# Presentation: 673175

## Abatacept

**Brian Daniels, M.D.**Senior Vice-PresidentGlobal Clinical DevelopmentBristol-Myers Squibb

## Abatacept:Introduction

**Anthony Waclawski, Ph.D.**Executive Director
- Global Regulatory Sciences
-  Bristol-Myers Squibb

## Abatacept

**Abatacept**

## Proposed Indication

**ORENCIA is indicated for: **
**Reducing signs and symptoms, inducing major clinical response**
**Inhibiting the progression of structural damage, and**
**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 **
**May be used in combination with methotrexate or other non-biologic DMARD therapy**

## 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**

## 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)

## 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)

## 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)

## Abatacept: Safety Database

**Abatacept: Safety Database**

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

## Presentation Outline

**Efficacy****	****.................****	****George Vratsanos, M.D.**
**Safety**** ****	****....................****	****Dan MacNeil, M.D.**
**Summary****	****...............****	****Brian Daniels, M.D.**

## Abatacept:Summary of Efficacy

**George Vratsanos, M.D.**Medical DirectorImmunology
- Bristol-Myers Squibb

## Outline of Presentation

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

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

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

**APC**

**Abatacept **

**MHC**

**TCR**

**CD28**

**T-cell**

## Role of Activated T-Cells in RA

**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**

## Proposed Mechanism of Action of Abatacept

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

## Dose Selection

## Phase II Dose Response StudiesDouble-Blind, Randomized, Placebo Controlled

|   | Dose Finding Study
IM103-002 |  |
| --- | --- | --- |
| 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) | 3 months |  |

|   | Dose Finding Study
IM103-002 | Dose Ranging Study
IM101-100 |
| --- | --- | --- |
| 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) | 3 months | 6 months |

**Phase II Dose Response Studies****Double-Blind, Randomized, Placebo Controlled**

## ACR 20 Response Rates Over TimeDose Ranging Study

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

- IM101-100

**ACR 20 Response Rates Over Time****Dose Ranging Study**

**Primary Endpoint**

## Rationale for Phase III Design

## Phase III Pivotal StudyPatients with Inadequate Response to Methotrexate

**Phase III Pivotal Study****Patients with Inadequate Response to Methotrexate**

**Methotrexate continued**
**Other DMARDs washout**

**Screening**

**6 Months **

**Co-primary e****ndpoint**
**ACR 20**

**Placebo (N = 219)**

**Abatacept (N = 433)**

**Randomization**

**1 Year**

- IM101-102

**Day 1**

**Co-primary**** ****endpoint**
**Physical Function**
**Structural damage**

**Double-blind**

**Open-label**

**Treated (N = 652)**

**10****mg/kg**

**Changes in DMARDs allowed**

## Demographic and Patient CharacteristicsPatients with Inadequate Response to Methotrexate

- IM101-102

|  | AbataceptN = 433 | PlaceboN = 219 |
| --- | --- | --- |
| Age in years, mean | 52 | 50 |
| Female (%) | 78  | 82 |
| Caucasian (%) | 88 | 88 |
| Disease duration in years, mean |   9 |   9 |
| RF+ (%) | 82 | 79 |
| Steroids (%) | 72 | 68 |
| Methotrexate dose, mean mg/wk | 16 | 16 |

## Clinical CharacteristicsPatients with Inadequate Response to Methotrexate

|  | Mean |  |
| --- | --- | --- |
|  | AbataceptN = 433 | PlaceboN = 219 |
| Number of tender joints | 31 | 32 |
| Number of swollen joints | 21 | 22 |
| Physical function, HAQ score | 1.7 | 1.7 |
| CRP, mg/dL | 3.3 | 2.8 |
| DAS-28 (ESR) | 6.8 | 6.8 |
| Percent Patients with Erosions | > 99 | 100 |

- IM101-102

## Patient Disposition at 1 YearPatients with Inadequate Response to Methotrexate 

- IM101-102

**	****	****Abatacept ****	****Placebo**
**	****	****N = 433****	****N = 219**
**Completed Double Blind Period****	****385 (89)****	****162 (74)**
**Discontinued****	****48 (11)****	****57 (26)**
**	****Adverse Events****	****18 (4.2)****	****4 (1.8)**
**	****Death****	****1 (0.2)****	****1 (0.5)**
**	****Lack of Efficacy****	****13 (3.0)****	****40 (18)**
**	****Lost to Follow-up****	****1 (0.2)****	****1 (0.5)**
**	****Withdrawal of Consent****	****10 (2.3)****	****5 (2.3)**
**	****Other****	****5 (1.2)****	****6 (2.7)**

**Patient Disposition at 1 Year****Patients with Inadequate Response to Methotrexate**** **

**Number (%) of Patients**

## ACR 20 Response Over TimePatients with Inadequate Response to Methotrexate

**ACR 20 Response Over Time****Patients with Inadequate Response to Methotrexate**

- IM101-102

- 	**	*p* < 0.001
- 	^	*p* < 0.01
- 	*	*p* < 0.05
- ITT analysis; All patients who D/C are considered non-responders

**Primary Endpoint**

## ACR 70 Response Over TimePatients with Inadequate Response to Methotrexate

- 	^	*p* < 0.01
- ITT analysis; All patients who D/C are considered non-responders

- IM101-102

**ACR 70 Response Over Time****Patients with Inadequate Response to Methotrexate**

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

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

- **

- ** *p* < 0.001

**Major Clinical Response**

- IM101-102

**% of Patients with Joint Counts of Zero**

- **

- **

- LOCF Analysis

## Summary of ACR 20 Subgroup Analyses at 6 MonthsPatients with Inadequate Response to Methotrexate

**All Patients**

- IM101-102

**Age**

**Gender**

**RF + or –**

**Body weight**

**Duration of RA**

**Treatment Difference with 95% CI**

**Abatacept Better**

**Placebo Better**

## Evaluation of Structural Damage ProgressionPatients with Inadequate Response to Methotrexate

**Assessed using Genant Modified Sharp scoring**** ****system**
**Paired radiographs obtained in over 90% of all randomized patients**
**Radiographs scored in blinded fashion using  validated method**
**Data analyzed using comparison of distribution of changes from baseline, mean and median changes**

## Genant Modified Sharp Scoring SystemPatients with Inadequate Response to Methotrexate

**Erosions (Maximum score: 145)**
**	****14 joints in each hand / wrist**
**	****6 joints in each foot**
**Joint Space Narrowing (Maximum score: 145)**
**	****13 joints in each hand / wrist**
**	****6 joints in each foot**

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

******

**^**

******

- IM101-102

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

- ** *p* < 0.001
-  ^ *p* < 0.01

- JSN = Joint Space Narrowing

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

- IM101-102

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

- JSN = Joint Space Narrowing

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

**Increasing score**

- IM101-102

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

- IM101-102

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

***p***** = 0.012 for Total Score**
***p***** = 0.029 for Erosion Score**
***p***** = 0.009 for JSN Score**

## Physical Function Responder Analysis (HAQ) at 1 YearPatients with Inadequate Response to Methotrexate

- IM101-102

- 	**	*p* < 0.001

******

******

******

******

**Primary Analysis**

## Clinically Important Improvement in Physical Function (Decrease in HAQ ≥ 0.3)Patients with Inadequate Response to Methotrexate

**Clinically Important Improvement in Physical Function (Decrease in HAQ ****≥ 0.3****)****Patients with Inadequate Response to Methotrexate**

- IM101-102

- 	**	*p* < 0.001
- 	^	*p* < 0.01
- 	*	*p* < 0.05
- ITT analysis; All patients who D/C are considered non-responders

## 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
     % Response |  | 84
55% | 

73
53% | 

64
53% |
|  |  |  |  |  |

- IM101-100

| Patients Who Discontinue Considered Non-responders |  |  |  |
| --- | --- | --- | --- |
|   All Patients (N = 84)
     % Response | 55% | 46% | 42% |
|   mHAQ Responders at 1 year (N = 46)
     % Response | — | 67% | 57% |

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

- IM101-102

******

**Physical Component Summary**

*****

- 	**	*p* < 0.001
- 	*	*p* < 0.05
- LOCF Analysis

**Mental Component Summary**

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

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

- IM101-102

- 	**	*p* < 0.001
- 	^	*p* < 0.01
- LOCF Analysis

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

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

**Placebo (N = 133)**

**Abatacept (N = 258)**

**Randomization**

**Day 1**

**Double-blind**

**Open-label**

**6 Months**

**Co-primary**** ****endpoint**
**ACR 20**
**Physical Function**

- IM101-029

**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**

## Key Requirements for EntryPatients with Inadequate Response to Anti-TNF Therapy

**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 **
**Lack of efficacy occurred immediately before enrollment (‘recent user’) or more distantly (‘prior user’)**
**Lack of efficacy directly observed in recent users**
**Source Documentation of inadequate response required for prior users**

- IM101-029

## Demographic and Patient CharacteristicsPatients with Inadequate Response to Anti-TNF Therapy

- IM101-029

|  | AbataceptN = 258 | PlaceboN = 133 |
| --- | --- | --- |
| Age in years, mean | 53 | 53 |
| Female (%) | 77 | 80 |
| Caucasian (%) | 96 | 93 |
| RA duration in years, mean | 12 | 11 |
| RF+ (%) | 73 | 73 |

## Anti-TNF Use Before StudyPatients with Inadequate Response to Anti-TNF Therapy

**Anti-TNF Use Before Study****Patients with Inadequate Response to Anti-TNF Therapy**

- IM101-029

|  | % of Patients |  |
| --- | --- | --- |
|  | AbataceptN = 258 | PlaceboN = 133 |
| History of Anti-TNF Use
	Recent Users | 38  | 41 |
| 	Prior Users | 62 | 59 |
| Type of Anti-TNF Use
	Infliximab Users
	Etanercept Users | 
68
32 | 
60
40 |
| 
	Both Infliximab & Etanercept  | 
21 | 
17 |

## Clinical CharacteristicsPatients with Inadequate Response to Anti-TNF Therapy

- IM101-029

|  | Mean |  |
| --- | --- | --- |
|  | AbataceptN = 258 | PlaceboN = 133 |
| Number of tender joints | 31 | 33 |
| Number of swollen joints  | 22 | 22 |
| Physical function, HAQ score | 1.8 | 1.8 |
| CRP, mg/dL | 4.6 | 4.0 |
| DAS-28 (ESR) | 6.9 | 6.9 |

## 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) |
| Death | 0 | 0 |
| Lack of Efficacy | 14 (5.4) | 27 (20) |
| Lost to Follow-up
Withdrawal of consent
Other | 5 (1.9)
5 (1.9)
2 (0.8) | 0
2 (1.5)
0 |

- IM101-029

## ACR 20 Responses Over TimePatients with Inadequate Response to Anti-TNF Therapy

**ACR 20 Responses Over Time****Patients with Inadequate Response to Anti-TNF Therapy**

- IM101-029

- 	**	*p* < 0.001
- 	^	*p* < 0.01
- ITT analysis; All patients who D/C are considered non-responders

**15**

**Primary Endpoint**

## Substantial Clinical ResponsesPatients with Inadequate Response to Anti-TNF Therapy

**15**

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

- IM101-029

**ACR 70**

**1**

**% of Patients with Joint Counts of Zero**

*****

*****

- LOCF Analysis

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

## Summary of ACR 20 Subgroup Analyses at 6 MonthsPatients with Inadequate Response to Anti-TNF Therapy

- IM101-029

**All Patients**

**Age**

**Gender**

**Anti-TNF History**

**Body weight**

**Type of Anti-TNF**

**Abatacept Better**

**Placebo Better**

**Treatment Difference with 95% CI**

## Physical Function Responder Analysis (HAQ) at 6 MonthsPatients with Inadequate Response to Anti-TNF Therapy

- IM101-029

- 	**	*p* < 0.001

******

******

******

******

**Primary Analysis**

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

- IM101-029

******

**Physical Component Summary**

**^**

**Mental Component Summary**

- 	**	*p* < 0.001
- 	^	*p* < 0.01
- LOCF Analysis

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

- IM101-029

- 	**	*p* < 0.001
- 	^	*p* < 0.01
- 	*	*p* < 0.05
- LOCF Analysis

******

******

******

******

******

******

*****

**^**

## Clinical Biomarker Data

## Mean Values of Biomarkers at 6 MonthsPatients with Inadequate Response to Anti-TNF Therapy

**Mean Values of Biomarkers at 6 Months****Patients with Inadequate Response to Anti-TNF Therapy**

- IM101-029

**TNF-****α**

**IL-6**

**MMP-3**

**Rheumatoid Factor**

**Pro-inflammatory Cytokines **

**Proteolytic Enzyme **

**Autoantibody **

**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 ****Range**

**Normal ****Range**

**B/L = baseline value**

## Conclusions

**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:**
**ACR 70 response**
**Major clinical response**
**Proportion of patients with no swollen or tender**** ****joints**

## Daniel J. MacNeil, M.D.Executive DirectorGlobal Pharmacovigilance Bristol-Myers Squibb

**Abatacept:****Summary of Safety**

## Abatacept Safety Presentation Topics

**Description of patient population and overview ****of general safety and tolerability**
**Clinical findings on infection and malignancy**
**Plans for further assessment of safety profile ****post-approval**

## Safety Assessment Methods 

**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) **
**Adverse events classified using standard coding dictionary, MedDRA **
**Severity classified by investigator according to regulatory and functional criteria **

## RA Safety Population

**RA Safety Population**

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

**Open-Label, Uncontrolled**

**N = 2,339**

**N = 2,688**

**	****Placebo**

**	****Abatacept**

**N = 1,955**(204)

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

**N = 989**(134)

- BLA/4M

- Q

- G

## Extent of Exposure to Abatacept

- Population: Treated patients in 5 Core RA studies

- Q

- G

## Patient Characteristics Double-Blind, Controlled Study Periods 

**% Female**
**% Caucasian**
**Disease duration in years**

**52**
**80**
**87**
**10**

**Placebo****N = 989**

**53**
**79**
**88**
**10**

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

**Abatacept**
**N = 1955**

- BLA

- Q

- G

## Overview of Patients with Adverse EventsDouble-Blind, Controlled Study Periods

**AEs**
**SAEs**
**Discontinuation due to AEs**
**Deaths**

**Abatacept**
**N = 1955**

**1736  (88.8)**
**266  (13.6)**
**107    (5.5) **
**10    (0.5)**

**Placebo****N = 989**

**840  (84.9)**
**122  (12.3)**
**39    (3.9)**
**6    (0.6)**

**Number (%) of Patients**

## Adverse Events with Difference Between Abatacept vs Placebo (≥ 2%) Double-Blind, Controlled Study Periods

**Total Patients with AE                                                                                                                  **
**  ****Headache**
**  ****Nasopharyngitis**
**  ****Dizziness**
**  ****Hypertension**
**  ****Dyspepsia**

**1736 (88.8)                                                                                                                  **
**356 (18.2)**
**  ****225 (11.5)**
**  ****183   (9.4)**
**  ****129   (6.6)**
**126   (6.4)  **

**840  (84.9)                                                                                                                  **
**125  (12.6)                  **
**  ****90    (9.1)                  **
**  ****69    (7.0)                  **
**43    (4.3)                 **
**42    (4.2)**

**Preferred Term**

**Abatacept****N = 1955**

**Placebo****N = 989**

- BLA

**Number (%) of Patients**

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

**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)**
**29 (1.5)**
**28 (1.4)**
**23 (1.2)**
**19 (1.0)**
**  ****18 (0.9)**

**System Organ Class**

**Abatacept**
**N = 1955**

**Placebo****N = 989**

**     ****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**

## DeathsDouble-Blind, Controlled Study Periods

**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)**
**1 (< 0.1)**
**     ****0**
**0**

**6 (0.6)**
**2 (0.2)**
**2 (0.2)**
**1 (****0****.1)**
**2 (0.2)**
**0**
**1 (0.1)**
**1 (0.1)**

**System Organ Class**

**Abatacept**
**N = 1955**

**Placebo**
**N = 989**

**Number (%) of Patients**

- 4M

## Safety in Combination with Other Biologic Therapies

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

**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 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 Therapy**

- BLA

**Number (%) of Patients**

## Special Topics:Infections and Malignancies

## Infections

**Frequency and Type of Infection **
**Overall **
**Most Common **
**Serious **
**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 **
**Infections of Particular Interest **
**Pneumonia **
**Herpes**
**Tuberculosis **

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

**Upper Respiratory Tract Infection**
**Nasopharyngitis**
**Sinusitis**
**Urinary Tract Infection        **
**Influenza**
**Bronchitis**

**1051  (53.8)**
**  ****248  (12.7)**
**  ****225  (11.5)**
**  ****125    (6.4)**
**  ****113    (5.8)**
**  ****111    (5.7)**
**  ****101    (5.2)**

**478  (48.3)**
**119  (12.0)**
**90    (9.1)        **
**  ****68    (6.9)        **
**  ****45    (4.6)        **
**  ****52    (5.3)        **
**  ****45    (4.6)        **

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

**Preferred Term**

**Abatacept**
**N = 1955**

**Placebo****N = 989**

**Number (%) of Patients**

- BLA

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

**   ****Pneumonia**
**   ****Cellulitis**
**   ****Urinary Tract Infection        **
**   ****Bronchitis   **
**   ****Diverticulitis**
**   ****Pyelonephritis Acute**
**   ****Sepsis**

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

**     ****58  (3.0)**
**9  (0.5)**
**      ****5  (0.3)**
**      ****4  (0.2)**
**      ****4  (0.2)**
**      ****3  (0.2)**
**      ****3  (0.2)**
**      ****1  (<0.1)**

**   ****19 (1.9)**
**5 (0.5)        **
**     ****2 (0.2)        **
**     ****1 (0.1)        **
**     ****0        **
**     ****0        **
**     ****0        **
**     ****3  (0.3)**

**Preferred Term**

**Abatacept**
**N = 1955**

**Placebo****N = 989**

**Number (%) of Patients**

- BLA

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

**Placebo**
**N = 989**

**Abatacept**
**N = 1955**

**24   (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**

## IV Antibiotics Use

| Study | # Months on Study Drug | Abatacept | Placebo |
| --- | --- | --- | --- |
| IM101-102(MTX-IR) | 0 – 6 | 9/433 (2.1) | 5/219 (2.3) |
|  | 6 – 12 | 15/401 (3.7)   | 7/174 (4.0) |
| IM101-029(Anti-TNF IR) | 0 – 6 | 3/258 (1.2) | 4/133 (3.0) |
| IM101-031(Safety) | 0 – 12 | 38/959 (4.0)   | 18/482 (3.7)   |

- BLA

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

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

| Total Discontinued Due to Infections

  Pneumonia |      24   (1.2)

       4  	(0.2) |    10   (1.0)

     1   (0.1) |
| --- | --- | --- |
|   Localized infections | 	3	(0.2) | 	0 |
|   Bronchitis | 	2	(0.1) |      	2   (0.2) |
|   Sepsis | 	1	(<0.1)  |      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**

## Deaths Due to Infectious Adverse EventsDouble-Blind, Controlled Study Periods

**Total Infectious Deaths**
**Aspergillosis**
**Pneumocystis**
**Sepsis**

**Abatacept**
**N = 1955**

**  ****1 (<0.1)**
**  ****1 (<0.1)**
**      ****0              **
**      ****0**

**Placebo****N = 989**

**2  (0.2)**
**0        **** **
**1  (0.1)**
**1  (0.1)**

**Number (%) of Patients**

- BLA

## Serious Infection Incidence Rates by Time IntervalsCumulative Study Periods – Through 4 Month Update

|  | Time Intervals (Months) |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | 0-6  | 6-12 | 12-18 | 18-24 | 24-30  | >30  |
| n/p-y* | 50/1285 | 39/1032 | 22/795 | 9/399 | 4/117 | 3/198 |
| IR/100 p-y** | 3.92 | 3.81 | 2.78 | 2.26 | 3.45 | 1.53 |
| (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

## Overview of PneumoniaDouble-Blind, Controlled Study Periods

|  | Number (%) of Patients |  |  |  |
| --- | --- | --- | --- | --- |
|   | Abatacept
N = 1955 |  | Placebo
N = 989 |  |
| Total Patients with Pneumonia | 42 |  (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) |
| Serious | 14 | (0.7) | 6 | (0.6) |
| Severe
Very Severe | 11
1 | (0.6)
(<0.1) | 1
2 | (0.1)
(0.2) |
| Discontinued | 5 | (0.3) | 1 | (0.1) |

**Overview of Pneumonia****Double-Blind, Controlled Study Periods**

- BLA

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

## 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) |
| Varicella | 3 | (0.2) | 0 |  |
| Epstein-Barr Virus | 0 |  | 0 |  |
| Cytomegalovirus | 0 |  | 0 |  |

- BLA

## TuberculosisCumulative Study Periods

**2 cases of presumed tuberculosis with abatacept**
**Tuberculous Infection (Double-Blind): **
**Presented with cervical lymphadenitis; diagnosis based on histology**
**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): **
**Unknown presentation; no definitive diagnosis**

## Infections: Conclusions

**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**

## Malignancy

**Presentation**
**Non-clinical findings**
**Overall clinical experience**
**Malignancies of particular interest**
**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**

## Carcinogenicity Study in Mice

**Duration: up to 88 weeks**
**Exposures: 0.8-, 1.9- and 3.0-fold human exposure**
**Sustained immunomodulation at all dose levels**
**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**

## Primate Toxicology Study

**Primate Toxicology Study**

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

## MalignanciesDouble-Blind, Controlled Study Periods

| 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 |

**Malignancies****Double-Blind, Controlled Study Periods**

**Abatacept**
**N = 1955**

**Placebo **
**N = 989**

**Type of Malignancy**

- 4M

**Number (%) of Patients**

## Malignancies – AbataceptDouble-Blind and Cumulative Study Periods

| Non-melanoma Skin  | 15 (0.89) |   24 (0.63) |
| --- | --- | --- |
| Solid |   9 (0.53) |   21 (0.55) |
|   Lung  |   4 (0.24) |     8 (0.21) |
|   Thyroid |   2 (0.12) |     2 (0.05) |
|   Breast |   1 (0.06) |     2 (0.05) |
|   Prostate |   1 (0.06) |     2 (0.05) |
|   Bladder |   1 (0.06) |     1 (0.03) |
|   Renal |   1 (0.06) |     1 (0.03) |
|   Ovarian |   0 |     2 (0.05) |
|   Melanoma |   0 |     1 (0.03) |
|   Endometrial / Uterine |   0 |     2 (0.05) |
|   Cervix |   0 |     1 (0.03) |
| Hematologic |   2 (0.12) |     5 (0.13) |
|   Lymphoma |   1 (0.06) |     4 (0.10) |
|   Myelodysplastic Syndrome |   1 (0.06) |     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

## Malignancies – Standardized Incidence RatiosCompared to U.S. General Population*Cumulative Study Periods

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

## Comparison of RA Cohorts to General PopulationsPublished Literature 

| Lymphoma |
| --- |
| Lung |
| Colon and Rectal |
| Breast |

## RA Cohorts – DMARD Specific

**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.)**

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

**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 |

## Lung Cancer – Abatacept Observed and ExpectedCumulative Study Periods and RA Observational Cohorts

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**20**

**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 |

## LymphomasCumulative Study Periods

| Patient No.
Age/Race/Gender | Adverse Event | Dose | Latency (Days) | Con  Meds* |
| --- | --- | --- | --- | --- |
| IM101-102-39-9
81 / W / F
 | B-cell Lymphoma / Hashimoto’s Thyroiditis | 750 mg
 | 241 D | MTX
[Infliximab]
 |
| IM101-102-136-15
46 / W / M
 | Diffuse Large B-cell Lymphoma (CD20 + Stage Ia) | 750 mg | 203 D | MTX
 |
| IM101-101-14-2
61 / W / F
 | Diffuse Large B-Cell Lymphoma (Stage IVb) | 750 mg | 1086 D | Etanercept |
| IM101-029-26-9
58 / W / M
 | Large T-cell Lymphoma (Stage IIb) | 750 mg | 505 D | MTX
LFN
[Infliximab] |

**Lymphomas****Cumulative Study Periods**

- 4M

- *[  ] = Previous medication

## Lung Cancer

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

## 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) |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | 0-6  |  | 6-12 | 12-18 | 18-24 | 24-30  | >30  |
| n/p-y* | 2/1285 |  | 2/1032 | 4/795 | 0/399 | 0/117 | 0/198 |
| IR/100 p-y** | 0.16  |  | 0.19  | 0.50 | 0  | 0 | 0  |
| (95% CI) | (0.02, 0.56) |  | (0.02, 0.70) | (0.14, 1.29) | (0, 0.92) | (0, 3.15) | (0, 1.86) |

- 4M

## Malignancies – AbataceptCumulative Study Periods

| Non-melanoma Skin |  24 (0.63) |  33 (0.70) |
| --- | --- | --- |
| Solid |  21 (0.55) |  28 (0.59) |
| 	Lung  |     8 (0.21) |  11 (0.23) |
| 	Thyroid |     2 (0.05) |    2 (0.04) |
| 	Breast |     2 (0.05) |    4 (0.08) |
| 	Prostate |     2 (0.05) |    3 (0.06) |
| 	Bladder |     1 (0.03) |    1 (0.02) |
| 	Renal |     1 (0.03) |    1 (0.02) |
| 	Ovarian |     2 (0.05) |    2 (0.04) |
| 	Melanoma |     1 (0.03) |    1 (0.02) |
| 	Endometrial / Uterine |     2 (0.05) |    2 (0.04) |
| 	Cervix |     1 (0.03) |    1 (0.02) |
| 	Gastric |     0 |    1 (0.02) |
| Hematologic |     5 (0.13) |    6 (0.13) |
| 	Lymphoma |     4 (0.10) |    4 (0.08) |
| 	Myelodysplastic Syndrome |     1 (0.03) |    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)**

## Malignancy Assessment

**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**
**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**

## Malignancy Assessment

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

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

## 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**
**Estimate incidence rates overall and in subgroups**
**Compare incidence rates with abatacept to other treatments**
**Monitor patterns of use**
**Investigate potential signals of unanticipated adverse events**

## Large Observational Studies:Insurance Claims Cohort

**Describe short-term incidence of targeted adverse events **
**Confirmation through chart review**
**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**

## Large Observational Studies:Prospective Cohort (Registry)

**Short-term and long-term incidence of adverse events**
**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**

## Overall Safety Summary

**Clinical development program demonstrates that abatacept is generally safe and well-tolerated**
**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**
**Pharmacovigilance plan includes 2 large observational studies to better define risk of rare events, including lymphoma, other malignancies, and serious infections**

## AbataceptSummary

**Brian Daniels, M.D.**Senior Vice-PresidentGlobal Clinical DevelopmentBristol-Myers Squibb

## 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 MedicineHead, 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