Abatacept (ORENCIA)
for Rheumatoid Arthritis
Biological License Application
Arthritis Advisory Committee
September 6, 2005
Abatacept
Proposed indications for abatacept:
For use in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more biologic or non-biologic DMARDs
Reducing signs and symptoms Inducing major clinical response Inhibiting the progression of structural damage Improving physical function
Abatacept may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARD therapy
2
Overview of FDA Presentation
Clinical Development Program and Study Design Efficacy Data
Improvement of Signs and Symptoms Improvement of Physical Function Inhibition of Radiographic Progression
Safety Data Summary
3
Abatacept BLA
CLINICAL DEVELOPMENT PROGRAM & STUDY DESIGN
4
Abatacept Clinical Trials
Randomized, Double-Blind, Placebo-Controlled
Cinical Trial IM101-100 (Phase II) 12-month doseranging study with concomitant DMARDs IM101-102 (Phase III) 12-month trial with concomitant MTX IM101-029 (Phase III) 6-month trial in TNF-blocker failures IM101-031 (Phase III) 12-month trial addon to standard of care IM103-002 (Phase II) 3-month doseranging monotherapy study IM101-101 (Phase II) 12-month trial with concomitant etanercept Total Control Subjects (n) Subjects Treated with Abatacept (n)
119
220
219 133 482
433 258 959
32
90
36
85
1021
2045
5
Study Design-Common Features
Randomized, double-blind, placebo-controlled studies Major Inclusion Criteria:
Diagnosis of RA (1987 ARA criteria) Active disease despite DMARD therapy at randomization
≥ 10 swollen joints (66 joint count) ≥ 12 tender joints (68 joint count) CRP ≥ 1 mg/dL
Stable doses of prednisone and NSAIDs allowed
Abatacept Dosing: Week 0, 2, and 4, then Q4 weeks
Weight-based dosing Weight-Tiered-based dosing
<60kg: Abatacept 500 mg IV 60 kg to 100 kg: Abatacept 750 mg IV > 100 kg: Abatacept 1000 mg IV
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Study Design-Common Features
Statistical Analyses
Modified ITT efficacy analyses performed for all trials Sequential testing for co-primary endpoints
Co-primary endpoint tested for significance only if preceding co-primary endpoint was statistically significant Type I error rate of 5% maintained
Adjustment for multiple doses performed using global testing then pairwise comparisons for individual doses
7
Study Design-Common Features
Statistical Analyses
ACR and Health Assessment Questionnaire (HAQ) response rates
Categorical Endpoints Chi-square Test Non-responder imputation for missing data
Radiographic Progression
Genant-modified Sharp Score Rank-based nonparametric ANCOVA model Linear extrapolation for missing data
8
Study IM101-102: Concomitant MTX Study
12 month study Active RA despite MTX therapy
656 patients randomized 2:1
Weight-Tiered-dose Abatacept + MTX (n=433) Placebo + MTX (n=219)
Sequential Co-Primary Endpoints
1. 2.
ACR 20 response at 6 months Improvement in Physical Function (HAQ) at 12 months
3.
Inhibition of Radiographic Progression at 12 months
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Study IM101-100: Dose-Ranging Study
12 month Study Active RA despite MTX therapy
339 patients randomized 1:1:1
Abatacept 10 mg/kg + MTX (n=115) Abatacept 2 mg/kg + MTX (n=105) Placebo + MTX (n=119)
Primary Endpoint
ACR 20 response at 6 months
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Study IM101-029: TNF-Blocker Failure Study
6 month Study Active RA despite TNF-blocker therapy ± DMARD
Etanercept or Infliximab
Following drug-washout 393 patients with active RA randomized 2:1
Weight-Tiered-dose Abatacept + DMARD (n=258) Placebo + DMARD (n=133) ACR 20 response at 6 months Improvement in Physical Function (HAQ) at 6 months
Co-Primary Endpoints
1.
2.
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Study IM101-031: Clinical Practice Study
12 month Study Active RA despite DMARD therapy
non-biologic and/or biologic DMARDs
Patients with co-morbid conditions permitted 1441 patients randomized 2:1
Baseline therapy + Weight-tiered dose Abatacept (n=959) Baseline therapy + Placebo (n=482) Safety Improvement in Physical Function (HAQ) at Day 365
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Primary Objective
Exploratory Endpoint
Clinical Studies-Study Conduct
Baseline Patient Demographics (mean):
52 years of age 79% Female 85% White and 4% Black
Baseline Disease Activity (mean):
10 years RA duration 21 swollen joints 31 tender joints 79% RF(+) MTX 16 mg Qweek
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Abatacept BLA
EFFICACY ANALYSES Signs and Symptoms
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IM101-102: Concomitant MTX Study
Signs & Symptoms: ACR Responses
Abatacept + MTX (n=424) Day 169 ACR 20 ACR 50 ACR 70 Day 365 ACR 20 ACR 50 ACR 70 288 (68%)* 169 (40%)* 84 (20%)* Placebo + MTX (n=214) 85 (40%) 36 (17%) 14 (7%)
310 (73%)* 205 (48%)* 122 (29%)*
*p<0.001
85 (40%) 39 (18%) 13 (6%)
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IM101-102: Concomitant MTX Study
Signs & Symptoms: ACR 20 Response Time Course
100 90 80 70 60 50 40 30 20 10 0 15 29 57
ACR 20 Responders (%)
Abatacept + MTX Placebo + MTX
85 113 141 169 225 281 365 Study Day
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IM101-102: Concomitant MTX Study
Signs & Symptoms: Major Clinical Response
Abatacept + MTX (n=424) Number of responders (%) Major Clinical Response p-value 60 (14%) <0.001
Placebo + MTX (n=214) 4 (2%)
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IM101-102: Concomitant MTX Study
Median % Improvement in ACR Components at Day 169
Median Baseline Score # Swollen Joints # Tender Joints Subject Pain Assessment Physical Function (HAQ) Subject Global Assessment Physician Global Assessment CRP 19 28 67 1.75 66 69 2.2 Abatacept + MTX (n=424) 74% 75% 45% 35% 56% 70% 59% Median Baseline Score 20 31 70 1.75 64 68 2.1 Placebo + MTX (n=24) 45% 55% 29% 21% 25% 41% 4%
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IM101-102: Concomitant MTX Study
DAS28 Response at Day 365
Abatacept + MTX (n=366) Baseline Mean Day 365 Patients with improvement (DAS28 change 1.2) Patients with EULARdefined low disease activity (DAS 3.2) Patients in EULAR- defined Remission (DAS <2.6) 6.8 4* 328 (88%) Placebo + MTX (n=179) 6.8 5.4 108 (59%)
103 (28%)
7 (4%)
65 (17%)
*p<0.001
4 (2%)
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IM101-100: Dose-Ranging Study
Signs & Symptoms: ACR Responses
Abatacept 10 mg/kg + MTX (n=115) Day 180 ACR 20 ACR 50 ACR 70 Day 360 ACR 20 ACR 50 ACR 70 70 (61%)* 42 (37%)* 19 (17%)* Abatacept 2 mg/kg + MTX (n=105) 44 (42%) 24 (23%)* 11 (11%)* Placebo + MTX (n=119) 42 (35%) 14 (12%) 2 (2%)
72 (63%)* 48 (42%)* 24 (21%)*
44 (42%) 24 (23%) 13 (12%)
*p≤0.03
43 (36%) 24 (20%) 9 (8%)
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IM101-029: TNF-Blocker Failure Study
Signs & Symptoms: ACR Responses at Day 169
Abatacept (n=258) Day 169 ACR 20 ACR 50 ACR 70 129 (50%)* 52 (20%)* 26 (10%)*
*p≤0.003
Placebo (n=133) 26 (20%) 5 (4%) 2 (2%)
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IM101-029: TNF-Blocker Failure Study
Signs & Symptoms: DAS28 Response at Day 169
Abatacept (n=366) Baseline Mean Day 169 Subjects with improvement (DAS28 change 1.2) Subjects with EULARdefined low disease activity (DAS 3.2) Subjects in EULAR- defined Remission (DAS <2.6) 6.9 4.9* 129 (71%) Placebo (n=179) 6.9 6.2 3 (2%)
30 (17%)
4 (4%)
19 (10%)
1 (1%)
*p<0.001
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Exploratory Analysis
Criteria to Assess Very Low Disease Activity
EULAR-definition of remission is defined as a DAS28<2.6 However, patients with a EULAR definition of remission can still have several swollen or tender joints Alternative criterion for very low disease activity DAS28<2.6 AND ≤ 1 swollen and ≤1 tender joint
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Criteria to Assess Very Low Disease Activity
IM101-102: Concomitant MTX Study
Abatacept + MTX N Day 169 Total Patients with EULAR-defined remission (DAS<2.6) Total Patients with EULAR-defined remission (DAS<2.6) AND ≤1 swollen and ≤1 tender joint N Day 365 Total Patients with EULAR-defined remission (DAS<2.6) Total Patients with EULAR-defined remission (DAS<2.6) AND ≤1 swollen and ≤1 tender joint 394 35 (9%) 17 (4%)* Placebo + MTX 195 1 (<1%) 1 (<1%)
406 65 (17%) 44 (11%)**
202 4 (2%) 2 (1%) *p<0.05; **p<0.001
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Criteria to Assess Very Low Disease Activity
IM101-029: TNF-Blocker Failure Study
Abatacept + MTX 202 19 (9%) 10 (5%)* Total Patients with EULAR-defined remission (DAS<2.6) AND ≤1 swollen and ≤1 tender joint *p<0.05 Placebo + MTX 111 1 (<1%) 0
N Day 169 Total Patients with EULAR-defined remission (DAS<2.6)
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Exploratory Analysis
Weight-Tiered-Dosing : ACR20 Responders
Abatacept Weight (kg) <50 50 to <60 60 to <70 70 to <80 80 to <90 90 to ≤100 101 to <110 >110 Approx. Abatacept
mg/kg
Placebo N 10 47 62 45 26 12 7 5 N(%) Response 5 (50%) 12 (26%) 28 (45%) 16 (36%) 16 (62%) 5 (42%) 2 (29%) 1 (20%) Est. of Diff. 13 39 20 36 14 38 44 24
N
Dose
N(%) Response 19 (63%) 50 (65%) 74 (66%) 62 (71%) 48 (75%) 19 (79%) 8 (73%) 8 (44%)
<12.5 9.1 11.5 10 8.8 7.9 9.5 >8.3
30 77 113 87 64 24 11 18
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Abatacept BLA
EFFICACY ANALYSES Improvement in Physical Function
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IM101-102: Concomitant MTX Study
Improvement in HAQ score ≥ 0.3u at Day 365
Abatacept + MTX (n=424) HAQ Number of responders achieving 0.3 units p-value 270 (64%) Placebo + MTX (n=214) 84 (39%)
<0.001
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IM101-100: Dose-Ranging Study
Improvement in HAQ score ≥ 0.3u at Day 360
Abatacept Abatacept 10 mg/kg + MTX 2 mg/kg + MTX Placebo + MTX (n=115) (n=105) (n=119) HAQ Number of responders achieving 0.3 units p-value
44 (38%)
31 (30%)
24 (20%)
0.002
0.104
-
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IM101-100: Dose-Ranging Study
Improvement in HAQ score ≥ 0.3u Open-Label Study
70
% Patients with Improvement
60 50 40 30 20 10 0 15 90 180 240 360
Abatacept 10 mg/kg Abatacept 2 mg/kg Placebo
450 630 720 810 900 1080
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Study Day
Abatacept BLA
EFFICACY ANALYSES Inhibition of Radiographic Progression
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IM101-102: Concomitant MTX Study
Mean Change In Genant-Modified Sharp Scores at Day 365
Abatacept + MTX (n=391) Total Score Baseline mean ± SD Mean change from baseline (± SD) Median change from baseline (range) p-value Placebo + MTX (n=195)
44u ± 37 1.21u ± 2.94 0.25 (0-1.78) 0.012
45u ± 38 2.32u ± 5.04 0.53 (0-2.54)
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IM101-102: Concomitant MTX Study
Mean Change in Genant-Modified Sharp Score Components
Abatacept + MTX (n=391) Erosion Score Baseline mean ± SD Mean change from baseline (± SD) Median change from baseline (range) p-value Joint Space Narrowing Baseline mean ± SD Mean change from baseline (± SD) Median change from baseline (range) p-value 23u ± 20 0.58u ± 1.54 0 (0-0.49) 0.009
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Placebo + MTX (n=195) 22u ± 19 1.14u ± 2.81 0.27 (0-1.27)
22u ± 18 0.63u ± 1.77 0 (0-1.02) 0.029
23u ± 20 1.18u ± 2.58 0.27 (0-0.97)
Study IM103-002: Monotherapy Study
3
month study
Active 112
RA despite DMARD therapy
(n=90)
patients randomized
0.5 mg/kg (n=26), 2 mg/kg (n=32), or 10 mg/kg (n=32)
Abatacept
Placebo
(n=32)
Primary Endpoint
ACR 20 response at Day 85
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Study IM103-002: Monotherapy Study
ACR Responses at Day 85
Abatacept 0.5 mg/kg (n=26) Day 85 ACR 20 ACR 50 ACR 70 6 (23%) 0 0 4 (44%) 6 (19%) 4 (13%) 7 (53%) 5 (16%) 2 (6%) 10 (31%) 2 (6%) 0 Abatacept 2 mg/kg (n=32) Abatacept 10 mg/kg (n=32) Placebo (n=32)
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Abatacept
Efficacy Analysis Subset Analyses by:
Baseline Demographics
Age Sex Race Weight
Baseline Disease Activity
Disease Duration Swollen & Tender Joints CRP Genant-modified Sharp Score HAQ
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Abatacept BLA
SAFETY ANALYSES
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Safety Analyses: Overview
Safety Assessment Based on 5 Studies:
IM101100, IM101101, IM101102, IM101029, IM101031 Double-Blind Periods:
1955 Abatacept-treated patients (1688 person-years) 989 Placebo-treated patients (795 person-years)
Open-Label Periods + Double-Blind Periods:
2688 Abatacept-treated patients
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Cumulative Extent of Exposure
Number (%) of Subjects Abatacept 0.5 mg/kg (n=26) 7 (27%) 19 (73%) 0 0 0 0 0 4 Abatacept 2 mg/kg (n=222) 19 (8%) 203 (92%) 157 (71%) 89 (40%) 0 0 0 12 Abatacept 10 mg/kg or Tiered-dose (n=2638) 460 (17%) 2178 (83%) 1868 (71%) 1596 (61%) 263 (10%) 223 (8%) 66 (2%) 14 All Abatacept (n=2760) 483 (17%) 2277 (83%) 1908 (70%) 1622 (60%) 282 (11%) 248 (10%) 151 (6%) 14
Months
<3 ≥3 ≥6 ≥12 ≥18 ≥24 36 Median (month)
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Deaths
26 total deaths
16 patients died during the double-blind periods
10
(0.5%) abatacept-treated patients
4 died from cardiovascular disorders 3 found dead at home 2 died from malignancies 1 died from infection
6
(0.6%) placebo-treated patients
2 died from cardiovascular disorders 1 found dead at home 1 died from malignancy 2 died from infection
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Deaths
Analysis of the individual deaths did not suggest a safety signal for any single type of AE 8 of the deaths in the Abatacept group occurred during a study that permitted enrollment of patients with co-morbidities
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Serious Adverse Events
14% of Abatacept-treated patients had an SAE compared to 12% placebo-treated patients
3% of Abatacept-treated patients had an infectious SAE compared to 2% placebotreated patients
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Malignancies: Double-Blind Periods
Malignant Abatacept: 29 (1.5%) Placebo: 11 (1.1%%)
Non-Melanoma Skin CA Abatacept: 15 (0.8%) Placebo: 6 (0.5%)
Solid Organ CA Abatacept: 13 (0.7%) Placebo: 5 (0.5%)
Hematologic Abatacept: 2 (0.1%) Placebo: 0
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Solid Organ Tumors
Abatacept-Treated Patients-Double Blind Periods
Subject Age/Gender/Race
69/F/W 68/M/W 72/F/W 83/M/W 53/M/W 71/F/W 63/F/W 74/M/W 52/F/W 42/F/W 70/F/W 39/F/W
No. of Infusions
3 5 13 13 8 14 4 5 6 7 6 5
Onset Day
29 100 320 332 203 349 42 97 115 237 85 69
Malignancy
Lung Neoplasm Non-small cell lung CA Sq. Cell lung CA Renal Cell CA Lung Neoplasm Bladder CA Breast CA Ovarian CA Prostate CA Thyroid CA Breast CA Cholangiocarcinoma Cervical CA
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Malignancies: Open-Label Periods
47 patients developed 52 neoplasms 26 malignancies
13
solid-organ tumors
4 lung cancers 2 ovarian cancers 2 endometrial cancers 1 case each of breast, prostate, melanoma, cervical, and rectal cancer
3
lymphomas
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Most Frequently Observed vs. Expected Malignancies
Malignancy Overall Lung Lymphoma Breast Prostate Thyroid Ovarian Endometrial
Observed 26 8 4 2 2 2 2 2
Expected 30.2 4.0 1.1 7.7 3.2 0.6 0.7 1.5
SIR 0.9 2.0 3.7 0.3 0.6 3.5 2.7 1.3
SIR 95% CI 0.6-1.3 0.9-4.0 1.0-9.5 0-0.9 0.1-2.2 0.4-12.5 0.3-9.7 0.2-4.9
46
Incidence Rates of Malignancies
N (rate/100 person-years) Days 1-180 Total Exposure (p-y) 1285 Days 181-360 1032 Days 361-540 795 Days 541-720 399 Days 721-900 117 Days 901-1080 198
Overall malignancies (excluding non-melanoma skin cancer)
3 (0.15)
0
2 (0.36)
1 (0.16)
1 (0.16)
1 (0.16)
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Malignancies
3 potentially concerning malignancies
Lung Cancer
8 cases of lung cancer in patients receiving abatacept
Breast Cancer and Lymphoma
Pre-clinical studies demonstrated increased rate of mammary tumors and lymphomas in mice that was believed to be secondary to abatacept-induced chronic immunosuppression and MMTV and MLV Immunosuppression and RA both associated with increased risk of lymphoma
48
Lung Cancer Incidence
Observed Events (95% CI) All Abatacept 8 (3.45, 15.76) Trial Expected Number of Events (95% CI) BC 9.95 (6.5, 16.3) NDB 3.58 (1.8, 8.3) NOAR 4.76 (1.1, 22.8) Expected Number of Events SEER 4 (0.9, 4.0)
49
Breast Cancer & Lymphoma
Breast Cancer 3 (0.1%) cases of breast cancer reported in abatacept-treated patients compared to 2 (0.2%) cases reported in placebo-treated patients Current evidence does not suggest abatacept increases the rate of breast cancer
Lymphoma 4 cases of lymphoma reported in patients receiving abatacept Approximately 4-fold higher than general US population However, increased rate of lymphoma in RA patients, particularly those with high disease activity
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Serious Infections
Serious Infection Preferred term Infectious SAE (n) Pneumonia Cellulitis Urinary tract infection Bronchitis Diverticulitis Acute Pyelonephritis Localized infection Sinusitis Subcutaneous abscess Abatacept (n=1955) 58 (3%) 14 (0.7%) 5 (0.3%) 4 (0.2%) 4 (0.2%) 3 (0.2%) 3 (0.2%) 2 (0.1%) 2 (0.1%) 2 (0.1%) Placebo (n=989) 19 (2%) 5 (0.5%) 2 (0.2%) 1 (0.1%) 0 0 0 0 0 0
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Infections of Special Interest
Infection Preferred term Infection of Special Interest Total Subjects All Herpes Infections Pneumonia Opportunistic Infections Herpes Zoster Oral Fungal Infection Tuberculosis Aspergillosis 30 (2%) 3 (0.1%) 2 (0.1%) 1 (<0.1) 16 (2%) 2 (0.1%) 1 (0.1%) 0
52
Abatacept (n=1955) 187 (10%) 72 (4%) 40 (2%)
Placebo (n=989) 70 (7%) 28 (3%) 8 (1%)
AEs in Abatacept w/ Biologic RA Therapy
A total of 204 patients received abatacept and concomitant biologic RA therapy during the double-blind period representing 173 person-years of exposure
Majority of patients were from studies IM101-101 (n=85) and IM101-031 (n=103)
>90% TNF-blocker therapy
Study IM101-101 compared the combination of abatacept 2 mg/kg + etanercept to placebo + etanercept
53
AEs in Abatacept w/ Biologic RA Therapy
Number (%) of Subjects Biologic RA Therapy Abatacept Placebo (n=204) (n=134) SAEs AEs 40 (20%) 192 (94%) 12 (9%) 113 (84%) Non-Biologic RA Therapy Abatacept Placebo (n=1751) (n=855) 226 (13%) 1544 (88%) 110 (13%) 727 (85%)
54
SAEs with Abatacept & Concomitant RA Therapy
Study IM101031
Background RA Therapy Total in Biologic Subgroup Etanercept Infliximab Adalimumab Anakinra Total in Non-Biologic Subgroup MTX Hydroxycholoquine/Chloroquine Sulfasalazine Leflunomide 1 DMARD 2 DMARDs 3 DMARDs 4 DMARDs Number of Subjects (%; n of subgroup) Abatacept Placebo 23 (22%; n=103) 8 (13%; n=64) 17 (26%; n=66) 5 (12%; n=42) 3 (15%; n=20) 0 (0%; n=5) 3 (27%; n=11) 1 (10%; n=10) 2 (15%; n=13) 2 (20%; n=10) 100 (12%;n=856) 73 (11%; n=691) 23 (12%; n=194) 15 (11%; n=137) 25 (24%; n=106) 66 (11%; n=598) 27 (13%; n=202) 6 (13%; n=45) 1 (10%; n=10) 51 (12%; n=418) 37 (11%; n=336) 10 (8%; n=123) 9 (13%; n=72) 9 (15%; n=59) 36 (14%; n=257) 14 (11%; n=123) 0 (0%; n=31) 1 (17%; n=6)
55
Infusion Reactions
Infusion Reactions within 1 hour post-infusion
9% of abatacept-treated patients vs. 6% placebotreated patients
Infusion Reactions within 24 hours postinfusion
23% of abatacept-treated patients vs. 19% placebo-treated patients
2 cases of anaphylactic reactions in patients receiving abatacept
56
Immunogenicity & Clinical Laboratory Values
Immunogenicity of Abatacept
Overall, 1.6% of patients treated with abatacept developed antibodies to abatacept 5.8% of abatacept patients who had discontinued therapy for at least 56 days developed antibodies to abatacept
Changes in Clinical Laboratory Values
no clinically meaningful differences between patients treated with abatacept compared to placebo regarding blood chemistry and hematologic laboratory values
57
Autoimmune Symptoms & Disorders
3% of Abatacept-treated patients reported autoimmune-related AEs compared to 2% of placebotreated patients during the Double-Blind period
Most common symptoms were associated with RA e.g., Keratoconjunctivitis sicca, Sjogren’s syndrome Psoriasis was more frequent in patients treated with abatacept compared to placebo (0.5% vs. 0.1%)
58
Autoimmune Symptoms & Disorders
ANA and ds-DNA Antibody Formation at 12 months
Anti-nuclear Antibody n (%) 93 (10%) 443 (11%) ds-DNA Antibody n (%) 29 (3%) 23 (5%)
Abatacept Placebo
N 962 575
N 1062 490
59
AEs in patients with Co-Morbidities
Study IM101031
Study IM101-031 permitted patients with comorbidities including COPD, diabetes, asthma, and CHF Diabetes, asthma, or CHF: no apparent increase in AEs or SAEs COPD: AEs reported in 97% of abatacept-treated patients vs. 88% of placebo-treated patients
Respiratory AEs more common with abatacept (43% vs. 24%) SAEs more common with (27% vs. 6%) No reported deaths
60
Summary
The studies presented here show abatacept-treatment associated differences regarding
improvement in signs and symptoms improvement of physical function Inhibition of radiographic progression
There was a higher rate of serious infections in patients treated with abatacept, especially with patients receiving concomitant TNF-blocking agents Overall malignancy rates were not substantially different between abatacept (1.5%) and placebo (1.1%) treated patients
However, abatacept treated patients had more cases of lung cancer and the rate of lymphomas was higher than expected compared to the general US population
61
Summary
Infusion-related reactions were observed including hypersensitivity reactions and 2 cases of anaphylaxis
Patients with COPD treated with abatacept had a higher incidence of adverse events and serious adverse events, particularly respiratory disorders
62