EULAR 2011 updates

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  • {"38":"<number>\n","16":"CAMERA-II: Computer Assisted Management of Early Rheumatoid Arthritis-II. (Computer Assisted Management of Early Rheumatoid Arthritis-II: Does prednisone inhibit progression of joint damage if early RA is treated very intensively with DMARDs?)\n<number>\n","28":"Hx: History\nCXR: Chest X- Ray\nIGRA: Interferon Gamma Release Assays. Interferon-Gamma Release Assays (IGRAs) are whole-blood tests that can aid in diagnosingMycobacterium tuberculosis infection, including both latent tuberculosis infection (LTBI) and tuberculosis (TB) disease. Two of the four IGRAs that have been approved by the U.S. Food and Drug Administration (FDA) are commercially available in the U.S. They are:\nQuantiFERON®-TB Gold In-Tube test (QFT-GIT); T-SPOT®.TB test (T-Spot)\nTST: Tuberculosis Skin Testing\nQuantiferon: The QuantiFERON®-TB Gold In-Tube (QFT-G) is a blood test for use as an aid in diagnosing Mycobacterium tuberculosis infection (both latent tuberculosis infection and active tuberculosis disease).\n<number>\n","17":"BARFOT: Better Anti-Rheumatic FarmacOTherapy\n<number>\n","56":"ACT-STAR: An open-label, randomized study to evaluate the safety, tolerability and efficacy of Actemra (Tocilizumab - TCZ) monotherapy or TCZ in combination with non-biologic DMARD’s in patients with moderate to severe active Rheumatoid Arthritis who have had an inadequate response to current non-biologic or biologic (disease modifying antirheumatic drugs) DMARD’s\n<number>\n","23":"BSRBR: British Society for Rheumatology Biologics Register \n<number>\n","12":"T2T: Treat to Target\nOPTIMA: Optimizing Treatment in Rheumatoid Arthritis\nEOW: Every Other Week\nOL: Open Label\n<number>\n","57":"<number>\n","13":"LDA: Low Disease Activity\n<number>\n","30":"The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment\n<number>\n","8":"DREAM: Dutch Rheumatoid Arthritis Monitoring\n<number>\n","36":"TENDER : Tocilizumab in patients with systemic juvenile idiopathic arthritis (sJIA)\n<number>\n","25":"DANBIO: Dansk Reumatologisk Database (a nationwide registry of biological therapies in Denmark.)\n<number>\n","64":"JCPyV: JC Polyomavirus\n<number>\n","42":"BeSt: Behandel Strategieen;  The Dutch Behandel Strategieen (BeSt) study of treatment strategies for early rheumatoid arthritis (RA) shows that the best approach is to use intensive treatment right away. \n<number>\n","20":"Certolizumab Pegol for the Treatment of Patients With Active Rheumatoid Arthritis (REALISTIC): A Phase IIIb Multicenter Study With a 12-week Double-blind, Placebo-controlled, Randomized Period Followed by an Open-label, Extension Phase Evaluating Safety/Efficacy of Certolizumab Pegol Given to Patients With Active Rheumatoid Arthritis.\n<number>\n","9":"TSS: Total Sharp Score\nBRASS: Brigham and Women's Rheumatoid Arthritis Sequential Study \n<number>\n","26":"DREAM: Dutch Rheumatoid Arthritis Monitoring\nThe GISEA (Gruppo Italiano Studio Early Arthritis) Study: Indirect Cost of Rheumatoid Arthritis Before and After Successful Initiation of Treatment With Biological Anti-TNFα Drugs\n<number>\n","15":"The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.\n<number>\n","4":"• NOR-VEAC: Norwegian Very Early Arthritis Clinic\n<number>\n","43":"The GISEA (Gruppo Italiano Studio Early Arthritis) Study: Indirect Cost of Rheumatoid Arthritis Before and After Successful Initiation of Treatment With Biological Anti-TNFα Drugs\n<number>\n","32":"ACT-RAY: a phase IIIb, double-blind two-year study designed to evaluate the efficacy and safety of RoACTEMRA in combination with methotrexate (MTX) versus switching from MTX to RoACTEMRA monotherapy in people with rheumatoid arthritis who do not respond to MTX.\n<number>\n","21":"ARTIS : Antirheumatic Therapies In Sweden\n<number>\n"}
  • EULAR 2011 updates

    1. 1. EULAR 2011-RA updates By A.Arputha Selvaraj APMP IIM Calcutta BMS India
    2. 2. Agenda We will discuss updates from EULAR 2011 about: 1. Diagnosis of RA 2. RA remission 3. Early RA 4. Safety of medications in RA 5. Imaging in RA 6. Other updates in RA
    3. 3. Diagnosis BMS India
    4. 4. 2010 ACR/EULAR RA criteria in clinical practice: Prediction of clinical RA & distribution of patients with early UA • New ACR/EULAR criteria → predicts risk of RA (early) - Tree format or scoring system → ≥ 6 points = RA • NOR-VEAC: (SJC ≥1 with ≤16 weeks duration, 18-75 ys) • 128/343 definite RA by both versions new criteria • 82/83 (98.8%) >10 joints = RA vs 3/111 (2.7%) 2-10 joints • 57/60 (95%) ↑ ACPA and/or RF = RA • Sensitivity 85.9%; specificity 80.5%; LR+ 4.4, LR- 0.18; area under the ROC curve (95% CI) was 0.92 (0.89-0.95) Criteria performed well in predicting clinical RA, particularly in seropositive patients Mjaavatten MD, et al. EULAR 2011, London, #SAT0373 BMS India
    5. 5. Comparison of 1987 & 2010 classification criteria for RA in patients with early arthritis • • • • • 253 pts with ≥1 swollen joint for ≥4 wks; symptoms < 1 y RF+ 34.4% pts CCP+ 28.6% pts Gold std: pts Dx after 2 ys f/u Estimate sensitivity, specificity, PPV, NPV, LR+ & LR- • RA diagnosis 108 pts (42.7%) with 2010 criteria • 114 pts (45.1%) with 1987 criteria 2010 1987 Sens. (%) 80 86 Spec. (%) 81.7 81.7 PPV (%) 74.1 75.4 NPV (%) 86.2 89.9 LR+ 4.37 4.7 LR- 0.245 0.171 LR = likelihood ratio No relevant differences in RA diagnosis using 1987 or 2010 criteria Fernandez-Ortiz AM, et al. EULAR 2011, London, #SAT0396 BMS India
    6. 6. Remission BMS India
    7. 7. CATCH: Remission prevalence in early RA new criteria vs other criteria RF+/ CCP+ (n) Bio % Mean CRP (mg/dL) 100 80 DAS28<2.8 56/62 7 0.33 60 DAS28<2.0 55/61 7 0.26 40 SDAI<3.3 59/64 9 0.32 CDAI<2.8 58/64 10 0.38 ACR/EULAR 54/65 8 0.27 % remission at 12 months 53 36 27 20 25 22 0 • ACR/EULAR criteria agrees with SDAI (k=0.75) & CDAI (k=0.73) • Fair agreement with DAS28<2.6 (k=0.32) & DAS28<2.0 (k=0.35) All remission is not the same1,2 1. Kuriya B, et al. EULAR 2011, London, #SAT0405; 2. Bernard M, et al. Ibid, #OP0027 BMS India
    8. 8. Utility of 2011 ACR/EULAR 2011 remission criteria • US VA and community practice cohort study1 - 1,341 VA patients / 9,700 visits (91% men) – 1,168 community practice patients / 6,362 visits (28% men) – Remission (US VA / community practice): • Cross-sectional: 8.9% / 8.3% • Cumulative: 24.4% / 19.0% over mean of 2.2 ys • 1.9 - 4.6% patients met remission at ≥2 visits • Among all patients, <3% had remission lasting 2 ys • Non-inclusion of feet may overestimate remission3 • Patients in ACR/EULAR remission have function capacity = to normal 4 Remission is uncommon in the clinic, especially long term 1. Michaud K, et al. EULAR 2011, London, #FRI0333; 2. Vermeer M, et al. Ibid, #OP0311; 3. Bakker MF, et al. Ibid, #SAT0376; 4. Listing J, et al. Ibid, #THU0351 BMS India
    9. 9. BRASS: Radiological progression in remission by new ACR/EULAR criteria vs other criteria DAS BL rem. TSS mean ann. change % w/ prog. LR+ good outcome DAS28(CRP)<2.6 106 0.93 (median 0) 30% 1.5 SDAI<3.3 37 0.65 (median 0) 24% 2.1 CDAI<2.8 26 0.37 (median 0) 19% 2.8 ACR/EULAR≤1 30 1.08 (median 0) 20% 2.6 ΔTSS in pts assessed to be in remission by DAS28, CDAI, ACR/EULAR 15 DAS28 2.6 10 CDAI 5 ACR/EULAR 0 0 10 20 30 40 50 % patients 60 70 80 New ACR/EULAR criteria performed similarly to established criteria Lillegraven S, et al. EULAR 2011, London, #SAT0398 90 100 BMS India
    10. 10. Power Doppler ultrasound is useful in determining true remission • 109 RA pts on TNFi in DAS28 remission for 6 months • 49.5% PDUS- / 50.4% PDUS+ • No PD signal, no radiological progression • 29.1% with PD signal had radiological progression Image courtesy of AF Wells, MD, PhD • Absence of PD signal guarantees arrest of radiologic progression, whereas pts with PD signal are at risk for progression despite treatment with TNFi • This risk increases with higher PD grades PDUS may be useful in evaluating pts considered to be in remission Raffeiner B, et al. EULAR 2011, London, #OP0029 BMS India
    11. 11. Early RA BMS India
    12. 12. T2T strategies in early RA: OPTIMA Study design • MTX-naive pts ≥18 ys with RA <1 y & active disease (DAS28>3.2, ESR ≥28 mm/h or CRP ≥1.5 mg/dL), and either >1 erosions, RF+ or anti-CCP+ n=207 n=466** ADA 40 mg EOW+MTX * n=460** MTX* 0w PERIOD 1 Yes DAS28 <3.2 No n=259 n=112 Yes DAS28 <3.2 No n=348 26 w MTX n=102 ADA 40 mg EOW+MTX n=105 OL ADA 40 mg EOW+MTX MTX OL ADA 40 mg EOW+MTX PERIOD 2 * MTX titrated to 20 mg/wk by Wk 8; ** Completed study period Smolen J, et al. EULAR 2011, London, #THU0243 ARM 1 ADA+MTX / MTX ARM 2 Sustained ADA+MTX ARM 3 ADA+MTX IR/ADA+MTX Primary efficacy outcome† ARM 4 Sustained MTX † DAS28 <3.2 ARM 5 MTX IR/ADA+MTX at Week 78 and mTSS <0.5 78 w BMS India
    13. 13. OPTIMA: ADA+MTX / MTX vs sustained ADA+MTX ADA+MTX / MTX (n=88) 100 Sustained ADA+MTX (n=94) ACR ACR20 Radiographic prog: % pts 100 ACR50 ACR70 80 80 89.0 88.0 89.0 85.0 89.0 60 81.0 40 60 20 40 26 30 34 38 42 46 50 54 58 62 66 70 74 78 Weeks 0 26 52 78 Weeks For many early RA patients in LDA on TNFi/MTX, TNFi can be withdrawn for a year; some patients may need continued treatment Smolen J, et al. EULAR 2011, London, #THU0243 BMS India
    14. 14. OPTIMA: Sustained ADA+MTX vs sustained MTX at Week 78 Sustained ADA+MTX (n=94) 100 80 Sustained MTX (n=98) * * X-ray progression 100 * 60 89 88 89 75 82 82 78 52 78 40 50 20 25 0 LDAS + mTSS 0.5 from BL ACR20 ACR50 ACR70 *P<0.05: ADA+MTX vs sustained MTX 0 26 • 44% Arm 2 v 24% Arm 1 achieved LDA during phase 1 Although both groups did well in LDA; patients on TNFi/ MTX did slightly better than those on MTX alone N Smolen J, et al. EULAR 2011, Lon don, #THU0243 BMS India
    15. 15. Is there a window of opportunity in early RA? • 8 year f/u of PREMIER: DBPCRCT of ADA, MTX, ADA + MTX early RA (<3 ys) 1 • After 2 ys all pts were on ADA; MTX could be added (30-35% did) 100 MTX (n=89) 80 60 ADA (n=92) MTX/ADA (n=89) 71.3 58.4 49.5 40 50.6 43.8 28.3 28.7 16.9 20 11.8 0 DAS28 <2.6 SDAI ≤ 3.3 DAS28<2.6 + HAQ ≤ 0.5 + ΔTSS ≤ 0.5 • Group 5 from OPTIMA (MTX/IR  MTX/ADA at 6 months): comparable response to MTX/ADA from the start2 Early aggressive therapy may achieve long-term benefit in early RA Breedveld F, et al. EULAR 2011, London, #THU0230 BMS India
    16. 16. Early addition of low-dose prednisone to tight control: CAMERA II • DB study, 236 early RA pts (<1 y) 80 • MTX + PBO vs MTX + Pred 10 mg QD 70 MTX+Pred M TX 60 - Pred continued for 2 ys - Evaluated once a month P=0.09 50 • ADA added for failure to reach target 40 • At 2 years: - Lower disease activity and disability in Pred group 30 - No ↑ DM, infections or fractures - Lower LFTs and ADA in Pred group P<0.001 20 10 0 % REM % on TNFi Low-dose prednisone at start of Tx leads to better control and no increase in toxicity Bakker MF, et al. EULAR 2011, London, #OP0138 % AE BMS India
    17. 17. Smokers have no “window of opportunity” Change in DAS28 over time • Data from BARFOT - 12 mo f/u in 1,587 early RA patients • Pts with early disease (<3 mos) show significant improvement, each month, when treated -0.05 Non smoker Current smoker -1.50 -2.50 • Smokers did not show this trend -3.50 2 - 12 months Smokers are less likely to respond to early treatment of RA Söderlin M, et al. EULAR 2011, London, #SAT0372 2 - 12 months BMS India
    18. 18. Stopping TNFi in RA • Japanese study: stop ADA if DAS28≤2.6 x 6 mos1 - Mean RA duration 8 ys - Stable MTX (mean dose 12.5 mg) - ADA for ≥1 y • 40/163 pts stopped ADA: data on 27 pts at 24 weeks - 16/27 in DAS remission; mean DAS28 = 1.8 at entry - 3/27 LDAS - 8/27 flared; mean DAS28 = 2.2 at entry • 90% of DAS28≤1.9 did not flare at 6 months TNFi may be stopped in patients who attain DAS remission for 6 months; especially with very low DAS28 Tanaka Y, et al. EULAR 2011, London, #OP0154 BMS India
    19. 19. Treat-to-Target in routine clinical care • 2 studies using DAS28 remission as target in “standard therapy” • No preset order of med use • DAS28 remission in 26.5%1 & 32%2 • ACR/EULAR remission in only 8.6%1 - Is ACR/EULAR remission too strict? • Use of most recent ESR/CRP (up to 3 mos from visit) does not effect validity of DAS283 Baseline Year 3 DAS28 median 4.0 3.1* Remission % 22.8 32* LDAS only % 12.5 19.6* 35.3 51.6* 1.35 1.25 LDAS + remission % HAQ median *P<0.001 Treating to a target feasible in routine clinical care using currently available therapies; results in high rates of remission and LDAS 1. Favarato MH, et al. EULAR 2011, London, #SAT0374; 2. Gullick NJ, et al. Ibid, #SAT0209; 3. Brode S, et al. Ibid, #SAT0202 BMS India
    20. 20. REALISTIC study: CZP in DMARD-IR and TNFi-IR RA pts • 1,063 pts, 37.6% with TNFi exposure; 20.3% received CZP as monotherapy 100 80 60 40 CZP (n=320) Control (n=80) P<0.001 P<0.01 53.5 47.2 27.5 51.9 47.6 25 20.8 20 27.8 52.3 25 53.5 25 46.7 48.3 30.6 12.5 0 Prior TNFi No prior TNFi ACR20 0 1 ≥2 No. of concomitant DMARDS 0 1 2 No. of prior TNFi CZP shows efficacy after TNFi exposure and as monotherapy in RA Weinblatt ME, et al. EULAR 2011, London, #FRI0214 BMS BMS India India
    21. 21. No mortality differences between TNF inhibitors • ARTIS database (Sweden); N=6,322 2 1.5 • • Compared mortality between ADA, ETN and IFX 211 deaths (3.3%) 1 Ref 0.5 0 ETN (n=2,686) ADA (n=1,609) (n=2,027) No difference in mortality regardless of adjustments for co-factors or other modeling techniques Simard J, et al. EULAR 2011, London, #OP0158 IFX BMS India
    22. 22. Safety BMS India
    23. 23. Effect of treatment on mortality in RA ETN pts • BSRBR RA pts, DAS28>4.2 DMARD controls >5 y f/u; ETN vs DMARDs N (pt-ys) 3,470 (14,382) 1,365 (5,583) • ETN: higher disease activity / Mean f/u 4.1 ys 4.1 ys Age 55.4 ys 59.5 ys* RA duration 13.6 ys 9.6 ys* HAQ 2.1 1.7 Deaths 188 127 Deaths/1000 pt-ys 13.1 22.2 • severity, less comorbidity • Mortality: adj. HR 0.59 (0.44-0.78) 0.786 (0.57-1.08): depends on time censure modeling • Caveats: patients excluded if switched to other biologics *P<0.001 Mortality not elevated; may be lower with TNFi therapy in RA Emery P, et al. EULAR 2011, London, #LB0007 BMS India
    24. 24. CV risk in RA is independent of disease duration but varies with disease activity • EULAR identifies RA disease duration >10 ys as CV risk factor However: • 855 pts (6,388 pt-ys) → 90 1st CV events: MI, CVA, heart failure • CV risk ↓↓ only with DAS28 <2.9 over time vs other groups (P=0.04) • No difference in survival distribution between disease duration < or > 10 ys Cumulative survival for different DAS28 levels (< 10 ys disease duration) 1.0 0.9 0.8 Low (<2.9) Low-medium (<2.9-3.6) Medium-high 3.6-4.3) High (>4.3) 0.7 0.0 5.0 10.0 15.0 20.0 Time to event (years) RA duration does not aggravate CV risk over time; CV risk not ↑ after 10 ys of disease duration vs 1st 10 ys; CV risk ↓↓ lower only with DAS28 <2.9 Arts EEA, et al. EULAR 2011, London, #OP0161 25.0 BMS India
    25. 25. Cancer risk and RA treatments: Two studies 8 BSRBR - DMARD1 (n=3,727; 148 w/cancer) Lym 7 Lung 4 1 0 13,699 pts; 5,598 on TNFi • Cancer in 313 NHL • RR: 1.05 (CI 95% 0.82-1.34) vs DMARD • Melan 5 2 • ph 6 3 DANBIO - TNFi2 No increase in any CA Myelo - Including NMSC & non-Hodgkins All excl. NMSC - No effect of duration of Tx Solid reast Colorect B - Also true for PsA & “other” arthritis DMARD use is associated with 50% increase in all cancers 1. Mercer LK, et al. EULAR 2011, London, #FRI0338; 2. Dreyer L, et al. Ibid, #FRI0203 BMS India
    26. 26. SIE with TNFi in RA: DREAM and GISEA registries 10 9 8 7 DREAM registry1 (N=2,157, since 2003) 10 GISEA registry2 (N=2,769) 8 6 5 6 4 3 4 2 1 2 0 0 ETN ADA IFX • Adj HR: 1.02 ADA vs IFX; 0.59 vs mAb • IFX pts tended to have worse prognosis ETN IFX • Sig diff in SI risk in ADA, ETN & IFX pts (P<0.0001) TNFi is associated with small but significant risk of SI 1. van Dartel S, et al. EULAR 2011, London, #FRI0222; 2. Atzeni F, et al. Ibid, #THU0229 ADA BMS India
    27. 27. Risk factors associated with GI perforation in RA patients Diverticulitis Diverticulosis w/o diverticulitis Other DMARDs w/ glucocorticoids Glucocorticoids w/o any DMARD MTX w/ glucocorticoids Biologics w/ glucocorticoids Biologics w/o glucocorticoids Other DMARDs w/o glucocorticoids No DMARDs or glucocorticoid NSAID Baseline CCI Age 65+ Age 40-64 Female Urban CCI = Charlson Comorbidity index 0 RR of GI perforation during f/u (adjusted results) HR (95% CI) 1 2 3 4 11 13 15 GI perforation is rare and increases with age, steroids, and especially history of diverticulitis; NSAIDs impose a minor risk Curtis J, et al. EULAR 2011, London, #OP0159 17 19 BMS India
    28. 28. Quantiferon (QTF) vs TST performance in TNFi-treated patients • 150 AS/RA pts screened by Hx, CXR, IGRA, TST • TST more frequently positive than QFT • Clinical suspicion of LTBI in 21 patients (based on LTBI risk factors) TST+ 45% 56% QFT+ 9.3% • 14 (9.3%) QTF+ & 67 (45%) TST+ - 56% agreement: TST + QTF (k=0.1; P=0.01) • 17% had indeterminate results - Assoc. w/ elderly, DMARD, pred. use - Results turn negative after TNFi • 6 QFT+ pts Tx for LTBI (INH/RIF x3 mo) - F/u QFT was negative in 4 pts Assoc. w/ LTBI risk factors 21% (RR=2.5) QFT+ more strongly associated with LTBI risk factors Indeterminates may convert to negative with 6 mos of TNFi Cabantous L, et al. EULAR 2011, London, #THU0249 50% (RR=4.8) BMS India
    29. 29. Imaging BMS India
    30. 30. Which comes first: JSN vs JE? PREMIER, MTX-naive, early RA 3 • 2 226/17,644 (1.3%) evaluable joints lacked JSN at Wk 26 but had JSN progression by Wk 52 - 49 (21.7%) JE-/SJ– 44 (19.5%) JE-/SJ+ 1 – 66 (29.2%) JE+/SJ– 67 (29.6%) JE+/SJ+ 0 JE @Wk26 All Swelling Wks 26-52 MTX vs ADA MTX vs ADA+MTX • Both JE & swelling assoc. with the onset of JSN at Week 52 Erosions contribute to JSN: JSN is the main driver of functional disability Landewe R, et al. EULAR 2011, London, #FRI0209; Aletaha D, et al. Ann Rheum Dis. 2011;70:733-9; Landewe R, et al. Ann Rheum Dis. 2011;70:717-8 BMS India
    31. 31. Do NSAIDs affect US activity in RA patients? N=58 Stopped NSAID Continued NSAID P-value SJC +1.5 -1.0 <0.001 TJC +2.5 0 <0.001 GSUS +9.5 +1.0 <0.001 PDUS +4 0 <0.001 GSUS score >0 4 joints 1 joint <0.001 PDUS score >0 2 joints 0 joints 0.005 NSAIDs may decrease both GSUS and PDUS signal resulting in lower scores despite ongoing disease activity; consideration should be given to NSAID effect in designing US clinical studies Zayat AS, et al. EULAR 2011, London, #OP0242 BMS India
    32. 32. Early reductions in synovitis & osteitis with TCZ are maintained through Week 52: ACT-RAY MRI substudy • RA pts (n=63) on stable MTX randomized to MTX or PBO + TCZ 8 mg/kg IV every 4 weeks • Decreases in synovitis & Synovitis Osteitis 20 15 osteitis at Week 12 sustained at Week 52 erosions over 52 weeks 5 • No patients developed new *P<0.05 vs BL 10 • No significant change in mean Erosions 0 regions of synovitis * * BL Week 12 Early reduction of synovitis & osteitis by MRI with TCZ maintained through 1 year Troum O, et al. EULAR 2011, London, #SAT0282 * * Week 52 BMS India
    33. 33. Xiralite vs ultrasound and MRI • Fluorescence optical imaging (IV indocyanine green) to assess inflammation of the hand • Information collected at various phases post-injection • Early-phase imaging showed good agreement with clinical exam, PDUS, MRI, and less with GSUS • 92% (53/57) swollen joints and 94% (63/67) joints with MRI synovitis showed positive findings • Limitations: thick skin, palmar tenosynovitis Comparison Method Sensitivity Specificity Clinical exam 58% 90% Xiralite P1 34% 95% Xiralite P2 83% 69% Xiralite P3 60% 92% Fluorescence optical imaging with Xiralite system sensitive in detecting early inflammation Werner, et al. EULAR 2011, London, #FRI0048; Werner, et al. Ibid, #SAT0101 BMS India
    34. 34. JIA BMS India
    35. 35. Switching in JIA • • In SoJIA (German JIA Registry, N=1,345), switching to 2nd TNFi or ABA was unsuccessful1 In PolyJIA switching to a 2nd TNFi gave favorable results1 20 Systemic JIA: Last response 0 response PedACR30 PedACR50 PedACR70 15 10 5 0 ETN n=26 • In some PolyJIA pts, switching to CZP may also be effective2 Switching from one biologic to another may be effective, but SoJIA patients respond differently than PolyJIA patients 1. Horneff G, et al. EULAR 2011, London, #FRI0176; 2. Tzaribachev N, et al. Ibid, #FRI0194 40 IFX ADA ANA TCZ ABA n=1 n=4 n=21 n=2 n=2 Poly JIA: Last response 30 20 10 0 ETN IFX ADA ANA TCZ ABA n=57 n=10 n=43 n=4 n=4 n=5 BMS India
    36. 36. TENDER: TCZ effective in persistent SoJIA • 12 wk DBPCRT followed by OL Tx • TCZ 8 (>30 kg) or 12 (<30 kg) mg/kg ACR30+no fever 100 • All patients received OL TCZ 8 or 12 mg/kg in part 2 Week 52 60 • Week 12 response maintained at Week 52; 52% pts able to D/C steroids Week 12 ACR90 80 • Primary outcome: ACR JIA 30 + no fever ACR70 40 • Safety: 15 SIEs; 1 infusion reaction; 2 grade IV neutropenias; 3 deaths (1 MVA; 1 pneumothorax; 1 unknown) 20 0 Control (n=37) One year of TCZ is highly effective and generally well tolerated in patients with SoJIA De Benedetti F, et al. EULAR 2011, London, #OP0006 TCZ (n=75) TCZ (n=88) BMS India
    37. 37. Miscellaneous BMS India
    38. 38. Work outcomes • GLM+MTX vs MTX ↑ employability % patients unemployable at BL and 40 employable at Week 241 33* by 0.96 ys (female)/0.87 ys (males)1 • RA imposes a burden similar to DM justifying cost of treatment2 30 *P<0.05 - Incremental cost (RA vs DM ) • $5,212 vs $3,698 vs $4,014 – Incremental days absent • 3.58 vs 2.73 vs 6.42 • Young patients more likely to consider themselves a burden3 20 15 10 0 Placebo + MTX Combined GLM + MTX RA imposes a significant burden to both employers and caregivers Treatment with TNFi + MTX can improve employability 1. Han C, et al. EULAR 2011, London, #THU0045; 2. Brook RA, et al. Ibid, #THU0031; 3. Bergman M, et al. Ibid, #FRI0241 BMS India
    39. 39. Alcohol intake and inflammatory polyarthritis (IP) in Norfolk Arthritis Register (NOAR) • 184 incident IP patients among 25,639 population 1.0 • 138 fulfilled 1987 RA criteria 0.8 • Smoking ↑ risk RA & IP 0.7 • EtOH 16% ↓ risk/unit consumed 1.3 ↓risk for every 1 unit/day consumed (hazard ratio) 0.6 0.5 IP RA Sero+ IP Fully adj. age, gender , smoking, BMI, diabetes, social class Fully adj. age, gender , smoking, BMI, diabetes, social class, parity & breastfeeding HR (95% CI) ↑ risk IP in smokers ↓ risk RA in smokers Alcohol intake ↓ risk of IP 1.70 (1.12-2.57) 1.68 (1.03-2.73) 0.84 (0.72-0.97) Alcohol consistently shown to decrease risk of IP and RA and negates effect of smoking Lahiri M, et al. EULAR 2011, London, #OP0025 BMS India
    40. 40. Sexual dysfunction in RA • 231 RA patients1 - 91 male/140 female • Among men - 49/91 (53.8%) reported ED • • • • • 18/49 mild 16/49 mild to moderate 13/49 moderate 2/49 severe Among women - 67/150 (44.6%) reported sexual dysfunction - Dyspareunia due to decrease lubrication most common complaint 1. El Miedany Y, et al. EULAR 2011, London, #SAT0232; 2. Sharma P et al. Ibid, #SAT0213 RA has a significant impact on my sex life2 100% 80% 60% 67% 65% 72% 40% 20% All Men Women 0% Sexual dysfunction is common in RA; strong association between sexual dysfunction and cardiovascular disease BMS India
    41. 41. Patient-reported outcome measures • • Japan1 & Finland2 - pts evaluated with RAPID3, CDAI and DAS28 Correlation:1 3 - RAPID3 vs DAS28 r=0.66 - RAPID 3 vs CDAI r=0.78 • • Standard change RAPID3 vs CDAI2 5 Remission agreement good between RAPID3, CDAI ACR/EULAR and DAS281 Any measure using 3 or 4 of ACR core data set will measure disease activity well3 4 2 1 0 -1 -2 -3 -4 -5 -5 -4 -3 -2 -1 0 1 2 3 4 Standard change of RAPID3 5 RAPID3 requires minimal input from physicians and can serve as a useful alternative to other measures in clinical practice 1. Seto Y, et al. EULAR 2011, London, #SAT0409; 2. Sokka T, et al. Ibid, #FRI0280; 3. Bergman M, et al. Ibid, #THU0300 BMS India
    42. 42. Utility of a biomarker test in RA • Multi-biomarker disease activity 0.9 (MBDA; sold as VECTRA™) test for RA • 0.8 126 pts from BeSt Predictors of X-ray progression Year 1 to 2 0.5 0.4 • Serum at BL and 1 y; correlated with ΔSHS (BL1, 2 ys) 0.7 0.6 0.3 0.2 0.1 0 Biomarker test results correlate with outcomes, including X-ray, as do other measures and markers Allaart C, et al. EULAR 2011, London, #THU0319 Weinblatt ME, et al. Ibid, #THU0339 BMS India
    43. 43. Anakinra as first-line biologic: Results from real-world Italian GISEA retrospective registry • RA patients starting biologics from 14 centers in Italy • 129 starting anakinra matched 1:4 with 515 starting ADA or ETN - Matched age, sex, disease activity, year of treatment (anakinra patients had increased disease duration, higher HAQ, higher PtG) • Results: remission at 12 months - Anakinra = 18.6%; TNFi = 26% - TNFi patients had significantly lower baseline disease duration, pain, global health and HAQ scores - Univariate analysis suggests that longer disease duration and higher HAQ score may account for difference in remission rates Anakinra remission rates somewhat lower than TNFi, but still remains proven biologic option in patients with active RA Sfriso P, et al. EULAR 2011, London, #SAT0283 BMS India
    44. 44. Periodontal disease (PD) and RA Severe PD occurs 10-15% RA pts • Dutch study:1 98 RA pts assessed with PD Screening and RA activity - 50% had PD (18% severe) – More RA smokers had PD (P=0.01); - PD assoc. w/ higher DAS28 & CRP P=0.047 6 • TJC 15 SJC CRP DAS28 10 5 4 0 w/ PD w/o PD BL 2 0 Brazilian study:2 18 pts had dental exams pre/post TNFi x 6 mo - Mostly IFX: 15 (83%) - Significant response to TNFi w/o change in PD status 6 mo BL 6 mo – PD+ (8/18): no improvement after 1-2 PD score 3-6 6 mos of TNFi treatment - PD- (10/18): respond best to TNFi PD prevalent in RA; TNFi treatment does not affect PD, but patients with PD may have blunted response to TNFi 1. De Smit M, et al. EULAR2011, London, #THU0289; 2. Savioli C, et al. Ibid, #SAT0138 BMS India
    45. 45. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in combination with traditional DMARDs (ORAL Sync) • 792 active RA: DMARD-IR (4:4:1:1) • PBO for 6 months (rescue at Mo 3) vs Tofa 5 or 10 mg BID • Multinational study: - 22% North America – 8.3% South America – 28.3% Europe (85% Eastern Europe) – 41.4% Rest of world (28% China) • Co-1° EP - ACR20 (NRI), Mo 6 - HAQ-DI ∆ from BL, Mo 3 - DAS28-4(ESR) <2.6, Mo 6 Kremer J, et al. EULAR 2011, London, #LB0005 BMS India
    46. 46. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in combination with traditional DMARDs (ORAL Sync) Tender joints (68), mean Swollen joints (66), mean HAQ-DI, mean DAS28-4(ESR), mean Prior DMARD use MTX, % Other traditional DMARDs, % TNFi, % Other Biologic DMARD use, % Disposition Patients completing, % D/C due to AE, % D/C due LOE, % 5 mg BID 10 mg BID PBO5 mg n=315 n=318 BID n=79 25.0 26.6 27.2 14.5 14.4 14.6 1.44 1.43 1.45 6.29 6.36 6.44 Kremer J, et al. EULAR 2011, London, #LB0005 PBO10 mg BID n=80 21.9 13.9 1.24 6.16 86.7 73.7 7.3 2.2 82.7 76.1 6.0 3.1 83.5 69.6 6.3 7.6 82.5 77.5 6.3 0.0 82.1 6.4 5.1 79.2 9.1 3.8 89.9 2.5 3.8 83.8 3.8 3.8 BMS India 78
    47. 47. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in combination with traditional DMARDs (ORAL Sync) ACR20 at Mo 6 70 PBO Tofa 5 mg Tofa 10 mg * 52.7 60 * 58.3 50 40 30 31.2 20 10 0 *P<0.0001 vs PBO Kremer J, et al. EULAR 2011, London, #LB0005 BMS India
    48. 48. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in combination with traditional DMARDs (ORAL Sync) HAQ-DI to Month 3 PBO Tofa 5 mg * 12 11.0 10 -0.21 8 -0.3 6 -0.4 -0.6 * 14.8 14 -0.1 -0.5 Tofa 10 mg 16 0 -0.2 DAS28<2.6 to Month 6 4 -0.46 2.7 2 * -0.56 * 0 *P<0.0001 vs PBO Kremer J, et al. EULAR 2011, London, #LB0005 BMS India
    49. 49. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in combination with traditional DMARDs (ORAL Sync) % Months 0-3 Months 3-6 Post Month 6 5 mg 10 mg 5 mg 10 mg PBO PBO 5 mg 10 mg PBO PBO BID BID PBO PBO BID BID 5 10 BID BID 5 10 n=315n=318n=159 n=81 n=315n=318 n=38 n=40 n=315n=318 n=79 n=80 SAE 2.9 2.5 3.8 0 1.6 2.2 0 0 2.2 2.8 2.5 0 SIE 0.6 1.2 0 0 0 0 0.3 0.3 1.0 2.5 0 0 D/C AE 4.1 4.1 1.3 1.2 1.9 2.5 0 2.5 0.3 2.8 0 1.3 Kremer J, et al. EULAR 2011, London, #LB0005 BMS India
    50. 50. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in combination with traditional DMARDs (ORAL Sync) PBO Month 3 Post Month 6 5 mg 10 mg PBO5 PBO10 5 mg 10 mg Change from baseline (LS Mean) ANC (103/mm3) -0.02 -0.75* -0.99* -0.72 -0.66 -0.79 -0.90 Hb (g/dL) -0.04 0.28 0.11 0.41 0.23 0.44 0.19 LDL (%) -0.61 15.65* 18.26* 7.72 12.85 16.24 19.93 Serum Cr (mg/dL) 0.02 0.03 0.06* 0.05 0.08 0.06 0.08 AST>1x ULN (%) 13.8 23.5 29.4 19.1 26.7 19.4 24.6 AST>3x ULN (%) <1.0 <1.0 <1.0 1.1 <1.0 0 1.4 ALT>1x ULN (%) 17.6 27.9 34.2 18.8 27.4 22.2 23.2 ALT>3x ULN (%) <1.0 1.9 <1.0 2.6 1.9 0 1.4 P<0.0001 vs PBO * Kremer J, et al. EULAR 2011, London, #LB0005 BMS India 82
    51. 51. Tofacitinib [Tofa] (oral JAK 3,1,2 inhibitor) in combination with traditional DMARDs (ORAL Sync) 4 deaths • • 81-year old man (US): Traumatic brain injury and intracranial hemorrhage following a fall 22 days after discontinuing 5 mg 37-year old man (China): Found dead on Day 174 of 10 mg - Cause of death: Acute heart failure due to valvular heart disease • 48-year old man (Russia): Hospitalized for worsening RA; discontinued 5 mg at Day 292; died 42 days later - Cause of death: Infection by DSMB • 58-year old man (US): Presented with DOE, CHF, anemia, renal insufficiency at Day 357 on 10 mg; developed progressive pulmonary infiltrates, respiratory failure and pulmonary hypertension resulting in death - Cause of death: Infection by DSMB 4 OIs: 1 disseminated H zoster; 1 cryptococcal pneumonia; 2 TB Tofacitinib effective in combination with DMARDs Overall safety still being evaluated Kremer J, et al. EULAR 2011, London, #LB0005 BMS India
    52. 52. Can you correct the lipid elevations caused by Tofa? OL Tofa with or without blinded atorvastatin (A) • Tofa 10 mg BID for 6 weeks, then randomized to A 10 mg QD vs PBO for 6 more weeks; 1° EP: % change in LDL-C Weeks 6-121 • Previous data suggests Tofa ↑LDL-C ≈ 25%2; A ↓LDL-C ≈ 26-37%3 Week 0 Week 6 Week 12 n=111 n=97 n=92 Total chol: A (n=50) 185.6 229.5 (24%↑) 170.0 (26.0%↓)** PBO (n=47) 202.0 244.4 (21%↑) 250.0 (2.3%↑) LDL-C: A (n=50) 109.1 126.0 (16%↑) 81.9 (35.3%↓)** PBO (n=47) 118.0 140.0 (19 %↑) 148.1 (5.8%↑) TGs: A (n=50) 99.5 109.0 (10%↑) 95.0 (14.7%↓)* PBO (n=47) 102.0 109.0 (7%↑) 115.0 (5.5%↑) HDL-C 50.5 66.6 (32%↑) ↑ no difference Apo A1 135.5 164.5 ( 21%↑) ↑ no difference Median LDL-C achieved in the ATP-III optimal target range (<100 mg/dL). Efficacy not diminished; similar safety 1. McInnes I, et al. EULAR 2011, London, #LB0003; 2. Kremer J, et al. Arth Rheum 2009;60(Supplement 10):1925; 3. Atorvastatin US approved package labeling, June 2009 *P<0.01; **P<0.0001 BMS BMS India India
    53. 53. Tofacitinib (Tofa): Phase III monotherapy (ORAL Solo)¹ ACR20 100 PBO (n=122) Tofa 5 mg (n=243) Tofa 10 mg (n=245) All P<0.05 or P<0.0001 versus placebo except Tofa 5 mg with prior biologic 80 60 40 20 0 • Pfizer press release on X-ray progression: 10 mg but not 5 mg Tofa effective2 • 21 patients in Korea (Phase IIb mono): Significantly less progression than on DMARD controls 3 Tofacitinib effective in multiple subgroups; DB X-ray data coming 1. Fleischmann R, et al. EULAR 2011, London, #SAT0243; 2. Pfizer Press Release April 15, 2011; 3. Choi IH, et al. EULAR 2011, London, #SAT0240 BMS India
    54. 54. ORAL Solo: SF-36 domain scores at Month 3 PF Age/Gender Norms Tofa 10 mg BID (n=224) Tofa 5 mg BID (n=223) PBO (n=108) Composite (Weighted balance) * MHI ** * RE 90 80 70 60 50 40 30 20 10 0 * RP * * BP *P<0.05 **P<0.01 ***P<0.001 *P<0.0001 vs BL GHP ** * SF * VIT Clinically meaningful improvements in ALL PROs Strand V, et al. EULAR 2011, London, #OP0063 * * * * * BMS India
    55. 55. Fostamatinib (Syk kinase inhibitor) and HRQOL: Phase II RCT • Pro-drug; currently in Phase III RCTs (OSKIRA trials) in RA1 • Phase II RCT: Syk vs PBO in MTX-IR RA at 6 mos2 - Pain (VAS); Patient global (VAS); HAQ-DI; SF-36, FACIT Patient Reported Outcomes PBO n=153 Mean ∆ from BL at Mo 6 SF-36 PCS SF-36 MCS FACIT-Fatigue 4.9 3.7 4.5 Fostamatinib n=304 150 mg QD 100 mg BID3 n=152 n=152 5.9 2.0 5.7 8.5** 4.0 7.4* *P<0.05; **P≤0.001 - Improvements at Week 1 in Pain and HAQ statistically significant in both Rx groups vs PBO; Patient global only in 100 mg BID; but not sustained Improvement in PROs at 6 months only in PCS and FACIT with 100 mg BID 1. Baluom M,et al. EULAR 2011, London, #SAT0247; 2. Weinblatt ME, et al. NEJM 2010;363:1303-12; 3. Weinblatt, ME et al. EULAR 2011, London, #OP0057 BMS India
    56. 56. Tocilizumab in the US (ACT-STAR) • • • • • 24-week OL study DMARD or DMARD + Bio IR at BL • TCZ 4 mg/kg + DMARD • TCZ 8 mg/kg + DMARD - Biologic-IR alone at BL • TCZ 8 mg/kg monotherapy 3 GI perforations: - 1 Crohn's, 2 diverticulitis (subsequently diagnosed) 21% on statins at BL, 11% added statins during the study 42% TCZ 4 mg/kg + DMARD maintained to Month 6 % Patients SAE SAE → D/C Deaths (n) SIE PMNs (Gr 3) ALT: 1.5-3x ULN >3x ULN LDL-C ≥130 (<130 at BL) TCZ 4/8 TCZ 8 TCZ 8 +DMARD +DMARD n=364 n=381 n=138 8.0 3.0 2 3.6 0.8 7.9 8.4 1.0 0 3.9 2.4 13.2 5.8 2.2 0 2.9 5.1 6.1 2.1 1.4 1.5 16.8 17.7 11.7 No difference in SAE, SIE or efficacy between COMBO & MONO TCZ Is 4 mg/kg really safer than 8 mg/kg? Weinblatt ME, et al. EULAR 2011, London, #LB0006 BMS India
    57. 57. ACT-STAR: Patient Disposition Patients enrolled (N=886) Randomized to TCZ 4 mg/kg* + DMARD n=363** Randomized to TCZ 8 mg/kg + DMARD n=360 Assigned to TCZ 8 mg/kg monotherapy n=163 Switched to TCZ 8 at Week 8 n=142 (39.2%) Completed study n=302 Completed study n=126 Switched to TCZ 8 after Week 8 n=68 (18.8%) Withdrew n=58 Withdrew n=37 Only exposed to TCZ 4 n=152 (42.0%) Safety n=17 Safety n=11 Completed study, n=303 Withdrew, n=60 (35 safety / 25 non-safety) Non-safety n=41 Non-safety n=26 *Patients randomized to TCZ 4 + DMARD may have withdrawn prior to Week 8 while still receiving TCZ 4, or after Week 8 while receiving TCZ 4 or TCZ 8; **1 patient randomized did not receive drug Weinblatt ME, et al. EULAR 2011, London, #LB0006 BMS India
    58. 58. Tocilizumab: Long-term safety in RCT • LTE; 4,009 pts (median treatment duration 3.6 ys); 12,293 pt-ys (to 02/2010) • Most patients on 8 mg/kg q month Event rate/100 pt-ys (95% CI) over 12-month periods SAE SIE CVA MI 0-12 15.7 (14.4, 17.1) 4.6 (3.9, 5.4) 0.3 (0.1, 0.5) 0.3 (0.1, 0.5) 13-24 13.9 (12.6, 15.2) 3.9 (3.2, 4.7) 0.1 (0.0, 0.3) 0.2 (0.1, 0.4) 25-36 15.2 (13.7, 16.7) 5.2 (4.3, 6.1) 0.2 (0.1, 0.4) 0.3 (0.1, 0.6) 37-48 14.4 (12.8, 16.0) 4.9 (4.0, 5.9) 0.1 (0.0, 0.3) 0.5 (0.3, 0.9) Overall 14.7 (14.0,15.4) 4.6 (4.3, 5.0) 0.2 (0.1,0.3) 0.3 (0.2, 0.4) • Most common AEs leading to discontinuation: Laboratory abnormalities - 1.1/100 pt-ys, transaminase elevations • GI perforations 0.24/100 pt-ys; RA background rate 0.17/100 pt-ys Stable rates of SAE, SIE and CV events over 4 years Genovese M, et al. EULAR 2011, London, #SAT0270 BMS India
    59. 59. In MTX-IR patients is it better to add TCZ or switch to TCZ? (ACT-RAY) 2-year RCT TCZ 8 Endpoint (%) +MTX - 24-week data n=277 - Biologic-naive DAS28<2.6 40.4 - 8.2 ys disease 61.7 - DAS28(ESR)=6.35 (median) LDAS - TCZ 8 mg/kg q 4 weeks ACR20 71.8 • 1º EP: DAS≤2.6 ACR70 24.9 LFT abnormalities (%) • Other than LFTs, safety 1.5-3x ULN 8.5 data no difference >3-5x ULN 1.7 • Efficacy equal whether switch or add. Do you want to switch rather than add? Dougados M, et al. EULAR 2011, London, #OP0020 TCZ 8 +PBO n=276 34.8 51.4* 70.7 25.7 4.4 0.4 *P=0.028 BMS India
    60. 60. aIL-6 mAb in MTX-IR • Asialated mAb to IL-6 NOT IL-6R • 80, 160, 320 mg vs PBO, IV+MTX q 8 wks1 • T½ = 30 days Responders (%) 1°EP: Week 12 ACR and LDAS ACR20 100 ACR50 *P<0.05 LDAS * * 82 81 * 80 ACR70 71 • SC vs IV dosing:2 - Bioavailability of ALD518 ≈ 60% for SC vs IV dosing - Rapid, sustained reductions in serum CRP all doses, IV or SC 60 * 50 * 40 34 27 27 9 • Phase III with SC dosing 3 7 12 * 25 21 20 33 46 13 0 PBO (n=33) Positive proof of concept at Week 12 1. Mease P, et al. ACR 2010, Atlanta, #2168; 2. Shakib S, et al. EULAR 2011, London, #SAT0296 80 mg (n=32) 160 mg (n=34) 320 mg (n=28) BMS BMS India India
    61. 61. aIL-6 mAb and HRQOL: SC in Phase III RCTs Combined BL Age/Gender Norms PBO+MTX n=30 80 mg+MTX n=29 160 mg+MTX n=33 320 mg+MTX n=26 *P< 0.05 †P<0.05 ‡P<0.05 -PF90 80 ‡* H 70 60 R ‡ 50 40 30 20 ‡* 10 E B *‡ 0 • SC dosing planned in Phase III RCTs Mean changes in SF-36 domains support dose selection ‡ * F and benefit of 320 mg Strand V, et al. EULAR 2011, London, #SAT0304; Shakib et al, Ibid, #SAT0296 G *‡ V *† ‡ BMS India
    62. 62. Other aIL-6 mAbs in development • CNTO 136: POC in Phase II RCT in DMARD-IR:1 - Part 1: 100 mg SC q 2 weeks x5 well tolerated; interim analysis at Week 12 - ACR20: 21% vs 75% (P=0.002); DAS28(CRP) -0.65 vs -1.66 (P=0.001); good/moderate EULAR: 11%/21% vs 38%/44% (P=0.015) in active group ACR components (P<0.05 for all, except patient pain) - 1 SAE: staphylococcal cellulitis in active - ↓PMNs; ↑ALT; ↑cholesterol in 2/14 PBO vs 3/5 active - Part 2: Dose-ranging • CDP6038: Single dose IV and SC administration in 67 healthy volunteers:2 - Selectively blocks final assembly step of IL-6 signaling complex - PK, PD after IV [0.001-10.0 mg/kg] and SC [0.3, 1.0 or 3.0 mg/kg] dosing - TEAE higher with PBO vs active: 52.9% vs 33.3%: ‟flu, diarrhea, URI - ↓PMN; WBC counts and ↑ALT without dose dependency; no ∆ in lipids - Median T½ = 31.1 days IV and SC; independent of dose 1. Hsu B, et al. EULAR 2011, London, #FRI0345; 2. Hickling M, et al. Ibid, #FRI0378 BMS India
    63. 63. Rituximab long-term safety in RCTs Incidence per 100 pt-ys PBO n=818 • RTX vs PBO: • Up to 9.5 years follow-up • Up to 17 courses of RTX • RTX 500/1000 mg x 2 • AE, SAE/100 pt-ys: Similar, courses 1-6 • Malignancy SIR: 0.99 vs SEER Pt-ys AE SAE Infection SIE SOI All RTX >5 ys RTX n=3,194 n=627 1,107 11,962 4,418 315 14 90 3.8 0.09 263 14 82 3.9 0.06 254 14 75 3.3 NR NR, not reported RTX safety appears to be stable from course to course and over time in patients who remain in LTE studies van Vollenhoven RF, et al. EULAR 2011, London, #SAT0267 BMS India
    64. 64. Rituximab potpourri • B-cell count at Week 26 may predict subsequent response to RTX1 - Absence of B-cells at Week 26: 100% stable/improving DAS28 at Week 40 - Presence of B-cells at Week 26: 45% worse DAS28 at Week 40 • Impaired response to pneumococcal vaccination with RTX2 - RTX and MTX (not TNF-IR) associated with impaired antibody response following vaccination with heptavalent pneumococcal conjugate vaccine • JCPyV infections in RTX-treated patients3 - 38% of RTX-treated patients with multiple tests for JCPyV DNA had virus in urine (generally reported at approximately >75% in the normal population4) - Isolates belonged to different genotypes not associated with PML • Patients treated with the addition of RTX to a biologic over 26 weeks 5 - SIE 1.7% vs 1.9% in REFLEX; only 42.6% EULAR moderate/good response 1. Vital E, et al. EULAR 2011, London #OP0012; 2. Kapetanovic MC, et al. Ibid, #OP00163; 3. Verheyen J, et al. Ibid, #SAT0268; 4. Walker DL, Padgett BL Prog Clin Biol Res 1983;105:99-106; 5. Rigby W, et al. EULAR 2011, London, #SAT0308 BMS India
    65. 65. Ofatumumab (OFA), a fully human aCD20 mAb, in biologic-naive RA • Phase III double-blind vs PBO1 • MTX-IR; mean 8.5 ys disease • • • 700 mg OFA at Weeks 0 and 2, + 100 mg IV MP 1º EP: ACR20 at Week 24 Safety - No immunogenicity - Rash (21%); urticaria (12%) vs <1% PBO • SC in development without steroid pre-treatment2 ACR20 ACR50 60 ACR70 ** 50 50 40 30 ** 27 27 * 13 20 11 10 2 0 PBO Small delta in ACR responses; SC in development 1. Taylor PC, et al. EULAR 2011, London, #OP0019; 2. Kurrasch R, et al. Ibid, #SAT0288 OFA n=131 n=129 *P<0.01; **P<0.001 BMS India
    66. 66. Anti-BAFF mAb in RA1 80 ACR20 70 • 156 MTX-IR; active RA 61 54 44 45 • LY 1, 3, 10, 30, 60,120 mg SC q 4 wks x6 47 40 40 30 7* ACR50 60 50 • Human mAb; neutralizes membrane-bound and soluble BAFF 38 33 22 20 10 10 10 11 0 PBO 1 3 10 30 LY mg *P<0.05 vs PBO (one-sided Fisher‟s exact test) 8 • 1° EP: Dose response of ACR50 • Safety: - SAE: 10% LY vs 11.1% PBO - SIE: 2.5% LY vs 0% PBO • Decreases in mean IgM and IgA at higher LY doses: Not associated with infections 60 120 • Study with LY IV Q 3 weeks X3 at 30 or 80 mg vs PBO in TNF-IR; ACR50 at Wk 16 as 1° EP, not statistically different2 Anti-BAFF mAb, at these doses and frequency, not effective in RA 1. Genovese M, et al. EULAR 2011, London, #OP0017; 2. Genovese M, et al. Ibid, #SAT0275 BMS India
    67. 67. Safety of SC abatacept in patients with RA: Analysis of five RCTs ≤4.5 years • Exposure (SC)1 - 1,879 patients - 3,086 pt-ys - 1,191 (63%) treated >18 mos - Mean duration of treatment 20 mos (range: 2-56) • Exposure (IV)2 - 4,149 patients - 12,132 pt-ys - 1,165 (28%) treated ≥5 ys - Mean duration of treatment 36 mos (range: 2-104) Safety SC ≈ IV abatacept 1. Alten R, et al. EULAR 2011, London, #SAT0292; 2. Hochberg MC, et al. ACR 2010, Atlanta, #390 SAEs IV ABA 10 mg/kg 0.55 0.60 (0.47-0.76) 9.53 14.61 (8.46-10.72) Deaths SC ABA 125 mg/wk (0.34-0.89) Incidence rates: Events/100 pt-ys (13.85-15.41) Serious infections SIEs Pneumonia Lobar pneumonia Herpes zoster TB 1.94 2.87 (1.50-2.50) (2.57-3.19) 0.36 0.46 (0.20-0.65) (0.34-0.59) 0.10 0.11 (0.03-0.30) (0.06-0.18) 0.10 0.03 (0.03-0.30) (0.01-0.08) 0.03 0.03 (0.00-0.23) (0.00-0.23) BMS BMS India India
    68. 68. Does SC abatacept require IV loading? • 1.6 1.4 1.2 Comparison of two Phase III trials, with or without IV loading1 HAQ-DI 6.0 Baseline Month 3 1.0 1.1 4.0 3.0 0.8 0.6 0.7 0.4 5.4 4.7 3.8 3.2 2.0 1.0 0.2 0.0 0.0 IV loading (n=167) No IV loading (n=100) • Baseline Month 3 5.0 1.4 1.3 DAS(CRP) IV loading (n=167) No IV loading (n=100) Similar Cmin in both studies2 Not head-to-head; IV probably not needed 1. Nash P, et al. EULAR 2011, London, #SAT0287; 2. Murphy, B et al. Ibid, #FRI0346 BMS India
    69. 69. Abatacept potpourri One can effectively and safely switch from IV to SC1 • IV vs SC in a head-to-head is equal in efficacy 2 • Subset analysis of fixed dose of ABA SC vs IV for weight and disease duration have equal benefits and similar safety3 • It appears that we can effectively and safely start and stop SC ABA3 • 1. Keystone E, et al. EULAR 2011, London, #FRI0351; 2. Genovese M, et al. Ibid, #OP0023; 3. Kaine JL, et al. Ibid, #FRI0366 BMS India
    70. 70. Abatacept & tocilizumab in routine care (DANBIO) • ABA (n=150), TCZ (n=178) - almost all after first biologic • 48-week results • Drug survival: - ABA 50% - TCZ 60% DAS28 variables: Time since treatment initiation (weeks) 6 14 Abatacept Tocilizumab 5 4 • DAS28(CRP) remission: - ABA 26% (n=38) - TCZ 58% (n=19) EULAR good/moderate: - ABA 77% - TCZ 84% 6 2 4 1 2 0 0 6 36 12 48 24 70 Abatacept 80 Tocilizumab 60 50 40 30 20 10 0 0 6 12 24 36 In TNF-IR, 2/3 of ABA, TCZ survive to 48 weeks Leffers HC, et al. EULAR 2011, London, #FRI0358 Tocilizumab 10 8 3 0 • Abatacept 12 48 0 6 12 24 20 18 16 14 12 10 8 6 4 2 0 36 48 Abatacept Tocilizumab 0 6 12 24 36 48 BMS India
    71. 71. Abatacept & rituximab use after malignancy: AIR & ORA registries • Prospective 5-yr registries ABA - AIR = RTX; n=2,000 - ORA = ABA; n=1,000 • History of cancer 268 RTX (13.6%) – 54 ABA (5.4%) Death RTX 1 (infection) 5 (cancer) 1 3 - • • Most common cancer: Breast Median duration after cancer to first infusion - RTX 4 ys - ABA 7 ys • 191/268 RTX, 41/54 ABA had follow-up New cancer New metastasis Severe infection 6 1 (18 mos after 1st infusion) 7.4% 7.1% Is it really preferable to use rituximab vs other biologics in patients with previous cancer? Gottenberg JE, et al. EULAR 2011, London, #FRI0363 BMS India
    72. 72. Drug retention in TNF-IR: 2nd TNFi or ABA/RTX/TCZ • Swiss RA cohort SCQM-RA; 1,497 biologic courses in TNF-IR - – • Time to discontinuation of biologic agents 858 2nd TNF 629 non-TNF biologic Total of 2,142 pt-ys on biologics - Higher GC and MTX in TNF group - Prior TNFs: 2.7 TNF group vs 2.0 non-TNF group • Drug retention: - • 2nd TNF vs non-TNF: Adjusted HR 2.12 (1.74-2.6) Other BIO Anti-TNF 80 60 40 20 P<0.001 Median survival time - 2nd TNF = 21 mos (IQR 8-53) – Non-TNF = 32 mos (IQR 14-64) • 100 Reasons for discontinuation unknown 0 0 1 2 3 4 Time (year) Swiss conclude: After first TNF, non-TNF biologics are better; do you agree? Martin-du-Pan Prujim S, et al. EULAR 2011, London, #SAT0298 5 BMS India
    73. 73. Not ready for prime time • Oral S1P lyase inhibitor LX3305: Failed in Phase II to show efficacy in MTX IR in RA with a good safety profile - Higher doses will be explored in a further IB study for efficacy and safety¹ • IL-10 producing T-reg 1 cells: In human serum in patients with severe RA, migration to synovium and suppressive capacity demonstrated2 • Anti-lymphotoxin mAb: Phase I RCT in DMARD-IR RA: SAD, MAD: 3 mg/kg q 2 wks x 3: at Week 6 preliminary efficacy; linear PK, biologic effect: ↓↓ CXCL-13 demonstrated with acceptable safety; not POC3 • Rheumavax: Autologous tolerizing dendritic cells exposed to citrullinated peptides: Phase I in 18 DR+ACPA+DMARD-IR RA vs 11 controls [OL]4: - 7 maintained DAS<2.6 over 6 mos; 6 attained DAS<2.6 for 3-6 mos; 5: NR – 9 controls: NR; 2: DAS ↓ 1. 2. 3. 4. Fleischmann R, et al. EULAR 2011, London, #OP0059; Asnagli H, et al. Ibid, #OP0119; Emu B, et al. Ibid, #OP0018; Thomas R, et al. Ibid, #LB0004 BMS India
    74. 74. BMS India

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