Abatacept (ORENCIA) for Rheumatoid Arthritis Biological License Application Arthritis Advisory...

Abatacept (ORENCIA)Abatacept (ORENCIA) for Rheumatoid Arthritisfor Rheumatoid Arthritis

Biological License ApplicationBiological License Application

Arthritis Advisory CommitteeArthritis Advisory CommitteeSeptember 6, 2005September 6, 2005

2

AbataceptAbatacept Proposed indications for abatacept:Proposed indications for abatacept:

For use in adult patients with moderately to For use in adult patients with moderately to severely active rheumatoid arthritis who have had severely active rheumatoid arthritis who have had an inadequate response to one or more biologic an inadequate response to one or more biologic or non-biologic DMARDs or non-biologic DMARDs Reducing signs and symptomsReducing signs and symptoms Inducing major clinical responseInducing major clinical response Inhibiting the progression of structural damageInhibiting the progression of structural damage Improving physical function Improving physical function

Abatacept may be used as monotherapy or Abatacept may be used as monotherapy or concomitantly with methotrexate or other non-concomitantly with methotrexate or other non-biologic DMARD therapybiologic DMARD therapy

3

Overview of FDA PresentationOverview of FDA Presentation

Clinical Development Program and Study Clinical Development Program and Study DesignDesign

Efficacy DataEfficacy Data Improvement of Signs and SymptomsImprovement of Signs and Symptoms Improvement of Physical FunctionImprovement of Physical Function Inhibition of Radiographic ProgressionInhibition of Radiographic Progression

Safety DataSafety Data SummarySummary

4

Abatacept BLAAbatacept BLA

CLINICAL DEVELOPMENT PROGRAMCLINICAL DEVELOPMENT PROGRAM

&&

STUDY DESIGNSTUDY DESIGN

5

Abatacept Clinical TrialsAbatacept Clinical TrialsRandomized, Double-Blind, Placebo-ControlledRandomized, Double-Blind, Placebo-Controlled

Cinical Trial

Control Subjects

(n)

Subjects Treated with Abatacept

(n) IM101-100 (Phase II) 12-month dose-ranging study with concomitant DMARDs

119 220

IM101-102 (Phase III) 12-month trial with concomitant MTX

219 433

IM101-029 (Phase III) 6-month trial in TNF-blocker failures

133 258

IM101-031 (Phase III) 12-month trial add-on to standard of care

482 959

IM103-002 (Phase II) 3-month dose-ranging monotherapy study

32 90

IM101-101 (Phase II) 12-month trial with concomitant etanercept

36 85

Total 1021 2045

6

Study Design-Common FeaturesStudy Design-Common Features Randomized, double-blind, placebo-controlled studiesRandomized, double-blind, placebo-controlled studies Major Inclusion Criteria:Major Inclusion Criteria:

Diagnosis of RA (1987 ARA criteria)Diagnosis of RA (1987 ARA criteria) Active disease despite DMARD therapy at randomizationActive disease despite DMARD therapy at randomization

≥ ≥ 10 swollen joints (66 joint count)10 swollen joints (66 joint count) ≥ ≥ 12 tender joints (68 joint count)12 tender joints (68 joint count) CRP ≥ 1 mg/dLCRP ≥ 1 mg/dL

Stable doses of prednisone and NSAIDs allowedStable doses of prednisone and NSAIDs allowed

Abatacept Dosing: Week 0, 2, and 4, then Q4 weeks Abatacept Dosing: Week 0, 2, and 4, then Q4 weeks Weight-based dosingWeight-based dosing

Weight-Tiered-based dosingWeight-Tiered-based dosing <60kg: Abatacept 500 mg IV<60kg: Abatacept 500 mg IV 60 kg to 100 kg: Abatacept 750 mg IV60 kg to 100 kg: Abatacept 750 mg IV > 100 kg: Abatacept 1000 mg IV> 100 kg: Abatacept 1000 mg IV

7

Study Design-Common FeaturesStudy Design-Common Features Statistical AnalysesStatistical Analyses

Modified ITT efficacy analyses performed for all Modified ITT efficacy analyses performed for all trials trials

Sequential testing for co-primary endpointsSequential testing for co-primary endpoints Co-primary endpoint tested for significance only if Co-primary endpoint tested for significance only if

preceding co-primary endpoint was statistically preceding co-primary endpoint was statistically significantsignificant

Type I error rate of 5% maintainedType I error rate of 5% maintained Adjustment for multiple doses performed using Adjustment for multiple doses performed using

global testing then pairwise comparisons for global testing then pairwise comparisons for individual dosesindividual doses

8

Study Design-Common FeaturesStudy Design-Common Features Statistical AnalysesStatistical Analyses

ACR and Health Assessment Questionnaire (HAQ) ACR and Health Assessment Questionnaire (HAQ) response ratesresponse rates Categorical Endpoints Categorical Endpoints Chi-square TestChi-square Test Non-responder imputation for missing dataNon-responder imputation for missing data

Radiographic ProgressionRadiographic Progression Genant-modified Sharp ScoreGenant-modified Sharp Score Rank-based nonparametric ANCOVA modelRank-based nonparametric ANCOVA model Linear extrapolation for missing dataLinear extrapolation for missing data

9

Study IM101-102: Concomitant MTX StudyStudy IM101-102: Concomitant MTX Study

12 month study12 month study

Active RA despite MTX therapyActive RA despite MTX therapy

656 patients randomized 2:1656 patients randomized 2:1 Weight-Tiered-dose Abatacept + MTX (n=433)Weight-Tiered-dose Abatacept + MTX (n=433) Placebo + MTX (n=219)Placebo + MTX (n=219)

Sequential Co-Primary EndpointsSequential Co-Primary Endpoints1.1. ACR 20 response at 6 monthsACR 20 response at 6 months

2.2. Improvement in Physical Function (HAQ) at 12 monthsImprovement in Physical Function (HAQ) at 12 months

3.3. Inhibition of Radiographic Progression at 12 monthsInhibition of Radiographic Progression at 12 months

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Study IM101-100: Dose-Ranging StudyStudy IM101-100: Dose-Ranging Study 12 month Study12 month Study

Active RA despite MTX therapyActive RA despite MTX therapy

339 patients randomized 1:1:1339 patients randomized 1:1:1 Abatacept 10 mg/kg + MTX (n=115)Abatacept 10 mg/kg + MTX (n=115) Abatacept 2 mg/kg + MTX (n=105)Abatacept 2 mg/kg + MTX (n=105) Placebo + MTX (n=119)Placebo + MTX (n=119)

Primary EndpointPrimary Endpoint ACR 20 response at 6 monthsACR 20 response at 6 months

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Study IM101-029: TNF-Blocker Failure StudyStudy IM101-029: TNF-Blocker Failure Study

6 month Study 6 month Study

Active RA despite TNF-blocker therapy ± DMARDActive RA despite TNF-blocker therapy ± DMARD Etanercept or InfliximabEtanercept or Infliximab

Following drug-washout 393 patients with active Following drug-washout 393 patients with active RA randomized 2:1 RA randomized 2:1

Weight-Tiered-dose Abatacept + DMARD (n=258)Weight-Tiered-dose Abatacept + DMARD (n=258) Placebo + DMARD (n=133)Placebo + DMARD (n=133)

Co-Primary EndpointsCo-Primary Endpoints1.1. ACR 20 response at 6 monthsACR 20 response at 6 months2.2. Improvement in Physical Function (HAQ) at 6 monthsImprovement in Physical Function (HAQ) at 6 months

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Study IM101-031: Clinical Practice StudyStudy IM101-031: Clinical Practice Study 12 month Study12 month Study

Active RA despite DMARD therapyActive RA despite DMARD therapy non-biologic and/or biologic DMARDsnon-biologic and/or biologic DMARDs

Patients with co-morbid conditions permittedPatients with co-morbid conditions permitted

1441 patients randomized 2:11441 patients randomized 2:1 Baseline therapy + Weight-tiered dose Abatacept (n=959)Baseline therapy + Weight-tiered dose Abatacept (n=959) Baseline therapy + Placebo (n=482)Baseline therapy + Placebo (n=482)

Primary ObjectivePrimary Objective SafetySafety

Exploratory Endpoint Exploratory Endpoint Improvement in Physical Function (HAQ) at Day 365Improvement in Physical Function (HAQ) at Day 365

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Clinical Studies-Study ConductClinical Studies-Study Conduct Baseline Patient Demographics (mean):Baseline Patient Demographics (mean):

52 years of age52 years of age 79% Female79% Female 85% White and 4% Black85% White and 4% Black

Baseline Disease Activity (mean):Baseline Disease Activity (mean): 10 years RA duration10 years RA duration 21 swollen joints21 swollen joints 31 tender joints31 tender joints 79% RF(+)79% RF(+) MTX 16 mg QweekMTX 16 mg Qweek

14


EFFICACY ANALYSESEFFICACY ANALYSES

Signs and SymptomsSigns and Symptoms

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IM101-102: Concomitant MTX StudyIM101-102: Concomitant MTX Study Signs & Symptoms:Signs & Symptoms: ACR ResponsesACR Responses

Abatacept + MTX (n=424)

Placebo + MTX (n=214)

Day 169 ACR 20 288 (68%)* 85 (40%) ACR 50 169 (40%)* 36 (17%) ACR 70 84 (20%)* 14 (7%) Day 365 ACR 20 310 (73%)* 85 (40%) ACR 50 205 (48%)* 39 (18%) ACR 70 122 (29%)* 13 (6%) *p<0.001

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IM101-102: Concomitant MTX StudyIM101-102: Concomitant MTX Study Signs & Symptoms:Signs & Symptoms: ACR 20 Response Time CourseACR 20 Response Time Course

0102030405060708090

100

15 29 57 85 113 141 169 225 281 365Study Day

AC

R 2

0 R

es

po

nd

ers

(%

)

Abatacept + MTX

Placebo + MTX

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IM101-102: Concomitant MTX StudyIM101-102: Concomitant MTX Study Signs & Symptoms:Signs & Symptoms: Major Clinical ResponseMajor Clinical Response



Number of responders (%) Major Clinical Response 60 (14%) 4 (2%) p-value <0.001

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IM101-102: Concomitant MTX StudyIM101-102: Concomitant MTX Study Median %Median % Improvement in ACR Components at Day 169Improvement in ACR Components at Day 169

Median Baseline

Score

Abatacept + MTX

(n=424)

Median Baseline

Score

Placebo + MTX

(n=24)

# Swollen Joints 19 74% 20 45%

# Tender Joints 28 75% 31 55%

Subject Pain Assessment 67 45% 70 29%

Physical Function (HAQ) 1.75 35% 1.75 21%

Subject Global Assessment 66 56% 64 25%

Physician Global Assessment 69 70% 68 41%

CRP 2.2 59% 2.1 4%

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IM101-102: Concomitant MTX StudyIM101-102: Concomitant MTX StudyDAS28 Response at Day 365DAS28 Response at Day 365



Baseline Mean 6.8 6.8 Day 365

4*

5.4

Patients with improvement (DAS28 change 1.2)

328 (88%)

108 (59%)

Patients with EULAR- defined low disease activity (DAS 3.2)

103 (28%)

7 (4%)

Patients in EULAR- defined Remission (DAS <2.6)

65 (17%)

4 (2%)

*p<0.001

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IM101-100: Dose-Ranging StudyIM101-100: Dose-Ranging Study Signs & Symptoms:Signs & Symptoms: ACR ResponsesACR Responses

Abatacept 10 mg/kg + MTX

(n=115)


(n=105)

Placebo + MTX

(n=119)

Day 180 ACR 20 70 (61%)* 44 (42%) 42 (35%) ACR 50 42 (37%)* 24 (23%)* 14 (12%) ACR 70 19 (17%)* 11 (11%)* 2 (2%) Day 360 ACR 20 72 (63%)* 44 (42%) 43 (36%) ACR 50 48 (42%)* 24 (23%) 24 (20%) ACR 70 24 (21%)* 13 (12%) 9 (8%)

*p≤0.03

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IM101-029: TNF-Blocker Failure Study IM101-029: TNF-Blocker Failure Study Signs & Symptoms:Signs & Symptoms: ACR Responses at Day 169ACR Responses at Day 169

Abatacept (n=258)

Placebo (n=133)

Day 169 ACR 20 129 (50%)* 26 (20%) ACR 50 52 (20%)* 5 (4%) ACR 70 26 (10%)* 2 (2%)

*p≤0.003

22

IM101-029: TNF-Blocker Failure Study IM101-029: TNF-Blocker Failure Study Signs & Symptoms:Signs & Symptoms: DAS28 Response at Day 169DAS28 Response at Day 169

Abatacept

(n=366)

Placebo (n=179)

Baseline Mean 6.9 6.9 Day 169

4.9*

6.2

Subjects with improvement (DAS28 change 1.2)

129 (71%)

3 (2%)

Subjects with EULAR- defined low disease activity (DAS 3.2)

30 (17%)

4 (4%)

Subjects in EULAR- defined Remission (DAS <2.6)

19 (10%)

1 (1%)

*p<0.001

23

Exploratory AnalysisExploratory AnalysisCriteria to Assess Very Low Disease ActivityCriteria to Assess Very Low Disease Activity

EULAR-definition of remission is defined as a EULAR-definition of remission is defined as a DAS28<2.6DAS28<2.6

However, patients with a EULAR definition of However, patients with a EULAR definition of remission can still have several swollen or remission can still have several swollen or tender jointstender joints

Alternative criterion for very low disease activity Alternative criterion for very low disease activity DAS28<2.6 AND ≤ 1 swollen and ≤1 tender jointDAS28<2.6 AND ≤ 1 swollen and ≤1 tender joint

24

Criteria to Assess Very Low Disease ActivityCriteria to Assess Very Low Disease Activity IM101-102: Concomitant MTX StudyIM101-102: Concomitant MTX Study

Abatacept + MTX Placebo + MTX

N 394 195 Day 169 Total Patients with EULAR-defined remission (DAS<2.6)

35 (9%) 1 (<1%)

Total Patients with EULAR-defined remission (DAS<2.6) AND ≤1 swollen and ≤1 tender joint

17 (4%)* 1 (<1%)


65 (17%) 4 (2%)


44 (11%)** 2 (1%)

*p<0.05; **p<0.001

25

Criteria to Assess Very Low Disease ActivityCriteria to Assess Very Low Disease Activity IM101-029: TNF-Blocker Failure StudyIM101-029: TNF-Blocker Failure Study

Abatacept + MTX

Placebo + MTX


19 (9%) 1 (<1%)


10 (5%)* 0

*p<0.05

26

Exploratory AnalysisExploratory AnalysisWeight-Tiered-Dosing : ACR20 Weight-Tiered-Dosing : ACR20

RespondersResponders Abatacept Placebo

Weight (kg)

Approx. Abatacept mg/kg Dose

N

N(%)

Response

N

N(%)

Response

Est. of Diff.

<50

<12.5

30

19 (63%)

10

5 (50%)

13

50 to <60 9.1 77 50 (65%) 47 12 (26%) 39 60 to <70 11.5 113 74 (66%) 62 28 (45%) 20 70 to <80 10 87 62 (71%) 45 16 (36%) 36 80 to <90 8.8 64 48 (75%) 26 16 (62%) 14 90 to ≤100 7.9 24 19 (79%) 12 5 (42%) 38 101 to <110 9.5 11 8 (73%) 7 2 (29%) 44 >110 >8.3 18 8 (44%) 5 1 (20%) 24

27



Improvement in Physical FunctionImprovement in Physical Function

28

IM101-102: Concomitant MTX StudyIM101-102: Concomitant MTX Study Improvement in HAQ score ≥ 0.3u at Day 365Improvement in HAQ score ≥ 0.3u at Day 365



HAQ Number of responders achieving 0.3 units

270 (64%) 84 (39%)

p-value <0.001

29

IM101-100: Dose-Ranging StudyIM101-100: Dose-Ranging Study Improvement in HAQ score ≥ 0.3u at Day 360Improvement in HAQ score ≥ 0.3u at Day 360


(n=115)


(n=105)

Placebo + MTX

(n=119) HAQ

Number of responders achieving 0.3 units

44 (38%) 31 (30%) 24 (20%)

p-value 0.002 0.104 -

30

IM101-100: Dose-Ranging StudyIM101-100: Dose-Ranging Study Improvement in HAQ score ≥ 0.3u Open-Improvement in HAQ score ≥ 0.3u Open-

Label StudyLabel Study

0

10

20

30

40

50

60

70

15 90 180 240 360 450 630 720 810 900 1080Study Day

% P

atie

nts w

ith

Impr

ovem

ent

Abatacept 10 mg/ kgAbatacept 2 mg/ kgPlacebo

31



Inhibition of Radiographic ProgressionInhibition of Radiographic Progression

32

IM101-102: Concomitant MTX StudyIM101-102: Concomitant MTX Study Mean Change In Genant-Modified Sharp Scores at Day Mean Change In Genant-Modified Sharp Scores at Day

365365

Abatacept + MTX

(n=391)

Placebo + MTX

(n=195) Total Score

Baseline mean ± SD 44u ± 37 45u ± 38 Mean change from baseline (± SD) 1.21u ± 2.94 2.32u ± 5.04

Median change from baseline (range) 0.25 (0-1.78) 0.53 (0-2.54) p-value 0.012

33

IM101-102: Concomitant MTX StudyIM101-102: Concomitant MTX Study Mean Change in Genant-Modified Sharp Score ComponentsMean Change in Genant-Modified Sharp Score Components

Abatacept + MTX

(n=391)

Placebo + MTX

(n=195) Erosion Score

Baseline mean ± SD 22u ± 18 22u ± 19

Mean change from baseline (± SD) 0.63u ± 1.77 1.14u ± 2.81

Median change from baseline (range)

0 (0-1.02) 0.27 (0-1.27)

p-value 0.029

Joint Space Narrowing

Baseline mean ± SD 23u ± 20 23u ± 20

Mean change from baseline (± SD) 0.58u ± 1.54 1.18u ± 2.58

Median change from baseline (range)

0 (0-0.49) 0.27 (0-0.97)

p-value 0.009

34

Study IM103-002: Monotherapy StudyStudy IM103-002: Monotherapy Study

3 month study3 month study

Active RA despite DMARD therapyActive RA despite DMARD therapy

112 patients randomized112 patients randomized Abatacept (n=90)Abatacept (n=90)

0.5 mg/kg (n=26), 2 mg/kg (n=32), or 10 mg/kg (n=32)0.5 mg/kg (n=26), 2 mg/kg (n=32), or 10 mg/kg (n=32) Placebo (n=32)Placebo (n=32)

Primary EndpointPrimary Endpoint ACR 20 response at Day 85ACR 20 response at Day 85

35

Study IM103-002: Monotherapy StudyStudy IM103-002: Monotherapy Study ACR Responses at Day 85ACR Responses at Day 85

Abatacept 0.5 mg/kg

(n=26)

Abatacept 2 mg/kg (n=32)

Abatacept 10 mg/kg

(n=32)

Placebo (n=32)

Day 85

ACR 20 6 (23%) 4 (44%) 7 (53%) 10 (31%)

ACR 50 0 6 (19%) 5 (16%) 2 (6%)

ACR 70 0 4 (13%) 2 (6%) 0

36

AbataceptAbataceptEfficacy AnalysisEfficacy Analysis

Subset Analyses by:Subset Analyses by: Baseline DemographicsBaseline Demographics

AgeAge SexSex RaceRace WeightWeight

Baseline Disease ActivityBaseline Disease Activity Disease DurationDisease Duration Swollen & Tender JointsSwollen & Tender Joints CRPCRP Genant-modified Sharp ScoreGenant-modified Sharp Score HAQHAQ

37


SAFETY ANALYSESSAFETY ANALYSES

38

Safety Analyses: OverviewSafety Analyses: Overview

Safety Assessment Based on 5 Studies:Safety Assessment Based on 5 Studies: IM101100, IM101101, IM101102, IM101029, IM101100, IM101101, IM101102, IM101029,

IM101031IM101031 Double-Blind Periods:Double-Blind Periods:

1955 Abatacept-treated patients (1688 person-years)1955 Abatacept-treated patients (1688 person-years) 989 Placebo-treated patients (795 person-years)989 Placebo-treated patients (795 person-years)

Open-Label Periods + Double-Blind Periods:Open-Label Periods + Double-Blind Periods: 2688 Abatacept-treated patients2688 Abatacept-treated patients

39

Cumulative Extent of ExposureCumulative Extent of Exposure

Number (%) of Subjects

Months Abatacept 0.5 mg/kg

(n=26)

Abatacept 2 mg/kg (n=222)

Abatacept 10 mg/kg or Tiered-dose

(n=2638)

All Abatacept (n=2760)

<3 7 (27%) 19 (8%) 460 (17%) 483 (17%) ≥3 19 (73%) 203 (92%) 2178 (83%) 2277 (83%) ≥6 0 157 (71%) 1868 (71%) 1908 (70%)

≥12 0 89 (40%) 1596 (61%) 1622 (60%) ≥18 0 0 263 (10%) 282 (11%) ≥24 0 0 223 (8%) 248 (10%) 36 0 0 66 (2%) 151 (6%)

Median (month)

4 12 14 14

40

DeathsDeaths 26 total deaths26 total deaths

16 patients died during the double-blind 16 patients died during the double-blind periodsperiods 10 (0.5%) abatacept-treated patients10 (0.5%) abatacept-treated patients

4 died from cardiovascular disorders4 died from cardiovascular disorders 3 found dead at home 3 found dead at home 2 died from malignancies2 died from malignancies 1 died from infection1 died from infection

6 (0.6%) placebo-treated patients6 (0.6%) placebo-treated patients 2 died from cardiovascular disorders2 died from cardiovascular disorders 1 found dead at home 1 found dead at home 1 died from malignancy1 died from malignancy 2 died from infection2 died from infection

41

DeathsDeaths

Analysis of the individual deaths did not Analysis of the individual deaths did not suggest a safety signal for any single type suggest a safety signal for any single type of AEof AE

8 of the deaths in the Abatacept group 8 of the deaths in the Abatacept group occurred during a study that permitted occurred during a study that permitted enrollment of patients with co-morbiditiesenrollment of patients with co-morbidities

42

Serious Adverse EventsSerious Adverse Events

14% of Abatacept-treated patients had an 14% of Abatacept-treated patients had an SAE compared to 12% placebo-treated SAE compared to 12% placebo-treated patientspatients

3% of Abatacept-treated patients had an 3% of Abatacept-treated patients had an infectious SAE compared to 2% placebo-infectious SAE compared to 2% placebo-treated patientstreated patients

43

Malignancies: Double-Blind PeriodsMalignancies: Double-Blind Periods

MalignantAbatacept: 29 (1.5%)Placebo: 11 (1.1%%)

Non-Melanoma Skin CAAbatacept: 15 (0.8%)

Placebo: 6 (0.5%)

Solid Organ CAAbatacept: 13 (0.7%)

Placebo: 5 (0.5%)

HematologicAbatacept: 2 (0.1%)

Placebo: 0

44

Solid Organ TumorsSolid Organ TumorsAbatacept-Treated Patients-Double Blind PeriodsAbatacept-Treated Patients-Double Blind Periods

Subject Age/Gender/Race

No. of Infusions

Onset Day Malignancy

69/F/W 3 29 Lung Neoplasm

68/M/W 5 100 Non-small cell lung CA

72/F/W

13 320 Sq. Cell lung CA

Renal Cell CA

83/M/W 13 332 Lung Neoplasm

53/M/W 8 203 Bladder CA

71/F/W 14 349 Breast CA

63/F/W 4 42 Ovarian CA

74/M/W 5 97 Prostate CA

52/F/W 6 115 Thyroid CA

42/F/W 7 237 Breast CA

70/F/W 6 85 Cholangiocarcinoma

39/F/W 5 69 Cervical CA

45

Malignancies: Open-Label PeriodsMalignancies: Open-Label Periods

47 patients developed 52 neoplasms47 patients developed 52 neoplasms 26 malignancies26 malignancies

13 solid-organ tumors13 solid-organ tumors 4 lung cancers4 lung cancers 2 ovarian cancers2 ovarian cancers 2 endometrial cancers2 endometrial cancers 1 case each of breast, prostate, melanoma, cervical, 1 case each of breast, prostate, melanoma, cervical,

and rectal cancerand rectal cancer 3 lymphomas3 lymphomas

46

Most Frequently Observed vs. Expected MalignanciesMost Frequently Observed vs. Expected Malignancies

Malignancy

Observed Expected SIR SIR 95% CI

Overall 26 30.2 0.9 0.6-1.3 Lung

8

4.0

2.0

0.9-4.0

Lymphoma 4 1.1 3.7 1.0-9.5 Breast 2 7.7 0.3 0-0.9 Prostate 2 3.2 0.6 0.1-2.2 Thyroid 2 0.6 3.5 0.4-12.5 Ovarian 2 0.7 2.7 0.3-9.7 Endometrial 2 1.5 1.3 0.2-4.9

47

Incidence Rates of MalignanciesIncidence Rates of Malignancies

N (rate/100 person-years)

Days 1-180

Days 181-360

Days 361-540

Days 541-720

Days 721-900

Days 901-1080

Total Exposure (p-y) 1285 1032 795 399 117 198

Overall malignancies (excluding non-melanoma skin cancer)

3 (0.15) 0 2 (0.36) 1 (0.16) 1 (0.16) 1 (0.16)

48

MalignanciesMalignancies 3 potentially concerning malignancies3 potentially concerning malignancies

Lung CancerLung Cancer 8 cases of lung cancer in patients receiving abatacept8 cases of lung cancer in patients receiving abatacept

Breast Cancer and LymphomaBreast Cancer and Lymphoma Pre-clinical studies demonstrated increased rate of Pre-clinical studies demonstrated increased rate of

mammary tumors and lymphomas in mice that was mammary tumors and lymphomas in mice that was believed to be secondary to abatacept-induced chronic believed to be secondary to abatacept-induced chronic immunosuppression and MMTV and MLVimmunosuppression and MMTV and MLV

Immunosuppression and RA both associated with Immunosuppression and RA both associated with increased risk of lymphomaincreased risk of lymphoma

49

Lung Cancer IncidenceLung Cancer Incidence

Observed Events (95% CI)

Trial Expected Number of Events (95% CI)

Expected Number of Events

All Abatacept BC NDB NOAR SEER

8 (3.45, 15.76)

9.95 (6.5, 16.3)

3.58 (1.8, 8.3)

4.76 (1.1, 22.8)

4 (0.9, 4.0)

50

Breast Cancer & LymphomaBreast Cancer & Lymphoma

Breast CancerBreast Cancer 3 (0.1%) cases of breast cancer reported in abatacept-treated 3 (0.1%) cases of breast cancer reported in abatacept-treated

patients compared to 2 (0.2%) cases reported in placebo-treated patients compared to 2 (0.2%) cases reported in placebo-treated patientspatients

Current evidence does not suggest abatacept increases the rate Current evidence does not suggest abatacept increases the rate of breast cancerof breast cancer

LymphomaLymphoma 4 cases of lymphoma reported in patients receiving abatacept4 cases of lymphoma reported in patients receiving abatacept Approximately 4-fold higher than general US populationApproximately 4-fold higher than general US population However, increased rate of lymphoma in RA patients, However, increased rate of lymphoma in RA patients,

particularly those with high disease activityparticularly those with high disease activity

51

Serious InfectionsSerious InfectionsSerious Infection Preferred term

Abatacept (n=1955)

Placebo (n=989)

Infectious SAE (n) 58 (3%) 19 (2%)

Pneumonia 14 (0.7%) 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

Acute Pyelonephritis 3 (0.2%) 0

Localized infection 2 (0.1%) 0

Sinusitis 2 (0.1%) 0

Subcutaneous abscess 2 (0.1%) 0

52

Infections of Special InterestInfections of Special InterestInfection Preferred term

Abatacept (n=1955)

Placebo (n=989)

Infection of Special Interest Total Subjects

187 (10%) 70 (7%)

All Herpes Infections 72 (4%) 28 (3%)

Pneumonia 40 (2%) 8 (1%)

Opportunistic Infections

Herpes Zoster 30 (2%) 16 (2%)

Oral Fungal Infection 3 (0.1%) 2 (0.1%)

Tuberculosis 2 (0.1%) 1 (0.1%)

Aspergillosis 1 (<0.1) 0

53

AEs in Abatacept w/ Biologic RA TherapyAEs in Abatacept w/ Biologic RA Therapy

A total of 204 patients received abatacept A total of 204 patients received abatacept and concomitant biologic RA therapy during and concomitant biologic RA therapy during the double-blind period representing 173 the double-blind period representing 173 person-years of exposureperson-years of exposure Majority of patients were from studies IM101-101 Majority of patients were from studies IM101-101

(n=85) and IM101-031 (n=103)(n=85) and IM101-031 (n=103) >90% TNF-blocker therapy>90% TNF-blocker therapy

Study IM101-101 compared the combination of Study IM101-101 compared the combination of abatacept 2 mg/kg + etanercept to placebo + abatacept 2 mg/kg + etanercept to placebo + etanerceptetanercept

54

AEs in Abatacept w/ Biologic RA TherapyAEs in Abatacept w/ Biologic RA Therapy

Number (%) of Subjects

Biologic RA Therapy

Non-Biologic RA Therapy

Abatacept (n=204)

Placebo (n=134)

Abatacept (n=1751)

Placebo (n=855)

SAEs 40 (20%) 12 (9%) 226 (13%) 110 (13%)

AEs 192 (94%) 113 (84%) 1544 (88%) 727 (85%)

55

SAEs withSAEs with Abatacept & Concomitant RA TherapyAbatacept & Concomitant RA TherapyStudy IM101031Study IM101031

Number of Subjects (%; n of subgroup)

Background RA Therapy Abatacept Placebo Total in Biologic Subgroup 23 (22%; n=103) 8 (13%; n=64) Etanercept 17 (26%; n=66) 5 (12%; n=42) Infliximab 3 (15%; n=20) 0 (0%; n=5) Adalimumab 3 (27%; n=11) 1 (10%; n=10) Anakinra 2 (15%; n=13) 2 (20%; n=10) Total in Non-Biologic Subgroup 100 (12%;n=856) 51 (12%; n=418) MTX 73 (11%; n=691) 37 (11%; n=336) Hydroxycholoquine/Chloroquine 23 (12%; n=194) 10 (8%; n=123) Sulfasalazine 15 (11%; n=137) 9 (13%; n=72) Leflunomide 25 (24%; n=106) 9 (15%; n=59) 1 DMARD 66 (11%; n=598) 36 (14%; n=257) 2 DMARDs 27 (13%; n=202) 14 (11%; n=123) 3 DMARDs 6 (13%; n=45) 0 (0%; n=31) 4 DMARDs 1 (10%; n=10) 1 (17%; n=6)

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Infusion ReactionsInfusion Reactions

Infusion Reactions within 1 hour post-infusionInfusion Reactions within 1 hour post-infusion 9% of abatacept-treated patients vs. 6% placebo-9% of abatacept-treated patients vs. 6% placebo-

treated patientstreated patients Infusion Reactions within 24 hours post-Infusion Reactions within 24 hours post-

infusioninfusion 23% of abatacept-treated patients vs. 19% 23% of abatacept-treated patients vs. 19%

placebo-treated patientsplacebo-treated patients 2 cases of anaphylactic reactions in patients 2 cases of anaphylactic reactions in patients

receiving abataceptreceiving abatacept

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Immunogenicity & Clinical Laboratory ValuesImmunogenicity & Clinical Laboratory Values

Immunogenicity of AbataceptImmunogenicity of Abatacept Overall, 1.6% of patients treated with abatacept developed Overall, 1.6% of patients treated with abatacept developed

antibodies to abataceptantibodies to abatacept

5.8% of abatacept patients who had discontinued therapy 5.8% of abatacept patients who had discontinued therapy for at least 56 days developed antibodies to abataceptfor at least 56 days developed antibodies to abatacept

Changes in Clinical Laboratory ValuesChanges in Clinical Laboratory Values no clinically meaningful differences between patients no clinically meaningful differences between patients

treated with abatacept compared to placebo regarding treated with abatacept compared to placebo regarding blood chemistry and hematologic laboratory valuesblood chemistry and hematologic laboratory values

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Autoimmune Symptoms & DisordersAutoimmune Symptoms & Disorders 3% of Abatacept-treated patients reported 3% of Abatacept-treated patients reported

autoimmune-related AEs compared to 2% of placebo-autoimmune-related AEs compared to 2% of placebo-treated patients during the Double-Blind periodtreated patients during the Double-Blind period

Most common symptoms were associated with RAMost common symptoms were associated with RA e.g., Keratoconjunctivitis sicca, Sjogren’s syndromee.g., Keratoconjunctivitis sicca, Sjogren’s syndrome

Psoriasis was more frequent in patients treated with Psoriasis was more frequent in patients treated with abatacept compared to placebo (0.5% vs. 0.1%)abatacept compared to placebo (0.5% vs. 0.1%)

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

N

Anti-nuclear Antibody n (%) N

ds-DNA Antibody n (%)

Abatacept 962 93 (10%) 1062 29 (3%) Placebo 575 443 (11%) 490 23 (5%)

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AEs in patients with Co-MorbiditiesAEs in patients with Co-MorbiditiesStudy IM101031Study IM101031

Study IM101-031 permitted patients with co-Study IM101-031 permitted patients with co-morbidities including COPD, diabetes, asthma, and morbidities including COPD, diabetes, asthma, and CHFCHF

Diabetes, asthma, or CHF: no apparent increase in Diabetes, asthma, or CHF: no apparent increase in AEs or SAEsAEs or SAEs

COPD: AEs reported in 97% of abatacept-treated COPD: AEs reported in 97% of abatacept-treated patients vs. 88% of placebo-treated patientspatients vs. 88% of placebo-treated patients Respiratory AEs more common with abatacept (43% vs. 24%)Respiratory AEs more common with abatacept (43% vs. 24%)

SAEs more common with (27% vs. 6%)SAEs more common with (27% vs. 6%)

No reported deathsNo reported deaths

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SummarySummary The studies presented here show abatacept-treatment The studies presented here show abatacept-treatment

associated differences regarding associated differences regarding improvement in signs and symptomsimprovement in signs and symptoms improvement of physical functionimprovement of physical function Inhibition of radiographic progressionInhibition of radiographic progression

There was a higher rate of serious infections in patients There was a higher rate of serious infections in patients treated with abatacept, especially with patients receiving treated with abatacept, especially with patients receiving concomitant TNF-blocking agentsconcomitant TNF-blocking agents

Overall malignancy rates were not substantially different Overall malignancy rates were not substantially different between abatacept (1.5%) and placebo (1.1%) treated between abatacept (1.5%) and placebo (1.1%) treated patients patients However, abatacept treated patients had more cases of lung cancer However, abatacept treated patients had more cases of lung cancer

and the rate of lymphomas was higher than expected compared to the and the rate of lymphomas was higher than expected compared to the general US populationgeneral US population

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SummarySummary Infusion-related reactions were observed including Infusion-related reactions were observed including

hypersensitivity reactions and 2 cases of anaphylaxishypersensitivity reactions and 2 cases of anaphylaxis

Patients with COPD treated with abatacept had a higher Patients with COPD treated with abatacept had a higher incidence of adverse events and serious adverse events, incidence of adverse events and serious adverse events, particularly respiratory disordersparticularly respiratory disorders

Date post:	25-Dec-2015
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