1. Module 1 Prof. Hassan Bassiouny, MD Prof. Of Rheumatology, Al-Azhar University Cairo, Egypt RHUHQ12PM028 Date of preparation: January 2012 Targeting the T cell in RA earlier Disease: Safety Concerns

2. 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 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 of long-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 demonstrates more favourable maintenance of long-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” 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

3. Module 1 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) % of patients with serious infection 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.

4. Module 1 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) Pneumonia1.8 (3)1.3 (2) Infection skin ulcer00.6 (1) Sinusitis00.6 (1) Bronchitis0.6 (1)0 Cellulitis0.6 (1)0 Encephalitis herpetic0.6 (1)0 Erysipelas0.6 (1)0 Gastroenteritis0.6 (1)0 Herpes zoster0.6 (1)0 Lung infection (pseudomonal)0.6 (1)0 Peritoneal tuberculosis0.6 (1)0 Pneumocystis jiroveci pneumonia0.6 (1)0 Postoperative wound infection0.6 (1)0 Lobar pneumonia0.6 (1)0 Pulmonary tuberculosis0.6 (1)0 Septic shock0.6 (1)0 ATTEST (MTX-IR) 0 There were 0 opportunistic 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.

5. Module 1 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 0.110.01.0 Favours biologicOdds ratio (95% CI)Favours placebo Adalimumab Anakinra Certolizumab Etanercept Golimumab Infliximab Rituximab Tocilizumab Overall Abatacept Forest plots: Serious adverse events and serious infections Adalimumab Anakinra Certolizumab Etanercept Golimumab Infliximab Rituximab Tocilizumab Overall Abatacept Serious infections P (drug)=0.027 COCHRANE META-ANALYSIS

6. Module 1 Incidence rates of serious infections are stable over time across 8 abatacept clinical trials 6 Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–5. Abstract 390. Patients with event, n 13170474023138 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 03215476 6.0 7.0 Incidence rate (per 100 p–y) Year

7. Module 1 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 Integrated safety summary 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 term (2,331 p–y) Long term (9,752 p–y) Cumulative (12,132 p–y) PlaceboAbatacept 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) NMSC 0.82 (0.33–1.70) 0.82 (0.49–1.28) 0.74 (0.58–0.93)0.73(0.58–0.90)

8. Module 1 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 0.010.1110100 Integrated safety summary

9. Module 1 Standardised incidence ratios of lung cancer for abatacept patients are not increased compared with non-biologic DMARD-treated RA population 9 Simon 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. Integrated safety summary Standardised incidence rations Abatacept RCT vs BC NDB GPRD NOAR Sweden ERA 0.1101

10. Module 1 Standardised incidence ratios of lymphoma for abatacept patients are not increased compared with non-biologic DMARD-treated RA population 10 Simon 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. Integrated safety summary Standardised incidence rations Abatacept RCT vs BC NDB GPRD NOAR Sweden ERA 0.1101

11. Module 1 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). InfectionsRABBIT 1 ORA 2 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–y n=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–y n=16 Anaphylactic reactions 0.48/100 p–y Not reported Severe infusion reactions leading to discontinuations Not reported n=9 11

12. Module 1 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% Infliximab 1 295/51162% Etanercept 2 429/58174% Adalimumab 3 147/26256% Abatacept 4 * (IM101102) 394/53973% 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 agents 5 *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

13. Module 1 Abatacept seems to have a favourable safety profile: Summary 13 Retention rates seen in real-life study were consistent with clinical trial data 4 No increases in incidence rates of malignancy 3 with abatacept over time Rates of serious infections lower with abatacept vs other biologic agents 1–3 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.

14. Module 1 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 agents 1 …has demonstrated more favourable maintenance of long-term efficacy... 2 …seems to have a favourable safety profile 3

15. Module 1 Supporting safety data Summary of safety Infections Tuberculosis Malignancies Autoimmune events Infusion events 15

16. Module 1 Supporting safety data Summary of safety Infections Tuberculosis Malignancies Autoimmune events Infusion events 16

17. Module 1 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 Integrated safety summary Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–5. Abstract 390.

18. Module 1 Abatacept integrated safety analysis: multiple large-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. PATIENTMTX-IR Etanercept -IR DMARDs and/or biologic-IR Anti-TNF-IR STUDY Phase II study n=339 1 AIM n=652 3 ATTEST n=431 6 Phase II ABA+ETA n=121 2 ASSURE n=1,441 5 ATTAIN n=391 4 ARRIVE n=1,046 7 Phase II MoA study n=16 8 Short-term period 12-mth DB, PC 6-mth DB, 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 Integrated safety summary

19. 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 AEs184.37 (166.78–203.30) Overall SAEs6.54 (4.77–8.76) Serious Infections1.83 (0.97–3.12) Malignancies 0.28 (0.03–1.01) MTX-IR N=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-IR N=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). Integrated safety summary

20. Module 1 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 SAEs18.15 (16.41–20.02) Deaths0.51 (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 Integrated safety summary Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–5. Abstract 390.

21. Module 1 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. Clinical trial experience Short term Long term (n=3,256) Cumulative (n=4,149) Placebo (n=1099) Abatacept (n=3,173) Infections Serious infections Patients with event, n 2285260332 Incidence rate 2.60 (1.63–3.94) 3.68 (2.94–4.55) 2.79 (2.46–3.15) 2.87 (2.57–3.19) Hospitalised infection Patients with event, n 2077241307 Incidence rate 2.36 (1.44–3.65) 3.33 (2.63–4.16) 2.58 (2.26–2.93) 2.64 (2.35–2.95) Integrated safety summary 2009 Database Lock

22. Module 1 Supporting safety data Summary of safety Infections Tuberculosis Malignancies Autoimmune events Infusion events 22

23. Module 1 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) Incidence/ 100 patient-years Cumulative period All abatacept-treated patients (2 years; n=399) Incidence/ 100 patient-years Adverse events326.0 (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) Infections99.8 (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.

24. Module 1 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 1–197Days 1–365 Abatacept + MTX (n=156) Placebo + MTX (n=110) Infliximab + MTX (n=165) Abatacept + MTX (n=156) Infliximab + MTX (n=165) Infections48.1 (75)51.8 (57)52.1 (86)59.6 (93)68.5 (113) Serious infections 1.3 (2)2.7 (3)4.2 (7)1.9 (3)8.5 (14) 24 ATTEST (MTX-IR)

25. Module 1 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. Clinical trial experience Short term Long term (n=3,256) Cumulative (n=4,149) Placebo (n=1099) Abatacept (n=3,173) Infections Serious infections Patients with event, n 2285260332 Incidence rate 2.60 (1.63–3.94) 3.68 (2.94–4.55) 2.79 (2.46–3.15) 2.87 (2.57–3.19) Hospitalised infection Patients with event, n 2077241307 Incidence rate 2.36 (1.44–3.65) 3.33 (2.63–4.16) 2.58 (2.26–2.93) 2.64 (2.35–2.95) Integrated safety summary 2009 Database Lock.

26. Module 1 Supporting safety data Summary of safety Infections Tuberculosis Malignancies Autoimmune events Infusion events 26

27. Module 1 Tuberculosis screening in abatacept clinical trials Data on file 27 PPD testing Prior treatment not documented Prior treatment not documented Prior treatment documented Prior treatment documented Diagnosis of latent TB RANDOMISERANDOMISE DO NOT RANDOMISE PPD positive Chest X-ray negative PPD positive Chest X-ray negative PPD positive/negative Positive chest X-ray PPD positive/negative Positive chest X-ray PPD negative Chest X-ray negative PPD negative Chest X-ray negative PPD=purified protein derivative; TB=tuberculosis.

28. Module 1 Tuberculosis exclusion criteria in abatacept clinical studies In the pivotal Phase II 1,2 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 ARRIVE 6 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.

29. Module 1 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.

30. Module 1 Supporting safety data Summary of safety Infections Tuberculosis Malignancies Autoimmune events Infusion events 30

31. Module 1 Incidence rates of total malignancies (excluding NMSC) in the abatacept clinical trial experience 31 Patients with event, n 221417141335 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) Integrated safety summary Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–5. Abstract 390. 0 0.5 1.0 1.5 2.0 2.5 0321 5 4 76 3.0 3.5 Incidence rate (per 100 p–y) Year 4.0

32. 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 skin Solid Lung Thyroid Breast Prostate Bladder Renal Ovarian Melanoma Endometrial/uterine Cervix Haematologic Lymphoma Myelodysplastic syndrome DB period n=1,955 (1,687 p–y) 1.61 0.95 0.53 0.24 0.12 0.06 0 0 0 0 0.12 0.06 Cumulative period n=4,149 (11,658 p–y) 1.43 0.72 0.59 0.17 0.02 0.10 0.05 0.03 0.01 0.02 0.03 0.13 0.06 0.04 December 2008 database lock.

33. Module 1 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 population 3 –Increasing duration of exposure to abatacept did not increase the risk of overall malignancy or major type/individual malignancy 1,4 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

34. Module 1 Supporting safety data Summary of safety Infections Tuberculosis Malignancies Autoimmune events Infusion events 34

35. Module 1 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 AE 1 n=48 2.07 (1.53–2.75) n=183 1.95 (1.68–2.25) n=232 1.99 (1.74–2.26) Integrated safety summary December 2009 database lock.

36. Module 1 Supporting safety data Summary of safety Infections Tuberculosis Malignancies Autoimmune events Infusion events 36

37. Module 1 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] Acute infusional events † Short term Long term (n=3256) Cumulative (n=4149) Placebo (n=1099) Abatacept (n=3173) Patients with event, n68225176377 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) Integrated safety summary 4149 pts; 12,132 p–y

38. Module 1 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 abatacept 1 –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 antibodies 1 1. Orencia SmPC November 2011. 38

39. Module 1 Thank You