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

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1 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

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 RA is a chronic inflammatory disease that most frequently affects the joints primarily but also other body systems. The cause of RA is unknown, but much progress in elucidating its pathogenesis has been made in the past decade. It is likely that many pathogenetic and environmental mechanisms are involved. The clinical course of RA is highly variable and unpredictable for an individual. Typically, joint symptoms progress slowly. The disease is characterized by progressive destruction of the synovial joints. This damage causes loss of cartilage and bone. The radiological signs are loss of joint space and bone density. In addition to joint destruction, RA also causes ligaments and tendons to be destroyed. Loss of joint function eventually occurs as a result of destruction of bone and cartilage. In addition, RA also may be associated with increased mortality and premature death. Grassi W, De Angelis R, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998;27(suppl 1):S18-S24.

3 Classification Criteria For RA

4 1987 ACR criteria Current trends in RA
ACR /EULAR classification criteria for RA Rationale 1987 ACR criteria Elaborated in established RA Considered as classification criteria Lack of sensitivity in early disease Current trends in RA Recognize the patients as soon as possible Treat the patients as soon as the diagnosis is made investigate new drugs/strategies at an early stage of the disease

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

6 To recognise the disease at an early stage.
ACR /EULAR classification criteria for RA Objectives To recognise the disease at an early stage. To develop a set of rules to be applied in newly patients with undifferentiated synovitis Identify the subset at high risk of chronicity & erosion Be used as a basis for initiating disease modifying therapy Aletaha D, et al. Ann Rheum Dis 2010 ; 69: ; Arthritis Rheum 2010;62:

7 New classification criteria for RA
2009 ACR / EULAR for the classification & diagnosis of rheumatoïd arthritis ≥1 1 swollen joint Not best explained by another disease Yes No yes New criteria for RA Fulfilled? No RA RA Typical RA erosion on X-ray* Joint involvement(0-5) 1 large joint 2-10 large joints 1 1-3 small joints (large joints not counted) 2 4-10 small joints (large joints not counted) 3 > 10 joints (at Least one small joint) 5 Sérology (0-3) RF négative ET ACPA négative RF low level (1 à 3 x ULN ) OR ACPA low level (1 à 3 x ULN) RF high level(> 3 x ULN) OR ACPA high level (> 3 x ULN) Symptoms duration (0-1) < 6 weeks ≥ 6 weeks Acute Phase reactants (0-1) CRP normal AND ESR normal CRP abnormal OR ESR abnormal Ces critères préliminaires ont pour objectifs d’aider le clinicien à prendre très tôt une décision thérapeutique par Méthotrexate ou par l’association biothérapie + MTX devant un rhumatisme inflammatoire indifférencié RA: score ≥ 6 Aletaha D, et al. Ann Rheum Dis 2010 ; 69: ; Arthritis Rheum 2010;62: * van der Heidje D et al Ann Rheum Dis Feb 7 7

8 management

9 Management of patients with RA Therapeutic objectives
Prevention / arrest of joint damage Prevention / reversal of disability Remission Sustained Remission Prevention of systemic co-morbidities: CV diseases, osteoporosis…. La rémission (disparition des symptômes et surtout arrêt de progression de la maladie = prévention des destructions ostéo-articulaires irréversibles) est aujourd’hui un objectif réaliste grâce aux nouvelles stratégies thérapeutiques (2-3-4) Les objectifs des traitements Faire disparaître les signes d’activité de la maladie Signes cliniques Syndrome inflammatoire biologique : VS, CRP Eviter ou du moins ralentir les destructions articulaires Evolution radiologique Prévenir les complications extra-articulaires Maintenir les fonctions articulaires et préserver la qualité de vie

10 Rheumatoid arthritis: Selection of therapeutic strategy
Predictive factors of severity Patient characteristics * age, comorbidities…. * Patient expectations Drugs : benefit / risk ratio Disease activity Plusieurs facteurs prédictifs de sévérité (destruction ostéo-cartilagineuse) de la PR ont été identifiés dans différentes cohortes : La présence d’érosions à un stade précoce de la maladie La VS ou la CRP élevée La présence de facteur rhumatoïde (surtout si titre élevé) La présence d’Ac anti-CCP La présence d’allèle HLA-DR4 Le risque de PR sévère est d’autant plus élevé que plusieurs facteurs de risque sont présents (effet cumulatif) Therapeutic strategy

11 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 activity as soon as possible in 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

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

13 Newer RA Treatment Strategies
• Intensive management • Treat to Target • Combination DMARD strategies • Remission induction

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

15 Combination Step-Down Therapy: COBRA Trial
1.6 Step-down (MTX + SSZ + Pred) 1.2 Pooled Index SSZ alone 0.8 Prednisolone 60 mg/day COBRA Trial: Step-Down Therapy In the COBRA trial (Combinatietherapie Bij Reumatoide Artritis), Boers and colleagues demonstrated the effectiveness of a step-down approach for suppressing disease in patients with RA. These investigators assessed the value of intensive combination therapy in early RA in a multicenter, double-blind, randomized trial (COBRA). They compared the combination of SSZ (2 g/d), MTX (7.5 mg/week), and prednisone (initially 60 mg/d, tapered in 6 weekly steps to 7.5 mg/d) with SSZ alone in 155 patients with early RA. The main outcomes were the pooled index (a weighted change score of five disease activity measures) and the Sharp/van der Heijde radiographic damage score in hands and feet. At week 28, the mean pooled index was 1.4 in the combined treatment group and 0.8 in the SSZ group (p < ). At this time, 55 (72%) and 39 (49%) of patients, respectively, were improved according to ACR criteria. The clinical difference between the groups decreased and was no longer significant after prednisone was stopped, and there were no further changes after MTX was stopped. At 28 weeks, the radiographic damage score had increased by a median of one in the combined therapy group and by four in the SSZ group (p < ). These investigators concluded that combined therapy immediately suppressed damage progression, whereas SSZ alone was less effective. Boers M, Verhoeven AC, Markusse HM, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997;350: 0.4 Step-down therapy Prednisolone 7.5 mg/day MTX 7.5 mg/week SSZ SSZ 2000 mg/day 0.0 16 28 Weeks Boers M et al. Lancet. 1997;350:

16 Tight control and predefined strategy
Systematic literature review: from 1995 to 2008  Meta-analysis of 6 studies Tight control without predefined protocol Van Tuyl, 2008 Fransen, 2003 Tight control with predefined protocol Fransen, 2005 Tight control without predefined protocol 0,25 (IC95 : 0,03-0,46) Grigor, 2002 Goekoop, 2009 Verstappen, 2007 Tight control with predefined protocol 0,97 (IC95 : 0,64-1,3) Le concept de contrôle serré (tight control) repose sur une gestion des traitements adaptée à l’activité de la PR. En fait, cela regroupe plusieurs réalités en pratique, ce qui a conduit des auteurs néerlandais à faire une revue systématique de la littérature publiée depuis 1995, date à laquelle cette notion est apparue (« It’s time to aim remission », avait dit P. Emery cette année-là). Au total, 6 essais contrôlés et randomisés comparant un contrôle serré à une stratégie de prise en charge usuelle ont été examinés et leurs données agrégées dans le cadre d’une méta-analyse en 2 parties. La première a concerné 3 essais dans lesquels un contrôle serré avait été mis en place dans l’un des bras sans être associé à la définition précise des enchaînements thérapeutiques en cas de réponse inadéquate (c’est-à-dire d’objectif thérapeutique non atteint). Ces 3 essais avaient mis en évidence un bénéfice potentiel du contrôle serré à la limite de la significativité ; l’analyse agrégée (différence pondérée des moyennes) révélait alors une différence significative (l’augmentation des effectifs dans l’analyse agrégée aboutissait à une plus grande puissance), mais de faible ampleur. À l’opposé, 3 essais combinant contrôlé serré et schéma d’escalade thérapeutique prédéfini, tous positifs, étaient associés dans une même méta-analyse, mettant en évidence à la fois une différence pondérée significativement positive et une intensité d’effet importante par rapport au bras témoin. -0,4 -0,2 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:

17 Retention Rates of DMARDs Cumulative Retention Rates
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 Legend: Methotrexate Sulfasalazine Chloroquine Parenteral Gold Oral Gold Penicillamine Azathioprine Cyclosporine Combination Cumulative Retention Rates Time (Months)

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

19 Phase I of EULAR RA Management Algorithm
Phase I of the EULAR RA Management Algorithm Following a clinical diagnosis of RA, the patients is assessed for contraindication for methotrexate (MTX) If MTX is not contraindicated, patient is started on MTX, with or without short-term low or high dose corticosteroids If MTX is contraindicated, patient is started on leflunomide, intramuscular gold or sulfasalazine, with or without short-term low- or high-dose corticosteroids The patient is then assessed for achievement of treatment target with 3–6 months Treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity If target is not reached, this is considered failure of phase I, and patients is progressed to phase II If target is reached, the patient continues with the phase I treatment regimen Smolen JS, et al. Ann Rheum Dis 2010;69:964–75 *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

20 Phase II of EULAR RA Management Algorithm
Following failure for lack of efficacy and/or toxicity in phase I, the patient is assessed for the presence or absence of prognostically unfavourable factors Prognostically unfavourable factors include: RF/ACPA, especially at high levels Very high disease activity Early joint damage If prognostically unfavourable factors are absent, a second synthetic DMARD should be started Leflunomide, sulfasalazine, MTX, intramuscular gold or Ev. combinations, with or without addition of glucocorticoids as before If treatment target is achieved with 3–6 months, the treatment regimen should be continued If treatment target is not achieved within 3–6 months, a TNF-blocking drug should be added If prognostically unfavourable factors are present, a TNF-blocking drug should be added If treatment target is not achieved within 3–6 months of adding a TNF-blocking drug, this is considered failure of phase II, and patients is progressed to phase III Treatment target is defined as clinical remission or, if remission is unlikely to be achieved, at least low disease activity, as in Phase I Smolen JS, et al. Ann Rheum Dis 2010;69:964–75 *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

21 Phase III of EULAR RA Management Algorithm
Following failure for lack of efficacy and/or toxicity in Phase II with a synthetic DMARD + biologic, biological treatment should be changed by one of the following options: Replace TNF-blocking by: Abatacept or Rituximab or Tocilizumab or Switch to second TNF-blocking drug If treatment target is then achieved within 3–6 months, the patient continues with the phase III treatment regimen If treatment target is not achieved within 3–6 months, the biological treatment should be changed again The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity, as in phases I and II Smolen JS, et al. Ann Rheum Dis 2010;69:964–75 *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

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

23 Down-regulation of T cell
Upstream T-cell Modulation with ORENCIA® (abatacept) APC APC APC MHC CTLA-4 T-cell receptor CD28 CD28 ORENCIA This is a build slide. Slide will be built on 2 clicks. Key Messages: Downstream Regulation ORENCIA is a fully human immunoglobulin-soluble receptor fusion protein. ORENCIA acts by binding to CD80/CD86 on antigen-presenting cells and preventing its interaction with CD28 on T cells.1 By selectively modulating the CD80/CD86:CD28 co-stimulatory pathway, ORENCIA is expected to allow other pathways to remain largely intact, such that T-cell activation is not expected to be completely blocked while other pathways that modulate T-cell activation may continue to function.2 By selectively targeting the co-stimulation of T cells upstream, ORENCIA helps modulate the downstream serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin (IL)-6, rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase, and TNF-. The relationship of these biologic response markers to the mechanisms by which ORENCIA exerts its effects in rheumatoid arthritis (RA) is unknown. 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. References: 1Kremer JM. J Clin Rheumatol. 2005;11:S55–S62. 2Elloso and Scott. J Immunol. 1999;162(11):6708–6715.

24 Forest plot of risk ratios for clinical remission
Efficacy of initial MTX vs MTX + biological agent in Early RA Forest plot of risk ratios for clinical remission RR 1.74; 95% CI (1.54, 1.98) no heterogeneity I2 0%; p = 0.496 The results for clinical remission are presented graphically here in the Forest plot. Risk ratios for individual studies favor combination therapy but the confidence intervals for some do cross the null association value of 1. However, the pooled risk ratio centered at 1.73 has a narrow confidence interval and is statistically significant. Furthermore, a sensitivity analysis revealed that no individual study appeared to change the pooled RR dramatically. Kuriya B et al. Ann Rheum Dis online first april 26, 2010 24

25 Forest plot of risk ratios for radiographic remission
Efficacy of initial MTX vs MTX + biological agent in Early RA Forest plot of risk ratios for radiographic remission RR 1.30; 95% CI (1.01, 1.68) Significant heterogeneity I2 0%; p = 0.001 Furthermore, looking at the Forest plot, the 95% confidence intervals of the studies minimally overlap each other also supporting the presence of heterogeneity.The overall pooled risk ratio centered at 1.30 has marginal statistical significance. In addition, the pooled estimate for clinical remission did not substantially change when only these 4 trials were evaluated. Kuriya B et al. Ann Rheum Dis online first april 26, 2010 25

26 Clinical Trials for Abatacept

27 AGREE (MTX-naïve) AGREE study design: patients with early RA and poor prognostic factors* Inclusion criteria Early RA (≤2 years) MTX-naïve RF+ and/or anti-CCP2+ ≥1 erosion Double-blind period1 Open-label period2 232 Abatacept + MTX** (n=256) 433 Abatacept + MTX Screening Placebo + MTX** 227 (n=253) Day 1 Year 1 Year 2 1:1 Randomisation Co-primary endpoints DAS28 (CRP) <2.6 Total Genant-modified Sharp score DAS28 (CRP) X-Ray progression HAQ-DI *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.

28 Proportion of patients achieving DAS28 remission (%)
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 Proportion of patients achieving DAS28 remission (%) p<0.001 50 40 41.4% 30 20 23.3% 10 *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.

29 Abatacept added to MTX alone group
AGREE (MTX-naïve) Early referral Abatacept provides sustained efficacy through 2 years in patients with early RA (≤2 years)* Year 1 Abatacept added to MTX alone group 100 90 80 70 60 55.2% Proportion of patients achieving DAS28-CRP remission (%, 95% CI) 46.1% 50 44.5% 40 30 26.9% 20 10 29 85 141 197 253 309 365 449 553 617 729 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

30 Adding abatacept to MTX slows the rate of radiographic progression*
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 Yr 1–2 1.48 baseline in Sharp total score Mean change from 1.0 0.84 0.65 ∆=0.18 Yr 1–2 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.

31 Proportion of patients achieving HAQ normalisation (%)
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 achieving HAQ normalisation (%) 50 40 30 20 10 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.

32 Efficacy and Safety of Abatacept or Infliximab Versus Placebo ATTEST Trial A 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 The slides will focus on the ATTEST trial Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

33 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 of the study was reduction in disease activity in the group receiving abatacept vs placebo at 6 months. Importantly, the primary endpoint was not designed to be a head-to-head comparison between abatacept and infliximab. Schiff M, et al. Ann Rheum Dis 2008;67:1096–103 the primary endpoint was not designed to be a head-to-head comparison between Abatacept and infliximab. Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

34 Abatacept + MTX and infliximab + MTX ACR20 response rates are similar at Month 3
ATTEST ACR 50 Abatacept Infliximab ACR 20 ACR 70 80 Visit day 10 20 30 40 50 60 70 1 29 57 85 113 141 169 197 225 253 281 309 337 365 ACR response rate (%) On this slide the ACR results are shown for abatacept and infliximab. Let’s first focus on the onset of action. The onset of action of infliximab was generally more rapid than abatacept up to Day 85 (Month 3) At three months abatacept and infliximab ACR20 response rates are similar ACR20: 66% for abatacept, 69% for infliximab Schiff M, et al. Ann Rheum Dis 2008;67:1096–103 The onset of action of infliximab was generally more rapid than abatacept however, by day 85, ACR 20 responses are similar Schiff M, et al. Ann Rheum Dis 2008;67:1096–103 34 34

35 ATTEST Further improvement from Month 6 to 12 was observed with abatacept + MTX in ACR 20 response ATTEST ACR 50 Abatacept Infliximab ACR 20 ACR 70 80 Visit day 10 20 30 40 50 60 70 1 29 57 85 113 141 169 197 225 253 281 309 337 365 ACR response rate (%) Further improvement from Month 6 to 12 was observed with abatacept in ACR 20 response (non-overlapping 95% CI for the estimate of difference); and by Day 365, ACR 20 responses were higher with abatacept than with infliximab At Day 365, the following response rates were observed for abatacept and infliximab, respectively ACR 20: 72.4 and 55.8% ACR 50: 45.5 and 36.4% ACR 70: 26.3 and 20.6% Data are for the ITT population, with patients who discontinued the study prematurely considered non-responders subsequent to the time of discontinuation Schiff M, et al. Ann Rheum Dis 2008;67:1096–103 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

36 ACR Responses at 6 Months
ATTEST At Day 197, ACR 20, 50 and 70 responses were significantly greater with abatacept versus placebo (ACR 20: 66.7 vs 41.8%, p <0.001; ACR 50: 40.4 vs 20.0%, p<0.001; and ACR 70: 20.5 vs 9.1%, p=0.019). ACR 20, 50 and 70 responses also were significantly higher in the infliximab group versus placebo (ACR 20: 59.4 vs 41.8%, p=0.006; ACR 50: 37.0 vs 20.0%, p=0.004; and ACR 70: 24.2 vs 9.1%, p=0.002). Schiff M, et al. Ann Rheum Dis 2008;67:1096–103 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 vs infliximab Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

37 ACR responses at 12 months
ATTEST At Day 365, ACR responses were: ACR 20: 72.4% with abatacept vs 55.8% with infliximab; (ACR 20: 72.4 vs 55.8%, difference of 16.7, 95% CI=5.5, 27.8). ACR50:45.5% with abatacept vs 36.4% with infliximab; overlapping 95% CIs for the estimate of difference for ACR 50: 45.5 vs 36.4%, estimate of difference [95% CI]= 9.1 [–2.2, 20.5]; ACR70: 26.3% with abatacept vs 20.6% with infliximab; estimate of difference [95% CI]= 5.7 [–4.2, 15.6]. Schiff M, et al. Ann Rheum Dis 2008;67:1096–103 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 vs infliximab Schiff M, et al. Ann Rheum Dis 2008;67:1096–103

38 Infliximab patients switched to abatacept
Abatacept+MTX Delivered Sustained Improvements in ACR Responses Over 2 Years ATTEST-LTE Visit (month) Infliximab patients switched to abatacept ACR Responders (%) Open label LTE period DB period 89% (83,94)* 69% (61,77)* 55% (46,64)* 43 (35,52)* 24% (16,31)* 31% (23,39)* 87% (80,93)* 84% (78,91)* 71% (63,79)* 61 (52,70)* 41% (32,50)* 45% (36,54)* The long term statement in the EULAR recommendations can also be shown for the ATTEST study: Abatacept delivers sustained improvements over 2 years in ACR responses. In addition in patients who switched from infliximab to abatacept after 1 year, efficacy benefits increased over year 2 and ACR response rates were comparable to levels observed for patients originally randomized to abatacept. Patient Numbers: Month: Abatacept ACR20: ACR50: ACR70: Infliximab: ACR20: ACR50: ACR70: Schiff M, Rheumatology 2011; 50: 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 Abatacept+MTX Infliximab 3mg/kg + MTX to abatacept Schiff M and Bessette L Clin Rheum 2010 ; 29:

39 ABATACEPT Short & long -term Efficacy

40 COCHRANE META-ANALYSIS GLIMMIX: Odds Ratio (95% CI)
Abatacept provides similar short-term efficacy at 6 months compared with other biologic agents Abatacept 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 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:CD 40

41 Cumulative incidence of time to RAPID≥3.6 response* (%)
Abatacept short-term efficacy is similar to other biologic agents in real life 80 Abatacept Etanercept Adalimumab Infliximab 60 Cumulative incidence of time to RAPID≥3.6 response* (%) 40 20 1 2 6 5 4 3 6 12 30 24 18 Month *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. Yazici Y, et al. Arthritis Rheum 2011; 63(Suppl 10):S873. Abstract

42 Adjusted mean change (95% confidence interval)
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 0.4 0.5 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

43 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.

44 Long term goal achievement by abatacept

45 An increasing proportion of abatacept patients show sustained LDAS or DAS28 remission over 7 years
Double-blind phase Open-label LTE phase 30 20 10 40 50 70 60 80 100 90 Response (95% CI) LDAS 48.2% (37.4, 58.9) n/N=40/83 69.7% (54.0, 85.4) n/N=23/33 Responders (%) Remission 51.5% (34.5, 68.6) n/N=17/33 25.3% (15.9, 34.7) n/N=21/83 0.5 1 2 3 4 5 6 7 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.

46 Mean change from baseline in Genant-modified sharp scores (TS)
AIM (MTX-IR) Abatacept has demonstrated increasing reductions in rate of structural damage progression through Year 5 *0.29 Year 1 *0.43 *0.68 *0.26 Mean change from baseline in Genant-modified sharp scores (TS) *0.74 *0.34 *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; Genant HK, et al. Ann Rheum Dis 2008;67(Suppl 2):193.

47 AIM (MTX-IR) Sustained improvement in physical function with abatacept over 5 years (HAQ-DI response) Double-blind phase 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 0.5 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 Bessette L. Clin Rheum 2010;29:583–591.

48 Subjects remaining at the end of 4 years of LTE
LT- RCT Abatacept has a retention rate that is comparable with or higher than the anti-TNF agents Subjects remaining at the end of 4 years of LTE n/N % Infliximab1 295/511 62% Etanercept2 429/581 74% Adalimumab3 147/262 56% Abatacept4* (IM101102) 394/539 73% Retention may be considered as a surrogate marker of long-term efficacy for biologic agents5 *Summation of the original abatacept plus placebo treatment groups who entered LTE. Data from literature search on the long-term efficacy results from open-label extension studies of anti-TNFs (in MTX-naïve and MTX-IR patients). 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.

49 Abatacept: Safety Issues
Acute infusion reactions 9.8% vs 6.7% placebo, mild-moderate Malignancy & Infection outcomes 4134 Abatacept-treated patients compared with 41,529 DMARD treated patients in 5 cohorts No increased rates of malignancy, infection over 6 years. aSibilia J, Westhovens R. Safety of T-cell costimulation modulation with abatacept in patients with rheumatoid arthritis. Clin Exp Rheumatol 2007;25 (5Suppl46):S bSimon TA et al. Malignancies In RA Abatacept clinical development program. ARD 2008.

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

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

52 Most Common Infections (≥ 5%) Double-Blind, Controlled Study Periods
Number (%) of Patients Abatacept N = 1955 Placebo N = 989 Preferred Term Total Patients with Infections Upper Respiratory Tract Infection Nasopharyngitis Sinusitis Urinary Tract Infection Influenza Bronchitis 1051 (53.8) 248 (12.7) 225 (11.5) (6.4) (5.8) (5.7) (5.2) 478 (48.3) 119 (12.0) 90 (9.1) 68 (6.9) 45 (4.6) 52 (5.3)

53 Serious Infections (≥ 0.2%) Double-Blind, Controlled Study Periods
Number (%) of Patients Abatacept N = 1955 Placebo N = 989 Preferred Term Total Patients with Serious Infections Pneumonia Cellulitis Urinary Tract Infection Bronchitis Diverticulitis Pyelonephritis Acute Sepsis 58 (3.0) 9 (0.5) 5 (0.3) 4 (0.2) 3 (0.2) 1 (<0.1) 19 (1.9) 5 (0.5) 2 (0.2) 1 (0.1) 3 (0.3)

54 Predictors and Risk of Infection in Rheumatoid Arthritis
Relative Risk to general population: [1.7 – 2.1] Best predictors: RA severity / disease activity Age Corticosteroid therapy Comorbid diseases: CVD, CHF, CRF, DM, lung disease Previous infection Joint surgery Contributory role of DMARDs not clearly defined Moreland et al. J Rheum 2001;28:

55 Tuberculosis Cumulative Study Periods
2 cases of presumed tuberculosis with abatacept Tuberculous Infection (Double-Blind): Presented with cervical lymphadenitis; diagnosis based on histology Pulmonary Tuberculosis Suspected (Open-Label) Presented with dry cough, fever, diaphoresis and crepitus; diagnosis based on clinical presentation and chest radiograph 1 case of presumed tuberculosis with placebo Tuberculosis - Suspect (Double-Blind): Unknown presentation; no definitive diagnosis

56 Malignancy

57 Clinical trial experience
Integrated safety summary Continued use of abatacept does not increase the risk of malignancy over time Clinical trial experience Short term (2,331 p–y) Long term (9,752 p–y) Cumulative (12,132 p–y) Placebo Abatacept Malignancies, incidence rate (95% CI) Malignancies (excluding NMSC) 0.59 (0.19–1.37) 0.69 (0.39–1.11) 0.74 (0.58–0.93) 0.73 (0.58–0.89) Lymphoma 0.04 (0.00–0.24) 0.08 (0.04–0.16) 0.07 (0.03–0.14) Total solid organ (combined) 0.60 (0.33–1.01) (0.45–0.77) (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) (0.49–1.28) (0.58–0.90) NMSC=non-melanoma skin cancer; Data over a 7-year period; Data lock December ,132 p–y of exposure (N=4,149). Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–5. Abstract 390.

58 Malignancies: Double-Blind studies
Malignant Abatacept: 29 (1.5%) Placebo: 11 (1.1%%) Non-Melanoma Skin CA Abatacept: 15 (0.8%) Placebo: 6 (0.5%) Solid Organ CA Abatacept: 13 (0.7%) Placebo: 5 (0.5%) Hematologic Abatacept: 2 (0.1%) Placebo: 0

59 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 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

60 BIOLOGICS AND PREGNANCY Fetal problems – Humans
Drug # cases Developmental toxicity - animals Fetal problems – Humans Drug Discontinuation? ETA 51 - Preterm , VACTERL Vert,anal, CVS, tracheobr fistula, renal, & Limb At missed period, (+) pregnancy test INF 81 TOF, intestinal malrotation ADA 13 Preterm, limb reduction, Tracheobronchomalacia RIT 10 B cell depletion (2nd/3rd tri) Lymphopenia (1st tri) 12 mos pre-pregnancy ABAT +/None (?) unknown 10 wks pre-pregnancy *1 case each - CZP, ANA, 0 - GOL and ABA; no animal and human/fetal toxicity reported; drug discontinuation recommended for GOL, CZP, ANA Ostensen M, Forger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol 2009;5: UptoDate 2009

61 Conclusions Abatacept in RA:
Is efficacious in achieving remission in early RA Is efficacious in short and long term treatment Has a high retention rate Is a safe and reliable drug

62 Thank You


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