Abatacept (ORENCIA) for Rheumatoid Arthritis Biological License Application Arthritis Advisory Committee September 6, 2005

2 Abatacept Proposed indications for abatacept: Proposed indications for abatacept: For use in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more biologic or non-biologic DMARDs For use in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more biologic or non-biologic DMARDs Reducing signs and symptoms Reducing signs and symptoms Inducing major clinical response Inducing major clinical response Inhibiting the progression of structural damage Inhibiting the progression of structural damage Improving physical function Improving physical function Abatacept may be used as monotherapy or concomitantly with methotrexate or other non- biologic DMARD therapy Abatacept may be used as monotherapy or concomitantly with methotrexate or other non- biologic DMARD therapy

3 Overview of FDA Presentation Clinical Development Program and Study Design Clinical Development Program and Study Design Efficacy Data Efficacy Data Improvement of Signs and Symptoms Improvement of Signs and Symptoms Improvement of Physical Function Improvement of Physical Function Inhibition of Radiographic Progression Inhibition of Radiographic Progression Safety Data Safety Data Summary Summary

4 Abatacept BLA CLINICAL DEVELOPMENT PROGRAM & STUDY DESIGN

5 Abatacept Clinical Trials Randomized, Double-Blind, Placebo-Controlled

6 Study Design-Common Features Randomized, double-blind, placebo-controlled studies Randomized, double-blind, placebo-controlled studies Major Inclusion Criteria: Major Inclusion Criteria: Diagnosis of RA (1987 ARA criteria) Diagnosis of RA (1987 ARA criteria) Active disease despite DMARD therapy at randomization Active disease despite DMARD therapy at randomization ≥ 10 swollen joints (66 joint count) ≥ 10 swollen joints (66 joint count) ≥ 12 tender joints (68 joint count) ≥ 12 tender joints (68 joint count) CRP ≥ 1 mg/dL CRP ≥ 1 mg/dL Stable doses of prednisone and NSAIDs allowed Stable doses of prednisone and NSAIDs allowed Abatacept Dosing: Week 0, 2, and 4, then Q4 weeks Abatacept Dosing: Week 0, 2, and 4, then Q4 weeks Weight-based dosing Weight-based dosing Weight-Tiered-based dosing Weight-Tiered-based dosing <60kg: Abatacept 500 mg IV <60kg: Abatacept 500 mg IV 60 kg to 100 kg: Abatacept 750 mg IV 60 kg to 100 kg: Abatacept 750 mg IV > 100 kg: Abatacept 1000 mg IV > 100 kg: Abatacept 1000 mg IV

7 Study Design-Common Features Statistical Analyses Statistical Analyses Modified ITT efficacy analyses performed for all trials Modified ITT efficacy analyses performed for all trials Sequential testing for co-primary endpoints Sequential testing for co-primary endpoints Co-primary endpoint tested for significance only if preceding co-primary endpoint was statistically significant Co-primary endpoint tested for significance only if preceding co-primary endpoint was statistically significant Type I error rate of 5% maintained Type I error rate of 5% maintained Adjustment for multiple doses performed using global testing then pairwise comparisons for individual doses Adjustment for multiple doses performed using global testing then pairwise comparisons for individual doses

8 Study Design-Common Features Statistical Analyses Statistical Analyses ACR and Health Assessment Questionnaire (HAQ) response rates ACR and Health Assessment Questionnaire (HAQ) response rates Categorical Endpoints Categorical Endpoints Chi-square Test Chi-square Test Non-responder imputation for missing data Non-responder imputation for missing data Radiographic Progression Radiographic Progression Genant-modified Sharp Score Genant-modified Sharp Score Rank-based nonparametric ANCOVA model Rank-based nonparametric ANCOVA model Linear extrapolation for missing data Linear extrapolation for missing data

9 Study IM : Concomitant MTX Study 12 month study 12 month study Active RA despite MTX therapy Active RA despite MTX therapy 656 patients randomized 2:1 656 patients randomized 2:1 Weight-Tiered-dose Abatacept + MTX (n=433) Weight-Tiered-dose Abatacept + MTX (n=433) Placebo + MTX (n=219) Placebo + MTX (n=219) Sequential Co-Primary Endpoints Sequential Co-Primary Endpoints 1. ACR 20 response at 6 months 2. Improvement in Physical Function (HAQ) at 12 months 3. Inhibition of Radiographic Progression at 12 months

10 Study IM : Dose-Ranging Study 12 month Study 12 month Study Active RA despite MTX therapy Active RA despite MTX therapy 339 patients randomized 1:1:1 339 patients randomized 1:1:1 Abatacept 10 mg/kg + MTX (n=115) Abatacept 10 mg/kg + MTX (n=115) Abatacept 2 mg/kg + MTX (n=105) Abatacept 2 mg/kg + MTX (n=105) Placebo + MTX (n=119) Placebo + MTX (n=119) Primary Endpoint Primary Endpoint ACR 20 response at 6 months ACR 20 response at 6 months

11 Study IM : TNF-Blocker Failure Study 6 month Study 6 month Study Active RA despite TNF-blocker therapy ± DMARD Active RA despite TNF-blocker therapy ± DMARD Etanercept or Infliximab Etanercept or Infliximab Following drug-washout 393 patients with active RA randomized 2:1 Following drug-washout 393 patients with active RA randomized 2:1 Weight-Tiered-dose Abatacept + DMARD (n=258) Weight-Tiered-dose Abatacept + DMARD (n=258) Placebo + DMARD (n=133) Placebo + DMARD (n=133) Co-Primary Endpoints Co-Primary Endpoints 1. ACR 20 response at 6 months 2. Improvement in Physical Function (HAQ) at 6 months

12 Study IM : Clinical Practice Study 12 month Study 12 month Study Active RA despite DMARD therapy Active RA despite DMARD therapy non-biologic and/or biologic DMARDs non-biologic and/or biologic DMARDs Patients with co-morbid conditions permitted Patients with co-morbid conditions permitted 1441 patients randomized 2: patients randomized 2:1 Baseline therapy + Weight-tiered dose Abatacept (n=959) Baseline therapy + Weight-tiered dose Abatacept (n=959) Baseline therapy + Placebo (n=482) Baseline therapy + Placebo (n=482) Primary Objective Primary Objective Safety Safety Exploratory Endpoint Exploratory Endpoint Improvement in Physical Function (HAQ) at Day 365 Improvement in Physical Function (HAQ) at Day 365

13 Clinical Studies-Study Conduct Baseline Patient Demographics (mean): Baseline Patient Demographics (mean): 52 years of age 52 years of age 79% Female 79% Female 85% White and 4% Black 85% White and 4% Black Baseline Disease Activity (mean): Baseline Disease Activity (mean): 10 years RA duration 10 years RA duration 21 swollen joints 21 swollen joints 31 tender joints 31 tender joints 79% RF(+) 79% RF(+) MTX 16 mg Qweek MTX 16 mg Qweek

14 Abatacept BLA EFFICACY ANALYSES Signs and Symptoms

15 IM : Concomitant MTX Study Signs & Symptoms: ACR Responses *p<0.001

16 IM : Concomitant MTX Study Signs & Symptoms: ACR 20 Response Time Course

17 IM : Concomitant MTX Study Signs & Symptoms: Major Clinical Response

18 IM : Concomitant MTX Study Median % Improvement in ACR Components at Day 169

19 IM : Concomitant MTX Study DAS28 Response at Day 365 *p<0.001

20 IM : Dose-Ranging Study Signs & Symptoms: ACR Responses *p≤0.03

21 IM : TNF-Blocker Failure Study Signs & Symptoms: ACR Responses at Day 169 *p≤0.003

22 IM : TNF-Blocker Failure Study Signs & Symptoms: DAS28 Response at Day 169 *p<0.001

23 Exploratory Analysis Criteria to Assess Very Low Disease Activity EULAR-definition of remission is defined as a DAS28<2.6 EULAR-definition of remission is defined as a DAS28<2.6 However, patients with a EULAR definition of remission can still have several swollen or tender joints However, patients with a EULAR definition of remission can still have several swollen or tender joints Alternative criterion for very low disease activity DAS28<2.6 AND ≤ 1 swollen and ≤1 tender joint Alternative criterion for very low disease activity DAS28<2.6 AND ≤ 1 swollen and ≤1 tender joint

24 Criteria to Assess Very Low Disease Activity IM : Concomitant MTX Study

25 Criteria to Assess Very Low Disease Activity IM : TNF-Blocker Failure Study

26 Exploratory Analysis Weight-Tiered-Dosing : ACR20 Responders

27 Abatacept BLA EFFICACY ANALYSES Improvement in Physical Function

28 IM : Concomitant MTX Study Improvement in HAQ score ≥ 0.3u at Day 365

29 IM : Dose-Ranging Study Improvement in HAQ score ≥ 0.3u at Day 360

30 IM : Dose-Ranging Study Improvement in HAQ score ≥ 0.3u Open-Label Study

31 Abatacept BLA EFFICACY ANALYSES Inhibition of Radiographic Progression

32 IM : Concomitant MTX Study Mean Change In Genant-Modified Sharp Scores at Day 365

33 IM : Concomitant MTX Study Mean Change in Genant-Modified Sharp Score Components

34 Study IM : Monotherapy Study 3 month study 3 month study Active RA despite DMARD therapy Active RA despite DMARD therapy 112 patients randomized 112 patients randomized Abatacept (n=90) Abatacept (n=90) 0.5 mg/kg (n=26), 2 mg/kg (n=32), or 10 mg/kg (n=32) 0.5 mg/kg (n=26), 2 mg/kg (n=32), or 10 mg/kg (n=32) Placebo (n=32) Placebo (n=32) Primary Endpoint Primary Endpoint ACR 20 response at Day 85 ACR 20 response at Day 85

35 Study IM : Monotherapy Study ACR Responses at Day 85

36 Abatacept Efficacy Analysis Subset Analyses by: Baseline Demographics Age Sex Race Weight Baseline Disease Activity Disease Duration Swollen & Tender Joints CRP Genant-modified Sharp Score HAQ

37 Abatacept BLA SAFETY ANALYSES

38 Safety Analyses: Overview Safety Assessment Based on 5 Studies: Safety Assessment Based on 5 Studies: IM101100, IM101101, IM101102, IM101029, IM IM101100, IM101101, IM101102, IM101029, IM Double-Blind Periods: Double-Blind Periods: 1955 Abatacept-treated patients (1688 person-years) 1955 Abatacept-treated patients (1688 person-years) 989 Placebo-treated patients (795 person-years) 989 Placebo-treated patients (795 person-years) Open-Label Periods + Double-Blind Periods: Open-Label Periods + Double-Blind Periods: 2688 Abatacept-treated patients 2688 Abatacept-treated patients

39 Cumulative Extent of Exposure

40Deaths 26 total deaths 26 total deaths 16 patients died during the double-blind periods 16 patients died during the double-blind periods 10 (0.5%) abatacept-treated patients 10 (0.5%) abatacept-treated patients 4 died from cardiovascular disorders 4 died from cardiovascular disorders 3 found dead at home 3 found dead at home 2 died from malignancies 2 died from malignancies 1 died from infection 1 died from infection 6 (0.6%) placebo-treated patients 6 (0.6%) placebo-treated patients 2 died from cardiovascular disorders 2 died from cardiovascular disorders 1 found dead at home 1 found dead at home 1 died from malignancy 1 died from malignancy 2 died from infection 2 died from infection

41Deaths Analysis of the individual deaths did not suggest a safety signal for any single type of AE Analysis of the individual deaths did not suggest a safety signal for any single type of AE 8 of the deaths in the Abatacept group occurred during a study that permitted enrollment of patients with co-morbidities 8 of the deaths in the Abatacept group occurred during a study that permitted enrollment of patients with co-morbidities

42 Serious Adverse Events 14% of Abatacept-treated patients had an SAE compared to 12% placebo-treated patients 14% of Abatacept-treated patients had an SAE compared to 12% placebo-treated patients 3% of Abatacept-treated patients had an infectious SAE compared to 2% placebo- treated patients 3% of Abatacept-treated patients had an infectious SAE compared to 2% placebo- treated patients

43 Malignancies: Double-Blind Periods Malignant Abatacept: 29 (1.5%) Placebo: 11 (1.1%) Non-Melanoma Skin CA Abatacept: 15 (0.8%) Placebo: 6 (0.5%) Solid Organ CA Abatacept: 13 (0.7%) Placebo: 5 (0.5%) Hematologic Abatacept: 2 (0.1%) Placebo: 0

44 Solid Organ Tumors Abatacept-Treated Patients-Double Blind Periods

45 Malignancies: Open-Label Periods 47 patients developed 52 neoplasms 47 patients developed 52 neoplasms 26 malignancies 26 malignancies 13 solid-organ tumors 13 solid-organ tumors 4 lung cancers 4 lung cancers 2 ovarian cancers 2 ovarian cancers 2 endometrial cancers 2 endometrial cancers 1 case each of breast, prostate, melanoma, cervical, and rectal cancer 1 case each of breast, prostate, melanoma, cervical, and rectal cancer 3 lymphomas 3 lymphomas

46 Most Frequently Observed vs. Expected Malignancies

47 Incidence Rates of Malignancies

48 Malignancies 3 potentially concerning malignancies 3 potentially concerning malignancies Lung Cancer Lung Cancer 8 cases of lung cancer in patients receiving abatacept 8 cases of lung cancer in patients receiving abatacept Breast Cancer and Lymphoma Breast Cancer and Lymphoma Pre-clinical studies demonstrated increased rate of mammary tumors and lymphomas in mice that was believed to be secondary to abatacept-induced chronic immunosuppression and MMTV and MLV Pre-clinical studies demonstrated increased rate of mammary tumors and lymphomas in mice that was believed to be secondary to abatacept-induced chronic immunosuppression and MMTV and MLV Immunosuppression and RA both associated with increased risk of lymphoma Immunosuppression and RA both associated with increased risk of lymphoma

49 Lung Cancer Incidence

50 Breast Cancer & Lymphoma Breast Cancer Breast Cancer 3 (0.1%) cases of breast cancer reported in abatacept-treated patients compared to 2 (0.2%) cases reported in placebo-treated patients 3 (0.1%) cases of breast cancer reported in abatacept-treated patients compared to 2 (0.2%) cases reported in placebo-treated patients Current evidence does not suggest abatacept increases the rate of breast cancer Current evidence does not suggest abatacept increases the rate of breast cancer Lymphoma Lymphoma 4 cases of lymphoma reported in patients receiving abatacept 4 cases of lymphoma reported in patients receiving abatacept Approximately 4-fold higher than general US population Approximately 4-fold higher than general US population However, increased rate of lymphoma in RA patients, particularly those with high disease activity However, increased rate of lymphoma in RA patients, particularly those with high disease activity

51 Serious Infections

52 Infections of Special Interest

53 AEs in Abatacept w/ Biologic RA Therapy A total of 204 patients received abatacept and concomitant biologic RA therapy during the double-blind period representing 173 person-years of exposure A total of 204 patients received abatacept and concomitant biologic RA therapy during the double-blind period representing 173 person-years of exposure Majority of patients were from studies IM (n=85) and IM (n=103) Majority of patients were from studies IM (n=85) and IM (n=103) >90% TNF-blocker therapy >90% TNF-blocker therapy Study IM compared the combination of abatacept 2 mg/kg + etanercept to placebo + etanercept Study IM compared the combination of abatacept 2 mg/kg + etanercept to placebo + etanercept

54 AEs in Abatacept w/ Biologic RA Therapy

55 SAEs with Abatacept & Concomitant RA Therapy Study IM101031

56 Infusion Reactions Infusion Reactions within 1 hour post-infusion Infusion Reactions within 1 hour post-infusion 9% of abatacept-treated patients vs. 6% placebo- treated patients 9% of abatacept-treated patients vs. 6% placebo- treated patients Infusion Reactions within 24 hours post- infusion Infusion Reactions within 24 hours post- infusion 23% of abatacept-treated patients vs. 19% placebo-treated patients 23% of abatacept-treated patients vs. 19% placebo-treated patients 2 cases of anaphylactic reactions in patients receiving abatacept 2 cases of anaphylactic reactions in patients receiving abatacept

57 Immunogenicity & Clinical Laboratory Values Immunogenicity of Abatacept Immunogenicity of Abatacept Overall, 1.6% of patients treated with abatacept developed antibodies to abatacept Overall, 1.6% of patients treated with abatacept developed antibodies to abatacept 5.8% of abatacept patients who had discontinued therapy for at least 56 days developed antibodies to abatacept 5.8% of abatacept patients who had discontinued therapy for at least 56 days developed antibodies to abatacept Changes in Clinical Laboratory Values Changes in Clinical Laboratory Values no clinically meaningful differences between patients treated with abatacept compared to placebo regarding blood chemistry and hematologic laboratory values no clinically meaningful differences between patients treated with abatacept compared to placebo regarding blood chemistry and hematologic laboratory values

58 Autoimmune Symptoms & Disorders 3% of Abatacept-treated patients reported autoimmune-related AEs compared to 2% of placebo- treated patients during the Double-Blind period 3% of Abatacept-treated patients reported autoimmune-related AEs compared to 2% of placebo- treated patients during the Double-Blind period Most common symptoms were associated with RA Most common symptoms were associated with RA e.g., Keratoconjunctivitis sicca, Sjogren’s syndrome e.g., Keratoconjunctivitis sicca, Sjogren’s syndrome Psoriasis was more frequent in patients treated with abatacept compared to placebo (0.5% vs. 0.1%) Psoriasis was more frequent in patients treated with abatacept compared to placebo (0.5% vs. 0.1%)

59 Autoimmune Symptoms & Disorders ANA and ds-DNA Antibody Formation at 12 months

60 AEs in patients with Co-Morbidities Study IM Study IM permitted patients with co- morbidities including COPD, diabetes, asthma, and CHF Study IM permitted patients with co- morbidities including COPD, diabetes, asthma, and CHF Diabetes, asthma, or CHF: no apparent increase in AEs or SAEs Diabetes, asthma, or CHF: no apparent increase in AEs or SAEs COPD: AEs reported in 97% of abatacept-treated patients vs. 88% of placebo-treated patients COPD: AEs reported in 97% of abatacept-treated patients vs. 88% of placebo-treated patients Respiratory AEs more common with abatacept (43% vs. 24%) Respiratory AEs more common with abatacept (43% vs. 24%) SAEs more common with (27% vs. 6%) SAEs more common with (27% vs. 6%) No reported deaths No reported deaths

61Summary The studies presented here show abatacept-treatment associated differences regarding The studies presented here show abatacept-treatment associated differences regarding improvement in signs and symptoms improvement in signs and symptoms improvement of physical function improvement of physical function Inhibition of radiographic progression Inhibition of radiographic progression There was a higher rate of serious infections in patients treated with abatacept, especially with patients receiving concomitant TNF-blocking agents There was a higher rate of serious infections in patients treated with abatacept, especially with patients receiving concomitant TNF-blocking agents Overall malignancy rates were not substantially different between abatacept (1.5%) and placebo (1.1%) treated patients Overall malignancy rates were not substantially different between abatacept (1.5%) and placebo (1.1%) treated patients However, abatacept treated patients had more cases of lung cancer and the rate of lymphomas was higher than expected compared to the general US population However, abatacept treated patients had more cases of lung cancer and the rate of lymphomas was higher than expected compared to the general US population

62Summary Infusion-related reactions were observed including hypersensitivity reactions and 2 cases of anaphylaxis Infusion-related reactions were observed including hypersensitivity reactions and 2 cases of anaphylaxis Patients with COPD treated with abatacept had a higher incidence of adverse events and serious adverse events, particularly respiratory disorders Patients with COPD treated with abatacept had a higher incidence of adverse events and serious adverse events, particularly respiratory disorders