(0.02, 0.56) (0.02, 0.70)(0.02, 0.70) (0.14, 1.29)(0.14, 1.29) (0, 0.92)(0, 0.92) (0, 3.15)(0, 3.15) (0, 1.86)(0, 1.86)

4M

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Malignancies – AbataceptMalignancies – AbataceptCumulative Study PeriodsCumulative Study Periods

Non-melanoma SkinNon-melanoma Skin 24 (0.63)24 (0.63) 33 (0.70)33 (0.70)

SolidSolid 21 (0.55)21 (0.55) 28 (0.59)28 (0.59)

Lung Lung 8 (0.21)8 (0.21) 11 (0.23)11 (0.23)

ThyroidThyroid 2 (0.05)2 (0.05) 2 (0.04)2 (0.04)

BreastBreast 2 (0.05)2 (0.05) 4 (0.08)4 (0.08)

ProstateProstate 2 (0.05)2 (0.05) 3 (0.06)3 (0.06)

BladderBladder 1 (0.03)1 (0.03) 1 (0.02)1 (0.02)

RenalRenal 1 (0.03)1 (0.03) 1 (0.02)1 (0.02)

OvarianOvarian 2 (0.05)2 (0.05) 2 (0.04)2 (0.04)

MelanomaMelanoma 1 (0.03)1 (0.03) 1 (0.02)1 (0.02)

Endometrial / UterineEndometrial / Uterine 2 (0.05)2 (0.05) 2 (0.04)2 (0.04)

CervixCervix 1 (0.03)1 (0.03) 1 (0.02)1 (0.02)

GastricGastric 00 1 (0.02)1 (0.02)

HematologicHematologic 5 (0.13)5 (0.13) 6 (0.13)6 (0.13)

LymphomaLymphoma 4 (0.10)4 (0.10) 4 (0.08)4 (0.08)

Myelodysplastic SyndromeMyelodysplastic Syndrome 1 (0.03)1 (0.03) 2 (0.04)2 (0.04)

Type of MalignancyType of Malignancy

Through Jun 2005Through Jun 2005N = 2688 (p-y = 4764)N = 2688 (p-y = 4764)


MAA

Through 4 Month UpdateThrough 4 Month UpdateN = 2688 (p-y = 3827)N = 2688 (p-y = 3827)


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Malignancy AssessmentMalignancy Assessment

Frequency similar to placebo and US general Frequency similar to placebo and US general population overall and for major categories (skin, population overall and for major categories (skin, solid, hematologic)solid, hematologic)

For malignancies of special interest – lymphoma For malignancies of special interest – lymphoma and lung cancerand lung cancer

– Incidence greater than US general population, Incidence greater than US general population, but within reported ranges for RA patientsbut within reported ranges for RA patients

– Totality of evidence, including clinical Totality of evidence, including clinical presentation and incidence over time, does not presentation and incidence over time, does not suggest increased risk with abataceptsuggest increased risk with abatacept

Virally associated malignancies uncommonVirally associated malignancies uncommon

95

Malignancy AssessmentMalignancy Assessment

Overall, data does not indicate increased risk of Overall, data does not indicate increased risk of malignancy with abataceptmalignancy with abatacept

Assessment not definitive based on number of Assessment not definitive based on number of patients and duration of follow-uppatients and duration of follow-up

Pharmacovigilance program will provide further Pharmacovigilance program will provide further information to better define risk of malignancyinformation to better define risk of malignancy

96

Pharmacovigilance PlanPharmacovigilance Plan

Enhanced data collection for Clinical and Enhanced data collection for Clinical and Spontaneous reportsSpontaneous reports

– Special event formsSpecial event forms

– Telephone contactTelephone contact

Long-term clinical study extensions up to 5 yearsLong-term clinical study extensions up to 5 years

Pregnancy RegistryPregnancy Registry

Large observational safety studiesLarge observational safety studies

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Pharmacovigilance Plan Pharmacovigilance Plan Large Observational Safety StudiesLarge Observational Safety Studies

Purpose: Complementary assessment of abatacept use Purpose: Complementary assessment of abatacept use and its safety in the post-marketing period and its safety in the post-marketing period

Assess risks of targeted adverse events (malignancy Assess risks of targeted adverse events (malignancy and infection) in clinical practiceand infection) in clinical practice

– Estimate incidence rates overall and in subgroupsEstimate incidence rates overall and in subgroups

– Compare incidence rates with abatacept to other Compare incidence rates with abatacept to other treatmentstreatments

Monitor patterns of useMonitor patterns of use

Investigate potential signals of unanticipated adverse Investigate potential signals of unanticipated adverse eventsevents

98

Large Observational Studies:Large Observational Studies:Insurance Claims CohortInsurance Claims Cohort

Describe short-term incidence of targeted Describe short-term incidence of targeted adverse events adverse events

Confirmation through chart reviewConfirmation through chart review

Data source: UnitedHealthcareData source: UnitedHealthcare

– 2% of US prescriptions2% of US prescriptions

– Open cohort, 5 years cohort identificationOpen cohort, 5 years cohort identification

– Last enrolled patient will be followed forLast enrolled patient will be followed for2 years2 years

– Anticipate 1,200 new starts of abatacept Anticipate 1,200 new starts of abatacept patients within three years, matched to patients within three years, matched to patients on comparator drugspatients on comparator drugs

99

Large Observational Studies:Large Observational Studies:Prospective Cohort (Registry)Prospective Cohort (Registry)

Short-term and long-term incidence of adverse Short-term and long-term incidence of adverse eventsevents

Data source: Existing independent registryData source: Existing independent registry

– Enrollment through physiciansEnrollment through physicians

– 5,000 patients initiating abatacept5,000 patients initiating abatacept

– 15,000 patients initiating comparator treatments15,000 patients initiating comparator treatments

– Follow-up 5 years after last patient enrolledFollow-up 5 years after last patient enrolled

Benefit measured through HAQ and pain scoreBenefit measured through HAQ and pain score

100

Overall Safety SummaryOverall Safety Summary

Clinical development program demonstrates that Clinical development program demonstrates that abatacept is generally safe and well-toleratedabatacept is generally safe and well-tolerated

Major identified risk is infectionMajor identified risk is infection

– Frequency slightly increased (1% difference in Frequency slightly increased (1% difference in serious infection rate) but type, duration, serious infection rate) but type, duration, treatment, and outcome similar to placebotreatment, and outcome similar to placebo

Malignancy risk similar to placebo overall and for Malignancy risk similar to placebo overall and for major categories of malignancy (solid, major categories of malignancy (solid, hematologic) but current assessment is not hematologic) but current assessment is not definitivedefinitive

Pharmacovigilance plan includes 2 large Pharmacovigilance plan includes 2 large observational studies to better define risk of rare observational studies to better define risk of rare events, including lymphoma, other malignancies, events, including lymphoma, other malignancies, and serious infectionsand serious infections

101

AbataceptAbataceptSummarySummary

Brian Daniels, M.D.Brian Daniels, M.D.Senior Vice-PresidentSenior Vice-President

Global Clinical DevelopmentGlobal Clinical DevelopmentBristol-Myers SquibbBristol-Myers Squibb

102

ConsultantsConsultants

Roger B. Cohen, M.D.Roger B. Cohen, M.D.Director, Phase I Program & Director, Phase I Program & Member, Thoracic Oncology Team,Member, Thoracic Oncology Team,Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, PAPhiladelphia, PA

Mark Genovese, M.D.Mark Genovese, M.D.Associate Professor of Medicine, Associate Professor of Medicine, Associate Division Chief, Division of Associate Division Chief, Division of Immunology and Rheumatology, Immunology and Rheumatology, Stanford University School of Medicine, Stanford University School of Medicine, Palo Alto, CAPalo Alto, CA

Princy Kumar, M.D.Princy Kumar, M.D.Professor of Medicine and Microbiology, Professor of Medicine and Microbiology, Chief, Division of Infectious Disease, Chief, Division of Infectious Disease, Associate Dean of Students, Georgetown Associate Dean of Students, Georgetown University School of Medicine, University School of Medicine, Washington, DCWashington, DC

Harry K. Genant, M.D.Harry K. Genant, M.D.Professor Emeritus, Professor Emeritus, University of California, San Francisco University of California, San Francisco Board Member, SYNARC, Inc.Board Member, SYNARC, Inc.San Francisco, CASan Francisco, CA

Marc Hochberg, M.D., M.P.H.Marc Hochberg, M.D., M.P.H.Professor of MedicineProfessor of MedicineHead, Division of Rheumatology and Head, Division of Rheumatology and Clinical Immunology, Clinical Immunology, University of Maryland, Baltimore, MDUniversity of Maryland, Baltimore, MD

Désirée van der Heijde, M.D.Désirée van der Heijde, M.D.Professor of Rheumatology, Professor of Rheumatology, University Hospital, University Hospital, Maastricht, the NetherlandsMaastricht, the Netherlands

Documents

1 Abatacept Brian Daniels, M.D. Senior Vice-President Global Clinical Development Bristol-Myers Squibb