Indirect Treatment Comparison for Abatacept with Methotrexate Versus Other Recommended Biologic Agents in the Treatment of Patie

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Indirect Treatment Comparison for Abatacept with Methotrexate versus other recommended Biologic Agents in the Treatment of Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy in the UK

Maximilian Lebmeier 1, Louisa Pericleous 1, Peter Taylor 2, Robin Christensen 3, Pieter Drost 4, Patricia Guyot 5, Indra Eijgelshoven 5, Gert Bergman 5

1Bristol-Myers Squibb Pharmaceuticals Ltd, Uxbridge, Middlesex, United Kingdom, 2Imperial College London, London, United Kingdom,3The Parker Institute: Musculoskeletal Statistics Unit (MSU), Copenhagen, Copenhagen, Denmark, 4Bristol-Myers Squibb, Braine-l’Alleud, Belgium, 5Mapi Values, Houten, Netherlands

Background Figure 1 – Study selection process Figure 5 – ACR response rates (relative risks): treatment effect relative to placebo  Rheumatoid arthritis (RA) is a chronic, disabling, systemic Search strategy: inflammatory disorder with immune-mediated attacks of the synovial * 1980 – Jan 2010: Datastar (Embase, Medline, Medline in progress), Cochrane RCT Library * Jan 2010 – Oct 2010: Ovid (Embase, Medline, Medline in Progress), Cochrane RCT Library ACR20 ACR50 ACR70 joints. Retrieved from: Datastar, Ovid and Cochrane RCT Library: 1744 Adalimumab + MTX  Abatacept, a selective co-stimulation modulator, inhibits the co- * Other sources: BMS CSR, Conferences 2008 – 2010: ACR and EULAR and NICE/STA submission ACR20: 2.49 (1.76;3.21) Retrieved from: Other sources: 2 BMS CSR, 106 abstracts, 1 STA submission ACR50: 4.50 (2.23;7.62) stimulation of T cells and is licensed for the treatment of moderate ACR70: 7.17 (2.21;18.88) Certolizumab pegol + MTX to severe active rheumatoid arthritis in adult patients who responded Abstracts Excluded: 1620 ACR20: 2.85 (2.22;3.41) Non-RCT (882) ACR50: 4.79 (2.47;7.91) inadequately to methotrexate (MTX). Other disease (258) ACR70: 8.86 (3.14;23.31) Juvenile arthritis or non-adults (61) Etanercept + MTX  Biological therapies have the following major advantages over Intervention or comparison out of scope (219) ACR20: 1.80 (1.06;2.77) Outcome not of interest (161) 1 ACR50: 2.65 (1.24;6.82) conventional Disease Modifying Anti-Rheumatic Drugs (DMARDs) : Potential relevant full text publications: Other (16) ACR70: 3.73 (1.38;18.93) Datastar, Ovid and Cochrane RCT Library: 124 Conferences excluded: (105)  their development followed an increased understanding of Golimumab + MTX Other sources: (all) 2 BMS CSR, 106 abstracts, Outcome not of interest or naïve patients (86) ACR20: 2.12 (1.00;3.09) 1 STA submission Publication available (duplicate) (19) pathogenesis of inflammatory arthritis; ACR50: 2.85 (0.71;6.76)  their target is highly specific, with the mode of action easier to ACR70: 4.14 (0.69;16.76) Excluded: 57 Infliximab + MTX elucidate than with traditional DMARDs; Study design (15) ACR20: 1.81 (1.03;2.68) Outcomes not of interest (13) ACR50: 2.14 (0.46;5.72)  their use in clinical practice has added to the confidence of health- Population (8) ACR70: 3.57 (0.55;13.16) No MTX background, etc. (16) care professionals and patients to be able to satisfactorily control Potential relevant clinical effectiveness documents Other (7) Abatacept + MTX selected: No full paper available (2: 2+0) ACR20: 1.90 (1.24;2.57) disease resistant to conventional therapies, and remission of disease ACR50: 2.62 (1.24;4.95) 63 relevant clinical publications, 2 CSR and 1 STA ACR70: 3.72 (1.50;10.52) is an increasingly realistic aim; and submission Excluded for MTC: 46 1 conference abstract 0.3 0.5 1.0 2.0 4.0 8.0 16.0 32.0  for anti-TNF drugs, and some of the newer biological drugs, Open-label extension (11) Outcome not of interest (15) Favours placebo Favours treatment their action is usually rapid, with good symptom control, and Other cDMARDS (5) Naïve patients (6) significantly greater slowing of radiological progression than Non-relevant biologic (8) conventional DMARDs. Duplicate information (1)  The British Society for Rheumatology recommends biological Included for MTC 21 documents: therapies as options for the treatment of adults who have the Abatacept (5 pub, 2 CSR), Adalimumab (2 pub), Certolizumab (3 pub) + (1 STA report), Etanercept (3 pub), Figure 6 – ACR response rates at 6 months all treatments following characteristics 1: Golimumab (1 pub) + (1 abstract) and Infliximab (3 pub)  (i) active RA as measured by DAS28>3.2 with at least three or more tender and three or more swollen joints; and  (ii) have undergone trials of two conventional DMARDs, including MTX (unless contraindicated). Figure 2 – Network of studies  In 2010, abatacept received a license extension for RA patients who inadequately respond to DMARDS including MTX. ATTEST (Schiff 2008, CSR)  The effectiveness of abatacept in this patient population has been Abatacept 10 mg/kg Infliximab 3 mg/kg Adalimumab 40 mg every 4 weeks + MTX every 8 weeks + MTX every other week + demonstrated in a series of randomised controlled trials (RCTs): MTX ATTEST, AIM and the Kremer trial 2-7.

 In the UK NICE recommends the use of adalimumab, etanercept, AIM (Kremer 2006, CSR) ATTEST (Schiff 2008, CSR) Kremer 2005 (Kremer 2003) ATTRACT (Maini 1999, Lipsky 2000) ARMADA (Weinblatt 2003) infliximab and certolizumab pegol as treatment options in patients ATTEST (Schiff 2008, CSR) DE019 (Keystone 2004) who inadequately respond to two DMARDS. In anticipation of its

approval Golimumab was also considered as a relevant treatment RAPID I (Keystone 2008) Weinblatt 1999 Certolizumab 200 mg certolizumab submission) TEMPO (Klareskog 2004, Etanercept 25 mg every other week + Placebo + MTX option for this study. RAPID II (Smolen 2009) Van der Heijde 2006) twice weekly + MTX MTX  Data demonstrating efficacy of abatacept compared to alternative certolizumab submission) biological agents is lacking, however this can be overcome by means Conclusions GO-FORWARD (Keystone 2009, of an indirect treatment comparison. Genovese 2008 abstract)  In order to compare treatment effects, an indirect treatment  The results of the indirect treatment comparison showed that comparison adhering to the NICE scope, comparing abatacept abatacept is expected to be more efficacious than placebo, Golimumab 50 mg to adalimumab, etanercept, infliximab, certolizumab pegol and every 4 weeks + MTX and of comparable efficacy relative to the other recommended golimumab was performed 8. biologic DMARDs, in combination with MTX in the UK.  Outcome of the indirect treatment comparison was a reduction in  All biological agents in combination with MTX are more functional status as measured by the Health Assessment Questionnaire efficacious in terms of HAQ and ACR response rates than (HAQ) score, ACR20, 50 and 70% response rates at 6 months. treatment with MTX alone.  The TEMPO18,19 trial included a DMARD-IR population as opposed to  Abatacept in combination with MTX is expected to result in a MTX-IR population for the other trials. However, since etanercept a comparable improvement in HAQ score at 6 months as all Objective is only evaluated in two trials (Weinblatt 199917 and TEMPO) and other biological agents Weinblatt 1999 is a relatively old and small study (89 patients  At 6 months, all biological agents evaluated are expected To compare the efficacy of abatacept and alternative recommended included), the TEMPO trial was kept in the base case analysis and the to result in comparable proportion of ACR20/50 and 70 biologic DMARDs, via HAQ score and ACR response rates at 6 months, impact of excluding was evaluated in a sensitivity analysis. responders, although certolizumab pegol is expected to have in patients in the UK who have RA and show inadequate response to  DE019 Keystone 200413 study included an early escape for non- higher ACR 20 responses. These results should be interpreted methotrexate (MTX-IR). responders. The certolizumab pegol studies specifically withdrew with caution as some differences between the study designs patients who did not show an ACR20 response at weeks 12 and 1414- were observed; in particular the certolizumab pegol studies 16. The GO-FORWARD20,21 study provided rescue therapy for patients withdrew patients that did not show ACR responses at 12 and Method who did not achieve at least 20% improvement in both Tender Joint 14 weeks. Count (TJC) and Swollen Joint Count (SJC) by week 16. Based on its unique mechanism of action, relative efficacy and Systematic review  Patient eligibility criteria in the ARMADA12 (adalimumab), Weinblatt et clinical trial safety profile, abatacept is a suitable alternative to  A systematic literature search covering the period 1980 to October al 199917 (etanercept), and ATTRACT 11 (infliximab) trials only required currently licensed biologic DMARDs, in particular to infliximab, the 2010 was performed in 2010. The literature review involved searching patients to have a SJC and TJC of ≥6, respectively. These criteria only other biologic delivered by intravenous administration, while in Datastar (1980 – Jan 2010) and Ovid (Jan 2010 – Oct 2010), in are less stringent than those in other trials, and may reflect a less offering another working mechanism. Abatacept in combination which Medline and Embase databases were searched simultaneously. advanced state of RA (for example, in the AIM trial eligible patients with MTX should be available to patients with moderate to severe Additional searches were undertaken using the Cochrane Library, required ≥10 swollen joints and ≥12 tender joints). RA who are refractory to MTX alone. NICE technology appraisals, ACR and EULAR conferences (2008 to 2010). Network meta-analysis results  For inclusion, the studies had to meet the following predefined  HAQ change from baseline at 6 months. References selection criteria:  All treatments were more efficacious versus placebo (Figure 3 & 4)  Study design and population: any RCT for the treatment of RA with  Abatacept is expected to be as efficacious as all other biologic 1. http://www.rheumatology.org.uk/includes/documents/cm_docs/2010/r/2_ra_guidelines_ an inadequate response or intolerance to previous treatment with on_eligibility_criteria_for_the_first_biological_therapy.pdf DMARDs, with point estimates ranging from -0.11 (vs. infliximab) 2. A Phase III, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Clinical Use Study at least one conventional DMARD (MTX, sulfasalazine, leflunomide, to 0.09 (vs. certolizumab pegol) to Evaluate the Efficacy and Safety of BMS-188667 in Combination with Methotrexate vs. azathioprine, gold salts or minocycline). Methotrexate Alone in Subjects with Active Rheumatoid Arthritis and Inadequate Response  Interventions: treatment combinations of MTX with abatacept, to Methotrexate: Bristol-Myers Squibb; 2004. Clinical Study Report IM101102. [AIM trial] Figure 3 – Relative HAQ CFB versus placebo at 6 months 3. Kremer J, Genant H, Moreland L, et al. Effects of abatacept in patients with methotrexate- infliximab, etanercept, adalimumab, certolizumab pegol resistant active rheumatoid arthritis: a randomized trial. Annals of Internal Medicine 2006; or golimumab in comparison with each other or with MTX 144(12):865-876. 4. Kremer J, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective monotherapy (placebo). Adalimumab + MTX -0.33 (-0.51;-0.16) inhibition of T-cell activation with fusion protein CTLA4Ig. The New England Journal of  Key outcome measures: HAQ change from baseline (CFB) and ACR Medicine 2003; 349(20):1907-1915. Certolizumab pegol + MTX response rates at 6 months (24-28 weeks) of treatment. -0.39 (-0.54;-0.23) 5. Kremer J, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double- blind, Etanercept + MTX randomized, placebo-controlled trial. Arthritis and Rheumatism 2005; 52(8):2263-2271. Data collection -0.28(-0.48;-0.08) 6. A Phase III, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Comparative  Golimumab + MTX Details of design, selection criteria, study population characteristics, -0.34(-0.58;-0.09) Study of abatacept or Infliximab in Combination with Methotrexate in Controlling Disease interventions, outcome measures, length of follow-up and results Activity in Subjects with Rheumatoid Arthritis Having an Inadeqaute Clinical Response to Infliximab + MTX were extracted for each study selected. -0.19(-0.35;-0.03) Methotrexate. Bristol-Myers Squibb; 2006. Clinical Study Report IM101043. [ATTEST trial] 7. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs  For the analyses, only data pertaining to treatments using the Abatacept + MTX -0.30(-0.42;-0.16) placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled recommended dosages licensed for treatment in the UK were study in patients with rheumatoid arthritis and an inadequate response to methotrexate. -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 Annals Rheum Dis 2008; 67(8):1096-1103. included. Favours treatment Favours placebo  8. http://guidance.nice.org.uk/TA/Wave24/16/Scope/pdf/English For HAQ CFB, the variability or uncertainty measures were directly 9. Jansen JP, Crawford B, Bergman G, et al. Bayesian Meta analysis of multiple treatment extracted from the publications. comparisons: an introduction to mixed treatment comparisons. Value Health 2008; 11: 956-64 Analysis 10. Lipsky PE, van d, St C, Furst DE, Breedveld F, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis  The quantitative results of the different interventions from the studies Figure 4 – Adjusted HAQ CFB at 6 months with Concomitant Therapy Study Group. The New England Journal of Medicine 2000; identified in the systematic review were combined simultaneously 343(22):1594-1602. using indirect treatment comparison techniques, also known as 11. Maini R, St C, Breedveld F, Furst D, et al. Infliximab chimeric anti-tumour necrosis factor 9 alpha monoclonal antibody versus placebo in rheumatoid arthritis patients receiving Bayesian network meta-analyses . concomitant methotrexate: a randomised phase III trial ATTRACT Study Group. Lancet  Analyses were performed for the endpoints of HAQ CFB (continuous 1999; 354(9194): 1932-1939. outcome) and ACR response criteria (dichotomous outcomes) using 12. Weinblatt M, Keystone E, Furst D, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients placebo (in combination with MTX) as the common comparator. taking concomitant methotrexate: the ARMADA trial. Arthritis and Rheumatism 2003; 48(1):35-45. 13. Keystone E, Kavanaugh A, Sharp J, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab a human anti-tumor necrosis factor monoclonal antibody Results in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis and Rheumatism 2004; Systematic review 50(5):1400-1411.  Figure 1 illustrates the selection process of the studies eventually 14. Certolizumab pegol (CIMZIA®) for the treatment of Rheumatoid Arthritis. Single Technology Appraisal (STA) manufacturer submission to NICE. June 22nd 2009. http://www.nice.org. identified for the indirect treatment comparison. Twenty-one uk/nicemedia/pdf/6.%20Final%20draft%20NICE%20submission%20CZP%20220609.pdf documents were identified by the literature search, including 11  ACR response criteria. 15. Keystone E, Heijde D, Mason D, Jr., et al. Certolizumab pegol plus methotrexate is individual studies for abatacept2-7, infliximab6,7,10,11, adalimumab12,13,  All treatments show better ACR responders to placebo at ACR 20, significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: 14-16 17-19 20,21 findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo- etanercept , certolizumab pegol , and golimumab . 50 and 70 (figure 5 and 6) controlled, parallel-group study. Arthritis and Rheumatism 2008; 58(11):3319-3329.  All studies were randomised, double-blind and placebo-controlled trials.  All biologic DMARDS evaluated are expected to result in 16. Smolen J, Landewé RB, Mease P, et al. Efficacy and safety of certolizumab pegol plus  Figure 2 illustrates the network of the RCTs used for the indirect comparable proportions of ACR20/50/70 responders, although methotrexate in active rheumatoid arthritis: the RAPID 2 studies a randomised controlled treatment comparison. All studies evaluated a one biologic agent to trial. Ann Rheum Dis 2009; 68(6):797-804. the findings suggest that certolizumab pegol is expected to have 17. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor 6,7 placebo in combination with MTX except for the ATTEST trial which a higher ACR20 response rate at 6 months than other biologic necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving compared both abatacept + MTX and infliximab + MTX to placebo in agents (figure 5 and 6). methotrexate. The New England Journal of Medicine 1999; 340(4):253-259. combination with MTX. 18. Van der Heijde DM, Klareskog L, Singh A, et al. Patient reported outcomes in a trial of combination therapy with etanercept and methotrexate for rheumatoid arthritis: the Sensitivity analyses TEMPO trial. Ann Rheum Dis 2006; 65(3):328-334. Comparability in study and patient characteristics across the  Removing the TEMPO trial did not significantly impact the mean HAQ 19. Klareskog L, van d, de J, Gough A, Kalden J, et al. Therapeutic effect of the combination studies CFB at 6 months. Abatacept still showed comparable efficacy to the of etanercept and methotrexate compared with each treatment alone in patients In general, all studies were similar in terms of study design, inclusion with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; other biologic treatments, including etanercept (difference in HAQ 363(9410):675-681. criteria and baseline patient characteristics. However, some notable CFB vs. etanercept-0.03 [95%CrL: -0.25; 0.19]). 20. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour differences should be mentioned and are listed below  In the base case analysis all randomised patients were included for necrosis factor given by monthly subcutaneous injections, in active rheumatoid arthritis  All studies reported similar HAQ scores at baseline, except for the AIM study, although patients from 1 site were excluded from despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis 2009; 68(6):789-796. 4,5 the study by Kremer 2005 which presented a lower mean HAQ the efficacy analyses because of protocol violations. The impact of 21. Genovese MC, Keystone EC, Hsia EC, et al. Golimumab Significantly Improves Physical baseline value. This difference was likely to be due to the use of the this on the findings was evaluated in a sensitivity analyses and did Function, Health-Related Quality of Life, and Fatigue in Rheumatoid Arthritis Patients: modified HAQ (mHAQ) instead of the traditional HA disability index. not change the relative efficacy of abatacept as compared to other Results from the GO-FORWARD Study Paper presented at: ACR/ARHP Annual Scientific Meeting 2008; Oct 24-29, 2008; San Francisco, CA. Both instruments are strongly correlated with a Pearson correlation biologic agents. 22. Uhlig T, Haavardsholm EA, Kvien TK. Comparison of the Health Assessment Questionnaire coefficient of 0.8822 so the difference in the instruments is assumed to (HAQ) and the modified HAQ (MHAQ) in patients with rheumatoid arthritis. Rheumatology have no impact on the relative treatment effect. (Oxford). 2006 Apr; 45(4):454-8.