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Abatacept treatment for rheumatoid arthritis

Abatacept treatment for rheumatoid arthritis Significant advances in our understanding of RA and its management have been made in the past decade, resulting in earlier intervention with biologic DMARDs, particularly in patients with evidence of aggressive, erosive disease. Here, one such biologic therapy, the T-cell co-stimulation modulator abatacept, is dis- cussed, exploring clinical evidence published to date on its use in patients with very early arthritis/early RA who are MTX naıve, and in patients with established RA and an inadequate response to MTX or TNF antagonists. Data from relevant clinical trials are overviewed, discussing the clinical efficacy of abatacept in early disease, the clinical outcomes over long-term treatment in different patient populations and the effects of abatacept on structural damage. Findings from integrated safety analyses of abatacept clinical trial data, representing 10 366 patient-years of exposure are described, and clinically important safety events, including serious infections, malignancies and autoimmune events, are highlighted. It is concluded that abatacept represents an effective treatment option with an established safety profile across different patient populations, including patients with both early and erosive RA and those with established disease. Furthermore, efficacy data from studies in patients with early disease suggest that the risk–benefit profile of abatacept may be more favourable when introduced earlier in the treatment paradigm. Key words: Rheumatoid arthritis, Biological therapies, Clinical trials, Abatacept. ´ ´ guidelines from the strategie therapeutique de la polyar- Introduction thrite (therapeutic strategies in RA) working group of the Significant advances in our understanding of RA and its French Society of Rheumatology (study and follow-up of management have demonstrated that early intervention, undifferentiated early arthritis). The latter specifically rec- particularly in patients with evidence of aggressive, ommend very early use (46 months from diagnosis) of erosive disease, can prevent the irreversible structural biologics in patients with poor prognostic factors [9]. damage characteristic of RA. The benefit observed is However, one needs to take into account the benefit– often optimized when combination treatment with both risk profile of the therapeutic options available when con- traditional and biologic DMARDs is administered [1–6]. sidering this course of action [10]. Clinical practice guidelines recommend that the majority Biologic DMARDs, including the TNF antagonists— of patients should start treatment with a conventional infliximab, etanercept, adalimumab, golimumab and DMARD, and in cases of treatment failure a biologic certolizumab—the B-cell depleter rituximab, the IL-6 should be added; however, combination therapy should receptor antagonist tocilizumab and the T-cell co- be considered early in DMARD-naı¨ve patients if they pre- stimulation modulator abatacept, have demonstrated sent with poor prognostic factors, such as erosion, posi- clinical efficacy and radiographic benefit in patients with tivity for anti-CCP or RF and high disease activity [7]. moderate-to-severe RA who have demonstrated an inad- Progress towards a framework for identifying patients equate response to at least one non-biologic DMARD [11– with early disease who are at high risk of developing ero- 18]. Furthermore, efficacy benefits have been seen with sive and progressive RA—and thus would benefit from some biologics in patients with severe, active and pro- early DMARD intervention—has been made in the form gressive early disease not previously treated with of joint guidelines from the EULAR and the ACR [8], and conventional DMARDs [19–23]. This review will focus on one of these biologic agents, abatacept, and the clinical experience to date examining School of Medicine, University of Colorado, Denver, CO, USA. intervention in various patient populations, including Submitted 31 March 2010; revised version accepted 29 July 2010. those with very early arthritis/early RA who are MTX naı¨ve Correspondence to: Michael Schiff, School of Medicine, University of [23, 24], and in patients with established RA and an inad- Colorado, 5400 South Monaco Street, Greenwood Village, CO 80111, USA. E-mail:[email protected] equate response to MTX [25, 26] or TNF antagonists [27]. The Author(s) 2010. Published by Oxford University Press on behalf of The British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. RE VIEW Michael Schiff Selective co-stimulation modulation seen in physical function at Year 1, for abatacept plus MTX- vs MTX alone-treated patients [23]. In addition, aba- Abatacept is a selective co-stimulation modulator that in- tacept plus MTX demonstrated a higher likelihood of hibits T-cell activation by binding to CD80/86, and mod- increasing or maintaining initial improvements in ACR re- ulating its interaction with CD28 [28]—a co-stimulatory sponses and physical function over 1 year than MTX alone signal necessary for the full activation of T cells. in patient-level post hoc analyses [35]. Activated T cells are implicated in the pathogenesis of Improvements in disease activity and ACR responses RA via amplification of the inflammatory cascade that were sustained or improved over the second year for pa- leads to joint inflammation and destruction in RA [29, tients remaining on abatacept plus MTX therapy, with 30]. The effect of abatacept on the inflammatory cascade 55.2% achieving remission at Year 2 [36]. After patients has been demonstrated by quantitative PCR studies and randomized to MTX alone were initiated on abatacept plus evaluation of synovial biopsies in patients with active MTX at Year 1, improvements in these efficacy endpoints RA who had previously failed TNF antagonist therapy. were seen, with 44.5% in remission at Year 2, increased Findings from these studies demonstrate a reduction in from 26.9% at Year 1 [36]. expression of most inflammatory genes, and a small, Changes from baseline to Year 1 in Genant-modified largely non-significant reduction in cellular content follow- Sharp TS and erosion score (ES) were significantly lower ing abatacept treatment; this suggests that abatacept re- for MTX-naıve patients randomized to abatacept plus duces the inflammatory status of the synovium without MTX vs MTX alone (Fig. 1A) [23]. Furthermore, there was disrupting cellular homoeostasis [31]. These observations an increasing degree of inhibition of progression in Year 2 are supported by clinical trial data, which have demon- relative to Year 1 for patients originally randomized strated a reduction in serum levels of inflammatory bio- to abatacept [37]. For patients originally receiving markers to within ‘normal’ levels following abatacept MTX alone, structural damage progression was reduced treatment, implying that abatacept may help to normalize over Year 2 relative to Year 1, following the addition of the levels of downstream inflammatory mediators. The abatacept [37]. However, overall structural damage pro- unique mechanism of action of abatacept may offer gression at Year 2 remained greater for these patients significant therapeutic benefit to patients by specifically compared with patients who received abatacept from addressing the underlying RA pathophysiology [32]. baseline [37]. Abatacept study to determine the effectiveness in Overview of abatacept clinical preventing the development of RA in patients with experience undifferentiated inflammatory arthritis and to evaluate safety and tolerability Early disease The potential for early treatment with abatacept to delay Abatacept study to gauge remission and joint damage the development or progression of RA in patients with progression in MTX-naı¨ve patients with early erosive RA very early disease was investigated in the Phase II, The 2-year abatacept study to gauge remission and joint exploratory, 2-year ADJUST trial [abatacept study to damage progression in MTX-naı¨ve patients with early ero- determine the effectiveness in preventing the develop- sive RA (AGREE) study consisted of a 12-month double- ment of RA in patients with undifferentiated inflammatory blind (DB) period followed by a 12-month open-label arthritis (UA) (ADJUST) trial and to evaluate safety and period in MTX-naı¨ve patients with early RA [23]. Patients tolerability]. Following 6 months of DB, randomized (1 : 1) had poor prognostic factors that are highly predictive of treatment with either abatacept at the approved dose an aggressive disease course, including high CRP levels, (n = 28) or placebo (n = 28), abatacept treatment was radiographic evidence of erosions and seropositivity for terminated. The proportion of patients who developed RF or anti-CCP2. Patients were randomized 1 : 1 to re- RA according to ACR 1987 criteria [38] or discontinued ceive abatacept (approved dose [33]) plus MTX (n = 256) due to lack of efficacy at Year 1 was assessed. or MTX alone (n = 253) [23]. All patients received open- Patients had a short disease duration (Table 1), and label abatacept plus MTX from Year 1 onwards. The although patients did not have RA according to ACR co-primary endpoints were 28-joint DAS (DAS-28)-defined 1987 criteria, more than half already had evidence of remission and joint damage progression [Genant-modified one or more erosion. As such it is likely that a significant [34] total score (TS)] at Year 1. At baseline, patients proportion had early RA. When abatacept was stopped at had short disease duration and high disease activity Month 6, 22 and 17 patients treated with abatacept and (Table 1). placebo, respectively, remained in the trial (i.e. had not At Year 1, significantly more patients treated with aba- developed RA); by Year 2, 7 and 4 patients remained in tacept plus MTX achieved DAS-28 (CRP)-defined remis- the trial. Numerically more placebo than abatacept pa- sion and ACR50 and ACR70 responses (Table 2), and the tients developed RA over 1 year (66.7 vs 46.2%), although difference between treatment arms was significant by CI overlapped. Radiographic assessments demonstrated Month 2. Over 1 year, 27.3 vs 11.9% of abatacept plus an inhibitory effect on structural damage progression at MTX- vs MTX alone-treated patients (P< 0.001) achieved Month 6, which was maintained for 6 months following a major clinical response (ACR70 maintained for 56 con- therapy cessation, with similar trends observed for MRI- secutive months) [23]. Significant improvements were also assessed osteitis, erosion and synovitis [24]. 438 www.rheumatology.oxfordjournals.org Abatacept in RA www.rheumatology.oxfordjournals.org 439 TABLE 1 Baseline demographics and clinical characteristics Patients with inadequate Patients with inadequate MTX-naı¨ve patients response to MTX response to anti-TNF agents Phase IIB AGREE ADJUST abatacept AIM ATTEST ATTAIN ARRIVE abatacept + MTX abatacept 10 mg/kg group abatacept + MTX abatacept + MTX abatacept + DMARD all patients Parameter group (n = 256) group (n = 28) (n = 115) group (n = 433) group (n = 156) group (n = 258) (n = 1046) Demographics Age, years 50.1 (12.4) 44.8 (10.9) 55.8 (range: 17–83) 51.5 (12.9) 49.0 (12.5) 53.4 (12.4) 54.4 (12.4) Women, % 76.6 71.4 75 77.8 83.3 77.1 81.2 Caucasian, % 78.9 89.3 87 87.5 80.8 96.1 92.4 Disease duration 6.2 (7.5) months 8.8 (4.2) months 9.7 (9.8) years 8.5 (7.3) years 7.9 (8.5) years 12.2 (8.5) years 11.6 (9.5) years MTX dose, mg/week NA NA 15.0 (4.4) 16.1 (3.6) 16.5 (3.7) 15.2 (5.3) – Clinical characteristics Tender joints, n 31.3 (14.8) – 30.8 (12.2) 31.0 (13.2) 31.6 (13.9) 31.2 (13.0) 17.8 (6.0) Swollen joints, n 22.9 (11.3) – 21.3 (8.4) 21.4 (8.8) 21.3 (8.6) 22.3 (10.2) 13.6 (5.5) Pain, 100 mm VAS – – 62.1 (21.4) 63.3 (21.1) – 70.8 (19.8) – HAQ-DI score (0–3) 1.7 (0.7) 0.8 (0.6) M-HAQ: 1.0 (0.5) 1.7 (0.7) 1.8 (0.6) 1.8 (0.6) 1.7 (0.6) Patient global assessment, 100 mm VAS – – 60.1 (20.7) 62.7 (21.2) – 69.2 (19.7) 72.9 (16.5) Physician global assessment, 100 mm VAS – – 62.1 (14.8) 68.0 (16.0) – 68.8 (17.7) – DAS-28 CRP: 6.3 (1.0) CRP: 3.6 (1.1) CRP: 5.5 (0.63) – ESR: 6.9 (1.0) – CRP: 6.2 (0.7) CRP level, mg/dl 3.1 (3.1) 1.12 (1.43) 2.9 (2.8) 3.3 (3.1) 3.1 (2.7) 4.6 (4.0) 2.1 (3.0) RF, % 96.1 85.7 – 81.8 87.2 73.3 61.3 ES 5.4 (6.1) 3.2 (3.5) NA 21.7 (18.1) NA NA NA JSN score 2.1 (4.2) 0.1 (0.4) NA 22.8 (20.2) NA NA NA TS 7.5 (9.7) 3.3 (3.6) NA 44.5 (37.3) NA NA NA Anti-rheumatic medication at enrolment, n (%) MTX 0 0 99.1% 433 (100) 156 (100) 195 (75.6) 730 (69.8) Other DMARDs 7 (2.7) 0 16.5% 53 (12.2) – 72 (27.9) – Biologics 0 0 NA 1 (0.2) – 7 (2.7) – CS 131 (51.2) 5 (17.9) 60.0% 312 (72.1) 118 (75.6) 181 (70.2) 611 (58.4) NSAIDs 203 (79.3) 22 (78.6) – 370 (85.5) 133 (85.3) 181 (70.2) – Other – – – 1 (0.2) – – – Data are taken from [23, 24, 75, 39, 42, 46, 49, 51]. Data are mean (standard error) unless otherwise stated. Data for placebo control arms not shown. NA: not applicable; VAS: visual analogue scale. Michael Schiff Established disease MTX-inadequate responders Phase IIb trial The Phase IIb trial in MTX-inadequate responders was a 12-month, randomized (1 : 1 : 1) DB study designed to evaluate the safety and efficacy of abatacept [2 mg/kg (n = 105) or 10 mg/kg (n = 115)] plus MTX compared with placebo plus MTX (n = 119) [39]. The primary endpoint was ACR20 response at Month 6. Patients completing the DB period were eligible to enter an open-label long-term ex- tension (LTE), in which all patients received abatacept (approved dose). Results from the LTE have been pub- lished up to 5 years [25], with experience reported up to 7 years [40]. Patients had high baseline disease activity (Table 1). At Year 1, significantly greater improvements in RA signs and symptoms (Table 2) and clinically meaningful improvements in physical function were seen with abat- acept 10 mg/kg vs placebo [39]. The 2 mg/kg dose was considered suboptimal and was not pursued in Phase III. Over 12 months, serum levels of inflammatory biomark- ers were significantly lower with abatacept 10 mg/kg vs placebo treatment, with numerical reductions in TNF-a and RF also reported [41]. In particular, sIL-2R, IL-6, soluble E-selectin and TNF-a were brought to within the range considered normal. Of the patients who entered the LTE, 59 and 52% re- mained on treatment at Years 5 and 7, respectively, with 11.0% discontinuing due to lack of efficacy [25, 40]. Sustained efficacy improvements over 5 years were observed in patients remaining on treatment (Fig. 2) [25]. Furthermore, low disease activity state (LDAS) and ACR70 were reported in 70 and 50% of patients at Year 7, respectively [40]. Reductions in functional disability were also maintained over 5 and 7 years [25, 40]. Abatacept in inadequate responders to MTX The Phase III AIM trial included a similar patient popula- tion of MTX-inadequate responders with established dis- ease and high baseline disease activity (Table 1) [26, 42]; however, this trial also evaluated radiographic outcomes. The design of this trial has been reported extensively [18, 42]. Here, patients received either abatacept (approved dose; n = 433) or placebo (n = 219) on a background of MTX for 1 year, after which patients who continued into the LTE received open-label abatacept [26]. The co-primary endpoints were ACR20 response, clinically meaningful improvement in physical function and joint damage progression as assessed by Genant-modified ES. Approximately three-quarters of patients who entered the LTE were still participating after 5 years, with 5.0% of discontinuations during the LTE due to lack of efficacy and 8.7% to AEs [26]. Yearly discontinuations were generally low (Years 2, 3, 4 and 5: 12.2, 6.3, 7.1 and 8.0%, respectively). Through the 1-year DB period, improvements in clinical efficacy and physical function were significantly greater for abatacept vs placebo (Table 2; [42]). Post hoc analyses demonstrated statistically significant improvements from 440 www.rheumatology.oxfordjournals.org TABLE 2 Clinical efficacy with abatacept across clinical trials Patients with inadequate response MTX-naı¨ve patients Patients with inadequate response to MTX to anti-TNF agents Efficacy outcome AGREE, Year 1 [23] Phase IIb, Year 1 [38] AIM, Year 1 [41] ATTEST, Month 6 [45] ATTAIN, Month 6 [48] Abatacept vs placebo ACR20, % NR 62.6 vs 36.1 (P< 0.001) 73.1 vs 39.7 (P< 0.001) 66.7 vs 41.8 (P< 0.001) 50.4 vs 19.5 (P< 0.001) ACR50, % 57.4 vs 42.3 (P< 0.001) 41.7 vs 20.2 (P< 0.001) 48.3 vs 18.2 (P< 0.001) 40.4 vs 20.0 (P< 0.001) 20.3 vs 3.8 (P< 0.001) ACR70, % 42.6 vs 27.3 (P< 0.001) 20.9 vs 7.6 (P = 0.003) 28.8 vs 6.1 (P< 0.001) 20.5 vs 9.1 (P = 0.019) 10.2 vs 1.5 (P = 0.003) LDAS, % 54.3 vs 36.8 (P< 0.001) 49.6 vs 21.9 (P< 0.05) 42.5 vs 9.9 (P< 0.001) 20.7 vs 10.8 17.1 vs 3.1 (P< 0.001) Remission, % 41.4 vs 23.3 (P< 0.001) 34.8 vs 10.1 (P< 0.001) 23.8 vs 1.9 (P< 0.001) 11.3 vs 2.9 10.0 vs 0.8 (P< 0.001) HAQ-DI response, % 71.9 vs 62.1 (P = 0.024) 49.6 vs 27.7 (P< 0.001) 63.7 vs 39.3 (P< 0.001) 61.5 vs 40.9 (P = 0.001) 47.3 vs 23.3 (P< 0.001) a b Data are taken from [23, 39, 42, 46, 49]. Abatacept data are for the 10 mg/kg group. Data on file; LDAS: DAS-28 43.2; remission: DAS-28< 2.6; HAQ response: change from baseline in HAQ-DI50.3 U for all trials except for the Phase IIb trial, defined as HAQ-DI mean change from baseline 50.22 U; NR: not reported. Abatacept in RA FIG.1 Radiographic progression in early and established RA over 1 year of abatacept treatment. (A) Mean change from baseline in TS, ES and JSN at Year 1 of the AGREE trial for abatacept plus MTX- and MTX alone-treated patients [23]. Adapted from Westhovens et al. [23] copyright 2009, with permission from the BMJ Publishing Group Ltd. (B) Mean change from baseline in TS, ES and JSN at Year 1 of the AIM trial for abatacept- and placebo-treated patients [42]. ABA: abatacept; PBO: placebo. Adapted from Kremer et al. [42]. Months 6 to 12 in the proportions of abatacept-treated still achieve a clinically meaningful response over time patients achieving ACR50 and ACR70 responses [42]. [43]. The sustainability of patient-level responses was Throughout the open-label LTE, efficacy improvements also evaluated for the LTE [44], revealing that the majority were maintained for patients who remained on treatment of patients who had achieved LDAS, remission or normal- [18, 26]. At Year 5, 33.7% of patients had achieved ized physical function (i.e. HAQ-DI4 0.5) by Year 1 DAS-28-defined remission, with 83.6, 61.1 and 39.6% of sustained these outcomes through 5 years. patients achieving ACR20, ACR50 and ACR70 responses, At the end of the DB period, a significant inhibition of respectively [26]. Approximately three-quarters of patients structural damage progression was seen with abatacept achieved clinically meaningful improvements in physical vs placebo, with 50% reduction in change from baseline function [improvement of 50.3 in HAQ-disability index in Genant-modified Sharp scores compared with placebo (Fig. 1B) [42]. Progressive reductions in changes from (HAQ-DI)] at Year 5 [26]. In post hoc, patient-level analyses from AIM, the major- baseline were observed in ES, joint-space narrowing ity of patients maintained or improved their treatment re- (JSN) score and TS over 5 years, for patients originally sponse or disease status from Months 3 to 12, suggesting randomized to abatacept, with progression reduced that patients who have not responded by Month 3 may by 50% in the second year relative to the first and www.rheumatology.oxfordjournals.org 441 Michael Schiff FIG.2 Long-term clinical efficacy over 5 years of treatment with abatacept. The proportion of patients originally randomized to the 10 mg/kg abatacept group of the Phase IIb trial experiencing LDAS (DAS-28 CRP43.2) and DAS-28-defined remission (DAS-28 CRP< 2.6) by visit day. Responses are based on the intent-to-treat population for patients with data available at the visit of interest (as-observed analysis). Broken line represents the DB period; data are presented with 95% CIs. Reproduced from Westhovens et al. [25] with permission from the Journal of Rheumatology. continued reductions in yearly progression up to Year 5. with abatacept (Table 2). Improvements in ACR20, ACR50 A similar trend was also seen over 2 years in MTX-naı¨ve and ACR70 responses at Month 6 were significantly patients, in the AGREE trial [37]. Once the patients origin- greater vs placebo for both abatacept and infliximab. ally randomized to placebo had switched to abatacept, The onset of ACR20 responses was generally more annual mean changes progressively decreased in a similar rapid for infliximab than abatacept, but responses were trend; however, differences in structural damage were still similar by Month 3. By Year 1, DAS-28 (ESR) reductions seen between the groups at Year 5 [45]. Furthermore, ap- of 2.88 and 2.25 were seen for abatacept- and proximately half of all patients treated with abatacept over infliximab-treated patients, respectively, and ACR re- the entire study period exhibited no structural damage sponses were maintained from Month 6 with abatacept progression (change in TS of 40) through 5 years. but not with infliximab treatment (Fig. 3) [46]. The ATTEST trial continued through 2 years; during the Abatacept or infliximab versus placebo, a trial for second year of treatment, patients receiving infliximab tolerability, efficacy and safety in treating RA were switched to abatacept. Efficacy benefits observed A third trial in MTX-inadequate responders provided the with abatacept in Year 1 were maintained through opportunity to evaluate two biologics in a single study. 2 years, as demonstrated by assessments of signs and The placebo- and active-controlled ATTEST (abatacept symptoms, physical function and disease activity [47]. In or infliximab versus placebo, a trial for tolerability, efficacy patients who switched from infliximab to abatacept at and safety in treating RA) study, although not powered to Year 1, efficacy benefits increased over the second year detect superiority, provided information on the relative and were similar to the original abatacept group by Year 2 efficacy and safety profiles of abatacept and infliximab [47]. In addition, a considerable proportion of infliximab vs placebo in the same population [46]. Patients with non-responders (i.e. ACR20 non-responders, or patients an inadequate response to MTX were randomized with high disease activity state) who switched to abata- (3 : 3 : 2) to abatacept (approved dose, n = 156), infliximab cept after 1 year achieved improved clinical responses (3 mg/week, n = 165) or placebo (n = 110), with back- with abatacept over the second year [48]. For patients ground MTX. At Month 6, patients in the placebo group who had achieved LDAS or remission following 1 year of were switched to abatacept, and infliximab and abatacept infliximab, a high proportion were able to maintain these groups continued to Year 1, with blinding maintained. disease states over Year 2. The primary endpoint of this trial, reduction in DAS-28 TNF antagonist-inadequate responders abatacept trial in (ESR) at Month 6 for abatacept vs placebo, was met, with treatment of anti-TNF inadequate responders mean reductions of 2.53 vs 1.48 (P< 0.001), respect- ively. The proportion of patients achieving states of low The efficacy of abatacept in patients with RA who have an disease activity and DAS-28 remission was also greater inadequate response to TNF antagonists was examined in 442 www.rheumatology.oxfordjournals.org Abatacept in RA FIG.3 Clinical efficacy over 1 year in the ATTEST trial. ACR responses achieved over Year 1 of the ATTEST trial. Data are presented for the intent-to-treat population with a last observation carried forward analysis. Infliximab was administered on Days 1, 15, 43, 85 and then every 56 days thereafter; abatacept dosing occurred at each visit day. Reproduced from Schiff et al. [46] copyright 2008, with permission from the BMJ Publishing Group Ltd. the Phase III ATTAIN (abatacept trial in treatment of Patients in this trial had high levels of disease activity at anti-TNF inadequate responders) trial [49]. Patients had baseline (Table 1); overall, the inclusion criteria resulted in a patient population that was more representative of clin- an inadequate response to 53 months of treatment with etanercept, infliximab or both. Patients were randomized ical practice than often included in randomized controlled (2 : 1) to receive abatacept (n = 258) or placebo (n = 133), trials [51]: patients had an inadequate response to up to plus one or more background DMARD, for the 6-month three TNF antagonists that they could have failed for effi- cacy, safety or tolerability reasons. Patients were eligible DB period; patients entering the LTE received open-label even if they had a positive purified protein-derivative test abatacept. The co-primary endpoints were ACR20 re- result. Abatacept could be administered as monotherapy sponse and improvement in physical function. Patients (USA only), and patients were not limited to a particular had high baseline disease activity (Table 1). After 4 background DMARD. years of open-label therapy, approximately half of all pa- Similar, clinically meaningful, improvements were seen tients who entered the LTE remained on treatment [50]. in disease activity, physical function and health-related At the end of the 6-month DB period, improvements in quality of life, regardless of whether there was a washout clinical efficacy and physical function were significantly period or not. Post hoc analyses revealed that numerically greater for abatacept vs placebo (Table 2). The proportion more patients who had previously failed one TNF antag- of patients achieving improvements in ACR20, ACR50 and onist achieved DAS-28-defined remission and LDAS than ACR70 responses increased over 4.5 years of treatment those who had failed two or more [51]. for patients who remained on treatment, as did the proportions of patients achieving LDAS and remission (18.3 vs 37.1% and 11.1 vs 25.7% at Month 6 vs Year Safety summary 4.5, respectively), and clinically meaningful improvements in physical function [50]. Safety assessments from the trials discussed above have demonstrated that the incidence of overall AEs and ser- Abatacept researched in rheumatoid arthritis patients ious AEs (SAEs) was generally comparable for abatacept- with an inadequate anti-TNF response to validate and placebo-treated patients [23, 24, 39, 42, 46, 49], effectiveness although in some trials the frequency of SAEs was re- The second trial conducted in TNF-inadequate respond- ported to be higher with abatacept [42]. The safety of ers was a Phase IIIb/IV, 6-month, open-label study. The long-term abatacept treatment is reported to be consist- ARRIVE (abatacept researched in rheumatoid arthritis ent, with the incidence of overall AEs and SAEs remaining patients with an inadequate anti-TNF response to validate stable up to 7 years [40]. effectiveness) trial was the first to assess the safety of Events that are of significant interest to the treatment of abatacept in patients who switched directly from TNF RA with biologic DMARDs, including serious infections, antagonist therapy without undergoing washout [51]. malignancies and autoimmune events, were examined in This approach may be more clinically relevant for an integrated safety analysis that pooled data from the day-to-day practice. Phase IIb, AIM, ATTAIN, ATTEST and ARRIVE studies www.rheumatology.oxfordjournals.org 443 Michael Schiff TABLE 3 Incidence of serious infections and autoimmune events in the integrated safety summary by annual intervals [54, 57] Events/100 patient-years (95% CI) Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Total exposure, patient-years 3500 2400 1900 1500 700 180 All serious infections 3.68 (3.07, 4.37) 2.77 (2.14, 3.53) 2.41 (1.75, 3.23) 2.61 (1.84, 3.60) 2.16 (1.21, 3.57) 3.05 (0.99, 7.13) Hospitalized infections 3.31 (2.73, 3.97) 2.55 (1.94, 3.28) 2.34 (1.70, 3.16) 2.46 (1.72, 3.42) 1.87 (1.00, 3.20) 3.02 (0.98, 7.06) Autoimmune events 1.64 (1.25, 2.13) 2.02 (1.49, 2.68) 1.61 (1.09, 2.30) 1.25 (0.74, 1.97) 0.99 (0.40, 2.04) 0 (0, 1.99) Data are for all those patients who received at least one dose of abatacept during the cumulative study period, for the eight core abatacept trials. Hospitalized infection is a subset of serious infection. Adapted from Smitten et al. [54] with permission from BMJ Publishing Group Ltd, and Smitten et al. [57] with permission from the author. overviewed here, a Phase IIb study of abatacept 2 mg/kg low and did not increase with increasing exposure (0.59 in combination with etanercept [52], the Phase III ASSURE and 0.71/100 patient-years in the DB and cumulative per- (abatacept study of safety in use with other RA therapies) iods) [56]. Incidence of lung cancer and lymphoma, in par- study of abatacept with or without a biologic or non- ticular, did not increase between the DB and cumulative biologic DMARD [53], and a Phase II synovial biopsy periods, with 0.24 and 0.16 lung cancers, and 0.06 and study [31], through December 2007. This included 0.07 lymphomas/100 patient-years, respectively [56]. 4150 patients who were exposed to abatacept, represent- The incidence of malignancy in the abatacept clinical trial ing 10 365 patient-years of exposure, with an average programme, as assessed in the integrated safety analyses, exposure period of 2.5 years [54–57]. was compared with the incidence in five, observational non-biologic DMARD-treated RA patient cohorts—the Serious infections British Columbia RA Cohort, the National Data Bank for Rheumatic Diseases, the UK General Practice Research In the integrated safety analysis, the incidence of serious Database, the UK Norfolk Arthritis Registry and the infections and related serious infections was generally Sweden Early Rheumatoid Arthritis Register Cohort [56]. low, although it was higher for abatacept- compared The SIRs calculated suggested that the overall risk of with placebo-treated patients over 1 year (serious infec- malignancy (excluding NMSC) was not significantly tions: 3.47 vs 2.41 events/100 patient-years, respectively) increased in abatacept- compared with non-biologic [54]. The incidence rates of serious infection and hospitalized DMARD-treated patients; SIRs ranged from 0.40 to infection remained stable for the DB vs cumulative 1.06 for the cohorts. The risk of lung cancer did not periods, with 3.47 vs 2.98 serious infections, and 3.05 vs appear to be increased with abatacept (SIRs ranged from 2.73 hospitalized infections/100 patient-years, respective- 0.65 to 1.84), and there appeared to be a comparable risk ly [54]. The risk for serious infections did not appear for lymphoma (SIRs ranged from 0.60 to 1.23) [56]. to increase over time, as evidenced by incidence rates at annual intervals (Table 3) [54]. The most common hos- Autoimmune events pitalized infections were pneumonia, bronchitis, cellulitis and urinary tract infection [55]. There were few opportun- During the integrated DB periods, autoimmune events istic infections observed, including Mycobacterium were reported in 28 (1.4%) abatacept- and 8 (0.8%) tuberculosis (TB; 0.06 events/100 patient-years), aspergil- placebo-treated patients; most events were mild or mod- losis (0.02), blastomycosis (0.01) and systemic candida erate in intensity [57]. Incidence of autoimmune disorders (0.01) [55]. was generally low and did not increase with increasing Standardized incidence rates (SIRs) were calculated by exposure to abatacept (1.43 and 1.59/100 patient-years comparing the observed number of hospitalized infections in the DB and cumulative periods, respectively) [57]. When in the abatacept cumulative experience with that ex- incidence was assessed at annual intervals, the rate pected from external cohorts of RA patients treated with remained stable over time [57]. Psoriasis, the most non-biologic DMARDs [55]. Hospitalized infections were frequently reported autoimmune event, did not increase not increased for abatacept-treated patients compared between the DB and cumulative periods, with rates of with established RA patients [55]. 0.53 and 0.56 events/100 patient-years, respectively. Abatacept has not been reported to lead to increased Malignancies formation of ANA and anti-dsDNA antibodies, compared As reported in the integrated safety analyses, the inci- with placebo [33]. The integrated safety analyses support dence of malignancies [excluding non-melanoma skin this suggestion, reporting a lower proportion of abata- cancer (NMSC)] during DB treatment was reported to be cept- vs placebo-treated patients seroconverting to posi- 0.59 vs 0.63 events/100 patient-years for abatacept- vs tive anti-ANA status and positive anti-dsDNA status over 6 placebo-treated patients [56]. Incidence was generally and 12 months [58]. 444 www.rheumatology.oxfordjournals.org Abatacept in RA Safety in ARRIVE Similarly to data for other biologics, the long-term effi- cacy data for abatacept discussed here are based on Comparable safety was seen in the ARRIVE trial (n = 1046) as-observed analyses, with no imputation rule for missing for both direct-switch and washout patients, with no in- data. In addition, some results are from post hoc assess- crease in the overall frequency of AEs seen between ments, and data such as these should be interpreted with groups either in the 6-month study period or monthly caution. As-observed analyses are more vulnerable to the after initiation of abatacept therapy [51]. In addition, no discontinuation of patients, and may result in a perceived cases of TB were reported, and no opportunistic infec- increase in efficacy (as the proportion of responders is tions occurred. Safety was also comparable regardless calculated only from those patients still on treatment) of the number of prior TNF antagonists received [59]. compared with the more conservative intent-to-treat analysis. However, the trials discussed here report Safety in ATTEST relatively high patient retention with long-term treatment. The ATTEST trial examined the relative safety profiles of Furthermore, following only those patients who actually two agents with differing mechanisms of action under the remain on therapy may be more relevant over the long same study conditions. Over 1 year of DB treatment, SAEs term, given that the extrapolation of data over many (9.6 vs 18.2%), serious infections (1.9 vs 8.5%), acute years from the start of a study is generally not recom- infusional events (7.1 vs 24.8%) and discontinuations mended. The data discussed here have been interpreted due to AEs (3.2 vs 7.3%) were less frequent in abatacept- with these concerns in mind. vs infliximab-treated patients [46]. Infections and infest- Beneficial effects on radiographic progression have ations were reported in 59.6 and 68.5%, and serious been seen with abatacept plus MTX vs placebo plus infections in 1.9 and 8.5%, respectively. The most fre- MTX, in patients with both early and long-standing RA. quently reported serious infection was pneumonia (1.3 Reductions in the annual rate of structural damage pro- and 1.8%, respectively). Five serious opportunistic infec- gression observed in both patient populations suggest tions were reported with infliximab treatment (herpetic en- that abatacept has an increasing disease-modifying cephalitis, pseudomonas lung infection, peritoneal TB, effect on structural damage over time in the majority of Pneumocystis jiroveci pneumonia and pulmonary TB); no patients who respond. For patients with early RA treated opportunistic infections were reported with abatacept. with MTX alone over 1 year, structural damage progres- Autoimmune events were uncommon in both groups (1.3 sion is reduced following the addition of abatacept; how- vs 0.6% for abatacept vs infliximab groups) [46]. ever, overall structural damage progression at Year 2 (after 1 year of abatacept treatment) remains greater for these patients compared with patients who receive aba- Discussion and conclusions tacept from baseline. These findings suggest that delaying biologic therapy in this population has a significant and The studies summarized here, encompassing up to lasting impact on irreversible structural damage, and 7 years of treatment, demonstrate that abatacept support the earlier initiation of abatacept. In addition, find- provides clinically meaningful and sustained benefits ings in patients with early erosive disease suggest that across multiple efficacy measures (signs and symptoms, earlier addition of abatacept to MTX provides clinically structural damage and physical function), without dose meaningful benefits over delayed initiation in the preven- adjustment, for patients with early, erosive disease who tion of irreversible structural damage; when structural are MTX naı¨ve, and patients with established, damage progression was assessed in patients with very moderate-to-severe disease and an inadequate response early disease who were treated with abatacept for to MTX/DMARDs, or to TNF antagonists. 6 months, the inhibitory effect was maintained for at As with other biologics [60], abatacept demonstrates least 6 months following treatment cessation. These statistical significance in achieving clinical efficacy data suggest that it may be possible to alter the progres- outcomes compared with placebo, over short-term, DB sion of RA when abatacept is administered at a very early treatment at the group level. Furthermore, the clinical stage in disease. efficacy improvements seen with abatacept have been Clinical responses and radiographic benefits with observed at the individual patient level, with post hoc ¨ve analyses suggesting that patients responding to treatment abatacept appear to be greater in MTX-naı patients had a high probability of maintaining or further improving compared with patients who have failed MTX or other responses over time. Sustained/improved long-term DMARDs. In addition, patients who previously failed MTX treatment demonstrate higher clinical responses effects were demonstrated with abatacept for signs and than patients who have failed TNF antagonists. Although symptoms, physical function and structural damage, with abatacept provides considerable efficacy benefits irre- data up to 7 years available in MTX-inadequate respond- spective of the number of previous TNF antagonists ers. Given that this type of sustained as opposed to inter- mittent treatment response could have an impact on received, there is a trend towards greater treatment re- long-term reduction of radiographic progression and sponses in patients who have failed fewer agents, demon- improvement in physical function, these data are of strating that the efficacy of abatacept can be optimized particular interest, and evaluating this is strongly advised when patients are switched through fewer prior TNF by guidelines from EULAR and ACR [61]. antagonists. www.rheumatology.oxfordjournals.org 445 Michael Schiff Taken together, these results suggest that introducing stable with increasing exposure to abatacept [54], abatacept earlier in the treatment paradigm may lead to consistent with trends seen with anti-TNF agents. more favourable results—a trend that has also been seen Patients with RA may be at higher risk for lung cancer with other biologic agents [19–22]. This shift towards ear- and lymphoma than the general population [73, 74]; it is, therefore, important to assess the incidence of malignan- lier, aggressive treatment in suitable patients will be cies in patients treated with biologic agents. The risk for further facilitated by the recently published joint EULAR malignancies, including lung cancer and lymphoma, re- and ACR guidelines for early RA [8]. ported for abatacept in the integrated safety analyses Abatacept has demonstrated similar efficacy in patients was generally low and comparable to that of the general with early RA relative to other approved biologics [62]. A DMARD-treated RA population. meta-analysis in MTX-naı¨ve patients with early disease The Cochrane Review meta-analysis assessed safety was conducted to assess clinical remission and radio- across the biologic DMARDs based on withdrawals from graphic non-progression after 1 year of treatment with clinical trials due to AEs [63]. Based on this criterion, there abatacept, adalimumab, etanercept or infliximab, plus was a trend towards a favourable safety profile of abata- MTX. Each of the biologics demonstrated favourable cept vs placebo, relative to adalimumab or infliximab [63]. results for inducing clinical remission and radiographic In general, this is consistent with data from the ATTEST non-progression compared with MTX monotherapy at trial in patients with an inadequate response to MTX, Year 1. Despite some limitations, these results provided which reported a higher frequency of SAEs and serious a broad view of the comparability of the efficacy of these infections (including opportunistic infections) with inflixi- biologics [62]. Similar findings were reported in a mab compared with abatacept. Cochrane Review meta-analysis of randomized, DB trials In summary, abatacept represents an effective treatment of biologic DMARDs for RA treatment (abatacept, adali- option with an established safety profile in DMARD-naı¨ve mumab, anakinra, etanercept, infliximab and rituximab), patients with early disease, and in patients with RA who which concluded that the different biologic agents have experienced an inadequate response to either non- showed similar efficacy in patients with established RA, biologic or biologic DMARDs. Moving forwards, it will be of with the exception of anakinra [63]. The observations interest to evaluate efficacy and safety outcomes with aba- made in the Cochrane Review meta-analysis are sup- tacept treatment in clinical practice, as opposed to the ported by the findings from the ATTEST study, which pro- clinical trial settings discussed here. Further evaluation of vided a unique opportunity to evaluate two biologic the efficacy and safety of abatacept in early and very early agents in a single study. Abatacept and infliximab demon- disease will also be of high clinical importance, along with strated comparable efficacy over 6 months of treatment in investigation into the factors associated with response to MTX-inadequate responders. Furthermore, patients who abatacept therapy. were switched from infliximab to abatacept treatment at Year 1 maintained or improved their responses over Rheumatology key messages Year 2, suggesting that patients who achieve a good response to infliximab but need to switch therapies, due . Abatacept represents an effective biologic treat- to safety concerns, for example, could expect to maintain ment with acceptable safety across the spectrum or improve their response with abatacept. of RA-patient populations. Long-term integrated safety data from up to eight . The risk–benefit profile of abatacept may be more abatacept trials, representing >10 000 patient-years of favourable when introduced earlier in the RA treat- ment paradigm. exposure, confirm that, overall, abatacept has a favour- able safety profile that is consistent with observations from the short-term experience in all RA populations studied, with no new clinically important safety issues Acknowledgements identified with long-term compared with short-term findings. This is supported by a recent Cochrane Review The author would like to thank Eve Guichard, Medicus that reported the safety profile of abatacept to be International, for editorial assistance, which was funded acceptable [60]. by Bristol-Myers Squibb. The increased risk of serious infections associated with Funding: Funding for editorial support of the review was TNF antagonists has been well documented [64–68]. provided by Bristol-Myers Squibb. Funding to pay the Serious infections, as reported in the integrated safety Open Access publication charges for this article was analyses discussed here, are more frequent in abatacept- provided by Bristol-Myers Squibb. compared with placebo-treated patients over 1 year [54, 58]. However, the incidence rate of serious infections Disclosure statement: M.S. is a consultant for and has with abatacept is at the lower end of the range observed received grant support from Bristol-Myers Squibb. in RA patients treated with other biologics [69–71], and an independent meta-analysis by Salliot et al. [72] reported References that this risk was not significantly increased with abata- cept treatment compared with placebo. Importantly, the 1 Landewe RB, Boers M, Verhoeven AC et al. 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Malignant arthritis: EULAR/ACR collaborative recommendations. lymphomas in autoimmunity and inflammation: a review Ann Rheum Dis 2008;67:1360–4. of risks, risk factors, and lymphoma characteristics. 62 Kuriya B, Arkema V, Bykerk VP, Keystone E. Efficacy Cancer Epidemiol Biomarkers Prev 2006;15:2069–77. of initial methotrexate monotherapy versus combination 74 Smitten AL, Simon TA, Hochberg MC, Suissa S. A therapy with a biologic agent in early rheumatoid meta-analysis of the incidence of malignancy in adult arthritis: a meta-analysis of clinical and radiographic patients with rheumatoid arthritis. Arthritis Res Ther 2008; remission. Abstract 2010. Arthritis Rheum 2009;60: 10:R45. S751–2. 75 Kremer JM, Westhovens R, Leon M. Treatment of rheu- 63 Singh A, Christensen R, Wells GA et al. Biologics for matoid arthritis by selective inhibition of T-cell activation rheumatoid arthritis: an overview of Cochrane reviews. with fusion protein CTLA4Ig. N Engl J Med 2003;349: Cochrane Database of Syst Rev 2009;4:CD007848. 1907–15. www.rheumatology.oxfordjournals.org 449 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology (Oxford, England) Pubmed Central

Abatacept treatment for rheumatoid arthritis

Schiff, Michael
Rheumatology (Oxford, England) , Volume 50 (3) – Sep 27, 2010
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Abstract

Significant advances in our understanding of RA and its management have been made in the past decade, resulting in earlier intervention with biologic DMARDs, particularly in patients with evidence of aggressive, erosive disease. Here, one such biologic therapy, the T-cell co-stimulation modulator abatacept, is dis- cussed, exploring clinical evidence published to date on its use in patients with very early arthritis/early RA who are MTX naıve, and in patients with established RA and an inadequate response to MTX or TNF antagonists. Data from relevant clinical trials are overviewed, discussing the clinical efficacy of abatacept in early disease, the clinical outcomes over long-term treatment in different patient populations and the effects of abatacept on structural damage. Findings from integrated safety analyses of abatacept clinical trial data, representing 10 366 patient-years of exposure are described, and clinically important safety events, including serious infections, malignancies and autoimmune events, are highlighted. It is concluded that abatacept represents an effective treatment option with an established safety profile across different patient populations, including patients with both early and erosive RA and those with established disease. Furthermore, efficacy data from studies in patients with early disease suggest that the risk–benefit profile of abatacept may be more favourable when introduced earlier in the treatment paradigm. Key words: Rheumatoid arthritis, Biological therapies, Clinical trials, Abatacept. ´ ´ guidelines from the strategie therapeutique de la polyar- Introduction thrite (therapeutic strategies in RA) working group of the Significant advances in our understanding of RA and its French Society of Rheumatology (study and follow-up of management have demonstrated that early intervention, undifferentiated early arthritis). The latter specifically rec- particularly in patients with evidence of aggressive, ommend very early use (46 months from diagnosis) of erosive disease, can prevent the irreversible structural biologics in patients with poor prognostic factors [9]. damage characteristic of RA. The benefit observed is However, one needs to take into account the benefit– often optimized when combination treatment with both risk profile of the therapeutic options available when con- traditional and biologic DMARDs is administered [1–6]. sidering this course of action [10]. Clinical practice guidelines recommend that the majority Biologic DMARDs, including the TNF antagonists— of patients should start treatment with a conventional infliximab, etanercept, adalimumab, golimumab and DMARD, and in cases of treatment failure a biologic certolizumab—the B-cell depleter rituximab, the IL-6 should be added; however, combination therapy should receptor antagonist tocilizumab and the T-cell co- be considered early in DMARD-naı¨ve patients if they pre- stimulation modulator abatacept, have demonstrated sent with poor prognostic factors, such as erosion, posi- clinical efficacy and radiographic benefit in patients with tivity for anti-CCP or RF and high disease activity [7]. moderate-to-severe RA who have demonstrated an inad- Progress towards a framework for identifying patients equate response to at least one non-biologic DMARD [11– with early disease who are at high risk of developing ero- 18]. Furthermore, efficacy benefits have been seen with sive and progressive RA—and thus would benefit from some biologics in patients with severe, active and pro- early DMARD intervention—has been made in the form gressive early disease not previously treated with of joint guidelines from the EULAR and the ACR [8], and conventional DMARDs [19–23]. This review will focus on one of these biologic agents, abatacept, and the clinical experience to date examining School of Medicine, University of Colorado, Denver, CO, USA. intervention in various patient populations, including Submitted 31 March 2010; revised version accepted 29 July 2010. those with very early arthritis/early RA who are MTX naı¨ve Correspondence to: Michael Schiff, School of Medicine, University of [23, 24], and in patients with established RA and an inad- Colorado, 5400 South Monaco Street, Greenwood Village, CO 80111, USA. E-mail:[email protected] equate response to MTX [25, 26] or TNF antagonists [27]. The Author(s) 2010. Published by Oxford University Press on behalf of The British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. RE VIEW Michael Schiff Selective co-stimulation modulation seen in physical function at Year 1, for abatacept plus MTX- vs MTX alone-treated patients [23]. In addition, aba- Abatacept is a selective co-stimulation modulator that in- tacept plus MTX demonstrated a higher likelihood of hibits T-cell activation by binding to CD80/86, and mod- increasing or maintaining initial improvements in ACR re- ulating its interaction with CD28 [28]—a co-stimulatory sponses and physical function over 1 year than MTX alone signal necessary for the full activation of T cells. in patient-level post hoc analyses [35]. Activated T cells are implicated in the pathogenesis of Improvements in disease activity and ACR responses RA via amplification of the inflammatory cascade that were sustained or improved over the second year for pa- leads to joint inflammation and destruction in RA [29, tients remaining on abatacept plus MTX therapy, with 30]. The effect of abatacept on the inflammatory cascade 55.2% achieving remission at Year 2 [36]. After patients has been demonstrated by quantitative PCR studies and randomized to MTX alone were initiated on abatacept plus evaluation of synovial biopsies in patients with active MTX at Year 1, improvements in these efficacy endpoints RA who had previously failed TNF antagonist therapy. were seen, with 44.5% in remission at Year 2, increased Findings from these studies demonstrate a reduction in from 26.9% at Year 1 [36]. expression of most inflammatory genes, and a small, Changes from baseline to Year 1 in Genant-modified largely non-significant reduction in cellular content follow- Sharp TS and erosion score (ES) were significantly lower ing abatacept treatment; this suggests that abatacept re- for MTX-naıve patients randomized to abatacept plus duces the inflammatory status of the synovium without MTX vs MTX alone (Fig. 1A) [23]. Furthermore, there was disrupting cellular homoeostasis [31]. These observations an increasing degree of inhibition of progression in Year 2 are supported by clinical trial data, which have demon- relative to Year 1 for patients originally randomized strated a reduction in serum levels of inflammatory bio- to abatacept [37]. For patients originally receiving markers to within ‘normal’ levels following abatacept MTX alone, structural damage progression was reduced treatment, implying that abatacept may help to normalize over Year 2 relative to Year 1, following the addition of the levels of downstream inflammatory mediators. The abatacept [37]. However, overall structural damage pro- unique mechanism of action of abatacept may offer gression at Year 2 remained greater for these patients significant therapeutic benefit to patients by specifically compared with patients who received abatacept from addressing the underlying RA pathophysiology [32]. baseline [37]. Abatacept study to determine the effectiveness in Overview of abatacept clinical preventing the development of RA in patients with experience undifferentiated inflammatory arthritis and to evaluate safety and tolerability Early disease The potential for early treatment with abatacept to delay Abatacept study to gauge remission and joint damage the development or progression of RA in patients with progression in MTX-naı¨ve patients with early erosive RA very early disease was investigated in the Phase II, The 2-year abatacept study to gauge remission and joint exploratory, 2-year ADJUST trial [abatacept study to damage progression in MTX-naı¨ve patients with early ero- determine the effectiveness in preventing the develop- sive RA (AGREE) study consisted of a 12-month double- ment of RA in patients with undifferentiated inflammatory blind (DB) period followed by a 12-month open-label arthritis (UA) (ADJUST) trial and to evaluate safety and period in MTX-naı¨ve patients with early RA [23]. Patients tolerability]. Following 6 months of DB, randomized (1 : 1) had poor prognostic factors that are highly predictive of treatment with either abatacept at the approved dose an aggressive disease course, including high CRP levels, (n = 28) or placebo (n = 28), abatacept treatment was radiographic evidence of erosions and seropositivity for terminated. The proportion of patients who developed RF or anti-CCP2. Patients were randomized 1 : 1 to re- RA according to ACR 1987 criteria [38] or discontinued ceive abatacept (approved dose [33]) plus MTX (n = 256) due to lack of efficacy at Year 1 was assessed. or MTX alone (n = 253) [23]. All patients received open- Patients had a short disease duration (Table 1), and label abatacept plus MTX from Year 1 onwards. The although patients did not have RA according to ACR co-primary endpoints were 28-joint DAS (DAS-28)-defined 1987 criteria, more than half already had evidence of remission and joint damage progression [Genant-modified one or more erosion. As such it is likely that a significant [34] total score (TS)] at Year 1. At baseline, patients proportion had early RA. When abatacept was stopped at had short disease duration and high disease activity Month 6, 22 and 17 patients treated with abatacept and (Table 1). placebo, respectively, remained in the trial (i.e. had not At Year 1, significantly more patients treated with aba- developed RA); by Year 2, 7 and 4 patients remained in tacept plus MTX achieved DAS-28 (CRP)-defined remis- the trial. Numerically more placebo than abatacept pa- sion and ACR50 and ACR70 responses (Table 2), and the tients developed RA over 1 year (66.7 vs 46.2%), although difference between treatment arms was significant by CI overlapped. Radiographic assessments demonstrated Month 2. Over 1 year, 27.3 vs 11.9% of abatacept plus an inhibitory effect on structural damage progression at MTX- vs MTX alone-treated patients (P< 0.001) achieved Month 6, which was maintained for 6 months following a major clinical response (ACR70 maintained for 56 con- therapy cessation, with similar trends observed for MRI- secutive months) [23]. Significant improvements were also assessed osteitis, erosion and synovitis [24]. 438 www.rheumatology.oxfordjournals.org Abatacept in RA www.rheumatology.oxfordjournals.org 439 TABLE 1 Baseline demographics and clinical characteristics Patients with inadequate Patients with inadequate MTX-naı¨ve patients response to MTX response to anti-TNF agents Phase IIB AGREE ADJUST abatacept AIM ATTEST ATTAIN ARRIVE abatacept + MTX abatacept 10 mg/kg group abatacept + MTX abatacept + MTX abatacept + DMARD all patients Parameter group (n = 256) group (n = 28) (n = 115) group (n = 433) group (n = 156) group (n = 258) (n = 1046) Demographics Age, years 50.1 (12.4) 44.8 (10.9) 55.8 (range: 17–83) 51.5 (12.9) 49.0 (12.5) 53.4 (12.4) 54.4 (12.4) Women, % 76.6 71.4 75 77.8 83.3 77.1 81.2 Caucasian, % 78.9 89.3 87 87.5 80.8 96.1 92.4 Disease duration 6.2 (7.5) months 8.8 (4.2) months 9.7 (9.8) years 8.5 (7.3) years 7.9 (8.5) years 12.2 (8.5) years 11.6 (9.5) years MTX dose, mg/week NA NA 15.0 (4.4) 16.1 (3.6) 16.5 (3.7) 15.2 (5.3) – Clinical characteristics Tender joints, n 31.3 (14.8) – 30.8 (12.2) 31.0 (13.2) 31.6 (13.9) 31.2 (13.0) 17.8 (6.0) Swollen joints, n 22.9 (11.3) – 21.3 (8.4) 21.4 (8.8) 21.3 (8.6) 22.3 (10.2) 13.6 (5.5) Pain, 100 mm VAS – – 62.1 (21.4) 63.3 (21.1) – 70.8 (19.8) – HAQ-DI score (0–3) 1.7 (0.7) 0.8 (0.6) M-HAQ: 1.0 (0.5) 1.7 (0.7) 1.8 (0.6) 1.8 (0.6) 1.7 (0.6) Patient global assessment, 100 mm VAS – – 60.1 (20.7) 62.7 (21.2) – 69.2 (19.7) 72.9 (16.5) Physician global assessment, 100 mm VAS – – 62.1 (14.8) 68.0 (16.0) – 68.8 (17.7) – DAS-28 CRP: 6.3 (1.0) CRP: 3.6 (1.1) CRP: 5.5 (0.63) – ESR: 6.9 (1.0) – CRP: 6.2 (0.7) CRP level, mg/dl 3.1 (3.1) 1.12 (1.43) 2.9 (2.8) 3.3 (3.1) 3.1 (2.7) 4.6 (4.0) 2.1 (3.0) RF, % 96.1 85.7 – 81.8 87.2 73.3 61.3 ES 5.4 (6.1) 3.2 (3.5) NA 21.7 (18.1) NA NA NA JSN score 2.1 (4.2) 0.1 (0.4) NA 22.8 (20.2) NA NA NA TS 7.5 (9.7) 3.3 (3.6) NA 44.5 (37.3) NA NA NA Anti-rheumatic medication at enrolment, n (%) MTX 0 0 99.1% 433 (100) 156 (100) 195 (75.6) 730 (69.8) Other DMARDs 7 (2.7) 0 16.5% 53 (12.2) – 72 (27.9) – Biologics 0 0 NA 1 (0.2) – 7 (2.7) – CS 131 (51.2) 5 (17.9) 60.0% 312 (72.1) 118 (75.6) 181 (70.2) 611 (58.4) NSAIDs 203 (79.3) 22 (78.6) – 370 (85.5) 133 (85.3) 181 (70.2) – Other – – – 1 (0.2) – – – Data are taken from [23, 24, 75, 39, 42, 46, 49, 51]. Data are mean (standard error) unless otherwise stated. Data for placebo control arms not shown. NA: not applicable; VAS: visual analogue scale. Michael Schiff Established disease MTX-inadequate responders Phase IIb trial The Phase IIb trial in MTX-inadequate responders was a 12-month, randomized (1 : 1 : 1) DB study designed to evaluate the safety and efficacy of abatacept [2 mg/kg (n = 105) or 10 mg/kg (n = 115)] plus MTX compared with placebo plus MTX (n = 119) [39]. The primary endpoint was ACR20 response at Month 6. Patients completing the DB period were eligible to enter an open-label long-term ex- tension (LTE), in which all patients received abatacept (approved dose). Results from the LTE have been pub- lished up to 5 years [25], with experience reported up to 7 years [40]. Patients had high baseline disease activity (Table 1). At Year 1, significantly greater improvements in RA signs and symptoms (Table 2) and clinically meaningful improvements in physical function were seen with abat- acept 10 mg/kg vs placebo [39]. The 2 mg/kg dose was considered suboptimal and was not pursued in Phase III. Over 12 months, serum levels of inflammatory biomark- ers were significantly lower with abatacept 10 mg/kg vs placebo treatment, with numerical reductions in TNF-a and RF also reported [41]. In particular, sIL-2R, IL-6, soluble E-selectin and TNF-a were brought to within the range considered normal. Of the patients who entered the LTE, 59 and 52% re- mained on treatment at Years 5 and 7, respectively, with 11.0% discontinuing due to lack of efficacy [25, 40]. Sustained efficacy improvements over 5 years were observed in patients remaining on treatment (Fig. 2) [25]. Furthermore, low disease activity state (LDAS) and ACR70 were reported in 70 and 50% of patients at Year 7, respectively [40]. Reductions in functional disability were also maintained over 5 and 7 years [25, 40]. Abatacept in inadequate responders to MTX The Phase III AIM trial included a similar patient popula- tion of MTX-inadequate responders with established dis- ease and high baseline disease activity (Table 1) [26, 42]; however, this trial also evaluated radiographic outcomes. The design of this trial has been reported extensively [18, 42]. Here, patients received either abatacept (approved dose; n = 433) or placebo (n = 219) on a background of MTX for 1 year, after which patients who continued into the LTE received open-label abatacept [26]. The co-primary endpoints were ACR20 response, clinically meaningful improvement in physical function and joint damage progression as assessed by Genant-modified ES. Approximately three-quarters of patients who entered the LTE were still participating after 5 years, with 5.0% of discontinuations during the LTE due to lack of efficacy and 8.7% to AEs [26]. Yearly discontinuations were generally low (Years 2, 3, 4 and 5: 12.2, 6.3, 7.1 and 8.0%, respectively). Through the 1-year DB period, improvements in clinical efficacy and physical function were significantly greater for abatacept vs placebo (Table 2; [42]). Post hoc analyses demonstrated statistically significant improvements from 440 www.rheumatology.oxfordjournals.org TABLE 2 Clinical efficacy with abatacept across clinical trials Patients with inadequate response MTX-naı¨ve patients Patients with inadequate response to MTX to anti-TNF agents Efficacy outcome AGREE, Year 1 [23] Phase IIb, Year 1 [38] AIM, Year 1 [41] ATTEST, Month 6 [45] ATTAIN, Month 6 [48] Abatacept vs placebo ACR20, % NR 62.6 vs 36.1 (P< 0.001) 73.1 vs 39.7 (P< 0.001) 66.7 vs 41.8 (P< 0.001) 50.4 vs 19.5 (P< 0.001) ACR50, % 57.4 vs 42.3 (P< 0.001) 41.7 vs 20.2 (P< 0.001) 48.3 vs 18.2 (P< 0.001) 40.4 vs 20.0 (P< 0.001) 20.3 vs 3.8 (P< 0.001) ACR70, % 42.6 vs 27.3 (P< 0.001) 20.9 vs 7.6 (P = 0.003) 28.8 vs 6.1 (P< 0.001) 20.5 vs 9.1 (P = 0.019) 10.2 vs 1.5 (P = 0.003) LDAS, % 54.3 vs 36.8 (P< 0.001) 49.6 vs 21.9 (P< 0.05) 42.5 vs 9.9 (P< 0.001) 20.7 vs 10.8 17.1 vs 3.1 (P< 0.001) Remission, % 41.4 vs 23.3 (P< 0.001) 34.8 vs 10.1 (P< 0.001) 23.8 vs 1.9 (P< 0.001) 11.3 vs 2.9 10.0 vs 0.8 (P< 0.001) HAQ-DI response, % 71.9 vs 62.1 (P = 0.024) 49.6 vs 27.7 (P< 0.001) 63.7 vs 39.3 (P< 0.001) 61.5 vs 40.9 (P = 0.001) 47.3 vs 23.3 (P< 0.001) a b Data are taken from [23, 39, 42, 46, 49]. Abatacept data are for the 10 mg/kg group. Data on file; LDAS: DAS-28 43.2; remission: DAS-28< 2.6; HAQ response: change from baseline in HAQ-DI50.3 U for all trials except for the Phase IIb trial, defined as HAQ-DI mean change from baseline 50.22 U; NR: not reported. Abatacept in RA FIG.1 Radiographic progression in early and established RA over 1 year of abatacept treatment. (A) Mean change from baseline in TS, ES and JSN at Year 1 of the AGREE trial for abatacept plus MTX- and MTX alone-treated patients [23]. Adapted from Westhovens et al. [23] copyright 2009, with permission from the BMJ Publishing Group Ltd. (B) Mean change from baseline in TS, ES and JSN at Year 1 of the AIM trial for abatacept- and placebo-treated patients [42]. ABA: abatacept; PBO: placebo. Adapted from Kremer et al. [42]. Months 6 to 12 in the proportions of abatacept-treated still achieve a clinically meaningful response over time patients achieving ACR50 and ACR70 responses [42]. [43]. The sustainability of patient-level responses was Throughout the open-label LTE, efficacy improvements also evaluated for the LTE [44], revealing that the majority were maintained for patients who remained on treatment of patients who had achieved LDAS, remission or normal- [18, 26]. At Year 5, 33.7% of patients had achieved ized physical function (i.e. HAQ-DI4 0.5) by Year 1 DAS-28-defined remission, with 83.6, 61.1 and 39.6% of sustained these outcomes through 5 years. patients achieving ACR20, ACR50 and ACR70 responses, At the end of the DB period, a significant inhibition of respectively [26]. Approximately three-quarters of patients structural damage progression was seen with abatacept achieved clinically meaningful improvements in physical vs placebo, with 50% reduction in change from baseline function [improvement of 50.3 in HAQ-disability index in Genant-modified Sharp scores compared with placebo (Fig. 1B) [42]. Progressive reductions in changes from (HAQ-DI)] at Year 5 [26]. In post hoc, patient-level analyses from AIM, the major- baseline were observed in ES, joint-space narrowing ity of patients maintained or improved their treatment re- (JSN) score and TS over 5 years, for patients originally sponse or disease status from Months 3 to 12, suggesting randomized to abatacept, with progression reduced that patients who have not responded by Month 3 may by 50% in the second year relative to the first and www.rheumatology.oxfordjournals.org 441 Michael Schiff FIG.2 Long-term clinical efficacy over 5 years of treatment with abatacept. The proportion of patients originally randomized to the 10 mg/kg abatacept group of the Phase IIb trial experiencing LDAS (DAS-28 CRP43.2) and DAS-28-defined remission (DAS-28 CRP< 2.6) by visit day. Responses are based on the intent-to-treat population for patients with data available at the visit of interest (as-observed analysis). Broken line represents the DB period; data are presented with 95% CIs. Reproduced from Westhovens et al. [25] with permission from the Journal of Rheumatology. continued reductions in yearly progression up to Year 5. with abatacept (Table 2). Improvements in ACR20, ACR50 A similar trend was also seen over 2 years in MTX-naı¨ve and ACR70 responses at Month 6 were significantly patients, in the AGREE trial [37]. Once the patients origin- greater vs placebo for both abatacept and infliximab. ally randomized to placebo had switched to abatacept, The onset of ACR20 responses was generally more annual mean changes progressively decreased in a similar rapid for infliximab than abatacept, but responses were trend; however, differences in structural damage were still similar by Month 3. By Year 1, DAS-28 (ESR) reductions seen between the groups at Year 5 [45]. Furthermore, ap- of 2.88 and 2.25 were seen for abatacept- and proximately half of all patients treated with abatacept over infliximab-treated patients, respectively, and ACR re- the entire study period exhibited no structural damage sponses were maintained from Month 6 with abatacept progression (change in TS of 40) through 5 years. but not with infliximab treatment (Fig. 3) [46]. The ATTEST trial continued through 2 years; during the Abatacept or infliximab versus placebo, a trial for second year of treatment, patients receiving infliximab tolerability, efficacy and safety in treating RA were switched to abatacept. Efficacy benefits observed A third trial in MTX-inadequate responders provided the with abatacept in Year 1 were maintained through opportunity to evaluate two biologics in a single study. 2 years, as demonstrated by assessments of signs and The placebo- and active-controlled ATTEST (abatacept symptoms, physical function and disease activity [47]. In or infliximab versus placebo, a trial for tolerability, efficacy patients who switched from infliximab to abatacept at and safety in treating RA) study, although not powered to Year 1, efficacy benefits increased over the second year detect superiority, provided information on the relative and were similar to the original abatacept group by Year 2 efficacy and safety profiles of abatacept and infliximab [47]. In addition, a considerable proportion of infliximab vs placebo in the same population [46]. Patients with non-responders (i.e. ACR20 non-responders, or patients an inadequate response to MTX were randomized with high disease activity state) who switched to abata- (3 : 3 : 2) to abatacept (approved dose, n = 156), infliximab cept after 1 year achieved improved clinical responses (3 mg/week, n = 165) or placebo (n = 110), with back- with abatacept over the second year [48]. For patients ground MTX. At Month 6, patients in the placebo group who had achieved LDAS or remission following 1 year of were switched to abatacept, and infliximab and abatacept infliximab, a high proportion were able to maintain these groups continued to Year 1, with blinding maintained. disease states over Year 2. The primary endpoint of this trial, reduction in DAS-28 TNF antagonist-inadequate responders abatacept trial in (ESR) at Month 6 for abatacept vs placebo, was met, with treatment of anti-TNF inadequate responders mean reductions of 2.53 vs 1.48 (P< 0.001), respect- ively. The proportion of patients achieving states of low The efficacy of abatacept in patients with RA who have an disease activity and DAS-28 remission was also greater inadequate response to TNF antagonists was examined in 442 www.rheumatology.oxfordjournals.org Abatacept in RA FIG.3 Clinical efficacy over 1 year in the ATTEST trial. ACR responses achieved over Year 1 of the ATTEST trial. Data are presented for the intent-to-treat population with a last observation carried forward analysis. Infliximab was administered on Days 1, 15, 43, 85 and then every 56 days thereafter; abatacept dosing occurred at each visit day. Reproduced from Schiff et al. [46] copyright 2008, with permission from the BMJ Publishing Group Ltd. the Phase III ATTAIN (abatacept trial in treatment of Patients in this trial had high levels of disease activity at anti-TNF inadequate responders) trial [49]. Patients had baseline (Table 1); overall, the inclusion criteria resulted in a patient population that was more representative of clin- an inadequate response to 53 months of treatment with etanercept, infliximab or both. Patients were randomized ical practice than often included in randomized controlled (2 : 1) to receive abatacept (n = 258) or placebo (n = 133), trials [51]: patients had an inadequate response to up to plus one or more background DMARD, for the 6-month three TNF antagonists that they could have failed for effi- cacy, safety or tolerability reasons. Patients were eligible DB period; patients entering the LTE received open-label even if they had a positive purified protein-derivative test abatacept. The co-primary endpoints were ACR20 re- result. Abatacept could be administered as monotherapy sponse and improvement in physical function. Patients (USA only), and patients were not limited to a particular had high baseline disease activity (Table 1). After 4 background DMARD. years of open-label therapy, approximately half of all pa- Similar, clinically meaningful, improvements were seen tients who entered the LTE remained on treatment [50]. in disease activity, physical function and health-related At the end of the 6-month DB period, improvements in quality of life, regardless of whether there was a washout clinical efficacy and physical function were significantly period or not. Post hoc analyses revealed that numerically greater for abatacept vs placebo (Table 2). The proportion more patients who had previously failed one TNF antag- of patients achieving improvements in ACR20, ACR50 and onist achieved DAS-28-defined remission and LDAS than ACR70 responses increased over 4.5 years of treatment those who had failed two or more [51]. for patients who remained on treatment, as did the proportions of patients achieving LDAS and remission (18.3 vs 37.1% and 11.1 vs 25.7% at Month 6 vs Year Safety summary 4.5, respectively), and clinically meaningful improvements in physical function [50]. Safety assessments from the trials discussed above have demonstrated that the incidence of overall AEs and ser- Abatacept researched in rheumatoid arthritis patients ious AEs (SAEs) was generally comparable for abatacept- with an inadequate anti-TNF response to validate and placebo-treated patients [23, 24, 39, 42, 46, 49], effectiveness although in some trials the frequency of SAEs was re- The second trial conducted in TNF-inadequate respond- ported to be higher with abatacept [42]. The safety of ers was a Phase IIIb/IV, 6-month, open-label study. The long-term abatacept treatment is reported to be consist- ARRIVE (abatacept researched in rheumatoid arthritis ent, with the incidence of overall AEs and SAEs remaining patients with an inadequate anti-TNF response to validate stable up to 7 years [40]. effectiveness) trial was the first to assess the safety of Events that are of significant interest to the treatment of abatacept in patients who switched directly from TNF RA with biologic DMARDs, including serious infections, antagonist therapy without undergoing washout [51]. malignancies and autoimmune events, were examined in This approach may be more clinically relevant for an integrated safety analysis that pooled data from the day-to-day practice. Phase IIb, AIM, ATTAIN, ATTEST and ARRIVE studies www.rheumatology.oxfordjournals.org 443 Michael Schiff TABLE 3 Incidence of serious infections and autoimmune events in the integrated safety summary by annual intervals [54, 57] Events/100 patient-years (95% CI) Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Total exposure, patient-years 3500 2400 1900 1500 700 180 All serious infections 3.68 (3.07, 4.37) 2.77 (2.14, 3.53) 2.41 (1.75, 3.23) 2.61 (1.84, 3.60) 2.16 (1.21, 3.57) 3.05 (0.99, 7.13) Hospitalized infections 3.31 (2.73, 3.97) 2.55 (1.94, 3.28) 2.34 (1.70, 3.16) 2.46 (1.72, 3.42) 1.87 (1.00, 3.20) 3.02 (0.98, 7.06) Autoimmune events 1.64 (1.25, 2.13) 2.02 (1.49, 2.68) 1.61 (1.09, 2.30) 1.25 (0.74, 1.97) 0.99 (0.40, 2.04) 0 (0, 1.99) Data are for all those patients who received at least one dose of abatacept during the cumulative study period, for the eight core abatacept trials. Hospitalized infection is a subset of serious infection. Adapted from Smitten et al. [54] with permission from BMJ Publishing Group Ltd, and Smitten et al. [57] with permission from the author. overviewed here, a Phase IIb study of abatacept 2 mg/kg low and did not increase with increasing exposure (0.59 in combination with etanercept [52], the Phase III ASSURE and 0.71/100 patient-years in the DB and cumulative per- (abatacept study of safety in use with other RA therapies) iods) [56]. Incidence of lung cancer and lymphoma, in par- study of abatacept with or without a biologic or non- ticular, did not increase between the DB and cumulative biologic DMARD [53], and a Phase II synovial biopsy periods, with 0.24 and 0.16 lung cancers, and 0.06 and study [31], through December 2007. This included 0.07 lymphomas/100 patient-years, respectively [56]. 4150 patients who were exposed to abatacept, represent- The incidence of malignancy in the abatacept clinical trial ing 10 365 patient-years of exposure, with an average programme, as assessed in the integrated safety analyses, exposure period of 2.5 years [54–57]. was compared with the incidence in five, observational non-biologic DMARD-treated RA patient cohorts—the Serious infections British Columbia RA Cohort, the National Data Bank for Rheumatic Diseases, the UK General Practice Research In the integrated safety analysis, the incidence of serious Database, the UK Norfolk Arthritis Registry and the infections and related serious infections was generally Sweden Early Rheumatoid Arthritis Register Cohort [56]. low, although it was higher for abatacept- compared The SIRs calculated suggested that the overall risk of with placebo-treated patients over 1 year (serious infec- malignancy (excluding NMSC) was not significantly tions: 3.47 vs 2.41 events/100 patient-years, respectively) increased in abatacept- compared with non-biologic [54]. The incidence rates of serious infection and hospitalized DMARD-treated patients; SIRs ranged from 0.40 to infection remained stable for the DB vs cumulative 1.06 for the cohorts. The risk of lung cancer did not periods, with 3.47 vs 2.98 serious infections, and 3.05 vs appear to be increased with abatacept (SIRs ranged from 2.73 hospitalized infections/100 patient-years, respective- 0.65 to 1.84), and there appeared to be a comparable risk ly [54]. The risk for serious infections did not appear for lymphoma (SIRs ranged from 0.60 to 1.23) [56]. to increase over time, as evidenced by incidence rates at annual intervals (Table 3) [54]. The most common hos- Autoimmune events pitalized infections were pneumonia, bronchitis, cellulitis and urinary tract infection [55]. There were few opportun- During the integrated DB periods, autoimmune events istic infections observed, including Mycobacterium were reported in 28 (1.4%) abatacept- and 8 (0.8%) tuberculosis (TB; 0.06 events/100 patient-years), aspergil- placebo-treated patients; most events were mild or mod- losis (0.02), blastomycosis (0.01) and systemic candida erate in intensity [57]. Incidence of autoimmune disorders (0.01) [55]. was generally low and did not increase with increasing Standardized incidence rates (SIRs) were calculated by exposure to abatacept (1.43 and 1.59/100 patient-years comparing the observed number of hospitalized infections in the DB and cumulative periods, respectively) [57]. When in the abatacept cumulative experience with that ex- incidence was assessed at annual intervals, the rate pected from external cohorts of RA patients treated with remained stable over time [57]. Psoriasis, the most non-biologic DMARDs [55]. Hospitalized infections were frequently reported autoimmune event, did not increase not increased for abatacept-treated patients compared between the DB and cumulative periods, with rates of with established RA patients [55]. 0.53 and 0.56 events/100 patient-years, respectively. Abatacept has not been reported to lead to increased Malignancies formation of ANA and anti-dsDNA antibodies, compared As reported in the integrated safety analyses, the inci- with placebo [33]. The integrated safety analyses support dence of malignancies [excluding non-melanoma skin this suggestion, reporting a lower proportion of abata- cancer (NMSC)] during DB treatment was reported to be cept- vs placebo-treated patients seroconverting to posi- 0.59 vs 0.63 events/100 patient-years for abatacept- vs tive anti-ANA status and positive anti-dsDNA status over 6 placebo-treated patients [56]. Incidence was generally and 12 months [58]. 444 www.rheumatology.oxfordjournals.org Abatacept in RA Safety in ARRIVE Similarly to data for other biologics, the long-term effi- cacy data for abatacept discussed here are based on Comparable safety was seen in the ARRIVE trial (n = 1046) as-observed analyses, with no imputation rule for missing for both direct-switch and washout patients, with no in- data. In addition, some results are from post hoc assess- crease in the overall frequency of AEs seen between ments, and data such as these should be interpreted with groups either in the 6-month study period or monthly caution. As-observed analyses are more vulnerable to the after initiation of abatacept therapy [51]. In addition, no discontinuation of patients, and may result in a perceived cases of TB were reported, and no opportunistic infec- increase in efficacy (as the proportion of responders is tions occurred. Safety was also comparable regardless calculated only from those patients still on treatment) of the number of prior TNF antagonists received [59]. compared with the more conservative intent-to-treat analysis. However, the trials discussed here report Safety in ATTEST relatively high patient retention with long-term treatment. The ATTEST trial examined the relative safety profiles of Furthermore, following only those patients who actually two agents with differing mechanisms of action under the remain on therapy may be more relevant over the long same study conditions. Over 1 year of DB treatment, SAEs term, given that the extrapolation of data over many (9.6 vs 18.2%), serious infections (1.9 vs 8.5%), acute years from the start of a study is generally not recom- infusional events (7.1 vs 24.8%) and discontinuations mended. The data discussed here have been interpreted due to AEs (3.2 vs 7.3%) were less frequent in abatacept- with these concerns in mind. vs infliximab-treated patients [46]. Infections and infest- Beneficial effects on radiographic progression have ations were reported in 59.6 and 68.5%, and serious been seen with abatacept plus MTX vs placebo plus infections in 1.9 and 8.5%, respectively. The most fre- MTX, in patients with both early and long-standing RA. quently reported serious infection was pneumonia (1.3 Reductions in the annual rate of structural damage pro- and 1.8%, respectively). Five serious opportunistic infec- gression observed in both patient populations suggest tions were reported with infliximab treatment (herpetic en- that abatacept has an increasing disease-modifying cephalitis, pseudomonas lung infection, peritoneal TB, effect on structural damage over time in the majority of Pneumocystis jiroveci pneumonia and pulmonary TB); no patients who respond. For patients with early RA treated opportunistic infections were reported with abatacept. with MTX alone over 1 year, structural damage progres- Autoimmune events were uncommon in both groups (1.3 sion is reduced following the addition of abatacept; how- vs 0.6% for abatacept vs infliximab groups) [46]. ever, overall structural damage progression at Year 2 (after 1 year of abatacept treatment) remains greater for these patients compared with patients who receive aba- Discussion and conclusions tacept from baseline. These findings suggest that delaying biologic therapy in this population has a significant and The studies summarized here, encompassing up to lasting impact on irreversible structural damage, and 7 years of treatment, demonstrate that abatacept support the earlier initiation of abatacept. In addition, find- provides clinically meaningful and sustained benefits ings in patients with early erosive disease suggest that across multiple efficacy measures (signs and symptoms, earlier addition of abatacept to MTX provides clinically structural damage and physical function), without dose meaningful benefits over delayed initiation in the preven- adjustment, for patients with early, erosive disease who tion of irreversible structural damage; when structural are MTX naı¨ve, and patients with established, damage progression was assessed in patients with very moderate-to-severe disease and an inadequate response early disease who were treated with abatacept for to MTX/DMARDs, or to TNF antagonists. 6 months, the inhibitory effect was maintained for at As with other biologics [60], abatacept demonstrates least 6 months following treatment cessation. These statistical significance in achieving clinical efficacy data suggest that it may be possible to alter the progres- outcomes compared with placebo, over short-term, DB sion of RA when abatacept is administered at a very early treatment at the group level. Furthermore, the clinical stage in disease. efficacy improvements seen with abatacept have been Clinical responses and radiographic benefits with observed at the individual patient level, with post hoc ¨ve analyses suggesting that patients responding to treatment abatacept appear to be greater in MTX-naı patients had a high probability of maintaining or further improving compared with patients who have failed MTX or other responses over time. Sustained/improved long-term DMARDs. In addition, patients who previously failed MTX treatment demonstrate higher clinical responses effects were demonstrated with abatacept for signs and than patients who have failed TNF antagonists. Although symptoms, physical function and structural damage, with abatacept provides considerable efficacy benefits irre- data up to 7 years available in MTX-inadequate respond- spective of the number of previous TNF antagonists ers. Given that this type of sustained as opposed to inter- mittent treatment response could have an impact on received, there is a trend towards greater treatment re- long-term reduction of radiographic progression and sponses in patients who have failed fewer agents, demon- improvement in physical function, these data are of strating that the efficacy of abatacept can be optimized particular interest, and evaluating this is strongly advised when patients are switched through fewer prior TNF by guidelines from EULAR and ACR [61]. antagonists. www.rheumatology.oxfordjournals.org 445 Michael Schiff Taken together, these results suggest that introducing stable with increasing exposure to abatacept [54], abatacept earlier in the treatment paradigm may lead to consistent with trends seen with anti-TNF agents. more favourable results—a trend that has also been seen Patients with RA may be at higher risk for lung cancer with other biologic agents [19–22]. This shift towards ear- and lymphoma than the general population [73, 74]; it is, therefore, important to assess the incidence of malignan- lier, aggressive treatment in suitable patients will be cies in patients treated with biologic agents. The risk for further facilitated by the recently published joint EULAR malignancies, including lung cancer and lymphoma, re- and ACR guidelines for early RA [8]. ported for abatacept in the integrated safety analyses Abatacept has demonstrated similar efficacy in patients was generally low and comparable to that of the general with early RA relative to other approved biologics [62]. A DMARD-treated RA population. meta-analysis in MTX-naı¨ve patients with early disease The Cochrane Review meta-analysis assessed safety was conducted to assess clinical remission and radio- across the biologic DMARDs based on withdrawals from graphic non-progression after 1 year of treatment with clinical trials due to AEs [63]. Based on this criterion, there abatacept, adalimumab, etanercept or infliximab, plus was a trend towards a favourable safety profile of abata- MTX. Each of the biologics demonstrated favourable cept vs placebo, relative to adalimumab or infliximab [63]. results for inducing clinical remission and radiographic In general, this is consistent with data from the ATTEST non-progression compared with MTX monotherapy at trial in patients with an inadequate response to MTX, Year 1. Despite some limitations, these results provided which reported a higher frequency of SAEs and serious a broad view of the comparability of the efficacy of these infections (including opportunistic infections) with inflixi- biologics [62]. Similar findings were reported in a mab compared with abatacept. Cochrane Review meta-analysis of randomized, DB trials In summary, abatacept represents an effective treatment of biologic DMARDs for RA treatment (abatacept, adali- option with an established safety profile in DMARD-naı¨ve mumab, anakinra, etanercept, infliximab and rituximab), patients with early disease, and in patients with RA who which concluded that the different biologic agents have experienced an inadequate response to either non- showed similar efficacy in patients with established RA, biologic or biologic DMARDs. Moving forwards, it will be of with the exception of anakinra [63]. The observations interest to evaluate efficacy and safety outcomes with aba- made in the Cochrane Review meta-analysis are sup- tacept treatment in clinical practice, as opposed to the ported by the findings from the ATTEST study, which pro- clinical trial settings discussed here. Further evaluation of vided a unique opportunity to evaluate two biologic the efficacy and safety of abatacept in early and very early agents in a single study. Abatacept and infliximab demon- disease will also be of high clinical importance, along with strated comparable efficacy over 6 months of treatment in investigation into the factors associated with response to MTX-inadequate responders. Furthermore, patients who abatacept therapy. were switched from infliximab to abatacept treatment at Year 1 maintained or improved their responses over Rheumatology key messages Year 2, suggesting that patients who achieve a good response to infliximab but need to switch therapies, due . Abatacept represents an effective biologic treat- to safety concerns, for example, could expect to maintain ment with acceptable safety across the spectrum or improve their response with abatacept. of RA-patient populations. Long-term integrated safety data from up to eight . The risk–benefit profile of abatacept may be more abatacept trials, representing >10 000 patient-years of favourable when introduced earlier in the RA treat- ment paradigm. exposure, confirm that, overall, abatacept has a favour- able safety profile that is consistent with observations from the short-term experience in all RA populations studied, with no new clinically important safety issues Acknowledgements identified with long-term compared with short-term findings. This is supported by a recent Cochrane Review The author would like to thank Eve Guichard, Medicus that reported the safety profile of abatacept to be International, for editorial assistance, which was funded acceptable [60]. by Bristol-Myers Squibb. The increased risk of serious infections associated with Funding: Funding for editorial support of the review was TNF antagonists has been well documented [64–68]. provided by Bristol-Myers Squibb. Funding to pay the Serious infections, as reported in the integrated safety Open Access publication charges for this article was analyses discussed here, are more frequent in abatacept- provided by Bristol-Myers Squibb. compared with placebo-treated patients over 1 year [54, 58]. However, the incidence rate of serious infections Disclosure statement: M.S. is a consultant for and has with abatacept is at the lower end of the range observed received grant support from Bristol-Myers Squibb. in RA patients treated with other biologics [69–71], and an independent meta-analysis by Salliot et al. [72] reported References that this risk was not significantly increased with abata- cept treatment compared with placebo. Importantly, the 1 Landewe RB, Boers M, Verhoeven AC et al. 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Rheumatology (Oxford, England) – Pubmed Central

Published: Sep 27, 2010

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