Presentation on theme: "Treat to Target, Role of Orencia in Achieving the target."— Presentation transcript:
1 Treat to Target, Role of Orencia in Achieving the target. ELAR congress, Alexandria 2013Treat to Target, Role of Orencia in Achieving the target.Prof. Hassan El-ShahalyProfessor of Rheumatology and RehabilitationSuez Canal University
2 Rheumatoid Arthritis Challenges Complex, multifactorial pathogenesisFluctuating clinical course; unpredictable prognosisCharacterized by:Progressive joint destructionLoss of physical functionPoor quality of lifeRA 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.
4 1987 ACR criteria Current trends in RA ACR /EULAR classification criteria for RARationale1987 ACR criteriaElaborated in established RAConsidered as classification criteriaLack of sensitivity in early diseaseCurrent trends in RARecognize the patients as soon as possibleTreat the patients as soon as the diagnosis is madeinvestigate new drugs/strategies at an early stage of the disease
5 Early treatment reduces disability 5 years later 0.00.51.01.52.02.53.0Degree of Disability*after 5 Years<6 months(n = 60)6-12 months(n = 47)>12 months(n = 76)0.92.42.3* Odds ratio of HAQ ≥1according to: Wiles NJ, et al. Arthritis Rheum 2001; 44:
6 To recognise the disease at an early stage. ACR /EULAR classification criteria for RAObjectivesTo recognise the disease at an early stage.To develop a set of rules to be applied in newly patients with undifferentiated synovitisIdentify the subset at high risk of chronicity & erosionBe used as a basis for initiating disease modifying therapyAletaha 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 jointNot best explained by another diseaseYesNoyesNew criteriafor RAFulfilled?No RARATypical RAerosionon X-ray*Joint involvement(0-5)1 large joint2-10 large joints11-3 small joints (large joints not counted)24-10 small joints (large joints not counted)3> 10 joints (at Least one small joint)5Sérology (0-3)RF négative ET ACPA négativeRF 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 weeksAcute Phase reactants (0-1)CRP normal AND ESR normalCRP abnormal OR ESR abnormalCes critères préliminaires ont pour objectifs d’aider le clinicien à prendre très tôt une décision thérapeutique par Méthotrexateou par l’association biothérapie + MTX devant un rhumatisme inflammatoire indifférenciéRA: score ≥ 6Aletaha D, et al. Ann Rheum Dis 2010 ; 69: ; Arthritis Rheum 2010;62:* van der Heidje D et al Ann Rheum Dis Feb 77
9 Management of patients with RA Therapeutic objectives Prevention /arrest ofjoint damagePrevention / reversal of disabilityRemissionSustainedRemissionPrevention of systemicco-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 traitementsFaire disparaître les signes d’activité de la maladieSignes cliniquesSyndrome inflammatoire biologique : VS, CRPEviter ou du moins ralentir les destructions articulairesEvolution radiologiquePrévenir les complications extra-articulairesMaintenir les fonctions articulaires et préserver la qualité de vie
10 Rheumatoid arthritis: Selection of therapeutic strategy Predictivefactors of severityPatient characteristics* age, comorbidities….* Patient expectationsDrugs :benefit / risk ratioDiseaseactivityPlusieurs 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 maladieLa VS ou la CRP élevéeLa présence de facteur rhumatoïde (surtout si titre élevé)La présence d’Ac anti-CCPLa présence d’allèle HLA-DR4Le risque de PR sévère est d’autant plus élevé que plusieurs facteurs de risque sont présents (effet cumulatif)Therapeuticstrategy
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 madeRECOMMENDATION 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: 34-45Smolen J. et al.Ann Rheum Dis 2010;-69:964-75
15 Combination Step-Down Therapy: COBRA Trial 1.6Step-down(MTX + SSZ + Pred)1.2Pooled IndexSSZ alone0.8Prednisolone60 mg/dayCOBRA Trial: Step-Down TherapyIn 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;350:0.4Step-downtherapyPrednisolone 7.5 mg/dayMTX 7.5 mg/weekSSZSSZ 2000 mg/day0.01628WeeksBoers M et al. Lancet. 1997;350:
16 Tight control and predefined strategy Systematic literature review: from 1995 to 2008 Meta-analysis of 6 studiesTight control without predefined protocolVan Tuyl, 2008Fransen, 2003Tight control with predefined protocolFransen, 2005Tight control without predefined protocol0,25 (IC95 : 0,03-0,46)Grigor, 2002Goekoop, 2009Verstappen, 2007Tight control with predefined protocol0,97 (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.-0,4-0,20,20,40,60,81,01,21,41,61,82,0Mean difference in DAS28 changeRandomised effect modelSchipper LG et al Rheumatology 2010;49:
17 Retention Rates of DMARDs Cumulative Retention Rates Traditional DMARDs Are Effective but Do Not Maintain Long-term ResponseRetention Rates of DMARDs100908070605040302010Legend:MethotrexateSulfasalazineChloroquineParenteral GoldOral GoldPenicillamineAzathioprineCyclosporineCombinationCumulative Retention RatesTime (Months)
18 Taking steps to improve clinical outcome EULAR RECOMMENDATIONSMain targetAlternative targetAdapt therapy according to disease activityRemissionLow disease activityUse a composite measure of disease activity every 1–3 monthsAdapt therapy if state is lostSustained remissionSustained low disease activityAssess disease activity about every 3–4 monthsMain long-term targetAlternative long-term targetActive RASmolen 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 AlgorithmFollowing 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 corticosteroidsIf MTX is contraindicated, patient is started on leflunomide, intramuscular gold or sulfasalazine, with or without short-term low- or high-dose corticosteroidsThe patient is then assessed for achievement of treatment target with 3–6 monthsTreatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activityIf target is not reached, this is considered failure of phase I, and patients is progressed to phase IIIf target is reached, the patient continues with the phase I treatment regimenSmolen 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 activitySmolen JS, et al. Ann Rheum Dis 2010;69:964–7519
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 factorsPrognostically unfavourable factors include:RF/ACPA, especially at high levelsVery high disease activityEarly joint damageIf prognostically unfavourable factors are absent, a second synthetic DMARD should be startedLeflunomide, sulfasalazine, MTX, intramuscular gold or Ev. combinations, with or without addition of glucocorticoids as beforeIf treatment target is achieved with 3–6 months, the treatment regimen should be continuedIf treatment target is not achieved within 3–6 months, a TNF-blocking drug should be addedIf prognostically unfavourable factors are present, a TNF-blocking drug should be addedIf 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 IIITreatment target is defined as clinical remission or, if remission is unlikely to be achieved, at least low disease activity, as in Phase ISmolen 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 activitySmolen JS, et al. Ann Rheum Dis 2010;69:964–7520
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 orRituximab orTocilizumab orSwitch to second TNF-blocking drugIf treatment target is then achieved within 3–6 months, the patient continues with the phase III treatment regimenIf treatment target is not achieved within 3–6 months, the biological treatment should be changed againThe treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity, as in phases I and IISmolen 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 activitySmolen 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)APCAPCAPCMHCCTLA-4T-cell receptorCD28CD28ORENCIAThis is a build slide. Slide will be built on 2 clicks.Key Messages:Downstream RegulationORENCIA 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.1By 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.2By 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 cellT cellCTLA-4 binding: down-regulationof T cellORENCIA 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 agentin Early RAForest plot of risk ratios for clinical remissionRR 1.74; 95% CI (1.54, 1.98)no heterogeneity I2 0%; p = 0.496The 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, 201024
25 Forest plot of risk ratios for radiographic remission Efficacy of initial MTX vs MTX + biological agentin Early RAForest plot of risk ratios for radiographic remissionRR 1.30; 95% CI (1.01, 1.68)Significant heterogeneity I2 0%; p = 0.001Furthermore, 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, 201025
27 AGREE (MTX-naïve)AGREE study design: patients with early RA and poor prognostic factors*Inclusion criteriaEarly RA (≤2 years)MTX-naïveRF+ and/or anti-CCP2+≥1 erosionDouble-blind period1Open-label period2232Abatacept + MTX**(n=256)433Abatacept + MTXScreeningPlacebo + MTX**227(n=253)Day 1Year 1Year 21:1 RandomisationCo-primary endpointsDAS28 (CRP) <2.6Total Genant-modified Sharp scoreDAS28 (CRP)X-Ray progressionHAQ-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*100Abatacept + MTX (n=256)90Placebo + MTX (n=253)807060Proportion of patients achieving DAS28 remission (%)p<0.001504041.4%302023.3%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)EarlyreferralAbatacept provides sustained efficacy through 2 years in patients with early RA (≤2 years)*Year 1Abatacept added to MTX alone group1009080706055.2%Proportion of patients achieving DAS28-CRP remission (%, 95% CI)46.1%5044.5%403026.9%20102985141197253309365449553617729Visit dayAbatacept 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*2.0Abatacept added to MTX alone group1.75∆=0.25 Yr 1–21.48baseline in Sharp total scoreMean change from1.00.840.65∆=0.18 Yr 1–2p<0.001 for ∆Yr 1–2 vs ∆ BL–Yr 1 Patients with X-rays at all timepoints (n=207)∆=0.66 BL-Yr 10.0BaselineYear 1Year 2Visit dayAbatacept plus MTXMTX aloneMTX 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*100Abatacept + MTX (n=232)90MTX alone (n=227)80MTX alone switched to abatacept + MTX (n=227)7060Proportion of patients achieving HAQ normalisation (%)5040302010Year 1Year 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 MethotrexateThe slides will focus on the ATTEST trialSchiff M, et al. Ann Rheum Dis 2008;67:1096–103
33 Primary ObjectiveATTESTTo 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 monthsThe 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;67:1096–103the 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 ATTESTACR 50AbataceptInfliximabACR 20ACR 7080Visit day102030405060701295785113141169197225253281309337365ACR 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 similarACR20: 66% for abatacept, 69% for infliximabSchiff M, et al. Ann Rheum Dis 2008;67:1096–103The onset of action of infliximab was generally more rapid than abatacept however, by day 85, ACR 20 responses are similarSchiff M, et al. Ann Rheum Dis 2008;67:1096–1033434
35 ATTESTFurther improvement from Month 6 to 12 was observed with abatacept + MTX in ACR 20 responseATTESTACR 50AbataceptInfliximabACR 20ACR 7080Visit day102030405060701295785113141169197225253281309337365ACR 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 infliximabAt Day 365, the following response rates were observed for abatacept and infliximab, respectivelyACR 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 discontinuationSchiff M, et al. Ann Rheum Dis 2008;67:1096–103The onset of action of infliximab was generally more rapid than abatacept up to Day 85By 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 ATTESTAt 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;67:1096–103ITT population; D/C =Non responders *p<0.001; †p<0.05 and ‡p<0.01; Χ square test; p-values represent active drug versus placeboThe study was conducted in RA patients with inadequate response to MTX and was not designed to demonstrate non-inferiority or superiority of ORENCIA vs infliximabSchiff M, et al. Ann Rheum Dis 2008;67:1096–103
37 ACR responses at 12 months ATTESTAt 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;67:1096–103ITT population; D/c =Non respondersThe study was conducted in RA patients with inadequate response to MTX and was not designed to demonstrate non-inferiority or superiority of ORENCIA vs infliximabSchiff 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 YearsATTEST-LTEVisit (month)Infliximab patients switched to abataceptACR Responders (%)Open label LTE periodDB period89% (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:AbataceptACR20: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 intervalsAbatacept+MTXInfliximab 3mg/kg + MTX to abataceptSchiff M and Bessette L Clin Rheum 2010 ; 29:
40 COCHRANE META-ANALYSIS GLIMMIX: Odds Ratio (95% CI) Abatacept provides similar short-term efficacy at 6 months compared with other biologic agentsAbataceptPlacebo-adjusted analysis, based on ACR50 responsesMixed populations included:MTX-IRDMARD-IRAnti-TNF-IRAll biologic agents showed significantly greater efficacy compared with placebo, except anakinraAdalimumabAnakinraEtanerceptInfliximabRituximab0.11.010Favours PlaceboFavours BiologicGLIMMIX: Odds Ratio (95% CI)Studies included only approved dosages.Singh JA, et al. Cochrane Database Syst Rev 2009;4:CD40
41 Cumulative incidence of time to RAPID≥3.6 response* (%) Abatacept short-term efficacy is similar to other biologic agents in real life80AbataceptEtanerceptAdalimumabInfliximab60Cumulative incidence of time to RAPID≥3.6 response* (%)4020126543612302418Month*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 dataSynovitisOsteitisErosion3.02.01.51.01.00.40.5Adjusted mean change (95% confidence interval)0.0-0.3-1.0-2.0-1.9-3.0Abatacept + 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 RADisease duration: 3 yearsRheumatoid factor: positiveAnti-CCP Ab: positiveDAS28: 6.9Finger pain: VAS 616 months later:DAS28: 2.4Finger pain: VAS 016 MonthsConclusion: Excellent responderPersonal communication, Walter Grassi.
45 An increasing proportion of abatacept patients show sustained LDAS or DAS28 remission over 7 years Double-blind phaseOpen-label LTE phase302010405070608010090Response (95% CI)LDAS48.2% (37.4, 58.9) n/N=40/8369.7% (54.0, 85.4) n/N=23/33Responders (%)Remission51.5% (34.5, 68.6) n/N=17/3325.3% (15.9, 34.7) n/N=21/830.51234567YearDAS28 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*0.29Year 1*0.43*0.68*0.26Mean 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 ScoreSchiff 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 phaseOpen-label LTE phase100908074.2%(69.0, 79.4)Responders (%)7071.8%(67.2, 76.4)60504030200.51.01.52.02.53.03.54.04.55.0YearData 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- RCTAbatacept has a retention rate that is comparable with or higher than the anti-TNF agentsSubjects remaining at the end of 4 years of LTEn/N%Infliximab1295/51162%Etanercept2429/58174%Adalimumab3147/26256%Abatacept4*(IM101102)394/53973%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 reactions9.8% vs 6.7% placebo, mild-moderateMalignancy & Infection outcomes4134 Abatacept-treated patients compared with 41,529 DMARD treated patients in 5 cohortsNo 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) AbataceptPlaceboN = 1,955 (204)N = 989 (134)Double-Blind, Controlled (Biologic Background)N = 2,339Open-Label, UncontrolledN = 2,688Cumulative (Double-Blind and Open-Label)BLA/4MQG
51 Overview of Patients with Adverse Events Double-Blind, Controlled Study Periods Number (%) of PatientsAbataceptN = 1955Placebo N = 989AEsSAEsDiscontinuation due to AEsDeaths1736 (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 PatientsAbataceptN = 1955Placebo N = 989Preferred TermTotal Patients with InfectionsUpper Respiratory Tract InfectionNasopharyngitisSinusitisUrinary Tract InfectionInfluenzaBronchitis1051 (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 PatientsAbataceptN = 1955Placebo N = 989Preferred TermTotal Patients with Serious InfectionsPneumoniaCellulitisUrinary Tract InfectionBronchitisDiverticulitisPyelonephritis AcuteSepsis58 (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 activityAgeCorticosteroid therapyComorbid diseases: CVD, CHF, CRF, DM, lung diseasePrevious infectionJoint surgeryContributory role of DMARDs not clearly definedMoreland et al. J Rheum 2001;28:
55 Tuberculosis Cumulative Study Periods 2 cases of presumed tuberculosis with abataceptTuberculous Infection (Double-Blind):Presented with cervical lymphadenitis; diagnosis based on histologyPulmonary Tuberculosis Suspected (Open-Label)Presented with dry cough, fever, diaphoresis and crepitus; diagnosis based on clinical presentation and chest radiograph1 case of presumed tuberculosis with placeboTuberculosis - Suspect (Double-Blind):Unknown presentation; no definitive diagnosis
57 Clinical trial experience Integrated safety summaryContinued use of abatacept does not increase the risk of malignancy over timeClinical trial experienceShort term(2,331 p–y)Long term(9,752 p–y)Cumulative(12,132 p–y)PlaceboAbataceptMalignancies, 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 cancer0.21(0.07–0.50)0.13(0.07–0.23)0.15(0.09–0.23)NMSC0.82(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.
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 abataceptIn patients assessed for antibodies at least 42 days after discontinuation of abatacept, incidence of immunogenicity was 5.5% (103/1,888)1There 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# casesDevelopmentaltoxicity - animalsFetal problems – HumansDrug Discontinuation?ETA51-Preterm , VACTERLVert,anal, CVS, tracheobr fistula, renal, & LimbAt missed period, (+) pregnancy testINF81TOF, intestinal malrotationADA13Preterm, limb reduction, TracheobronchomalaciaRIT10B cell depletion (2nd/3rd tri)Lymphopenia (1st tri)12 mos pre-pregnancyABAT+/None (?)unknown10 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, ANAOstensen 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 RAIs efficacious in short and long term treatmentHas a high retention rateIs a safe and reliable drug