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Clinical Overview – Phase III by dfhdhdhdhjr

VIEWS: 9 PAGES: 102

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



                              1
    Abatacept:
   Introduction
Anthony Waclawski, Ph.D.
    Executive Director
Global Regulatory Sciences
   Bristol-Myers Squibb



                             2
Abatacept




            3
               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
                                                           4
              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




                                                                  5
    Overview of Clinical Development Program
             in Rheumatoid Arthritis

        Phase II                Phase III        Ongoing
                                                Open-Label
   Dose finding           Methotrexate     Extension Studies
    monotherapy study       inadequate
    (IM103002)              responder            IM101100LT
   Dose ranging in         (IM101102)
                                                 IM101101LT
    methotrexate           TNF inadequate
    inadequate              responder            IM101102LT
    responders              (IM101029)
    (IM101100)                                   IM101029LT
                           Safety Trial
   Combination with        (IM101031)           IM101031LT
    etanercept
    (IM101101)



                                                                 6
    Overview of Clinical Development Program
             in Rheumatoid Arthritis

        Phase II                Phase III        Ongoing
                                                Open-Label
   Dose finding           Methotrexate     Extension Studies
    monotherapy study       inadequate
    (IM103002)              responder            IM101100LT
   Dose ranging in         (IM101102)
                                                 IM101101LT
    methotrexate           TNF inadequate
    inadequate              responder            IM101102LT
    responders              (IM101029)
    (IM101100)                                   IM101029LT
                           Safety Trial
   Combination with        (IM101031)           IM101031LT
    etanercept
    (IM101101)



                                                                 7
    Overview of Clinical Development Program
             in Rheumatoid Arthritis

        Phase II                Phase III        Ongoing
                                                Open-Label
   Dose finding           Methotrexate     Extension Studies
    monotherapy study       inadequate
    (IM103002)              responder            IM101100LT
   Dose ranging in         (IM101102)
                                                 IM101101LT
    methotrexate           TNF inadequate
    inadequate              responder            IM101102LT
    responders              (IM101029)
    (IM101100)                                   IM101029LT
                           Safety Trial
   Combination with        (IM101031)           IM101031LT
    etanercept
    (IM101101)



                                                                 8
            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




                                                           9
             Presentation Outline


Efficacy ................. George Vratsanos, M.D.

Safety .................... Dan MacNeil, M.D.

Summary …............ Brian Daniels, M.D.




                                                    10
   Abatacept:
Summary of Efficacy
  George Vratsanos, M.D.
      Medical Director
         Immunology
    Bristol-Myers Squibb



                           11
            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




                                                         12
    Abatacept Selectively Modulates
Co-Stimulation via CD80/86:CD28 Pathway




        APC     MHC    TCR    T-cell
                       CD28




           Abatacept


                                          13
Role of Activated T-Cells in RA

        Activation
                       Activated
                        T-cell




 Activated                               Activated
Macrophage              Fibroblast        B-cell



  TNF-a              IL-6    MMPs    Autoantibodies,
                                         e.g. RF


  Inflammation & Joint Destruction
                                                       14
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




                                                    15
Dose Selection




                 16
           Phase II Dose Response Studies
         Double-Blind, Randomized, Placebo Controlled

                       Dose Finding Study     Dose Ranging Study
                           IM103-002              IM101-100
Patient Population          DMARD                 Methotrexate
                     Inadequate Responders   Inadequate Responders


Background                   None                Methotrexate
Medication               (Monotherapy)


Abatacept Doses            10 mg/kg                10 mg/kg
                            2 mg/kg                 2 mg/kg
                           0.5 mg/kg


Primary Endpoint           3 months                6 months
(ACR 20)


                                                                   17
                           ACR 20 Response Rates Over Time
                                               Dose Ranging Study

                      80
                                                      Primary Endpoint
                      70
                                                **          **           **          **          **
                      60             **   ^
                                                       **
       % Responders




                      50

                      40

                      30

                      20                                             Abatacept 10mg/kg (N=115)
                                                                     Abatacept 2 mg/kg (N=105)
                      10
                                                                     Placebo (N=119)
                       0
                           1015 30   60   90    120   150   180   210    240   270   300   330   360
                                                        Visit Days
** p < 0.001 vs placebo
 ^ p < 0.01 vs placebo

IM101-100                                                                                              18
Rationale for Phase III Design




                                 19
                      Phase III Pivotal Study
            Patients with Inadequate Response to Methotrexate



                                             Double-blind      Open-label

                       Abatacept (N = 433)

 Treated (N = 652)                           Changes in                       10
                                             DMARDs
                                                                             mg/kg
   Methotrexate                              allowed
    continued         Placebo (N = 219)
  Other DMARDs
     washout    Day 1                 6 Months              1 Year

Screening     Randomization      Co-primary endpoint      Co-primary endpoint
                                   ACR 20                  Physical Function
                                                            Structural damage




IM101-102                                                                        20
   Demographic and Patient Characteristics
            Patients with Inadequate Response to Methotrexate


                                           Abatacept    Placebo
                                            N = 433     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




IM101-102                                                         21
                    Clinical Characteristics
            Patients with Inadequate Response to Methotrexate

                                                   Mean
                                          Abatacept     Placebo
                                           N = 433      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                                                         22
                  Patient Disposition at 1 Year
            Patients with Inadequate Response to Methotrexate

                                          Number (%) of Patients
                                         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)

IM101-102                                                          23
                                 ACR 20 Response Over Time
                 Patients with Inadequate Response to Methotrexate
                      80
                                                    Primary Endpoint   **        **               **
                      70                       **     **   **
                                          **
                      60             **
       % Responders




                      50

                      40         ^
                      30
                             *
                      20

                      10                                                    Abatacept (N = 424)
                                                                            Placebo (N = 214)
                       0
                           1 15 29   57   85 113 141 169 197 225 253 281 309 337 365
 ** p < 0.001                               Visit Days
  ^ p < 0.01
  * p < 0.05
ITT analysis; All patients who D/C are considered non-responders
IM101-102                                                                                              24
                                   ACR 70 Response Over Time
               Patients with Inadequate Response to Methotrexate
                           35
                                          Abatacept (N = 424)
                           30                                                           **
                                          Placebo (N = 214)
                                                                          **   **
                           25
            % Responders




                                                               **
                           20                           **
                           15
                                               **   ^

                           10

                            5

                            0
                                1 15 29   57   85   113 141 169 197 225 253 281 309 337 365
                                                             Visit Days
 ** p < 0.001
  ^ p < 0.01
ITT analysis; All patients who D/C are considered non-responders
IM101-102                                                                                     25
                  Substantial Clinical Responses at 1 Year
                        Patients with Inadequate Response to Methotrexate

                                                                               % of Patients with
                      Major Clinical Response                                 Joint Counts of Zero
                 25                                                 25
                              Abatacept (N = 424)                                        Abatacept (N = 424)

                 20           Placebo (N = 214)                                          Placebo (N = 212)
                                                                    20
                                                                              **
  % Responders




                                                                             18
                                                                                                 **



                                                    % of Patients
                 15          **                                     15                           16
                             14
                 10                                                 10


                  5                                                  5
                                                                                   4.2                 3.8
                                     1.9
                  0                                                  0
                                                                          No Swollen Joints   No Tender Joints

 ** p < 0.001                                                            LOCF Analysis
IM101-102                                                                                                        26
  Summary of ACR 20 Subgroup Analyses at 6 Months
            Patients with Inadequate Response to Methotrexate
                                                         Placebo       Abatacept
                                                          Better        Better
    All Patients                    All (N=638)

    Age                   < 65 years (N = 547)
                           ≥ 65 years (N = 91)

    Gender                    Female (N = 507)
                                Male (N = 131)

    Body weight               < 60 kg (N = 164)
                            60-100 kg (N = 433)
                              > 100 kg (N = 41)

    RF + or –                 Negative (N = 75)
                             Positive (N = 520)

    Duration of RA          ≤ 2 years (N = 136)
                       > 2 to ≤ 5 years (N =137)
                     > 5 to ≤ 10 years (N = 159)
                           > 10 years (N = 206)

                                                   -20             0          20   40   60      80
                                                             Treatment Difference with 95% CI        27
IM101-102
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



                                                          28
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




                                                    29
          Mean Change in Radiographic Scores at 1 Year
                                Patients With Inadequate Response to Methotrexate

                                3
    Mean Change from Baseline



                                        Abatacept (N = 391)
                                        Placebo (N = 195)
                                                                                   2.32
                                2


                                                                             **
                                1            1.14                    1.18   1.21
                                       ^                       **
                                      0.63                    0.58
                                0
                                      Erosion                   JSN          Total
 ** p < 0.001
  ^ p < 0.01
 JSN = Joint Space Narrowing
IM101-102                                                                                 30
   Median Change in Radiographic Scores at 1 Year
                                  Patients With Inadequate Response to Methotrexate

                                  0.7
    Median Change from Baseline



                                           Abatacept (N = 391)
                                  0.6
                                           Placebo (N = 195)
                                  0.5                                               0.53
                                  0.4

                                  0.3

                                  0.2           0.27                         0.25

                                  0.1
                                         0.00                    0.00 0.00
                                   0
                                          Erosion                  JSN        Total


 JSN = Joint Space Narrowing
IM101-102                                                                                  31
Distribution of Radiographic Changes in Total Score at 1 Year
                                   Patients with Inadequate Response to Methotrexate

                           40

                                          Placebo (N = 195)
                           30
    Change from Baseline




                           20                                               Increasing score

                           10
                                              Unchanged
                            0

                                       Lower Score
                           -10
                                 0.0    0.1    0.2   0.3      0.4    0.5    0.6    0.7   0.8   0.9   1.0
                                                              Cumulative Probability

 IM101-102                                                                                                 32
                                 Comparison of Distribution of
                          Radiographic Changes in Total Score at 1 Year
                                  Patients with Inadequate Response to Methotrexate

                          40
                                       Abatacept (N = 391)
                                       Placebo (N = 195)
                          30
   Change from Baseline




                          20
                                      p = 0.012 for Total Score
                                      p = 0.029 for Erosion Score
                          10
                                      p = 0.009 for JSN Score


                           0


                          -10
                                0.0    0.1    0.2    0.3     0.4    0.5   0.6    0.7   0.8   0.9   1.0
                                                            Cumulative Probability

IM101-102                                                                                                33
Physical Function Responder Analysis (HAQ) at 1 Year
                     Patients with Inadequate Response to Methotrexate


                    80

                    70     **                                           Abatacept (N = 424)
                           69              **
                    60                                      **          Placebo (N = 214)
                                           64
     % Responders




                                                            58
                    50

                    40          44                                             **
                                                39                             39
                    30                                           33
                    20
                                                                                    21
                    10

                     0
                            ≥ 0.22          ≥ 0.3             ≥ 0.5             ≥ 0.8
                         Improvement    Improvement       Improvement       Improvement


           ** p < 0.001                Primary Analysis

IM101-102                                                                                     34
    Clinically Important Improvement in Physical Function
                    (Decrease in HAQ ≥ 0.3)
                   Patients with Inadequate Response to Methotrexate

                                            80
            % Responders (decrease ≥ 0.3)


                                            70
                                                                                    **      **             **
                                                                **   **   ^   **
                                            60
                                                           *
                                            50

                                            40

                                            30

                                            20
                                                                                     Abatacept (N = 424)
                                            10                                       Placebo (N = 214)
                                             0
                                                 1 15 29   57   85 113 141 169 197 225 253 281 309 337 365
 ** p < 0.001                                  Visit Days
  ^ p < 0.01
  * p < 0.05
ITT analysis; All patients who D/C are considered non-responders
IM101-102                                                                                                       35
    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                    84            73     64
     % Response                           55%           53%    53%




   Patients Who Discontinue Considered Non-responders
    All Patients (N = 84)
      % Response                          55%           46%    42%

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


IM101-100                                                             36
Improvement in Quality of Life (SF-36) at 1 Year
                                   Patients with Inadequate Response to Methotrexate


                               Physical Component Summary                                                 Mental Component Summary
                              12                                                                     12
                                                   Abatacept (N = 417)                                                 Abatacept (N = 417)
                                                   Placebo (N = 207)                                                   Placebo (N = 207)




                                                                         Mean Change from Baseline
                              10                                                                     10
  Mean Change from Baseline




                                              **
                               8          9.1                                                         8
                                                                                                                  *
                               6                                                                      6          6.9

                               4                        5.0                                           4                      4.7

                               2                                                                      2

                               0                                                                      0

                               ** p < 0.001
                                * p < 0.05
                              LOCF Analysis

IM101-102                                                                                                                                    37
Improvement in Quality of Life (SF-36) at 1 Year
                                  Patients with Inadequate Response to Methotrexate


                            15
                                                                                                 Abatacept            Placebo
                                                         **
Mean Change from Baseline




                                                         11.6
                            10                **                                                          ^
                                  **                                              **           **
                                             9.4
                                                                                                          8.8
                                 8.0                                  **          8.1         8.4                       ^
                                                                      6.5                                              6.3
                             5                     5.7          5.9
                                                                                                    5.3         5.5
                                       4.5                                              4.7
                                                                            4.2                                              4.2



                             0
                                 Physical     Role-      Bodily       General     Vitality     Social    Role-         Mental
                                 Function    Physical     Pain         Health                 Function Emotional       Health

                             ** p < 0.001
                              ^ p < 0.01
                            LOCF Analysis
IM101-102                                                                                                                          38
   Phase III Pivotal Study
Patients with Inadequate Response
       to Anti-TNF Therapy




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



                                              Double-blind   Open-label

  Treated (N = 391)             Abatacept (N = 258)
Stratified Recent vs Prior                                                 10
                                                                          mg/kg
  DMARDs continued
                                Placebo (N = 133)
  Anti-TNF washout
        period          Day 1                          6 Months
    (28–60 days)

                       Randomization                   Co-primary endpoint
                                                         ACR 20
                                                         Physical Function



IM101-029                                                                     40
               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                                                        41
   Demographic and Patient Characteristics
      Patients with Inadequate Response to Anti-TNF Therapy


                                     Abatacept    Placebo
                                      N = 258     N = 133
    Age in years, mean                 53          53
    Female (%)                         77          80

    Caucasian (%)                      96          93

    RA duration in years, mean         12          11

    RF+ (%)                            73          73




IM101-029                                                     42
              Anti-TNF Use Before Study
      Patients with Inadequate Response to Anti-TNF Therapy

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

        Both Infliximab & Etanercept      21           17



IM101-029                                                      43
                  Clinical Characteristics
      Patients with Inadequate Response to Anti-TNF Therapy

                                              Mean
                                     Abatacept     Placebo
                                      N = 258      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




IM101-029                                                     44
             Patient Disposition at Six Months
      Patients with Inadequate Response to Anti-TNF Therapy


                                         Number (%) of Patients
                                        Abatacept    Placebo
                                         N = 258     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                    5 (1.9)       0
     Withdrawal of consent                5 (1.9)     2 (1.5)
     Other                                2 (0.8)       0

IM101-029                                                         45
                                ACR 20 Responses Over Time
      Patients with Inadequate Response to Anti-TNF Therapy
                       80
                                     Abatacept (N = 256)                     Primary
                       70                                                   Endpoint
                                     Placebo (N = 133)
                       60
                                                                      **
                                                                                **
        % Responders




                       50                                  **   **
                                                 **
                       40              ^
                       30

                       20        ^

                       10

                        0
                            1   15     29        57        85   113   141       169

  ** p < 0.001                              Visit Days
   ^ p < 0.01
 ITT analysis; All patients who D/C are considered non-responders
IM101-029                                                                              46
                              Substantial Clinical Responses
                    Patients with Inadequate Response to Anti-TNF Therapy
                                                                                                % of Patients with
                                     ACR 70                                                    Joint Counts of Zero
               14                                                                   10
                           Abatacept (N = 256)                                                            Abatacept (N = 254)
               12                                                                                         Placebo (N = 130)
                           Placebo (N = 133)                  ^                      8         *
                                                        **                                                         *
               10                                                                            7.9
% Responders




                                                                                                                 7.5




                                                                    % of Patients
                                              ^                                      6
                8
                                       *
                6               *                                                    4
                4
                                                                                     2              1.5
                2                                                                                                       0.8
                0                                                                    0
                    1 15 29
                    1           57     85     113       141   169                        No Swollen Joints    No Tender Joints
                                     Visit Days
               ITT analysis; All patients who D/C are                                    LOCF Analysis
               considered non-responders
      ** p < 0.001
       ^ p < 0.01
       * p < 0.05
  IM101-029                                                                                                                      47
  Summary of ACR 20 Subgroup Analyses at 6 Months
        Patients with Inadequate Response to Anti-TNF Therapy
                                                             Placebo       Abatacept
                                                              Better        Better
  All Patients                             All (N = 389)

  Age                            < 65 years (N = 318)
                                   ≥ 65 years (N = 71)

  Gender                              Female (N = 304)
                                         Male (N = 85)

  Body weight                         < 60 kg (N = 68)
                                   60-100 kg (N = 266)
                                     > 100 kg (N = 53)

  Anti-TNF History                   Recent (N = 152)
                                      Prior (N = 237)


  Type of Anti-TNF                Etanercept (N = 104)
                                   Infliximab (N = 208)
                     Etanercept and Infliximab (N = 77)


                                                           -20         0         20    40   60   80
                                                             Treatment Difference with 95% CI         48
IM101-029
Physical Function Responder Analysis (HAQ) at 6 Months
             Patients with Inadequate Response to Anti-TNF Therapy


                    80
                                                                        Abatacept (N = 256)
                    70                                                  Placebo (N = 133)
                    60     **
     % Responders




                           59
                    50                     **
                                           47               **
                    40
                                                            41
                    30          33
                    20                                                          **
                                                23
                                                                               20
                    10                                           14
                                                                                     4.5
                     0
                            ≥ 0.22          ≥ 0.3             ≥ 0.5              ≥ 0.8
                         Improvement    Improvement       Improvement        Improvement

  ** p < 0.001                         Primary Analysis

IM101-029                                                                                     49
Improvement in Quality of Life (SF-36) at 6 Months
                              Patients with Inadequate Response to Anti-TNF Therapy


                               Physical Component Summary                                           Mental Component Summary
                              10                                                               10
                                             Abatacept (N = 242)                                                 Abatacept (N = 242)
                                             Placebo (N = 129)                                                   Placebo (N = 129)




                                                                   Mean Change from Baseline
  Mean Change from Baseline




                               8                                                                8
                                        **
                               6       6.6                                                      6           ^
                                                                                                           5.2
                               4                                                                4


                               2                                                                2
                                                                                                                     2.1
                                                   1.1
                               0                                                                0

   ** p < 0.001
    ^ p < 0.01
  LOCF Analysis

IM101-029                                                                                                                              50
Improvement in Quality of Life (SF-36) After 6 Months
                                 Patients with Inadequate Response to Anti-TNF Therapy

                            15
                                    Abatacept         Placebo
Mean Change from Baseline




                            10
                                                           **
                                                           8.7                                 **
                                                **                                 **                      *
                                                                                               7.3
                                   **          6.5                                 6.6
                             5                                                                             6.0
                                   5.3                                  **                                             ^
                                                                       4.0                                             4.3

                                                                 2.5                                 2.4         2.5
                                         1.3         1.3                     0.7         1.8                                 1.6
                             0
                                  Physical      Role-      Bodily      General     Vitality     Social    Role-        Mental
                                  Function     Physical     Pain        Health                 Function Emotional      Health

                     ** p < 0.001
                      ^ p < 0.01
                      * p < 0.05
                    LOCF Analysis
IM101-029                                                                                                                          51
Clinical Biomarker Data




                          52
                Mean Values of Biomarkers at 6 Months
            Patients with Inadequate Response to Anti-TNF Therapy
           Pro-inflammatory Cytokines                                        Proteolytic Enzyme
                            TNF-α                                                       MMP-3
           50                                                          100
           40                                                           80




                                                               ng/mL
  pg/mL




           30                                                           60
           20                                                           40
                                                                                                              Normal
           10                                        Normal             20                                    Range
            0                                        Range               0
                 B/L 6 Mo            B/L    6 Mo                             B/L 6 Mo           B/L    6 Mo
                 Abatacept           Placebo                                  Abatacept         Placebo

                                                                                 Autoantibody
                              IL-6                                             Rheumatoid Factor
           50                                                          300
           40                                                          250
                                                                       200
   pg/mL




                                                               U/mL
           30
                                                                       150
           20
                                                                       100
           10                                       Normal
                                                                        50                                     Normal
                                                    Range
            0                                                            0                                     Range
                 B/L   6 Mo           B/L   6 Mo                              B/L   6 Mo         B/L   6 Mo
                  Abatacept          Placebo                                  Abatacept         Placebo

 B/L = baseline value                              Abatacept           Placebo
IM101-029                                                                                                               53
                    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

                                                       54
   Abatacept:
Summary of Safety
 Daniel J. MacNeil, M.D.
     Executive Director
 Global Pharmacovigilance
    Bristol-Myers Squibb



                            55
  Abatacept Safety Presentation Topics


 Descriptionof patient population and overview
 of general safety and tolerability

 Clinical   findings on infection and malignancy

 Plansfor further assessment of safety profile
 post-approval




                                                    56
          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



                                                       57
                      RA Safety Population

  Abatacept             Placebo
  N = 1,955             N = 989   Double-Blind, Controlled
         (204)           (134)    (Biologic Background)



                 N = 2,339        Open-Label, Uncontrolled


                 N = 2,688        Cumulative
                                  (Double-Blind and Open-Label)

BLA/4M
                                                                  58
                Extent of Exposure to Abatacept
                                     Double-Blind         Cumulative
                                       N = 1955            N = 2688
        Person-Years
        Exposure                           1688               3827

        Median Months
        Exposure (Range)                12 (2, 14)         20 (2, 48)
        Exposure
        in Months                         Number (%) of Patients

         6                            1567 (80)          2467 (92)
          12                          1330 (68)          1792 (67)
          18                              –              1471 (55)
          24                              –               278 (10)
          36                              –               162 (6)

Population: Treated patients in 5 Core RA studies                       59
                  Patient Characteristics
             Double-Blind, Controlled Study Periods

                                  Abatacept   Placebo
                                   N = 1955   N = 989
      Age in years, mean             53          52

      % Female                       79          80

      % Caucasian                    88          87

      Disease duration in years      10          10

      Double-Blind Concomitant
      Medication Use:
       Methotrexate                 82%         83%
       Systemic Steroid             74%         75%
       Biologic                     10%         14%

BLA                                                     60
 Overview of Patients with Adverse Events
          Double-Blind, Controlled Study Periods


                                  Number (%) of Patients
                                Abatacept          Placebo
                                 N = 1955          N = 989

AEs                             1736 (88.8)     840 (84.9)
SAEs                             266 (13.6)     122 (12.3)
Discontinuation due to AEs       107   (5.5)       39   (3.9)
Deaths                            10   (0.5)        6   (0.6)




                                                                61
                Adverse Events with Difference
             Between Abatacept vs Placebo (≥ 2%)
                   Double-Blind, Controlled Study Periods

                                           Number (%) of Patients
                                            Abatacept       Placebo
      Preferred Term                         N = 1955       N = 989
      Total Patients with AE               1736 (88.8)   840 (84.9)
       Headache                             356 (18.2)   125 (12.6)
       Nasopharyngitis                      225 (11.5)      90   (9.1)
       Dizziness                            183 (9.4)       69   (7.0)
       Hypertension                         129 (6.6)       43   (4.3)
       Dyspepsia                            126 (6.4)       42   (4.2)




BLA
                                                                         62
          Serious Adverse Events (≥ 1.0%)
             Double-Blind, Controlled Study Periods

                                                  Number (%) of Patients
                                                  Abatacept     Placebo
System Organ Class                                 N = 1955     N = 989
Total Patients with SAEs                          266 (13.6)   122 (12.3)
Musculoskeletal and                                 59 (3.0)     37 (3.7)
Connective Tissue Disorders
Infections and Infestations                         58 (3.0)     19 (1.9)
Injury, Poisoning, and Procedural Complications     29 (1.5)       7 (0.7)
Neoplasms Benign, Malignant and Unspecified         28 (1.4)      11 (1.1)
Gastrointestinal Disorders                          23 (1.2)     13 (1.3)
Nervous System Disorders                            19 (1.0)     14 (1.4)
Cardiac Disorders                                   18 (0.9)     17 (1.7)



                                                                             63
                                   Deaths
               Double-Blind, Controlled Study Periods

                                             Number (%) of Patients
                                        Abatacept          Placebo
     System Organ Class                  N = 1955          N = 989
     Total Patient Deaths                 10 (0.5)           6 (0.6)
     Cardiac Disorders                         4 (0.2)       2 (0.2)
     General Disorders                         3 (0.2)       2 (0.2)
     Neoplasms Benign, Malignant &             2 (0.1)       1 (0.1)
     Unspecified
     Infections and Infestations             1 (< 0.1)       2 (0.2)
     Injury, Poisoning & Procedural          1 (< 0.1)            0
     Complications
     Nervous System Disorders                       0        1 (0.1)
     Investigations (Diagnostic Procedures          0        1 (0.1)
     or Findings)
4M                                                                     64
Safety in Combination with
 Other Biologic Therapies




                             65
      Overview of Safety in Patients Treated with
            Biologic Background Therapy
               Double-Blind, Controlled Study Periods


                               Number (%) of Patients
                               Biologic RA Therapy
                            Abatacept        Placebo
                             N = 204          N = 134
      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

BLA                                                          66
       Special Topics:
Infections and Malignancies




                              67
                        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
                                                           68
             Most Common Infections (≥ 5%)
              Double-Blind, Controlled Study Periods

                                       Number (%) of Patients
                                      Abatacept         Placebo
 Preferred Term                        N = 1955         N = 989
 Total Patients with Infections       1051 (53.8)      478 (48.3)
 Upper Respiratory Tract Infection     248 (12.7)      119 (12.0)
 Nasopharyngitis                       225 (11.5)       90   (9.1)
 Sinusitis                             125   (6.4)      68   (6.9)
 Urinary Tract Infection               113   (5.8)      45   (4.6)
 Influenza                             111   (5.7)      52   (5.3)
 Bronchitis                            101   (5.2)      45   (4.6)

BLA                                                                  69
                Serious Infections (≥ 0.2%)
               Double-Blind, Controlled Study Periods

                                         Number (%) of Patients
                                          Abatacept     Placebo
Preferred Term                             N = 1955     N = 989
Total Patients with Serious Infections    58 (3.0)      19 (1.9)
  Pneumonia                                9 (0.5)       5 (0.5)
  Cellulitis                               5 (0.3)       2 (0.2)
  Urinary Tract Infection                  4 (0.2)       1 (0.1)
  Bronchitis                               4 (0.2)            0
  Diverticulitis                           3 (0.2)            0
  Pyelonephritis Acute                     3 (0.2)            0
  Sepsis                                  1 (<0.1)      3 (0.3)

BLA                                                                70
                    Intensity of Infections
               Double-Blind, Controlled Study Periods


                                       Number (%) of Patients
                                         Abatacept     Placebo
                                          N = 1955     N = 989
      Total Patients with Infections    1051 (53.8)   478 (48.3)
      Mild                               699 (35.8)   319 (32.3)

      Moderate                           537 (27.5)   227 (23.0)

      Severe                              58 (3.0)     24 (2.4)

      Very Severe                          4 (0.2)      4 (0.4)



BLA                                                                71
                  IV Antibiotics Use
                                     n/N (%) of Patients
                  # Months on
  Study           Study Drug     Abatacept        Placebo

                     0–6         9/433 (2.1)     5/219 (2.3)
  IM101-102
  (MTX-IR)
                    6 – 12      15/401 (3.7)     7/174 (4.0)

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

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


BLA                                                            72
                Discontinuation Due to Infections*
                       Double Blind, Controlled Study Periods

                                                           Number (%) of Patients
                                                          Abatacept       Placebo
   Preferred Term                                          N = 1955       N = 989

   Total Discontinued Due to Infections                    24 (1.2)      10 (1.0)

     Pneumonia                                              4 (0.2)        1 (0.1)

     Localized infections                                   3 (0.2)        0

     Bronchitis                                             2 (0.1)        2 (0.2)

     Sepsis                                                 1 (<0.1)       2 (0.2)




* AEs that led to discontinuation in 2 or more patients                              73
      Deaths Due to Infectious Adverse Events
               Double-Blind, Controlled Study Periods


                                       Number (%) of Patients
                                      Abatacept         Placebo
                                       N = 1955         N = 989
  Total Infectious Deaths                1 (<0.1)        2 (0.2)

      Aspergillosis                      1 (<0.1)        0

      Pneumocystis                       0               1 (0.1)

      Sepsis                             0               1 (0.1)




BLA                                                                74
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)




 * n/p-y = Number of patients / person-years
** IR/100 p-y = Incidence rates per 100 person-years
  4M                                                                                         75
                     Overview of Pneumonia
                 Double-Blind, Controlled Study Periods

                                                  Number (%) of Patients
                                               Abatacept         Placebo
                                                N = 1955          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                                          11 (0.6)                 1 (0.1)
Very Severe                                      1 (<0.1)                2 (0.2)

Discontinued                                     5 (0.3)                 1 (0.1)
* Onset and duration calculated using specific PT of “Pneumonia” only.
 BLA
                                                                                    76
       Incidence of Infections in Herpes Family
                  Double-Blind, Controlled Study Periods


                                        Number (%) of Patients
                                        Abatacept     Placebo
      Preferred Term                     N = 1955     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                                                                  77
                    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

                                                            78
             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




                                                          79
                   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

                                                  80
        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
                                                        81
           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




                                                     82
                          Malignancies
             Double-Blind, Controlled Study Periods
                                    Number (%) of Patients
                                   Abatacept     Placebo
     Type of Malignancy             N = 1955     N = 989
     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
4M                                                           83
                  Malignancies – Abatacept
            Double-Blind and Cumulative Study Periods
                                 Double-Blind             Cumulative
                             N = 1955 (p-y = 1688)   N = 2688 (p-y = 3827)
     Type of Malignancy         n (per 100 p-y)         n (per 100 p-y)
 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)
4M                                                                           84
            Malignancies – Standardized Incidence Ratios
                Compared to U.S. General Population*
                                     Cumulative Study Periods

                              Overall**
                                  Lung
                 Colon and Rectum
                                 Breast
                              Prostate
                           Lymphoma
                  Melanoma of Skin
                               Bladder
                                  Renal
              Endometrial / Uterine
                               Thyroid
                               Ovarian
                                 Cervix

                                            0.01           0.1      1        10        100
                                                    Standardized Incidence Ratios***
   * SEER Cancer Statistics Review 1997-2002
 ** Excludes non-melanoma skin malignancies
*** Age and gender adjusted. Bars depict 95% confidence intervals                            85
Comparison of RA Cohorts to General Populations
                          Published Literature



  Lymphoma      0.55                              11.5

  Lung                 1.09                       12.4

  Colon and
  Rectal        0.5           1.2

  Breast      0.4                   1.68



0.1                       1                  10           100
                Published Standardized Incidence Ratios


                                                            86
      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.)




                                                    87
  Lymphoma – Abatacept Observed and Expected
           Cumulative Study Periods and Observational Cohorts


           Observed

                 US
             General

                   BC
Expected
               NOAR


                 NDB

                        0     1      2     3     4     5     6      7     8     9        10
                                               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.
 4M                                                                                           88
 Lung Cancer – Abatacept Observed and Expected
        Cumulative Study Periods and RA Observational Cohorts


           Observed

                 US
             General

                   BC
Expected
               NOAR


                 NDB

                         0     2      4     6     8     10    12    14    16     18      20
                                                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.
 4M                                                                                       89
                                  Lymphomas
                             Cumulative Study Periods


Patient No.                                                 Latency
Age/Race/Gender          Adverse Event              Dose     (Days)   Con Meds*
IM101-102-39-9           B-cell Lymphoma /         750 mg    241 D    MTX
81 / W / F               Hashimoto’s Thyroiditis                      [Infliximab]

IM101-102-136-15         Diffuse Large             750 mg    203 D    MTX
46 / W / M               B-cell Lymphoma
                         (CD20 + Stage Ia)

IM101-101-14-2           Diffuse Large             750 mg   1086 D    Etanercept
61 / W / F               B-Cell Lymphoma
                         (Stage IVb)

IM101-029-26-9           Large T-cell Lymphoma     750 mg    505 D    MTX
58 / W / M               (Stage IIb)                                  LFN
                                                                      [Infliximab]



*[ ] = Previous medication
  4M                                                                                 90
                    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


                                                         91
     Lung Cancer 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*             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)




 * n/p-y = Number of patients / person-years
** IR/100 p-y = Incidence rates per 100 person-years
   4M                                                                                       92
                     Malignancies – Abatacept
                          Cumulative Study Periods
                                    Through 4 Month Update     Through Jun 2005
                                      N = 2688 (p-y = 3827)   N = 2688 (p-y = 4764)
Type of Malignancy                       n (per 100 p-y)         n (per 100 p-y)
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)
MAA                                                                              93
             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


                                                         94
             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




                                                        95
          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




                                                        96
           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


                                                             97
        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
                                                     98
           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



                                                          99
             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
                                                          100
     Abatacept
     Summary
   Brian Daniels, M.D.
   Senior Vice-President
Global Clinical Development
   Bristol-Myers Squibb



                              101
                             Consultants
Roger B. Cohen, M.D.                      Harry K. Genant, M.D.
Director, Phase I Program &               Professor Emeritus,
Member, Thoracic Oncology Team,           University of California, San Francisco
Fox Chase Cancer Center,                  Board Member, SYNARC, Inc.
Philadelphia, PA                          San Francisco, CA

Mark Genovese, M.D.                       Marc Hochberg, M.D., M.P.H.
Associate Professor of Medicine,          Professor of Medicine
Associate Division Chief, Division of     Head, Division of Rheumatology and
Immunology and Rheumatology,              Clinical Immunology,
Stanford University School of Medicine,   University of Maryland, Baltimore, MD
Palo Alto, CA
                                          Désirée van der Heijde, M.D.
Princy Kumar, M.D.                        Professor of Rheumatology,
Professor of Medicine and Microbiology,   University Hospital,
Chief, Division of Infectious Disease,    Maastricht, the Netherlands
Associate Dean of Students, Georgetown
University School of Medicine,
Washington, DC

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