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Treat to Target, Role of Orencia in Achieving the target.

ELAR congress , Alexandria 2013. Treat to Target, Role of Orencia in Achieving the target. Prof. Hassan El-Shahaly Professor of Rheumatology and Rehabilitation Suez Canal University. Rheumatoid Arthritis Challenges. Complex, multifactorial pathogenesis

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Treat to Target, Role of Orencia in Achieving the target.

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  1. ELAR congress, Alexandria 2013 Treat to Target, Role of Orencia in Achieving the target. Prof. Hassan El-Shahaly Professor of Rheumatology and Rehabilitation Suez Canal University

  2. Rheumatoid Arthritis Challenges • Complex, multifactorial pathogenesis • Fluctuating clinical course; unpredictable prognosis • Characterized by: • Progressive joint destruction • Loss of physical function • Poor quality of life

  3. Classification Criteria For RA

  4. ACR /EULAR classification criteria for RA Rationale

  5. 3.0 2.4 2.5 2.3 2.0 Degree of Disability* after 5 Years 1.5 0.9 1.0 0.5 0.0 <6 months (n = 60) 6-12 months (n = 47) >12 months (n = 76) Early treatment reduces disability 5 years later * Odds ratio of HAQ ≥1 according to: Wiles NJ, et al. Arthritis Rheum 2001; 44: 1033 - 42

  6. ACR /EULAR classification criteria for RA Objectives Aletaha D, et al. Ann Rheum Dis 2010 ; 69:1580-8 ; ArthritisRheum 2010;62:2569-81

  7. 2009 ACR / EULAR for the classification & diagnosis of rheumatoïd arthritis ≥1 1 swollen joint Typical RA erosion on X-ray* Not best explained by another disease Yes RA New criteria for RA Fulfilled? yes No No RA RA: score ≥ 6 Aletaha D, et al. Ann Rheum Dis 2010 ; 69:1580-8 ; ArthritisRheum 2010;62:2569-81 * van der Heidje D et al Ann Rheum Dis 2013 Feb 7

  8. management

  9. Prevention / arrest of joint damage Prevention / reversal of disability Management of patients with RATherapeutic objectives Remission Sustained Remission Preventionof systemic co-morbidities: CV diseases, osteoporosis….

  10. EULAR RECOMMENDATIONS FOR THE MANAGEMENT OF RA WITH SYNTHETIC AND BIOLOGICAL DMARDs • RECOMMENDATION 1:Therapy with synthetic DMARDS should be started as soon as the diagnosis of RA is made • RECOMMENDATION 2:Treatment should be aimed at reaching a target of remission or low disease activityas soon aspossiblein every patient; as long as the target has not been reached, adjustment of the treatment should be done by frequent and strict monitoring. • RECOMMENDATION 3:Methotrexate should be part of the first treatment strategy in patients with active RA. Combe et al. Ann. Rheum. Dis. 2007; 66: 34-45 Smolen J. et al.Ann Rheum Dis 2010;-69:964-75

  11. Tight control using composite measures Pre- determined treatment targets Early referral Short & long -term goals Consider poor prognostic factors Remission or LDAS as soon as possible Starting biologic agents Treat to target Early institution of DMARDs Shared decision between doctor and patient Rheumatol-ogists are primary carers Maximising HRQOL for the long-term Turning recommendations into optimal treatment strategies

  12. Newer RA Treatment Strategies

  13. Aggressive Strategies • Monotherapy with frequent switches • Sawtooth (Fries) • Classical step-up (pyramid) • MTX+SSZ+HO-Chl (O’Dell) • MTX+Leflunomide • Others • Step-down • COBRA

  14. Combination Step-Down Therapy: COBRA Trial 1.6 Step-down (MTX + SSZ + Pred) 1.2 SSZ alone Pooled Index 0.8 Prednisolone 60 mg/day 0.4 Step-down therapy Prednisolone 7.5 mg/day MTX 7.5 mg/week SSZ SSZ 2000 mg/day 0.0 0 16 28 Weeks Boers M et al. Lancet. 1997;350:309-318.

  15. Tight control and predefined strategy • Systematicliteraturereview: from 1995 to 2008 •  Meta-analysisof 6 studies Tight controlwithout predefined protocol Van Tuyl, 2008 Fransen, 2003 Tight controlwith predefined protocol Fransen, 2005 Tight controlwithout predefined protocol 0,25 (IC95 : 0,03-0,46) Grigor, 2002 Goekoop, 2009 Verstappen, 2007 Tight controlwith predefined protocol 0,97 (IC95 : 0,64-1,3) -0,4 -0,2 0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 Mean difference in DAS28 change Randomised effect model Schipper LG et al Rheumatology 2010;49:2154-64

  16. Traditional DMARDs Are Effective but Do Not Maintain Long-term Response Retention Rates of DMARDs 100 90 80 70 60 50 40 30 20 10 0 Legend: Methotrexate Sulfasalazine Chloroquine Parenteral Gold Oral Gold Penicillamine Azathioprine Cyclosporine Combination Cumulative Retention Rates 0 12 24 36 48 60 72 84 96 108 120 Time (Months)

  17. EULAR RECOMMENDATIONS Taking steps to improve clinical outcome Main long-term target Main target Adapt therapy if state is lost Adapt therapy according to disease activity Active RA Remission Sustained remission Use a composite measure of disease activity every 1–3 months Assess disease activity about every 3–4 months Sustained low disease activity Low disease activity Adapt therapy if state is lost Adapt therapy according to disease activity Alternative long-term target Alternative target Smolen J, et al. Ann Rheum Dis 2010;69:631–637.

  18. Phase I of EULAR RA Management Algorithm *The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity Smolen JS, et al. Ann Rheum Dis 2010;69:964–75

  19. Phase II of EULAR RA Management Algorithm *The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity Smolen JS, et al. Ann Rheum Dis 2010;69:964–75

  20. Phase III of EULAR RA Management Algorithm *The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity Smolen JS, et al. Ann Rheum Dis 2010;69:964–75

  21. Different Biologics for RA Tracey D, et al. Pharmacology & Therapeutics 117 (2008) 244–279.

  22. APC Upstream T-cell Modulationwith ORENCIA® (abatacept) Down-regulation of T cell APC APC MHC CTLA-4 T-cell receptor CD28 CD28 ORENCIA T cell T cell CTLA-4 binding: down-regulation of T cell ORENCIA inhibits T-cell activation by binding to CD80 and CD86. The relationship of these biologic response markers to the mechanisms by which ORENCIA exerts its effects in rheumatoid arthritis (RA) is unknown. Adapted from Kremer JM. J Clin Rheumatol. 2005;11:S55–S62.

  23. Forest plot of risk ratios for clinical remission Efficacy of initial MTX vs MTX + biological agent in Early RA • RR 1.74; 95% CI (1.54, 1.98) • no heterogeneity I2 0%; p = 0.496 Kuriya B et al. Ann Rheum Dis online first april 26, 2010

  24. Forest plot of risk ratios for radiographic remission Efficacy of initial MTX vs MTX + biological agent in Early RA • RR 1.30; 95% CI (1.01, 1.68) • Significant heterogeneity I2 0%; p = 0.001 Kuriya B et al. Ann Rheum Dis online first april 26, 2010

  25. Clinical Trials for Abatacept

  26. AGREE (MTX-naïve) AGREE study design: patients with early RA and poor prognostic factors* Double-blind period1 Open-label period2 • Inclusion criteria • Early RA (≤2 years) • MTX-naïve • RF+ and/or anti-CCP2+ • ≥1 erosion 232 Abatacept + MTX** (n=256) 433 Abatacept + MTX Screening 227 Placebo + MTX** (n=253) Day 1 Year 1 Year 2 1:1 Randomisation • DAS28 (CRP) • X-Ray progression • HAQ-DI • Co-primary endpoints • DAS28 (CRP) <2.6 • Total Genant-modified Sharp score *Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients. **MTX initiated at 7.5 mg/week at study entry, then increased to 15 mg at Week 4 and up to 20 mg at Week 8 until study completion; Dose reduction to 15 mg/week was permitted due to toxicity or intolerability; AGREE=Abatacept study to Gauge Remission and joint damage progression in MTX naïve patients with Early Erosive RA; CCP2+=cyclic citrullinated peptide positive. 1. Westhovens R, et al. Ann Rheum Dis 2009;68:1870–1877; 2. Bathon J et al. Ann Rheum Dis. 2011;70:1949–1956.

  27. AGREE (MTX-naïve) Significantly greater proportion of abatacept-treated patients achieved DAS28 remission at Year 1* 100 Abatacept + MTX (n=256) 90 Placebo + MTX (n=253) 80 70 60 p<0.001 Proportion of patients achievingDAS28 remission (%) 50 40 41.4% 30 20 23.3% 10 0 *Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients. Data are based on an ITT population, with patients who discontinued considered non-responders. Westhovens R, et al. Ann Rheum Dis 2009;68:1870–1877.

  28. Early referral AGREE (MTX-naïve) Abatacept provides sustained efficacy through 2 years in patients with early RA (≤2 years)* Year 1 100 Abatacept added to MTX alone group 90 80 70 60 55.2% Proportion of patients achievingDAS28-CRP remission (%, 95% CI) 46.1% 50 44.5% 40 30 26.9% 20 10 0 729 617 553 449 365 309 253 197 141 85 29 0 Visit day Abatacept plus MTX (n=232) MTX alone (n=227) MTX alone switched to abatacept plus MTX (n=227) *Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients. Data are based on a modified ITT population, including patients who entered the open-label period and patients who discontinued considered non-responders. Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956.

  29. AGREE (MTX-naïve) Adding abatacept to MTX slows the rate of radiographic progression* 2.0 Abatacept added to MTX alone group 1.75 ∆=0.25 Yr1–2 1.48 Mean change from baseline in Sharp total score 1.0 0.84 0.65 ∆=0.18 Yr1–2 p<0.001 for ∆Yr 1–2 vs ∆ BL–Yr 1 Patients with X-rays at all timepoints (n=207) ∆=0.66 BL-Yr 1 0.0 Baseline Year 1 Year 2 Visit day Abatacept plus MTX MTX alone MTX alone switched to abatacept plus MTX *Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients. Data are as-observed for patients treated in the open-label period. Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956.

  30. AGREE (MTX-naïve) Abatacept leads to sustained HAQ normalisation (≤0.5) over 2 years in half of treated patients* 100 Abatacept + MTX (n=232) 90 MTX alone (n=227) 80 MTX alone switched to abatacept + MTX (n=227) 70 60 Proportion of patients achievingHAQ normalisation (%) 50 40 30 20 10 0 Year 1 Year 2 *Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients. Data are as-observed for all patients who entered the open-label extension. Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956.

  31. Efficacy and Safety of Abatacept or Infliximab Versus Placebo ATTEST TrialA Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled Trial on the efficacy and safety of abatacept or Infliximab versus placebo in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate

  32. Primary Objective ATTEST • To study the efficacy of Abatacept in reduction of disease activity in comparison to placebo as measured by disease activity score (DAS) 28 (ESR) at 6 months (day 197) • Determine ACR 20, 50, and ACR 70 response rates for subjects treated with placebo, abatacept, or infliximab at 6 months and 12 months the primary endpoint was not designed to be a head-to-head comparison between Abataceptand infliximab. Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

  33. Abatacept + MTX and infliximab + MTX ACR20 response rates are similar at Month 3 80 ACR 20 70 Abatacept 60 ACR 20 Infliximab 50 ACR 50 ACR response rate (%) Abatacept 40 ACR 50 30 Infliximab 20 ACR 70 Abatacept 10 ACR 70 Infliximab 0 1 29 57 85 113 141 169 197 225 253 281 309 337 365 Visit day ATTEST • The onset of action of infliximab was generally more rapid than abatacept however, by day 85, ACR 20 responses are similar 34 Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

  34. 80 ACR 20 70 Abatacept 60 ACR 20 Infliximab 50 ACR 50 ACR response rate (%) Abatacept 40 ACR 50 30 Infliximab 20 ACR 70 Abatacept 10 ACR 70 Infliximab 0 1 29 57 85 113 141 169 197 225 253 281 309 337 365 Visit day ATTEST Further improvement from Month 6 to 12 was observed with abatacept + MTX in ACR 20 response ATTEST • The onset of action of infliximab was generally more rapid than abatacept up to Day 85 • By Day 365, ACR 20 responses were higher with abatacept than with infliximab (ACR 20: 72.4 vs 55.8%, difference of 16.7 [95% CI: 5.5, 27.8]) Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

  35. ACR Responses at 6 Months ATTEST ITT population; D/C =Non responders *p<0.001; †p<0.05 and ‡p<0.01; Χ square test; p-values represent active drug versus placebo The study was conducted in RA patients with inadequate response to MTX and was not designed to demonstrate non-inferiority or superiority of ORENCIA vsinfliximab Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

  36. ACR responsesat 12 months ATTEST ITT population; D/c =Non responders The study was conducted in RA patients with inadequate response to MTX and was not designed to demonstrate non-inferiority or superiority of ORENCIA vsinfliximab Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

  37. Abatacept+MTX Infliximab 3mg/kg + MTX to abatacept Abatacept+MTX Delivered Sustained Improvements in ACR Responses Over 2 Years ATTEST-LTE Infliximab patients switched to abatacept Open label LTE period DB period 89% (83,94)* 87% (80,93)* 84% (78,91)* ACR Responders (%) 71% (63,79)* 69% (61,77)* 61 (52,70)* 55% (46,64)* 45% (36,54)* 43 (35,52)* 41% (32,50)* 31% (23,39)* 24% (16,31)* Visit (month) Data are for patients who entered the open-label period, and had data available at the considered time point (as-observed analysis) Treatment groups represent treatment received during the double-blind period *95% confidence intervals Schiff M and Bessette L Clin Rheum 2010 ; 29: 583-519 9

  38. ABATACEPTShort & long -term Efficacy

  39. Placebo-adjusted analysis, based on ACR50 responses Mixed populations included: MTX-IR DMARD-IR Anti-TNF-IR All biologic agents showed significantly greater efficacy compared with placebo, except anakinra COCHRANE META-ANALYSIS Abatacept provides similar short-term efficacy at 6 months compared with other biologic agents Abatacept Adalimumab Anakinra Etanercept Infliximab Rituximab 0.1 1.0 10 Favours Placebo Favours Biologic GLIMMIX: Odds Ratio (95% CI) Studies included only approved dosages. Singh JA, et al. Cochrane Database Syst Rev 2009;4:CD007848.

  40. Abatacept short-term efficacy is similar to other biologic agents in real life 80 60 Cumulative incidence of time to RAPID≥3.6 response* (%) 40 20 Abatacept Adalimumab Etanercept 0 Infliximab Month 0 0 1 6 2 12 3 18 4 24 5 6 30 • *Adjusted for age and duration of disease. • Prospective patient data from the Arthritis Registry Monitoring Database in patients receiving abatacept (n=114), etanercept (n=148), infliximab (n=38) and adalimumab (n=85). • 3,574 encounters were reviewed for this analysis. A total of 385 treatment courses were determined. 272 of the 385 courses represent the only biologic medication used by an individual; 40 individuals used two biologic medications at different times, while 11 had used three biologics. YaziciY, et al. Arthritis Rheum 2011; 63(Suppl 10):S873. Abstract 2233.

  41. Abatacept leads to reductions in synovitis and structural damage by Month 4 – MRI data Synovitis Osteitis Erosion 3.0 2.0 1.5 1.0 1.0 0.5 0.4 Adjusted mean change (95% confidence interval) 0.0 -0.3 -1.0 -2.0 -1.9 -3.0 Abatacept + MTX (n=25) Placebo + MTX (n=23) MRI (OMERACT RAMRIS) scores from baseline to Month 4 in MTX-IR patients treated with abatacept + MTX or placebo: synovitis of the wrist; osteitis and erosion scores of wrist and hand. Conaghan P, et al. Ann Rheum Dis 2011;70(Suppl 3):151

  42. Improvements with abatacept seen via sonographic monitoring • M.E. 51 year old man with RA • Disease duration: 3 years • Rheumatoid factor: positive • Anti-CCP Ab: positive • DAS28: 6.9 • Finger pain: VAS 6 • 16 months later: • DAS28: 2.4 • Finger pain: VAS 0 16 Months Conclusion: Excellent responder Personal communication, Walter Grassi.

  43. Long term goal achievementby abatacept

  44. An increasing proportion of abatacept patients show sustained LDAS or DAS28 remission over 7 years Double-blindphase Open-label LTE phase 100 Response (95% CI) 90 80 LDAS 69.7% (54.0, 85.4) n/N=23/33 48.2% (37.4, 58.9) n/N=40/83 70 60 Responders (%) Remission 50 51.5% (34.5, 68.6)n/N=17/33 40 30 25.3% (15.9, 34.7)n/N=21/83 20 10 0 0.5 1 2 3 4 5 6 7 0 Year DAS28 CRP-defined remission = DAS28 <2.6; LDAS=DAS28 (CRP) ≤3.2. Data are based on all patients originally randomised to 10 mg/kg abatacept who entered the LTE, with data available at the visit of interest (as-observed analysis). Mean disease duration was 9.9 (10.1) years. Westhovens R, et al. Ann Rheum Dis 2009;68(Suppl3):577. Poster SAT0108.

  45. AIM (MTX-IR) Abatacept has demonstrated increasing reductions in rate of structural damage progression through Year 5 *0.29 *0.43 Year 1 *0.68 *0.26 Mean change from baseline inGenant-modified sharp scores (TS) *0.34 *0.74 *0.37 *0.41 *1.48 *0.80 *Mean change in TS from year to year. Data are for those patients who entered the open-label period, and had evaluable radiographs available at the appropriate time points. Treatment groups represent treatment received in the double-blind period. TS=Total Score Schiff M, et al. Rheumatology 2011;50:437–449; Orencia SmPC November 2011; Data on file;GenantHK, et al. Ann Rheum Dis 2008;67(Suppl 2):193.

  46. AIM (MTX-IR) Sustained improvement in physical function with abatacept over 5 years (HAQ-DI response) Double-blindphase Open-label LTE phase 100 90 80 74.2% (69.0, 79.4) Responders (%) 70 71.8% (67.2, 76.4) 60 50 40 30 20 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Year Data are based on all patients originally randomised to abatacept who entered the long-term extension, with data available at the visit of interest (as-observed analysis). HAQ-DI response ≥ 0.3. Schiff M and BessetteL. ClinRheum 2010;29:583–591.

  47. 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

  48. Abatacept: Safety Issues aSibilia J, Westhovens R. Safety of T-cell costimulation modulation with abatacept in patients with rheumatoid arthritis. Clin Exp Rheumatol 2007;25 (5Suppl46):S46-56. bSimon TA et al. Malignancies In RA Abatacept clinical development program. ARD 2008.

  49. RA Safety Population • Abatacept • Placebo Double-Blind, Controlled(Biologic Background) N = 1,955(204) N = 989(134) N = 2,339 Open-Label, Uncontrolled N = 2,688 Cumulative (Double-Blind and Open-Label) BLA/4M Q G

  50. Overview of Patients with Adverse EventsDouble-Blind, Controlled Study Periods Number (%) of Patients Abatacept N = 1955 PlaceboN = 989 AEs SAEs Discontinuation due to AEs Deaths 1736 (88.8) 266 (13.6) 107 (5.5) 10 (0.5) 840 (84.9) 122 (12.3) 39 (3.9) 6 (0.6)

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