module 1 prof. hassan bassiouny, md prof. of rheumatology, al-azhar university cairo, egypt...

Module 1

Prof. Hassan Bassiouny, MD

Prof. Of Rheumatology,Al-Azhar University

Cairo, Egypt

RHUHQ12PM028Date of preparation: January 2012

Targeting the T cell in RA earlier Disease: Safety Concerns

Module 1

Abatacept is indicated as a first-line biologic agent in methotrexate inadequate responder (MTX-IR) patients

EPAR Orencia: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion_-_Variation/human/000701/WC500095025.pdf.

Abatacept demonstrates similar short-term efficacy compared with other biologic agents• “The data seem to indicate that abatacept has similar short-term efficacy when compared to

infliximab, etanercept and rituximab”

Abatacept demonstrates more favourable maintenance oflong-term efficacy• “It appears that the retention rates at the end of 4 years of the LT therapy were comparable or higher

in the abatacept study (73%) compared to the 3 TNF-antagonists (56–74%)”

• “The ACR50 and DAS28 response rates were comparable or higher in the abatacept study compared with the 3 TNF-antagonists”

Abatacept seems to have a favourable safety profile• “According to current safety database, the safety profile of abatacept seems to be better than that of

the TNF-inhibitors and rituximab. This is due to the lower occurrence of serious or other infections”

2

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Schiff M, et al. Ann Rheum Dis 2008;67:1096–1103. 3

9

8

3

2

1

0

5

4

7

6

8.5%

1.9%

Infliximab + MTX(n=165)

Abatacept + MTX(n=156)

% o

f p

atie

nts

wit

h s

erio

us

infe

ctio

n

Less than 2% of patients experienced serious infections with abatacept over 1 year

ATTEST (MTX-IR)

This study was not designed to demonstrate non-inferiority or superiority of abatacept vs infliximab.

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Abatacept shows a more acceptable safety profile than infliximab

Schiff M, et al. Ann Rheum Dis 2008;67:1096–1103. 4

Serious infection events, % (n) Infliximab + MTX (n=165) Abatacept + MTX (n=156)

Infections and infestations (total) 8.5 (14) 1.9 (3)

Pneumonia 1.8 (3) 1.3 (2)

Infection skin ulcer 0 0.6 (1)

Sinusitis 0 0.6 (1)

Bronchitis 0.6 (1) 0

Cellulitis 0.6 (1) 0

Encephalitis herpetic 0.6 (1) 0

Erysipelas 0.6 (1) 0

Gastroenteritis 0.6 (1) 0

Herpes zoster 0.6 (1) 0

Lung infection (pseudomonal) 0.6 (1) 0

Peritoneal tuberculosis 0.6 (1) 0

Pneumocystis jiroveci pneumonia 0.6 (1) 0

Postoperative wound infection 0.6 (1) 0

Lobar pneumonia 0.6 (1) 0

Pulmonary tuberculosis 0.6 (1) 0

Septic shock 0.6 (1) 0

ATTEST (MTX-IR)

There were

0opportunistic

infections in patients treated with abatacept

Serious infection events between Day 1 and Day 365. Orange bars indicate opportunistic infections.This study was not designed to demonstrate non-inferiority or superiority of abatacept vs infliximab.

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Abatacept is associated with fewer serious adverse events and serious infections compared to other biologic agents

Singh JA, et al. Cochrane Database Syst Rev 2011:16;2:CD008794. 5

Serious adverse events

P (drug)=0.099

0.1 10.01.0

Favours biologic Odds ratio (95% CI) Favours placebo

AdalimumabAnakinraCertolizumabEtanerceptGolimumabInfliximabRituximabTocilizumabOverall

Abatacept

Forest plots: Serious adverse events and serious infections

AdalimumabAnakinraCertolizumabEtanerceptGolimumabInfliximabRituximabTocilizumabOverall

Abatacept

Serious infections

P (drug)=0.027

COCHRANE META-ANALYSIS

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Incidence rates of serious infections are stable over time across 8 abatacept clinical trials

6Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–5. Abstract 390.

Patients withevent, n 131 70 47 40 23 13 8

Incidence rates per 100 p–y (95% CI)

3.7 (3.1–4.4)

2.9 (2.2–3.6)

2.4 (1.7–3.2)

2.5 (1.8–3.4)

1.9 (1.2–2.8)

2.5 (1.3–4.2)

3.1 (1.3–6.0)

Data lock December 2009; 12,132 p–y of exposure (N=4,149) Serious infection is a subset of serious adverse events; p–y=patient–years.

Integrated safety summary

0

1.0

2.0

3.0

4.0

5.0

0 321 54 76

6.0

7.0

Inci

den

ce

rate

(p

er 1

00 p

–y)

Year

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Continued use of abatacept does not increase the risk of malignancy over time

Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–5. Abstract 390. 7


NMSC=non-melanoma skin cancer; Data over a 7-year period; Data lock December 2009. 12,132 p–y of exposure (N=4,149).

Clinical trial experience

Short termShort term(2,331 p–y)

Long term(9,752 p–y)

Cumulative(12,132 p–y)

Placebo Abatacept Abatacept Abatacept

Malignancies, incidence rate (95% CI)

Malignancies (excluding NMSC)

0.59 (0.19–1.37)

0.69 (0.39–1.11)

0.74 (0.58–0.93)

0.73 (0.58–0.89)

Lymphoma –0.04

(0.00–0.24)0.08

(0.04–0.16)0.07

(0.03–0.14)

Total solid organ (combined)

0.59 (0.19–1.37)

0.60 (0.33–1.01)

0.60 (0.45–0.77)

0.59(0.46–0.75)

Lung cancer – 0.21

(0.07–0.50)0.13

(0.07–0.23)0.15

(0.09–0.23)

NMSC0.82

(0.33–1.70)0.82

(0.49–1.28)0.74

(0.58–0.93)0.73

(0.58–0.90)

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Standardised incidence ratios of malignancies for abatacept patients are comparable with the general population

Simon TA, et al. Ann Rheum Dis 2009;68:1819–1826. 8

Orange lines indicate the standard incidence ratio point estimates and the 95% confidence intervals for abatacept (2006 ISS database lock) compared with the SEER database of the general population; The diamonds represent SIR reported in the literature that compare RA patients with non-RA patients or general populations; SEER=Surveillance, Epidemiology and End Results.

Total(excluding non-melanoma skin)

Breast

Colon and rectal

Lung

Lymphoma

0.01 0.1 1 10 100


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Standardised incidence ratios of lung cancer for abatacept patients are not increased compared with non-biologic DMARD-treated RA population

9Simon TA, et al. Ann Rheum Dis 2009;68:1819–1826.

The diamonds indicate the standard incidence ratio point estimates and the horizontal line represent the 95% confidence intervals for abatacept (2006 ISS database lock) compared with the RA population treated with non-biologic DMARDs in cohorts.


Standardised incidence rations

Abatacept RCT vs

BC

NDB

GPRD

NOAR

Sweden ERA

0.1 101

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Standardised incidence ratios of lymphoma for abatacept patients are not increased compared with non-biologic DMARD-treated RA population

10Simon TA, et al. Ann Rheum Dis 2009;68:1819–1826.

The diamonds indicate the standard incidence ratio point estimates and the horizontal line represent the 95% confidence intervals for abatacept (2006 ISS database lock) compared with the RA population treated with non-biologic DMARDs in cohorts.


Standardised incidence rations

Abatacept RCT vs

BC

NDB

GPRD

NOAR

Sweden ERA

0.1 101

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Summary of safety experience with abatacept in RABBIT and ORA registries in anti-TNF-IR patients

• No opportunistic infection reported in RABBIT or ORA

1. Strangfeld A, personal communication; 2. Gottenberg JE, Ann Rheum Dis 2011;70(Suppl3):466.

REAL-LIFE DATA

†Number of solid malignancies (ITT population; 516 patient–years).

Infections RABBIT1 ORA2

Abatacept patients n=261; 420 p–y 1187.7 p–y exposure

Cut-off date 30 April 2011 December 2010

Serious infections 4.8/100 p–yn=66

5.6/100 p–y

Total malignancies 0.78/100 p–y†n=14

1.18/100 p–y

Deathsn=5

1.19/100 p–yn=16

Anaphylactic reactions 0.48/100 p–y Not reported

Severe infusion reactions leading to discontinuations

Not reported n=9

11

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1. Vander Cruyssen B, et al. Arthritis Res Ther 2006;8:R112; 2. Moreland LW, et al. J Rheum 2006;33:854–861; 3. Weinblatt M, et al. Ann Rheum Dis 2006;65:753–759; 4. Data on file; 5. Hetland ML, et al. Arthitis Rheum 2010;62:22–32.

Subjects remaining at the end of 4 years of LTE

n/N %

Infliximab1 295/511 62%

Etanercept2 429/581 74%

Adalimumab3 147/262 56%

Abatacept4*

(IM101102)394/539 73%

Abatacept has a retention rate that is comparable with or higher than the anti-TNF agents

• Retention may be considered as a surrogate marker of long-term efficacy for biologic agents5

*Summation of the original abatacept plus placebo treatment groups who entered LTE.Data from literature search on the long-term efficacy results from open-label extension studies of anti-TNFs (in MTX-naïve and MTX-IR patients).

12

LT- RCT

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Abatacept seems to have a favourable safety profile:Summary

13

Retention rates seen in real-life study wereconsistent with clinical trial data4

No increases in incidence rates of malignancy3

with abatacept over time

Rates of serious infections lower withabatacept vs other biologic agents1–3

1. Schiff M, et al. Ann Rheum Dis 2008;67:1096–1103; 2. Singh JA, et al. Cochrane Database Syst Rev. 2011:16;2:CD008794; 3. Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–165. Abstract 390; 4. Schiff M, et al. Int J Clin Rheum 2010;5:581–591.

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Abatacept…

1. Singh JA, et al. Cochrane Database Syst Rev 2009;4:CD007848; 2. Westhovens R, et al. Ann Rheum Dis 2009;68(Suppl3):577. Poster SAT0108; 3. Singh JA, et al. Cochrane Database Syst Rev. 2011:16;2:CD008794. 14

Has demonstrated similar short-term efficacy compared with other biologic agents1

…has demonstrated more favourable maintenance of long-term efficacy...2

…seems to have a favourable safety profile3

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Supporting safety data

• Summary of safety• Infections• Tuberculosis• Malignancies• Autoimmune events• Infusion events

15

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16

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Abatacept integrated safety analysis:Population

• Long-term safety using an integrated analysis of data from across 8 abatacept RA clinical trial programmes– All patients who received ≥1 dose of study drug were evaluated

• Cumulative period included 4,149 patients treated with abatacept with 12,132 patient-years of exposure – 1,165 (28.1%) had ≥5 years of exposure– Mean (SD) duration of exposure was 35.6 (26.2) months

17


Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–5. Abstract 390.

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Abatacept integrated safety analysis: multiplelarge-scale trials of varying RA patient populations

1. Kremer JM, et al. Arthritis Rheum 2005;52:2263–2271; 2. Weinblatt M, et al. Ann Rheum Dis 2007;66:228–234; 3. Kremer JM, et al. Ann Intern Med 2006;144:865–876; 4.Genovese MC, et al. N Engl J Med 2005;353:1114–1123; 5. Weinblatt M, et al. Arthritis Rheum 2006;54:2807–2816; 6. Schiff M, et al. Ann Rheum Dis 2008;67:1096–1103; 7. Schiff M, et al. Ann Rheum Dis 2009;68:1708–1714; 8. Buch MH, et al. Ann Rheum Dis 2009;68:1220–1227.

*Generally ended when abatacept became commercially available to the patient.

PATIENT MTX-IREtanercept

-IR

DMARDs and/or

biologic-IRAnti-TNF-IR

STUDY

Phase II study

n=3391

AIM

n=6523

ATTEST

n=4316

Phase IIABA+ETA

n=1212

ASSURE

n=1,4415

ATTAIN

n=3914

ARRIVE

n=1,0467

Phase II MoA study

n=168

Short-term period

12-mth DB, PC

6-mthDB, PC

6-mth OL

Long-term period

OL, long-term extension period* (includes patients who switched from placebo or active-comparator arms to abatacept after the DB, PC periods)

18


Module 1

Differences in observed AEs in abatacept in clinical trial experience depending on treatment background

Smitten A, et al. Ann Rheum Dis 2010;69(Suppl3):541. Poster SAT0164. 19

Incidence rate, event/100 p–y (95%CI)

MTX-naïve N=483 (717 p–y)

Overall AEs 184.37 (166.78–203.30)

Overall SAEs 6.54 (4.77–8.76)

Serious Infections 1.83 (0.97–3.12)

Malignancies 0.28 (0.03–1.01)

MTX-IRN=1,280 (4,465 p–y)

260.28 (246.00–275.17)

14.62 (13.37–15.97)

2.78 (2.28–3.30)

1.30 (0.98–1.68)

Anti-TNF-IRN=1,419 (1,986 p–y)

359.05 (339.18–179.78)

20.52 (18.33–22.90)

3.90 (3.06–4.89)

1.79 (1.25–2.49)

Data from 7 clinical trials (December 2008 database lock).


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Deaths and serious adverse events are stable over time in the abatacept clinical trial experience

20

Incidence rate (/100 p–y)

Short-term(n=3,173)2,331 p–y

Overall SAEs 18.15 (16.41–20.02)

Deaths 0.51 (0.27–0.90)

AEs leading to discontinuation

6.93 (5.90–8.09)

Long-term(n=3,256)9,752 p–y

14.31 (13.47–15.18)

0.62 (0.47–0.79)

2.79 (2.47–3.14)

Cumulative(n=4,149)

12,132 p–y

14.61 (13.85–15.41)

0.60 (0.47–0.76)

3.53 (3.20–3.88)

Data from 8 clinical trials (December 2009 database lock); p–y=person-years; AE=adverse event; SAE=serious adverse event



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Continued use of abatacept does not increase risk of serious infection over time

Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–5. Abstract 390.


Short termLong term(n=3,256)

Cumulative(n=4,149)Placebo

(n=1099)Abatacept (n=3,173)

Infections

Serious infections

Patients with event, n

22 85 260 332

Incidence rate2.60

(1.63–3.94)3.68

(2.94–4.55)2.79

(2.46–3.15)2.87

(2.57–3.19)

Hospitalised infection


20 77 241 307

Incidence rate2.36

(1.44–3.65)3.33

(2.63–4.16)2.58

(2.26–2.93)2.64

(2.35–2.95)


2009 Database Lock

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22

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Safety events were low in abatacept-treated patients over 2 years

23

Safety event(95% CI)

Double-blind period Abatacept arm(1 year; n=156)

Incidence/100 patient-years

Double-blind period Infliximab arm(1 year; n=165)


Cumulative periodAll abatacept-treated

patients(2 years; n=399)


Adverse events 326.0 (274.1–384.9) 448.6 (380.6–525.3) 257.5 (231.8–285.3)

Serious adverse events 11.8 (6.9–18.9) 21.1 (14.2–30.1) 15.2 (12.0–19.0)

Infections 99.8 (80.4–122.4) 134.1 (110.6–161.1) 86.2 (76.2–97.3)

Serious infections 2.0 (0.4–5.9) 9.2 (5.0–15.5) 1.6 (0.7–3.1)

ATTEST (MTX-IR)

The cumulative period consists of data from patients who were 1) randomised to abatacept; 2) randomised to placebo and switched to abatacept at Month 6; and 3) randomised to infliximab and switched to abatacept at Year 1.

Schiff M, et al. Ann Rheum Dis 2011;70:2003–2007.

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Rates of infections with abatacept are comparable with rates for placebo- and infliximab-treated patients

Schiff M, et al. Ann Rheum Dis 2008;67:1096–1103.

% (n)

Days 1–197 Days 1–365

Abatacept + MTX

(n=156)

Placebo + MTX (n=110)

Infliximab + MTX

(n=165)

Abatacept + MTX

(n=156)

Infliximab + MTX

(n=165)

Infections 48.1 (75) 51.8 (57) 52.1 (86) 59.6 (93) 68.5 (113)

Seriousinfections 1.3 (2) 2.7 (3) 4.2 (7) 1.9 (3) 8.5 (14)

24

ATTEST (MTX-IR)

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Continued use of abatacept does not increase risk of serious infection over time

Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–165. Abstract 390.


Short termLong term(n=3,256)

Cumulative(n=4,149)Placebo

(n=1099)Abatacept (n=3,173)

Infections

Serious infections


22 85 260 332

Incidence rate2.60

(1.63–3.94)3.68

(2.94–4.55)2.79

(2.46–3.15)2.87

(2.57–3.19)

Hospitalised infection


20 77 241 307

Incidence rate2.36

(1.44–3.65)3.33

(2.63–4.16)2.58

(2.26–2.93)2.64

(2.35–2.95)


2009 Database Lock.

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26

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Tuberculosis screening in abatacept clinical trials

Data on file 27

PPD testing

Prior treatment not documented

Prior treatment documented

Diagnosis of latent TB

RANDOMISE DO NOT RANDOMISE

PPD positiveChest X-ray negative

PPD positive/negativePositive chest X-ray

PPD negativeChest X-ray negative

PPD=purified protein derivative; TB=tuberculosis.

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Tuberculosis exclusion criteria in abataceptclinical studies

• In the pivotal Phase II1,2 and III studies (AIM, ATTAIN and ASSURE)3–5

– Patients with a history of active TB in the 3 years before study commencement were excluded

• In the pivotal Phase III studies (AIM, ATTAIN and ASSURE)3–5

– Patients with evidence of possible latent TB (skin testing) who had not received adequate chemoprophylaxis were excluded

• In the ARRIVE6 study– PPD-positive (skin testing) patients were excluded if they had positive chest

X-rays and had not received adequate chemoprophylaxis • In total, 26 PPD-positive patients with latent TB and negative chest X-rays were

enrolled in the study• No cases of TB were observed

1. Kremer JM, et al. Arthritis Rheum 2005;52:2263–2271; 2. Weinblatt M, et al. Ann Rheum Dis. 2007;66:228–234; 3. Kremer JM, et al. Ann Intern Med 2006;144:865–877; 4. Genovese MC, et al. N Engl J Med 2005;144:1114–1123; 5. Weinblatt M, et al. Arthritis Rheum 2006;54:2807–2816; 6. Schiff M, et al. Ann Rheum Dis 2009;68:1708–1714. 28

PPD=purified protein derivative.

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Tuberculosis: Clinical trial experience

• 6 cases of suspected TB with abatacept– Double-blind

• TB cervical lymphadenitis infection– Open-label (OL)

• 2 pulmonary TB • 1 Pott’s disease (thoracic); presented with transient fever,

non-productive cough followed by a persistent thoracic pain• 1 submandibular lymphadenitis; presented with enlarged lymph node• 1 latent TB

• 1 case of confirmed pulmonary TB with abatacept (OL)• 1 case of presumed tuberculosis with placebo

– Double-blind • Suspected TB, unknown presentation

Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–5. Abstract 390; Data on file. 29

December 2008 database lock.

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30

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Incidence rates of total malignancies (excluding NMSC) in the abatacept clinical trial experience

31

Patients withevent, n 22 14 17 14 13 3 5

Incidence rates per 100 p–y (95% CI)

0.6 (0.4–0.9)

0.6 (0.3–0.9)

0.8 (0.5–1.3)

0.8 (0.4–1.4)

1.0 (0.5–1.7)

0.5 (0.1–1.5)

1.7 (0.5–3.9)

NMSC=non-melanoma skin cancer; Data lock December 200912,132 p–y of exposure (n=4,149)



0

0.5

1.0

1.5

2.0

2.5

0 321 54 76

3.0

3.5

Inci

den

ce

rate

(p

er 1

00 p

–y)

Year

4.0

Module 1

Incidence rates of malignancies are stable over time in the abatacept clinical trial experience

1. Smitten A, et al. Arthritis Rheum 2008;59(Suppl9):S786. Poster 1675(397); 2. Data on file; 3. Orencia SmPC November 2011. 32

Number of events/100 p–y

Total malignancies Non-melanoma skinSolid

Lung ThyroidBreastProstateBladderRenalOvarianMelanomaEndometrial/uterineCervix

HaematologicLymphomaMyelodysplastic syndrome

DB periodn=1,955 (1,687 p–y)

1.610.950.530.240.120.060.060.060.06

0000

0.120.060.06

Cumulative periodn=4,149 (11,658 p–y)

1.430.720.590.170.020.100.050.030.010.020.030.030.030.130.060.04


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Malignancy: Summary

• In the cumulative abatacept experience (4,149 patients; 12,132 p–y):1,2

– Incidence of malignancy was 1.44 per 100 p–y – Annualized incidence rate remained stable

• Incidence of malignancies with abatacept were similar to placebo and the RA population3

– Increasing duration of exposure to abatacept did not increase the risk of overall malignancy or major type/individual malignancy1,4

• A risk management plan will provide further information to better define risk of malignancy

1. Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–165. Abstract 390. 2. Data on file; 3. Simon TA, et al. Ann Rheum Dis 2009;68:1819–1826; 4. Smitten A, et al. Ann Rheum Dis 2010;69(Suppl3):541. Poster SAT0163. 33

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34

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Incidence rates of autoimmune events are stable over time across 8 abatacept clinical trials

• The most common autoimmune events in the cumulative period were:• Psoriasis (IR [95% CI]: 0.57 [0.44–0.72])• Sjogren’s syndrome (0.19 [0.12–0.29]) • Vasculitis (0.18 [0.11–0.28])

Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–165. Abstract 390. 35

*Abatacept-treated patients; †All patients received abatacept during the open-label periods; ‡Abatacept-treated patients in the cumulative (short-term and open-label) study periods. Data are for 8 abatacept clinical trials (short-term and open-label periods).

Number IR, events/100 p–y (95%CI)

Short-term period*

(2,331 p–y)

Open-label period†

(9,752 p–y)

Cumulative periods‡

(12,132 p–y)

Total autoimmune AE1 n=482.07 (1.53–2.75)

n=1831.95 (1.68–2.25)

n=2321.99 (1.74–2.26)



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36

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Incidence rates of acute infusion events reported in abatacept-treated patients decline over time

Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S142. Abstract 390. 37

Database lock: December 2009.Events occurring within one hour of the start of the infusion, evaluated in only 6 studies:

• Short-term period, n=2868 [1939 p–y] for abatacept and n=944 [691 p–y] for placebo• Long-term period, n=2957 [8067 p–y] • Cumulative period, n=3755 [9662 p–y]

Acuteinfusional events†

Short termLong term(n=3256)

Cumulative(n=4149)Placebo

(n=1099)Abatacept (n=3173)

Patients with event, n 68 225 176 377

Incidence rate 9.84 (7.64–12.48)

11.61 (10.14–13.22)

2.18 (1.87–2.53)

3.9 (3.52–4.32)


4149 pts; 12,132 p–y

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Immunogenicity was low in the abatacept clinical trial program

• Overall incidence of anti-abatacept antibody responses was 4.8% (187/3,985) in patients treated for up to 8 years with abatacept1

– In patients assessed for antibodies at least 42 days after discontinuation of abatacept, incidence of immunogenicity was 5.5% (103/1,888)1

– There was no apparent correlation of antibody development to clinical response or adverse event based on this limited dataset of patients with antibodies1

1. Orencia SmPC November 2011. 38

Module 1

Thank You

module 1 prof. hassan bassiouny, md prof. of rheumatology, al-azhar university cairo, egypt...

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