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Prof. Hassan Bassiouny, MD Prof. Of Rheumatology, Al-Azhar University Cairo, Egypt

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

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Prof. Hassan Bassiouny, MD Prof. Of Rheumatology, Al-Azhar University Cairo, Egypt

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

  2. Abatacept is indicated as a first-line biologic agent in methotrexate inadequate responder (MTX-IR) patients • 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” • Abataceptseems 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” EPAR Orencia: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion_-_Variation/human/000701/WC500095025.pdf.

  3. ATTEST (MTX-IR) Less than 2% of patients experienced serious infections with abatacept over 1 year 8.5% 9 8 7 6 5 % of patients with serious infection 4 3 1.9% 2 1 0 Infliximab + MTX(n=165) Abatacept + MTX(n=156) This study was not designed to demonstrate non-inferiority or superiority of abataceptvs infliximab. Schiff M, et al. Ann Rheum Dis2008;67:1096–1103.

  4. ATTEST (MTX-IR) Abatacept shows a more acceptable safety profile than infliximab 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 abataceptvs infliximab. Schiff M, et al. Ann Rheum Dis2008;67:1096–1103.

  5. COCHRANE META-ANALYSIS Abatacept is associated with fewer serious adverse events and serious infections compared to other biologic agents Forest plots: Serious adverse events and serious infections Serious adverse events Abatacept Adalimumab Anakinra Certolizumab Etanercept Golimumab Infliximab Rituximab Tocilizumab Overall P (drug)=0.099 Serious infections Abatacept Adalimumab Anakinra Certolizumab Etanercept Golimumab Infliximab Rituximab Tocilizumab Overall P (drug)=0.027 0.1 1.0 10.0 Favours biologic Odds ratio (95% CI) Favours placebo Singh JA, et al. Cochrane Database Syst Rev 2011:16;2:CD008794.

  6. Integrated safety summary Incidence rates of serious infections are stable over time across 8 abatacept clinical trials 7.0 6.0 5.0 4.0 Incidence rate (per 100 p–y) 3.0 2.0 1.0 0 0 1 2 3 4 5 6 7 Year 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. Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–5. Abstract 390.

  7. Integrated safety summary Continued use of abatacept does not increase the risk of malignancy over time NMSC=non-melanoma skin cancer; Data over a 7-year period; Data lock December2009. 12,132 p–y of exposure (N=4,149). Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–5. Abstract 390.

  8. Integrated safety summary Standardised incidence ratios of malignancies for abatacept patients are comparable with the general population Total(excluding non-melanoma skin) Breast Colon and rectal Lung Lymphoma 0.01 0.1 1 10 100 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. Simon TA, et al. Ann Rheum Dis 2009;68:1819–1826.

  9. Integrated safety summary Standardised incidence ratios of lung cancer for abatacept patients are not increased compared with non-biologic DMARD-treated RA population Abatacept RCT vs BC NDB GPRD NOAR Sweden ERA 0.1 1 10 Standardised incidence rations 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. Simon TA, et al. Ann Rheum Dis 2009;68:1819–1826.

  10. Integrated safety summary Standardised incidence ratios of lymphoma for abatacept patients are not increased compared with non-biologic DMARD-treated RA population Abatacept RCT vs BC NDB GPRD NOAR Sweden ERA 0.1 1 10 Standardised incidence rations 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. Simon TA, et al. Ann Rheum Dis 2009;68:1819–1826.

  11. REAL-LIFE DATA Summary of safety experience with abatacept in RABBIT and ORA registries in anti-TNF-IR patients †Number of solid malignancies (ITT population; 516 patient–years). No opportunistic infection reported in RABBIT or ORA 1. Strangfeld A, personal communication; 2. Gottenberg JE, Ann Rheum Dis 2011;70(Suppl3):466.

  12. LT- RCT Abatacept has a retention rate that is comparable with or higher than the anti-TNF agents *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). 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. Retention may be considered as a surrogate marker of long-term efficacy for biologic agents5

  13. Abatacept seems to have a favourable safety profile:Summary Rates of serious infections lower withabatacept vs other biologic agents1–3 No increases in incidence rates of malignancy3 with abatacept over time Retention rates seen in real-life study wereconsistent with clinical trial data4 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. Abatacept… 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 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.

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

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

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

  18. Integrated safety summary Abatacept integrated safety analysis: multiplelarge-scale trials of varying RA patient populations *Generally ended when abatacept became commercially available to the patient. 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.

  19. Integrated safety summary Differences in observed AEs in abatacept in clinical trial experience depending on treatment background Data from 7 clinical trials (December 2008 database lock). Smitten A, et al. Ann Rheum Dis 2010;69(Suppl3):541. Poster SAT0164.

  20. Integrated safety summary Deaths and serious adverse events are stable over time in the abatacept clinical trial experience Data from 8 clinical trials (December 2009 database lock); p–y=person-years; AE=adverse event; SAE=serious adverse event Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–5. Abstract 390.

  21. Integrated safety summary Continued use of abataceptdoes not increase risk of serious infection over time 2009 Database Lock Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–5. Abstract 390.

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

  23. ATTEST (MTX-IR) Safety events were low in abatacept-treated patients over 2 years 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. ATTEST (MTX-IR) 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.

  25. Integrated safety summary Continued use of abataceptdoes not increase risk of serious infection over time 2009 Database Lock. Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–165. Abstract 390.

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

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

  28. Tuberculosis exclusion criteria in abataceptclinical studies PPD=purified protein derivative. 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.

  29. Tuberculosis: Clinical trial experience December 2008 database lock. 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.

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

  31. Integrated safety summary Incidence rates of total malignancies (excluding NMSC) in the abatacept clinical trial experience 4.0 3.5 3.0 2.5 Incidence rate (per 100 p–y) 2.0 1.5 1.0 0.5 0 5 0 1 2 3 6 7 4 Year NMSC=non-melanoma skin cancer; Data lock December200912,132 p–y of exposure (n=4,149) Hochberg M, et al. Arthritis Rheum 2010;62(Suppl10):S164–5. Abstract 390.

  32. Incidence rates of malignancies are stable over time in the abatacept clinical trial experience December 2008 database lock. 1. Smitten A, et al. Arthritis Rheum 2008;59(Suppl9):S786. Poster 1675(397); 2. Data on file; 3. Orencia SmPC November 2011.

  33. 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.

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

  35. Integrated safety summary Incidence rates of autoimmune events are stable over time across 8 abatacept clinical trials *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). December 2009 database lock. 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.

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

  37. Integrated safety summary Incidence rates of acute infusion events reported in abatacept-treated patients decline over time 4149 pts; 12,132 p–y • 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] Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S142. Abstract 390.

  38. 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.

  39. Thank You

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