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

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Presentation on theme: "1 Abatacept Brian Daniels, M.D. Senior Vice-President Global Clinical Development Bristol-Myers Squibb."— Presentation transcript:

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

2 2 Abatacept: Introduction Anthony Waclawski, Ph.D. Executive Director Global Regulatory Sciences Bristol-Myers Squibb Bristol-Myers Squibb

3 3 Abatacept

4 4 Proposed Indication ORENCIA is indicated for: Reducing signs and symptoms, inducing major clinical response Reducing signs and symptoms, inducing major clinical response Inhibiting the progression of structural damage, and Inhibiting the progression of structural damage, and Improving physical function Improving physical function Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more DMARDs, such as methotrexate, or TNF blocking agents Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more DMARDs, such as methotrexate, or TNF blocking agents May be used in combination with methotrexate or other non-biologic DMARD therapy May be used in combination with methotrexate or other non-biologic DMARD therapy

5 5 Regulatory Background IND for Rheumatoid Arthritis …………October 2000 Special Protocol Assessment November 2002 Fast Track Program August 2003 Pre-BLA meeting October 2004 Continuous Marketing Application....March 2005

6 6 Overview of Clinical Development Program in 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 7 Overview of Clinical Development Program in 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

8 8 Overview of Clinical Development Program in 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

9 9 Abatacept: Safety Database Placebo-controlled studies Placebo-controlled studies –1,955 patients representing 1,688 person-years of exposure –1,330 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 representing 3,827 person-years of exposure Combined double-blind and open-label: 2,688 patients representing 3,827 person-years of exposure Pharmacovigilance Plan Pharmacovigilance Plan

10 10 Presentation Outline Efficacy George Vratsanos, M.D. Safety Dan MacNeil, M.D. Summary… Brian Daniels, M.D.

11 11 Abatacept: Summary of Efficacy George Vratsanos, M.D. Medical Director Immunology Bristol-Myers Squibb

12 12 Outline of Presentation Mechanism of Action Mechanism of Action Dose selection from Phase II Trials Dose selection from Phase II Trials Results from Pivotal Phase III Efficacy Trials in: Results from Pivotal Phase III Efficacy Trials in: –Methotrexate Inadequate Responders –Anti-TNF Inadequate Responders

13 13 Abatacept Selectively Modulates Co-Stimulation via CD80/86:CD28 Pathway APC Abatacept MHCTCR CD80/86 CD28 T-cell

14 14 Fibroblast Role of Activated T-Cells in RA Activated Macrophage Activated B-cell IL-6 TNF-  MMPs Autoantibodies, e.g. RF Activated T-cell Inflammation & Joint Destruction Activation

15 15 Proposed Mechanism of Action of Abatacept Decrease T-cell activation and proliferation Decrease T-cell activation and proliferation Decrease pro-inflammatory cytokine secretion from activated synovial macrophages Decrease pro-inflammatory cytokine secretion from activated synovial macrophages Decrease autoantibody production (e.g. RF) Decrease autoantibody production (e.g. RF) No depletion of T-cells or other leukocytes No depletion of T-cells or other leukocytes

16 16 Dose Selection

17 17 Dose Finding Study IM Patient Population DMARD Inadequate Responders Background Medication None(Monotherapy) Abatacept Doses 10 mg/kg 2 mg/kg 0.5 mg/kg Primary Endpoint (ACR 20) (ACR 20) 3 months Dose Finding Study IM Dose Ranging Study IM Patient Population DMARD Inadequate Responders Methotrexate Inadequate Responders Background Medication None(Monotherapy)Methotrexate Abatacept Doses 10 mg/kg 2 mg/kg 0.5 mg/kg 10 mg/kg 2 mg/kg Primary Endpoint (ACR 20) (ACR 20) 3 months 6 months Phase II Dose Response Studies Double-Blind, Randomized, Placebo Controlled

18 **p < vs placebo ^p < 0.01 vs placebo IM ACR 20 Response Rates Over Time Dose Ranging Study ^ ** Primary Endpoint

19 19 Rationale for Phase III Design

20 20 Phase III Pivotal Study Patients with Inadequate Response to Methotrexate Methotrexate continued Other DMARDs washout Screening 6 Months Co-primary endpoint  ACR 20 Placebo (N = 219) Abatacept (N = 433) Randomization 1 Year IM Day 1 Co-primary endpoint  Physical Function  Structural damage Double-blindOpen-label Treated (N = 652) 10 mg/kg Changes in DMARDs allowed

21 21 Demographic and Patient Characteristics Patients with Inadequate Response to Methotrexate IM Abatacept N = 433 Placebo N = 219 Age in years, mean 5250 Female (%) 7882 Caucasian (%) 8888 Disease duration in years, mean 9 9 RF+ (%) 8279 Steroids (%) 7268 Methotrexate dose, mean mg/wk 1616

22 22 Clinical Characteristics Patients with Inadequate Response to Methotrexate Mean Abatacept N = 433 Placebo N = 219 Number of tender joints 3132 Number of swollen joints 2122 Physical function, HAQ score CRP, mg/dL DAS-28 (ESR) Percent Patients with Erosions > IM

23 23 IM Abatacept Placebo N = 433N = 219 Completed Double Blind Period385 (89)162 (74) Discontinued48 (11)57 (26) Adverse Events18 (4.2)4 (1.8) Death1 (0.2)1 (0.5) Lack of Efficacy13 (3.0)40 (18) Lost to Follow-up1 (0.2)1 (0.5) Withdrawal of Consent10 (2.3)5 (2.3) Other5 (1.2)6 (2.7) Patient Disposition at 1 Year Patients with Inadequate Response to Methotrexate Number (%) of Patients

24 24 ACR 20 Response Over Time Patients with Inadequate Response to Methotrexate IM ** * ^ 15 **p < ^p < 0.01 *p < 0.05 ITT analysis; All patients who D/C are considered non-responders Primary Endpoint

25 25 **p < ^p < 0.01 ITT analysis; All patients who D/C are considered non-responders IM ACR 70 Response Over Time Patients with Inadequate Response to Methotrexate ** ^ 15

26 26 Substantial Clinical Responses at 1 Year Patients with Inadequate Response to Methotrexate ** ** p < Major Clinical Response IM % of Patients with Joint Counts of Zero ** LOCF Analysis

27 27 Summary of ACR 20 Subgroup Analyses at 6 Months Patients with Inadequate Response to Methotrexate All Patients IM Age Gender RF + or – Body weight Duration of RA Treatment Difference with 95% CI Abatacept Better Placebo Better

28 28 Evaluation of Structural Damage Progression Patients with Inadequate Response to Methotrexate Assessed using Genant Modified Sharp scoring system Assessed using Genant Modified Sharp scoring system Paired radiographs obtained in over 90% of all randomized patients Paired radiographs obtained in over 90% of all randomized patients Radiographs scored in blinded fashion using validated method Radiographs scored in blinded fashion using validated method Data analyzed using comparison of distribution of changes from baseline, mean and median changes Data analyzed using comparison of distribution of changes from baseline, mean and median changes

29 29 Genant Modified Sharp Scoring System Patients with Inadequate Response to Methotrexate Erosions (Maximum score: 145) Erosions (Maximum score: 145) –14 joints in each hand / wrist –6 joints in each foot Joint Space Narrowing (Maximum score: 145) Joint Space Narrowing (Maximum score: 145) –13 joints in each hand / wrist –6 joints in each foot

30 30 ** ^ IM Mean Change in Radiographic Scores at 1 Year Patients With Inadequate Response to Methotrexate ** p < ^ p < 0.01 JSN = Joint Space Narrowing

31 31 IM Median Change in Radiographic Scores at 1 Year Patients With Inadequate Response to Methotrexate JSN = Joint Space Narrowing

32 32 Distribution of Radiographic Changes in Total Score at 1 Year Patients with Inadequate Response to Methotrexate Increasing score Unchanged Lower Score IM

33 33 IM Comparison of Distribution of Radiographic Changes in Total Score at 1 Year Patients with Inadequate Response to Methotrexate p = for Total Score p = for Erosion Score p = for JSN Score

34 34 Physical Function Responder Analysis (HAQ) at 1 Year Patients with Inadequate Response to Methotrexate IM **p < ** Primary Analysis

35 35 15 Clinically Important Improvement in Physical Function (Decrease in HAQ ≥ 0.3) Patients with Inadequate Response to Methotrexate IM * ** ^ **p < ^p < 0.01 *p < 0.05 ITT analysis; All patients who D/C are considered non-responders

36 36 Clinically Important Improvement in Physical Function (Decrease in mHAQ ≥ 0.3) Over 3 Years Dose-Ranging Study Patient Population (Randomized 10mg/kg; Entered open-label) 1 Yr 2 Yr 3 Yr As Observed All Patients Number of Patients All Patients Number of Patients % Response % Response8455%7353%6453% IM Patients Who Discontinue Considered Non-responders All Patients (N = 84) All Patients (N = 84) % Response % Response55%46%42% mHAQ Responders at 1 year (N = 46) mHAQ Responders at 1 year (N = 46) % Response % Response—67%57%

37 37 Improvement in Quality of Life (SF-36) at 1 Year Patients with Inadequate Response to Methotrexate IM ** Physical Component Summary * **p < *p < 0.05 LOCF Analysis Mental Component Summary

38 38 Improvement in Quality of Life (SF-36) at 1 Year Patients with Inadequate Response to Methotrexate IM ** ^ ^ **p < ^p < 0.01 LOCF Analysis

39 39 Phase III Pivotal Study Patients with Inadequate Response to Anti-TNF Therapy

40 40 Placebo (N = 133) Abatacept (N = 258) Randomization Day 1 Double-blindOpen-label 6 Months Co-primary endpoint  ACR 20  Physical Function IM Treated (N = 391) Stratified Recent vs Prior DMARDs continued Anti ­ TNF washout period (28–60 days) 10 mg/kg Phase III Pivotal Study Patients with Inadequate Response to Anti-TNF Therapy

41 41 Key Requirements for Entry Patients with Inadequate Response to Anti-TNF Therapy Only patients with lack of efficacy on Anti-TNF eligible Only patients with lack of efficacy on Anti-TNF eligible Minimum of 10 swollen and 12 tender joints with elevated CRP despite at least 3 months of Anti-TNF therapy required Minimum of 10 swollen and 12 tender joints with elevated CRP despite at least 3 months of Anti-TNF therapy required Lack of efficacy occurred immediately before enrollment (‘recent user’) or more distantly (‘prior user’) Lack of efficacy occurred immediately before enrollment (‘recent user’) or more distantly (‘prior user’) Lack of efficacy directly observed in recent users Lack of efficacy directly observed in recent users Source Documentation of inadequate response required for prior users Source Documentation of inadequate response required for prior users IM

42 42 Demographic and Patient Characteristics Patients with Inadequate Response to Anti-TNF Therapy IM Abatacept N = 258 Placebo N = 133 Age in years, mean53 Female (%)7780 Caucasian (%)9693 RA duration in years, mean1211 RF+ (%)73

43 43 Anti-TNF Use Before Study Patients with Inadequate Response to Anti-TNF Therapy IM % of Patients Abatacept N = 258 Placebo N = 133 History of Anti-TNF Use Recent Users 3841 Prior Users 6259 Type of Anti-TNF Use Infliximab Users Etanercept Users Both Infliximab & Etanercept 2117

44 44 Clinical Characteristics Patients with Inadequate Response to Anti-TNF Therapy IM Mean Abatacept N = 258 Placebo N = 133 Number of tender joints 3133 Number of swollen joints 2222 Physical function, HAQ score CRP, mg/dL DAS-28 (ESR)

45 45 Patient Disposition at Six Months Patients with Inadequate Response to Anti-TNF Therapy Number (%) of Patients Abatacept N = 258 Placebo N = 133 Completed Double Blind period 223 (86) 99 (74) Discontinued 35 (14) 34 (26) Adverse events 9 (3.5) 5 (3.8) Death00 Lack of Efficacy 14 (5.4) 27 (20) Lost to Follow-up Withdrawal of consent Other 5 (1.9) 2 (0.8) 0 2 (1.5) 0 IM

46 46 ACR 20 Responses Over Time Patients with Inadequate Response to Anti-TNF Therapy IM ** ^ ^ **p < ^p < 0.01 ITT analysis; All patients who D/C are considered non-responders 15 Primary Endpoint

47 47 Substantial Clinical Responses Patients with Substantial Clinical Responses Patients with Inadequate Response to Anti-TNF Therapy 15 * ^ ** ^ * **p < ^p < 0.01 *p < 0.05 IM ACR 70 1 % of Patients with Joint Counts of Zero * * LOCF Analysis ITT analysis; All patients who D/C are considered non-responders

48 48 Summary of ACR 20 Subgroup Analyses at 6 Months Patients with Inadequate Response to Anti-TNF Therapy IM All Patients Age Gender Anti-TNF History Body weight Type of Anti-TNF Abatacept Better Placebo Better Treatment Difference with 95% CI

49 49 Physical Function Responder Analysis (HAQ) at 6 Months Patients with Inadequate Response to Anti-TNF Therapy IM **p < ** Primary Analysis

50 50 Improvement in Quality of Life (SF-36) at 6 Months Patients with Inadequate Response to Improvement in Quality of Life (SF-36) at 6 Months Patients with Inadequate Response to Anti-TNF Therapy IM ** Physical Component Summary ^ Mental Component Summary **p < ^p < 0.01 LOCF Analysis

51 51 Improvement in Quality of Life (SF-36) After 6 Months Patients with Inadequate Response to Improvement in Quality of Life (SF-36) After 6 Months Patients with Inadequate Response to Anti-TNF Therapy IM **p < ^p < 0.01 *p < 0.05 LOCF Analysis ** * ^

52 52 Clinical Biomarker Data

53 53 Mean Values of Biomarkers at 6 Months Patients with Inadequate Response to Anti-TNF Therapy IM TNF-α IL-6 MMP-3 Rheumatoid Factor Pro-inflammatory Cytokines Proteolytic Enzyme Autoantibody AbataceptPlacebo B/L6 MoB/L6 Mo B/L6 MoB/L6 Mo B/L6 MoB/L6 Mo B/L6 MoB/L6 Mo Normal Range B/L = baseline value

54 54 Conclusions All primary and key secondary outcomes achieved: All primary and key secondary outcomes achieved: –Consistent effect on ACR 20, 50 and 70 –Inhibition of structural damage –Improvement in physical function and quality of life Major reductions in disease activity: Major reductions in disease activity: –ACR 70 response –Major clinical response –Proportion of patients with no swollen or tender joints

55 55 Daniel J. MacNeil, M.D. Executive Director Global Pharmacovigilance Bristol-Myers Squibb Abatacept: Summary of Safety

56 56 Abatacept Safety Presentation Topics Description of patient population and overview of general safety and tolerability Description of patient population and overview of general safety and tolerability Clinical findings on infection and malignancy Clinical findings on infection and malignancy Plans for further assessment of safety profile post-approval Plans for further assessment of safety profile post-approval

57 57 Safety Assessment Methods Based on safety data provided to and reviewed by FDA in BLA and 4 Month Safety Update Based on safety data provided to and reviewed by FDA in BLA and 4 Month Safety Update Tables include events occurring up to 56 days post last dose of study drug (5 half-lives) Tables include events occurring up to 56 days post last dose of study drug (5 half-lives) Adverse events classified using standard coding dictionary, MedDRA Adverse events classified using standard coding dictionary, MedDRA Severity classified by investigator according to regulatory and functional criteria Severity classified by investigator according to regulatory and functional criteria

58 58 RA Safety Population Cumulative (Double-Blind and Open-Label) Open-Label, Uncontrolled N = 2,339 N = 2,688 PlaceboAbatacept N = 1,955 (204) Double-Blind, Controlled (Biologic Background) N = 989 (134) BLA/4M QG

59 59 Extent of Exposure to Abatacept Population: Treated patients in 5 Core RA studies  (80) 2467 (92)  (68) 1792 (67)  18–1471 (55)  24–278 (10)  36– 162 (6) Exposure in Months Number (%) of Patients Number (%) of Patients QGCumulative N = 2688 Double-Blind N = 1955 Person-Years Exposure Median Months Exposure (Range)12 (2, 14) 20 (2, 48)

60 60 Age in years, mean % Female % Caucasian Disease duration in years Placebo N = Patient Characteristics Double-Blind, Controlled Study Periods Abatacept N = 1955 Double-Blind Concomitant Medication Use: Methotrexate Systemic Steroid Biologic 83%75%14%82%74%10% BLA QG

61 61 Overview of Patients with Adverse Events Double-Blind, Controlled Study Periods AEsSAEs Discontinuation due to AEs Deaths Abatacept N = (88.8) 266 (13.6) 107 (5.5) 10 (0.5) Placebo N = (84.9) 122 (12.3) 39 (3.9) 6 (0.6) Number (%) of Patients

62 62 Adverse Events with Difference Between Abatacept vs Placebo ( ≥ 2%) Double-Blind, Controlled Study Periods Total Patients with AE Headache Headache Nasopharyngitis Nasopharyngitis Dizziness Dizziness Hypertension Hypertension Dyspepsia Dyspepsia 1736 (88.8) 356 (18.2) 225 (11.5) 225 (11.5) 183 (9.4) 183 (9.4) 129 (6.6) 129 (6.6) 126 (6.4) 840 (84.9) 125 (12.6) 90 (9.1) 90 (9.1) 69 (7.0) 69 (7.0) 43 (4.3) 42 (4.2) Preferred Term Abatacept N = 1955 Placebo N = 989 BLA Number (%) of Patients

63 63 Total Patients with SAEs Musculoskeletal and Connective Tissue Disorders Infections and Infestations Injury, Poisoning, and Procedural Complications Neoplasms Benign, Malignant and Unspecified Gastrointestinal Disorders Nervous System Disorders Cardiac Disorders Serious Adverse Events (≥ 1.0%) Double-Blind, Controlled Study Periods 266 (13.6) 59 (3.0) 58 (3.0) 58 (3.0) 29 (1.5) 28 (1.4) 23 (1.2) 19 (1.0) 18 (0.9) 18 (0.9) System Organ Class Abatacept N = 1955 Placebo N = (12.3) 122 (12.3) 37 (3.7) 19 (1.9) 7 (0.7) 11 (1.1) 13 (1.3) 14 (1.4) 17 (1.7) Number (%) of Patients

64 64 Total Patient Deaths Cardiac Disorders General Disorders Neoplasms Benign, Malignant & Unspecified Infections and Infestations Injury, Poisoning & Procedural Complications Nervous System Disorders Investigations (Diagnostic Procedures or Findings) Deaths Double-Blind, Controlled Study Periods 10 (0.5) 4 (0.2) 3 (0.2) 2 (0.1) 1 (< 0.1) 00 6 (0.6) 2 (0.2) 1 (0.1) 2 (0.2) 0 1 (0.1) System Organ Class Abatacept N = 1955 Placebo N = 989 Number (%) of Patients 4M

65 65 Safety in Combination with Other Biologic Therapies

66 66 Abatacept N = 204 Placebo N = 134 Overview of Safety in Patients Treated with Biologic Background Therapy Double-Blind, Controlled Study Periods AEs 192 (94.1) 113 (84.3) All infections130 (63.7)58 (43.3) SAEs 40 (19.6) 12 (9.0) Serious Infections9 (4.4)2 (1.5) Malignancies3 (1.5)0 Deaths 0 0 Biologic RA Therapy BLA Number (%) of Patients

67 67 Special Topics: Infections and Malignancies

68 68 Infections Frequency and Type of Infection Frequency and Type of Infection –Overall –Most Common –Serious Severity of Infection Severity of Infection –% serious, % severe or very severe in intensity –% IV antibiotic therapy –% resulting in discontinuation of therapy –% resulting in death Incidence Rate of Infection over time Incidence Rate of Infection over time Infections of Particular Interest Infections of Particular Interest –Pneumonia –Herpes –Tuberculosis

69 69 Total Patients with Infections Upper Respiratory Tract Infection NasopharyngitisSinusitis Urinary Tract Infection InfluenzaBronchitis 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) 119 (12.0) 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%) Double-Blind, Controlled Study Periods Preferred Term Abatacept N = 1955 Placebo N = 989 Number (%) of Patients BLA

70 70 Total Patients with Serious Infections Pneumonia Pneumonia Cellulitis Cellulitis Urinary Tract Infection Urinary Tract Infection Bronchitis Bronchitis Diverticulitis Diverticulitis Pyelonephritis Acute Pyelonephritis Acute Sepsis Sepsis Serious Infections (≥ 0.2%) Double-Blind, Controlled Study Periods 58 (3.0) 58 (3.0) 9 (0.5) 5 (0.3) 5 (0.3) 4 (0.2) 4 (0.2) 3 (0.2) 3 (0.2) 1 (<0.1) 1 (<0.1) 19 (1.9) 19 (1.9) 5 (0.5) 2 (0.2) 2 (0.2) 1 (0.1) 1 (0.1) (0.3) 3 (0.3) Preferred Term Abatacept N = 1955 Placebo N = 989 Number (%) of Patients BLA

71 71 Intensity of Infections Double-Blind, Controlled Study Periods Placebo N = 989 Abatacept N = (2.4) 58 (3.0) Severe 4 (0.4) 4 (0.2) Very Severe 227 (23.0) 537 (27.5) Moderate 319 (32.3) 699 (35.8) Mild Number (%) of Patients BLA 478 (48.3) 1051 (53.8) Total Patients with Infections

72 72 IV Antibiotics Use Study # Months on Study Drug AbataceptPlacebo IM (MTX-IR) 0 – 6 9/433 (2.1) 5/219 (2.3) 6 – 12 15/401 (3.7) 15/401 (3.7) 7/174 (4.0) IM (Anti-TNF IR) 0 – 6 3/258 (1.2) 4/133 (3.0) IM (Safety) 0 – 12 38/959 (4.0) 38/959 (4.0) 18/482 (3.7) 18/482 (3.7) BLA n/N (%) of Patients

73 73 Total Discontinued Due to Infections Pneumonia Pneumonia 24 (1.2) 24 (1.2) 4 (0.2) 4 (0.2) 10 (1.0) 10 (1.0) 1 (0.1) 1 (0.1) Localized infections Localized infections 3(0.2) 0 Bronchitis Bronchitis 2(0.1) 2 (0.2) 2 (0.2) Sepsis Sepsis 1(<0.1) 2 (0.2) 2 (0.2) Discontinuation Due to Infections* Double Blind, Controlled Study Periods * AEs that led to discontinuation in 2 or more patients Preferred Term Abatacept N = 1955 Placebo N = 989 Number (%) of Patients

74 74 Deaths Due to Infectious Adverse Events Double-Blind, Controlled Study Periods Total Infectious Deaths AspergillosisPneumocystisSepsis Abatacept N = (<0.1) 1 (<0.1) 0 0 Placebo N = (0.2) 0 1 (0.1) Number (%) of Patients BLA

75 75 Time Intervals (Months) >30 n/p-y*50/128539/103222/7959/3994/1173/198 IR/100 p-y** (95% CI) (2.91, 5.17) (2.71, 5.20) (1.74, 4.21) (1.03, 4.29) (0.94, 8.83) (0.31, 4.46) Serious Infection Incidence Rates by Time Intervals Cumulative 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 76 Number (%) of Patients Abatacept N = 1955 Placebo N = 989 Total Patients with Pneumonia 42 (2.1) (2.1)10(1.0) Median Onset in Days (Range) * 161 (9, 358) 223 (53, 359) Median Duration in Days (Range) * 12 (2, 50) 14 (1, 51) Serious14(0.7)6(0.6) Severe Very Severe 111(0.6)(<0.1)12(0.1)(0.2) Discontinued5(0.3)1(0.1) Overview of Pneumonia Double-Blind, Controlled Study Periods BLA * Onset and duration calculated using specific PT of “Pneumonia” only.

77 77 Incidence of Infections in Herpes Family Double-Blind, Controlled Study Periods Number (%) of Patients Preferred Term Abatacept N = 1955 Placebo N = 989 Herpes Simplex 37(1.9)10(1.0) Herpes Zoster 30(1.5)16(1.6) Herpes Viral Infection 5(0.3)2(0.2) Varicella3(0.2)0 Epstein-Barr Virus 00 Cytomegalovirus00 BLA

78 78 Tuberculosis Cumulative Study Periods 2 cases of presumed tuberculosis with abatacept Tuberculous Infection (Double-Blind): Tuberculous Infection (Double-Blind): –Presented with cervical lymphadenitis; diagnosis based on histology Pulmonary Tuberculosis Suspected (Open-Label) Pulmonary Tuberculosis Suspected (Open-Label) –Presented with dry cough, fever, diaphoresis and crepitus; diagnosis based on clinical presentation and chest radiograph 1 case of presumed tuberculosis with placebo Tuberculosis - Suspect (Double-Blind): Tuberculosis - Suspect (Double-Blind): –Unknown presentation; no definitive diagnosis

79 79 Infections: Conclusions Abatacept treatment associated with an increase in frequency of infections, including 1% increase in serious infections Abatacept treatment associated with an increase in frequency of infections, including 1% increase in serious infections Infections occurring with abatacept were similar to those occurring on placebo in type, severity, treatment, duration, and outcome Infections occurring with abatacept were similar to those occurring on placebo in type, severity, treatment, duration, and outcome

80 80 Malignancy Presentation Presentation –Non-clinical findings –Overall clinical experience –Malignancies of particular interest Evaluation based on Evaluation based on –Frequency versus placebo in Double-Blind –Incidence over time in Cumulative Period –Incidence relative to reference databases (both general population and RA specific) –Clinical characteristics

81 81 Carcinogenicity Study in Mice Duration: up to 88 weeks Duration: up to 88 weeks Exposures: 0.8-, 1.9- and 3.0-fold human exposure Exposures: 0.8-, 1.9- and 3.0-fold human exposure Sustained immunomodulation at all dose levels Sustained immunomodulation at all dose levels Increased incidence of virally mediated tumors Increased incidence of virally mediated tumors –Lymphoma at all doses  Murine leukemia virus detected in genome of mice –Mammary gland tumors in females at top two doses  Mouse mammary tumor virus detected in tumors

82 82 Primate Toxicology Study Conventional toxicology study enhanced to evaluate lymphoid neoplasia Conventional toxicology study enhanced to evaluate lymphoid neoplasia Duration: One year study – cynomolgus monkeys Duration: One year study – cynomolgus monkeys Exposure multiples up to 9-fold human exposure Exposure multiples up to 9-fold human exposure Oncogenic virus in genome of 38/40 monkeys Oncogenic virus in genome of 38/40 monkeys No lymphoma or pre-lymphomatous changes No lymphoma or pre-lymphomatous changes

83 83 Total26 (1.3)11 (1.1) Non-melanoma Skin15 (0.8) 6 (0.6) Basal Cell Carcinoma10 (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 Malignancies Double-Blind, Controlled Study Periods Abatacept N = 1955 Placebo N = 989 Type of Malignancy 4M Number (%) of Patients

84 84 Non-melanoma Skin 15 (0.89) 24 (0.63) 24 (0.63) Solid 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) Thyroid Thyroid 2 (0.12) 2 (0.12) 2 (0.05) 2 (0.05) Breast Breast 1 (0.06) 1 (0.06) 2 (0.05) 2 (0.05) Prostate Prostate 1 (0.06) 1 (0.06) 2 (0.05) 2 (0.05) Bladder Bladder 1 (0.06) 1 (0.06) 1 (0.03) 1 (0.03) Renal Renal 1 (0.06) 1 (0.06) 1 (0.03) 1 (0.03) Ovarian Ovarian 0 2 (0.05) 2 (0.05) Melanoma Melanoma 0 1 (0.03) 1 (0.03) Endometrial / Uterine Endometrial / Uterine 0 2 (0.05) 2 (0.05) Cervix Cervix 0 1 (0.03) 1 (0.03) Hematologic 2 (0.12) 2 (0.12) 5 (0.13) 5 (0.13) Lymphoma Lymphoma 1 (0.06) 1 (0.06) 4 (0.10) 4 (0.10) Myelodysplastic Syndrome Myelodysplastic Syndrome 1 (0.06) 1 (0.06) 1 (0.03) 1 (0.03) Malignancies – Abatacept Double-Blind and Cumulative Study Periods Type of Malignancy Double-Blind N = 1955 (p-y = 1688) n (per 100 p-y) Cumulative N = 2688 (p-y = 3827) n (per 100 p-y) 4M

85 85 Malignancies – Standardized Incidence Ratios Compared to U.S. General Population* Cumulative Study Periods Standardized Incidence Ratios***Overall**Lung Colon and Rectum Breast Prostate Lymphoma Melanoma of Skin Bladder Renal Endometrial / Uterine Thyroid Ovarian Cervix * SEER Cancer Statistics Review ** Excludes non-melanoma skin malignancies *** Age and gender adjusted. Bars depict 95% confidence intervals

86 86 Comparison of RA Cohorts to General Populations Published Literature LymphomaLung Colon and Rectal Breast

87 87 RA Cohorts – DMARD Specific Patients treated with DMARDS in the following RA cohorts Patients treated with DMARDS in the following RA cohorts –British Columbia RA Registry (Canada) –National Data Bank for Rheumatic Diseases (U.S.) –Norfolk Arthritis Registry (U.K.)

88 88 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 Lung Cancer – Abatacept Observed and Expected Cumulative 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 90 Patient No. Age/Race/Gender Adverse Event Dose Latency (Days) Con Meds* IM / W / F B-cell Lymphoma / Hashimoto’s Thyroiditis 750 mg 241 D MTX[Infliximab] IM / W / M Diffuse Large B-cell Lymphoma (CD20 + Stage Ia) 750 mg 203 D MTX IM / W / F Diffuse Large B-Cell Lymphoma (Stage IVb) 750 mg 1086 D Etanercept IM / W / M Large T-cell Lymphoma (Stage IIb) 750 mg 505 D MTXLFN[Infliximab] Lymphomas Lymphomas Cumulative Study Periods 4M *[ ] = Previous medication

91 91 Lung Cancer Typical clinical presentation Typical clinical presentation –Older patients (all over 60 years of age) –Highly associated with smoking (7/8) –No predominant tumor type Short latency in two cases (29 and 100 days of treatment) making causal relationship to therapy unlikely Short latency in two cases (29 and 100 days of treatment) making causal relationship to therapy unlikely Pre-existing radiographic abnormalities indicative of malignancy identified in two other cases Pre-existing radiographic abnormalities indicative of malignancy identified in two other cases

92 92 Lung Cancer Incidence Rates by Time Intervals Cumulative 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) >30 n/p-y*2/12852/10324/7950/3990/1170/198 IR/100 p-y** (95% CI) (0.02, 0.56) (0.02, 0.70) (0.14, 1.29) (0, 0.92) (0, 3.15) (0, 1.86) 4M

93 93 Malignancies – Abatacept Cumulative Study Periods Non-melanoma Skin 24 (0.63) 24 (0.63) 33 (0.70) 33 (0.70) Solid 21 (0.55) 21 (0.55) 28 (0.59) 28 (0.59) Lung 8 (0.21) 8 (0.21) 11 (0.23) 11 (0.23) Thyroid 2 (0.05) 2 (0.05) 2 (0.04) 2 (0.04) Breast 2 (0.05) 2 (0.05) 4 (0.08) 4 (0.08) Prostate 2 (0.05) 2 (0.05) 3 (0.06) 3 (0.06) Bladder 1 (0.03) 1 (0.03) 1 (0.02) 1 (0.02) Renal 1 (0.03) 1 (0.03) 1 (0.02) 1 (0.02) Ovarian 2 (0.05) 2 (0.05) 2 (0.04) 2 (0.04) Melanoma 1 (0.03) 1 (0.03) 1 (0.02) 1 (0.02) Endometrial / Uterine 2 (0.05) 2 (0.05) 2 (0.04) 2 (0.04) Cervix 1 (0.03) 1 (0.03) 1 (0.02) 1 (0.02) Gastric 0 Hematologic 5 (0.13) 5 (0.13) 6 (0.13) 6 (0.13) Lymphoma 4 (0.10) 4 (0.10) 4 (0.08) 4 (0.08) Myelodysplastic Syndrome 1 (0.03) 1 (0.03) 2 (0.04) 2 (0.04) Type of Malignancy Through Jun 2005 N = 2688 (p-y = 4764) n (per 100 p-y) MAA Through 4 Month Update N = 2688 (p-y = 3827) n (per 100 p-y)

94 94 Malignancy Assessment Frequency similar to placebo and US general population overall and for major categories (skin, solid, hematologic) Frequency similar to placebo and US general population overall and for major categories (skin, solid, hematologic) For malignancies of special interest – lymphoma and lung cancer For malignancies of special interest – lymphoma and lung cancer –Incidence greater than US general population, but within reported ranges for RA patients –Totality of evidence, including clinical presentation and incidence over time, does not suggest increased risk with abatacept Virally associated malignancies uncommon Virally associated malignancies uncommon

95 95 Malignancy Assessment Overall, data does not indicate increased risk of malignancy with abatacept Overall, data does not indicate increased risk of malignancy with abatacept Assessment not definitive based on number of patients and duration of follow-up Assessment not definitive based on number of patients and duration of follow-up Pharmacovigilance program will provide further information to better define risk of malignancy Pharmacovigilance program will provide further information to better define risk of malignancy

96 96 Pharmacovigilance Plan Enhanced data collection for Clinical and Spontaneous reports Enhanced data collection for Clinical and Spontaneous reports –Special event forms –Telephone contact Long-term clinical study extensions up to 5 years Long-term clinical study extensions up to 5 years Pregnancy Registry Pregnancy Registry Large observational safety studies Large observational safety studies

97 97 Pharmacovigilance Plan Large Observational Safety Studies Purpose: Complementary assessment of abatacept use and its safety in the post-marketing period Assess risks of targeted adverse events (malignancy and infection) in clinical practice Assess risks of targeted adverse events (malignancy and infection) in clinical practice –Estimate incidence rates overall and in subgroups –Compare incidence rates with abatacept to other treatments Monitor patterns of use Monitor patterns of use Investigate potential signals of unanticipated adverse events Investigate potential signals of unanticipated adverse events

98 98 Large Observational Studies: Insurance Claims Cohort Describe short-term incidence of targeted adverse events Describe short-term incidence of targeted adverse events Confirmation through chart review Confirmation through chart review Data source: UnitedHealthcare Data source: UnitedHealthcare –2% of US prescriptions –Open cohort, 5 years cohort identification –Last enrolled patient will be followed for 2 years –Anticipate 1,200 new starts of abatacept patients within three years, matched to patients on comparator drugs

99 99 Large Observational Studies: Prospective Cohort (Registry) Short-term and long-term incidence of adverse events Short-term and long-term incidence of adverse events Data source: Existing independent registry Data source: Existing independent registry –Enrollment through physicians –5,000 patients initiating abatacept –15,000 patients initiating comparator treatments –Follow-up 5 years after last patient enrolled Benefit measured through HAQ and pain score Benefit measured through HAQ and pain score

100 100 Overall Safety Summary Clinical development program demonstrates that abatacept is generally safe and well-tolerated Clinical development program demonstrates that abatacept is generally safe and well-tolerated Major identified risk is infection Major identified risk is infection –Frequency slightly increased (1% difference in serious infection rate) but type, duration, treatment, and outcome similar to placebo Malignancy risk similar to placebo overall and for major categories of malignancy (solid, hematologic) but current assessment is not definitive Malignancy risk similar to placebo overall and for major categories of malignancy (solid, hematologic) but current assessment is not definitive Pharmacovigilance plan includes 2 large observational studies to better define risk of rare events, including lymphoma, other malignancies, and serious infections Pharmacovigilance plan includes 2 large observational studies to better define risk of rare events, including lymphoma, other malignancies, and serious infections

101 101 Abatacept Summary Brian Daniels, M.D. Senior Vice-President Global Clinical Development Bristol-Myers Squibb

102 102 Consultants Roger B. Cohen, M.D. Director, Phase I Program & Member, Thoracic Oncology Team, Fox Chase Cancer Center, Philadelphia, PA Mark Genovese, M.D. Associate Professor of Medicine, Associate Division Chief, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA Princy Kumar, M.D. Professor of Medicine and Microbiology, Chief, Division of Infectious Disease, Associate Dean of Students, Georgetown University School of Medicine, Washington, DC Harry K. Genant, M.D. Professor Emeritus, University of California, San Francisco Board Member, SYNARC, Inc. San Francisco, CA Marc Hochberg, M.D., M.P.H. Professor of Medicine Head, Division of Rheumatology and Clinical Immunology, University of Maryland, Baltimore, MD Désirée van der Heijde, M.D. Professor of Rheumatology, University Hospital, Maastricht, the Netherlands


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