SYNOPSIS - Clinical Trials - Bristol-Myers Squibb

Abatacept
BMS-188667
Name of Sponsor/Company:
Bristol-Myers Squibb
Name of Finished Product:
Abatacept (BMS-188667)
Name of Active Ingredient:
Abatacept (BMS-188667)
Individual Study Table Referring
to the Dossier
IM101100
Clinical Study Report
(For National Authority Use
Only)
SYNOPSIS
TITLE OF STUDY: A Phase IIB, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to
Evaluate the Safety and Clinical Efficacy of Two Different Doses of BMS-188667 (Abatacept)
Administered Intravenously to Subjects with Active Rheumatoid Arthritis While Receiving Methotrexate
INVESTIGATORS/STUDY CENTERS AND COUNTRIES: 66 sites worldwide: 32 sites in the
United States; 19 sites in Europe (Belgium, France, Germany, Ireland, Netherlands, and United Kingdom);
7 sites in Canada; 4 sites in Australia; 2 sites in Argentina; and 2 sites in South Africa
PUBLICATIONS:
1. Becker JP, Kremer J, Westhovens R et al. 2002 EULAR Annual Congress of Rheumatology. Abstract
Session 12: Treatment including biologics. [OP7000] A Phase IIB, multi-center, randomized,
double-blind, placebo-controlled study to evaluate the safety and clinical efficacy of two different doses
of CTLA4Ig administered intravenously to subjects with active rheumatoid arthritis.
2. Emery P, Williams GR, Li T et al. 2002 EULAR Annual Congress of Rheumatology. Health services,
economics and outcome research. [SAT0309] Treatment of patients with active rheumatoid arthritis
using methotrexate with CTLA4Ig improves health-related quality of life.
3. Kremer J, Westhovens R et al. A Phase 2B, multi-center, randomized, double-blind, placebo-controlled
study to evaluate the safety and clinical efficacy of two different doses of CTLA4Ig administered
intravenously to subjects with active rheumatoid arthritis while receiving methotrexate. Arthritis and
Rheumatism. September 2002; 46(9, supplement): S203.
4. Williams GR, Li T et al. Impact on health-related quality of life following treatment with CTLA4Ig in
patients with active rheumatoid arthritis using methotrexate. Arthritis and Rheumatism. September
2002; 46(9, supplement): S515.
5. Tugewell P, Emery P, Kremer J, Li T, Williams GR, Ge G, Nuamah I, Bombardier C. 2003 American
College of Rheumatology. Physical function after treatment of CTLA4Ig (BMS-188667), a costimulation
blocker, in patients with active rheumatoid arthritis using methotrexate.
6. Emery P, Russell A, Kremer J, Williams GR, Li T, Nuamah I, Becker JC, Weisman MH. 2003
American College of Rheumatology. Improvement in health-related quality of life with treatment of
CTLA4Ig (BMS-188667), a co-stimulation blocker, over one year in patients with active rheumatoid
arthritis using methotrexate.
7. Kremer KM, Westhovens R et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell
activation with fusion protein CTLA4IG. NEJM 2003; 349 (20): 1907-1915.
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Abatacept
BMS-188667
IM101100
Clinical Study Report
STUDY PERIOD:
First Subject, First Visit: 11-Dec-2000
Last Subject, Last 6-Month Visit: 11-Dec-2001
Last Subject, Last 12-Month Visit: 13-Jun-2002
CLINICAL PHASE: Phase IIB
OBJECTIVES:
Primary Objective: The primary objective of this study was to compare the clinical efficacy of two
different doses of abatacept (BMS-188667; 10 and 2 mg/kg) combined with methotrexate (MTX) with
MTX plus placebo in subjects with active rheumatoid arthritis (RA) as assessed by ACR 20 at 6 months.
Key Secondary Objectives:
1. ACR 70 assessed at all post-baseline visits.
2. ACR 50 at Day 180 (Month 6) and Day 360 (Month 12).
3. ACR 20, ACR 50, ACR 70, ACR-N at all post-baseline visits and ACR-N AUC.
4. Physical function as assessed by the Modified Health Assessment Questionnaire (mHAQ) and the
physical component summary scale of the Health Outcomes Questionnaire SF-36.
5. SF-36 to assess quality of life.
Tertiary Objective: Radiographic measurements of hands/wrists and feet (Genant modified Sharp score,
joint space narrowing, erosion counts) at 6 months and 1 year.
METHODOLOGY: Randomized, double-blind, placebo-controlled trial with parallel-dosing. The
12-month teatment period was divided into 2 periods Days 1 to 180 and Days 181 to 360. During Days 1 to
180, subjects were maintained on a stable dose of MTX (10-30 mg/wk). During Days 181 to 360,
adjustments in corticosteroids (maximum 10 mg/day) and MTX (maximum 30 mg/wk) were permitted as
was addition of either hydroxychloroquine, sulfasalazine, gold or azathioprine. No other changes in
anti-rheumatic therapy were allowed. After completing the 12-month treatment period, subjects could have
continued in a long-term extension. Results of the long-term extension will be reported separately.
NUMBER OF SUBJECTS: 339 subjects were randomized, 115 to receive abatacept 10 mg/kg plus MTX,
105 to receive abatacept 2 mg/kg plus MTX, and 119 to receive placebo plus MTX.
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION/EXCLUSION: Adult subjects with active
RA and inadequate response to MTX. Key inclusion/exclusion criteria: 1) Males or females ≥ 18 years of
age; 2) Diagnosis of RA and RA functional classes I, II, or III; 3) Treated with MTX (10-30 mg/wk) for at
least 6 months, at a stable dose for 28 days prior to Day 1; 4) Had the following criteria for disease activity
at entry: ≥ 10 swollen joints (66 joint count), ≥ 12 tender joints (68 joint count), and a CRP level
≥ 1.0 mg/mL.
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: Abatacept
(10 and 2 mg/kg) administered IV at Weeks 0, 2 and 4 and then once a month. Batch numbers were
C00157, C00196, and C98283.
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS:
Placebo administered IV at Weeks 0, 2 and 4 weeks and then once a month. Batch numbers for placebo
were C98247, C00113 and C01236. All subjects received MTX (10-30 mg/wk), orally.
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Abatacept
BMS-188667
CRITERIA FOR EVALUATION:
IM101100
Clinical Study Report
Efficacy: The primary efficacy endpoint was the proportion of subjects meeting the ACR criteria for
20% improvement (ACR 20) at 6 months (Day 180). Key secondary evaluations included 50%
improvement (ACR 50) and 70% improvement (ACR 70). Other efficacy measurements included
radiographic evaluation of joint damage progression and quality of life (SF-36).
Safety: Adverse events (AEs), vital signs, clinical laboratory tests, including immunoglobulin levels (IgG,
IgA, and IgM), and the presence of antibodies specific for abatacept (immunogenicity) were examined.
Pharmacokinetics: Blood samples for PK analysis were collected prior to dosing from all subjects.
Additional blood samples for a more complete PK profile were collected from subjects participating in a
site-specific PK substudy. PK parameters for abatacept included: maximum observed serum concentration
of (Cmax), time of occurrence of Cmax, area under the concentration time curve between Day 60 and
Day 90 (AUC[TAU]), trough serum concentration (Cmin), total body clearance normalized to body weight
(CLT), volume of distribution at steady-state normalized to body weight (VSS), and serum elimination
half-life (T 1/2 ).
Biomarker and Pharmacodynamics: Biomarker and PD outcome measures included CRP, sIL-2r, RF,
sICAM-1, E-selectin, sIL-6, and TNFα.
STATISTICAL METHODS: All statistical tests were carried out using a 5% level (two-tailed) of
significance. If comparison of the ACR 20 response between the 10 mg/kg and placebo groups was
significant, the comparison between the 2 mg/kg and placebo groups was to be carried out. This sequential
procedure using the Chi-square test was also used to test for differences in ACR 50 and ACR 70 responses.
All efficacy analyses used the intent-to-treat population (all subjects who received at least one dose of
study medication). For the ACR analyses, subjects who discontinued the study due to lack of efficacy were
considered ACR non-responders at all subsequent time points. Subjects who discontinued for other reasons,
their last ACR response was carried forward. For analyses of the individual components of the
ACR criteria, the last observation was carried forward (LOCF) for any subjects who discontinued from the
study.
SUBJECT POPULATION RESULTS: A greater proportion of subjects in the abatacept groups
completed 360 days of treatment compared with the placebo group: 78% of those randomized to the
10 mg/kg group, 71% randomized to the 2 mg/kg group and 60% randomized to the placebo group. Lack
of efficacy and AEs were the most common reasons for discontinuation.
Most subjects were white females, with a mean age of 55 years and a mean duration of RA of
approximately 9 to 10 years.
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Abatacept
BMS-188667
IM101100
Clinical Study Report
Baseline Characteristics
Abatacept
10 mg/kg
+ MTX
(n=115)
Abatacept
2 mg/kg
+ MTX
(n=105)
Placebo
+ MTX
(n=119)
Age (yrs), Mean (Range) 55.8 (17-83) 54.4 (23-80) 54.7 (23-80)
Gender (% females) 75 63 66
Race (% white) 87 87 87
Duration of RA (yrs), Mean ± SD 9.7 ± 9.8 9.7 ± 8.1 8.9 ± 8.3
Tender Joints (Mean ± SD) 30.8 ± 12.2 28.2 ± 12.0 29.2 ± 13.0
Swollen Joints (Mean ± SD) 21.3 ± 8.4 20.2 ± 8.9 21.8 ± 8.8
Physical Function (mHAQ 0-3), Mean ± SD 1.0 ± 0.5 1.0 ± 0.5 1.0 ± 0.6
CRP (mg/dL), Mean ± SD 2.9 ± 2.8 3.2 ± 2.5 3.2 ± 3.2
EFFICACY RESULTS:
Signs and Symptoms
• Primary efficacy variable: There was a statistically significant (p < 0.001) difference in ACR 20
response at Day 180 for abatacept 10 mg/kg (plus MTX) compared to placebo (MTX alone). There
was no statistically significant difference in ACR 20 responses at Day 180 between the 2 mg/kg group
and the placebo group.
• For abatacept 10 mg/kg, statistically significant differences from the placebo group were seen for ACR
20, 50 and 70 at both Day 180 and Day 360. For 2 mg/kg, statistically significant differences from
MTX alone were observed at Day 180 for ACR 50 and 70, but not at Day 360.
ACR Response Rates: Percentage of Subjects Meeting Criteria
Abatacept
10 mg/kg
+ MTX
(N=115)
Abatacept
2 mg/kg
+ MTX
(N=105)
Placebo
+ MTX
(N=119)
Day 180
ACR 20 60.9 a 41.9 35.3
ACR 50 36.5 a 22.9 a 11.8
ACR 70 16.5 a 10.5 a 1.7
Day 360
ACR 20 62.6 a 41.9 36.1
ACR 50 41.7 a 22.9 20.2
ACR 70 20.9 a 12.4 7.6
ITT Population
a Statistically significant difference for the comparison of abatacept vs. placebo (p < 0.05).
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Abatacept
BMS-188667
IM101100
Clinical Study Report
• Significantly more subjects in the 10 mg/kg group compared with the placebo group achieved a Major
Clinical Response (maintenance of an ACR 70 response over a continuous 6-month period) by
Day 360 (7.8% vs 0.8%, p = 0.008).
• There was rapid onset of action for subjects who received 10 mg/kg, that was demonstrable by
approximately 15 days from the start of study medication (significant differences compared to the
placebo group in subject reported measures of pain and disease activity). In the 10 mg/kg group
compared with the placebo group, statistically significant improvements in ACR 50 and ACR 70
responses were observed as early as Day 30 and for ACR 20 as early as Day 60.
• Mean percentage improvements in each individual ACR component (tender and swollen joint counts,
pain, subject global assessment, physician global assessment, CRP) at both Day 180 and Day 360 were
significantly higher for the 10 mg/kg group relative to improvements for the placebo group.
Physical Function:
• Subjects treated with 10 mg/kg had improvements in physical function (mHAQ) at both Day 180 and
Day 360 that were significantly (p < 0.05) higher relative to improvements for the placebo group.
Health Outcomes:
• Clinically and statistically significant (p < 0.05) improvement in all mental health and physical health
domains of the SF-36 were observed in the 10 mg/kg group compared with the placebo group at
Day 180 and Day 360.
Structural Damage:
• There was a trend for subjects treated with abatacept to demonstrate less progression of structural
damage than subjects treated with placebo, as measured by the percent of subjects with evidence of
radiographic progression.
Biomarkers:
• There was a dose related trend in the reduction of levels for most of the pro-inflammatory biomarkers
(sIL-2r, sIL-6, RF, sICAM-1, TNF-α and E-selectin) on both Days 180 and 360.
PHARMACOKINETIC RESULTS: The multiple-dose, steady-state, PK data indicate that both Cmax
and AUC(TAU) values increased proportionally to the dose increment. T 1/2 , CLT, and VSS values appeared
to be comparable and dose-independent. T 1/2 was approximately 13 days for both the 10 mg/kg and
2 mg/kg groups. The small VSS value (0.07 L/kg for both dose level) suggests that abatacept is confined
primarily to the vascular system and does not significantly distribute into extra-vascular spaces.
Comparison of mean Cmin values at Days 60, 90, and 180 indicated that abatacept did not appear to
accumulate following monthly dosing. The pharmacokinetic results for abatacept support once-a-month
dosing.
SAFETY RESULTS: The AE profile was generally similar among the 3 treatment groups.
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Abatacept
BMS-188667
IM101100
Clinical Study Report
Overview of Adverse Events
Abatacept
10 mg/kg
+ MTX
(N=115)
Number (%) of Subjects
Abatacept
2 mg/kg
+ MTX
(N=105)
Placebo
+ MTX
(N=119)
Deaths 0 1 (1.0) 0
Serious Adverse Events 14 (12.2) 19 (18.1) 19 (16.0)
Discontinuations due to Adverse Events 6 (5.2) 10 (9.5) 11 (9.2)
Adverse Events 104 (90.4) 104 (99.0) 112 (94.1)
Most Frequently (≥ 10% of Subjects in Any Group) Reported Adverse Events
Rheumatoid Arthritis a 28 (24.3) 41 (39.0) 50 (42.0)
Nasopharyngitis 17 (14.8) 19 (18.1) 11 (9.2)
Headache 17 (14.8) 17 (16.2) 18 (15.1)
Nausea 16 (13.9) 12 (11.4) 17 (14.3)
Cough 15 (13.0) 10 (9.5) 15 (12.6)
Diarrhea 13 (11.3) 10 (9.5) 9 (7.6)
Upper Respiratory Tract Infection 13 (11.3) 10 (9.5) 9 (7.6)
Dyspepsia 10 (8.7) 12 (11.4) 7 (5.9)
Hypertension 8 (7.0) 12 (11.4) 8 (6.7)
Fatigue 7 (6.1) 9 (8.6) 15 (12.6)
Arthralgia 7 (6.1) 17 (16.2) 13 (10.9)
All treated subjects
MedDRA Version 6.1
a The primary AE term “rheumatoid arthritis” included “worsening arthritis” and did not include other
non-rheumatoid arthritis AEs.
Additional safety results include:
• The majority of AEs reported with abatacept and placebo were mild to moderate in intensity.
• One subject (2 mg/kg) died due to complications following coronary artery bypass graft surgery
(considered by the investigator to be unrelated to study drug). One additional death was reported prior
to randomization.
• There was no increase in the frequency of malignancy with abatacept compared with placebo (4 events
in the 10 mg/kg group, 3 events in the placebo group).
• Infections were generally mild, treatable when serious and few subjects discontinued due to an
infection (1 subject in the 2 mg/kg group and 3 subjects in the placebo group).
• Infections (mainly respiratory infections) were seen in a higher proportion of subjects in the abatacept
groups (52-54%) than in the placebo group (44%). Serious infections were reported by 1% of subjects
in the 10 mg/kg group and 3% of subjects each in the 2 mg/kg and placebo groups. No opportunistic
infections were reported in the abatacept groups.
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Abatacept
BMS-188667
IM101100
Clinical Study Report
• The overall frequencies of peri-infusional AEs (within 24 hours following dosing) were similar among
the abatacept groups and the placebo group.
• No safety issues emerged from the evaluation of laboratory data.
• Abatacept was generally non-immunogenic. Two subjects (1%, one each from the 10 mg/kg and
2 mg/kg groups) seroconverted for antibodies to CTLA.
• No clinically significant decreases (below the normal range) in mean immunoglobulin levels were
observed at Day 180 and Day 360 compared with baseline levels for both doses of abatacept.
CONCLUSIONS: The following are the conclusions from the study:
• The 10 mg/kg dose of abatacept was significantly more effective than placebo (on a background of
MTX) in reducing signs and symptoms associated with RA, but the 2 mg/kg dose of abatacept was not.
• The ACR 20 response rate at Day 180 (the primary efficacy variable) was significantly
higher for the 10 mg/kg group compared with the placebo group (61% vs 35%, p < 0.001).
• The ACR 20 response rate at Day 180 was higher for the 2 mg/kg group compared with the
placebo group, however the difference was not statistically significant (42% vs 35%,
p = 0.31).
• When compared with the placebo group, the 10 mg/kg group had significant (p < 0.05) improvements
in all measurements of physical function and quality of life.
• Though not statistically significant, there was a trend for subjects treated with abatacept 10 mg/kg to
demonstrate less progression of structural damage (using the pre-specified analysis) than the placebo
group.
• There was a dose related reduction in most of the pro-inflammatory biomarker levels (sIL-2r, RF,
sICAM-1, E-selectin, IL-6).
• The overall rates of AEs, SAEs and discontinuations due to AEs with abatacept were comparable with
those for the placebo group.
• No increase in the frequency of malignancies was reported with abatacept compared with
placebo.
• There was an increase in the rate of non-serious infections, mainly upper respiratory
infections, in the abatacept groups compared with the placebo group (all infections: 52-54%
vs 44%), but few were serious (1% in the 10 mg/kg group, 3% in the 2 mg/kg and placebo
groups) or required discontinuation (0% in the 10 mg/kg group, 1% in the 2 mg/kg group,
3% in the placebo group) with similar frequencies among the treatment groups. No
opportunistic infections were reported in the abatacept groups.
• Frequencies of peri-infusional AEs were similar among the abatacept groups and the placebo
group.
• Abatacept was generally non-immunogenic. Two subjects (1%) treated with abatacept seroconverted
for antibodies to CTLA.
• Both doses of abatacept (10 and 2 mg/kg) given for 1 year were well tolerated and had a safety profile
similar to that of placebo.
DATE OF REPORT: 15-Jun-2004
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