Blockade of T-Cell Costimulatory Pathways

Introduction

Rheumatoid Arthritis (RA) is characterized by synovial membrane hyperplasia and inflammatory cell infiltrate, including activated T cells. Once activated by one or more unidentified autoantigens, autoreactive T cells proliferate and induce monocytes, macrophagessynovial fibroblasts to produce proinflammatory cytokines (e.g., tumor necrosis factor (TNF)α, interleukin (IL)-1, IL-6) and stimulate osteoclastogenesis and matrix metalloproteinase secretion, as well as immunoglobulin production by B cells. While the activated T cell appears to play a central role in the immunopathogenesis of RA, many attempts to biologically target T cells (e.g., via monoclonal antibodies against T-cell surface molecules) have been disappointing, with the exception of cyclosporine and the costimulatory inhibitor abatacept.

T cells require two signals for full activation: an antigen-specific signal and a costimulatory signal. The first signal is generated when an antigen/ major histocompatability complex (MHC) class II complex binds to the specific T-cell receptor. Although essential for initiating T-cell activation, signaling via the T-cell receptor is not sufficient to induce a productive immune response. The second, costimulatory signal occurs when cell-surface molecules on the antigen-presenting cell (APC) (e.g., CD80 or CD86) interact with a heterodimeric cell-surface protein receptor (e.g., CD28) on the T-cell surface (Figure 16-1). Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), an important negative regulator of CD80/CD86-CD28 interaction, is a molecule that is transiently expressed at the surface of the T cells. CTLA4 is expressed by T cells early after activation but not on resting T cells and transduces an inhibitory signal. As CTLA4 binds to CD80/CD86 (on the APC) with a greater avidity than CD28, it also competes with CD28 binding to CD80/CD86, thereby leading to incomplete T-cell activation.

The mechanism of dual-signal activation of T cells creates the potential for pharmacologic manipulation, including fusion proteins or monoclonal antibodies to prevent the engagement of costimulatory molecules required for full T-cell activation. This approach may be mechanistically distinct from that of other currently used therapies since it targets T-cell–driven events early, rather than late, in the immune responseit results in immunomodulation without evidence of immunosuppression.

Enlarge 

Abatacept (Orencia)

Abatacept is the first T-cell costimulatory pathway modulator approved for the treatment of patients with RA. Abatacept is a soluble fusion protein that consists of the extracellular domain of human CTLA-4 linked to the modified Fc portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in a mammalian-cell expression system.

Indications

Abatacept is indicated for the treatment of adult patients with moderately to severely active RA. Abatacept can be used as monotherapy or concomitantly with disease-modifying antirheumatic drug (DMARDs) other than TNF antagonists. Abatacept should not be administered concomitantly with a TNF antagonist, as such studies have shown increases in serious infections but no added clinical efficacy. Concomitant use of abatacept with anakinra (or other biologics) is not recommended. Abatacept is also indicated for reducing signs and symptoms in pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis.

Mechanism of Action

Abatacept inhibits T-cell activation by selectively binding to CD80 and CD86, thereby blocking interaction with CD28 (Figure 16-2). In vitro, abatacept decreases T-cell proliferation and inhibits the production of the cytokines TNFα, interferon-γIL-2. In a rat collagen-induced arthritis model, abatacept suppressed inflammation, decreased anticollagen antibody production reduced antigen specific production of interferon-α. Following 12 months’ treatment with abatacept 10 mg/kg in clinical trials, decreases were observed in serum levels of IL-6, soluble IL-2 receptor (sIL-2r), C-reactive protein(CRP), rheumatoid factor (RF), matrix metalloproteinase-3 (MMP3), TNFαsoluble CD62E (E-selectin) compared with treatment with placebo.

Enlarge 

Pharmacology

The pharmacokinetics of abatacept in healthy subjects and in RA patients appear to be comparable. The terminal half-life is 13 to 16 days. After multiple intravenous (IV) infusions in RA patients, the pharmacokinetics of abatacept showed proportional increases of Cmax and area under the curve (AUC) over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady state by day 60. In RA patients, there was a trend toward higher clearance of abatacept with increasing body weight. Gender, methotrexate (MTX), nonsteroidal anti-inflammatory drug (NSAIDs), corticosteroids TNF-blocking agents did not influence abatacept clearance. Abatacept has not been studied in patients with renal or hepatic failure.

Clinical Efficacy

The first evidence that a CTLA4/Ig fusion protein (abatacept) was clinically effective came from a small open-label trial in patients with psoriasis. Subsequently, the efficacy of abatacept in patients with active RA was evaluated in several double-blind, placebo-controlled studies. An early, dose-ranging study randomized 122 patients with active RA, in whom at least one nonbiologic DMARD or etanercept had failed, to receive one of three doses of abatacept (0.5, 2, or 10 mg/kg) or placebo. The results indicated that the 10-mg/kg dose was superior to the lower doses of abatacept in terms of ACR20 response criteria.

A 6-month, dose-ranging study randomized 339 patients with active RA despite MTX therapy to receive abatacept (2 mg/kg or 10 mg/kg) or placebo. All patients also continued to receive MTX during the study. Patients treated with abatacept 10 mg/kg were more likely to have an ACR20 response than were patients who received placebo (60 % vs 35%; P <0.001). A subsequent analysis of the 1-year data from this trial found significant improvements in quality-of-life measures using the SF-36 health survey in the abatacept 10-mg/kg group compared with the placebo group. Another separate 1-year analysis of this study also revealed that abatacept treatment was associated with a rapid and sustained increase in remission rates as defined by DAS28.

The Abatacept In Active, Established RA Despite Methotrexate (AIM) study was a larger, 12-month, phase 3 trial that randomized 652 patients with active RA despite ongoing MTX treatment to receive once-monthly abatacept (10 mg/kg) or placebo. At 6 months, the ACR20, ACR50ACR70 response rates were significantly higher in the abatacept-MTX group compared with the placebo-MTX group (Figure 16-3). At 1 year, the ACR20, ACR50ACR70 responses were maintained or increased with abatacept-MTX while these responses remained virtually unchanged with placebo-MTX (Figure 16-3). The addition of abatacept to ongoing MTX treatment also significantly improved physical function in 63.7% vs 39.3% of placebo patients (P <0.001). Furthermore, at 1 year, abatacept statistically significantly slowed the progression of structural joint damage compared with placebo.

A separate analysis of this trial showed patients treated with abatacept-MTX to have significant improvements in physical function, fatigueall eight domains of the SF-36.

The 3-year results of the AIM trial were reported. In patients originally randomized to abatacept, the proportions of ACR20, ACR50ACR70 responders were maintained from year 1 to year 3 (Figure 16-4). In addition, the proportions of abatacept-treated patients experiencing an LDA state (defined as DAS28-CRP levels ≤3.2) or remission (DAS28-CRP <2.6) increased through 3 years of abatacept treatment (Figure 16-5). Mean changes in total Genant-mTTS were reduced progressively over 3 years, with significantly greater inhibition during year 3 compared with year 2 (P = 0.022 for total score) (Figure 16-6). Similar reductions were observed in erosion and joint space narrowing scores. Of the 433 and 219 patients originally randomized to abatacept and placebo, respectively, 82.3% and 80.1% of these were continuing treatment at year 3.

The efficacy of abatacept in RA patients who had an inadequate response to anti-TNFα therapy was also evaluated in a 6-month, phase 3, placebo-controlled trial. A total of 393 patients were randomly assigned in a 2:1 ratio to receive a fixed dose of abatacept, approximating 10 mg/kg, or placebo, in addition to at least one DMARD. Patients discontinued anti-TNFα therapy before randomization. After 6 months, the ACR20 response was significantly (P <0.001) higher in the abatacept group compared with the placebo-treated group (50.4% vs 19.5%, respectively) (Figure 16-7). The respective rates of ACR50 and ACR70 responses were also significantly higher in the abatacept group (Figure 16-7). Also at 6 months, significantly (P <0.001) more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, reflected by improvement in the HAQ-DI (Figure 16-8).

Abatacept was also evaluated in patients with inadequate response to etanercept in a 1-year, randomized, placebo-controlled, double-blind study, followed by a 2-year open-label, long-term extension. A total of 121 patients continued etanercept (25 mg twice weekly) and were randomized to receive concomitant abatacept 2 mg/kg or placebo during the 1-year double-blind phase. Once the effective dose of abatacept was established as 10 mg/kg in a separate trial, all patients received abatacept 10 mg/kg and etanercept during the long-term extension phase. As shown in Figure 16-9, during the 1-year double-blind treatment phase, the difference in the percentage of patients achieving the primary end point (modified ACR20 response at 6 months) was not significant between groups (48.2% vs 30.6%; P = 0.072). Subsequent to the dosing change after 1 year, similar ACR responses were seen in both treatment groups during the long-term extension. However, significant improvements in health-related quality of life were observed in five of the eight SF36 subscales at 1 year in the abatacept and etanercept group vs the placebo and etanercept group.

The Abatacept or Infliximab vs Placebo, a Trial for Tolerability, Efficacy and Safety in Treating Rheumatoid Arthritis (ATTEST) trial was a 1-year, phase 3, randomized, double-blind, placebo-controlled study in 431 RA patients with an inadequate response to MTX. Patients were treated either with abatacept ~10 mg/kg every 4 weeks, infliximab 3 mg/kg every 8 weeks, or placebo every 4 weeks. All patients continued on background MTX. At 6 months, mean changes in DAS28(ESR) were significantly greater for abatacept vs placebo (-2.53 vs -1.48, P <0.001) and infliximab vs placebo (-2.25 vs -1.48, P <0.001). For abatacept vs infliximab treatment at day 365, reductions in the DAS28(ESR) were similar (-2.88 vs -2.25) but not significantly different. The onset of response, as assessed by ACR20 response rates, was generally more rapid for infliximab compared with abatacept, however, by day 85, responses were similar. Abatacept and infliximab demonstrated similar responses at 6 months. During the second 6 months of the trial, the responses associated with abatacept were maintained, while those observed with infliximab were not. At 1 year, ACR20 responses were higher with abatacept than with infliximab (ACR20: 72.4% vs 55.8%, difference of 16.7, 95% CI = 5.5, 27.8). Overall in this study, abatacept and infliximab demonstrated similar efficacy. However, abatacept had a relatively more acceptable safety and tolerability profile, with fewer serious adverse events, serious infections, acute infusional eventsdiscontinuations due to adverse events than infliximab.

The AGREE (Abatacept Trial to Gauge Remission and Joint Damage Progression in Methotrexate-naïve Patients With Early Erosive Rheumatoid Arthritis) trial evaluated and assessed the efficacy of abatacept in MTX-naïve adult patients with early RA (≤2 years) who were seropositive either for RF or anti-CCP2 or bothhad radiographic evidence of bone erosion of the hands/wrists/feet. The trial included a 1-year randomized, double-blind phase followed by a 1-year open-label extension. Initially, 509 patients were randomized 1:1 to receive abatacept (~10 mg/kg) plus MTX, or placebo plus MTX. During this phase, stable low-dose oral corticosteroids (≤10 mg prednisone equivalent daily) were permitted, plus up to two corticosteroid “pulses” (>10 mg prednisone or equivalent oral corticosteroids for at least 3 consecutive days or injectable corticosteroids) in any 6-month period. After 6 months, addition of one nonbiologic DMARD was permitted. The co-primary end points were the proportion of patients achieving DAS28-defined remission (CRP) and joint damage progression (Genant-mTSS) at year 1.

A significantly higher proportion of patients in the abatacept plus MTX group achieved DAS28 (CRP) remission vs the MTX group by day 57 (Figure 16-10)a significant difference was maintained up to 1 year (41.4% vs 23.3%, respectively; P <0.001). In addition at 1 year, a greater proportion of patients in the abatacept plus MTX vs MTX-alone groups achieved an ACR50 response (57.4% vs 42.3%, respectively; P <0.001), an ACR70 response (42.6% vs 27.3%, respectively; P <0.001), or an ACR90 response (16.4% vs 6.7%; P = 0.001). Also at year 1, changes from baseline in TSS were significantly lower in the abatacept plus MTX group compared with the MTX group (P = 0.04) (Figure 16-11). In addition, 71.9% of patients in the abatacept plus MTX group vs 62.1% of those in the MTX-alone group achieved a ≥0.3 unit change from baseline in HAQ-DI (P = 0.024 for abatacept plus MTX vs MTX alone). Significant improvements in the SF-36 were also observed.

After completing the 1-year double-blind period, 232 patients who received abatacept plus MTX continued on this regimen and 227 patients who received MTX alone were switched to abatacept plus MTX. DAS28 (CRP) remission and LDAS (the co-primary end points) were sustained through year 2 in the original abatacept plus MTX group, with 55.2% in remission at 2 years (Figure 16-12). After the addition of abatacept in the MTX-alone group, additional patients achieved DAS28 (CRP) remission (44.5% vs 26.9%) and LDAS (60.4% vs 43.2%) for year 2 compared with year 1. Less radiographic progression was observed at 2 years in the original abatacept plus MTX group than the MTX-alone group (change in TS 0.84 vs 1.75, P <0.001).

Abatacept for subcutaneous administration via a fixed-dose, prefilled syringe was approved for the same indications as for IV administration. The efficacy of abatacept SC or IV was compared in a phase 3b double-blind, double-dummy, 6-month noninferiority study in 1457 patients with RA and an inadequate response to MTX. Patients were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus a 10 mg/kg IV loading dose on day 1) plus IV placebo, or IV abatacept (10 mg/kg) and SC placebo on days 1, 1529 and every 4 weeks thereafter. Patients continued taking MTX at the same dosage they were receiving at randomization. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group achieving an ACR20 response at month 6. At this point, 76.0% of SC abatacept–treated patients vs 75.8% of IV abatacept–treated patients achieved an ACR20 response (Figure 16-13). The estimated difference between groups was 0.3% (95% CI interval -4.2, 4.8), confirming noninferiority of SC abatacept to IV abatacept. ACR50 and ACR70 response rates over 6 months were also comparable between treatment groups. In addition, onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept–treated groups.

The AMPLE (Abatacept versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate) study compared the safety, efficacy and radiographic outcomes of subcutaneous abatacept vs adalimumab in combination with MTX in a phase 3, randomized study. 646 patients with RA who had inadequate responses to MTX were randomized to receive 125 mg abatacept weekly or 40 mg adalimumab bi-weekly, both with a stable dose of MTX. The primary objective was to demonstrate the noninferiority of abatacept to adalimumab at 1 year, as measured by ACR20 response.

The study met the primary objective at year 1 by demonstrating noninferiority of abatacept plus MTX to adalimumab plus MTX, with comparable ACR20 response (64.8% vs 63.4%, respectively). ACR50, 7090 were also comparable between groups and with year 1 results. Results from year 2 that demonstrated continued inhibition of radiographic progression were comparable between treatment groups, showing that both agents were similarly effective at inhibiting radiographic progression through 2 years. Adverse event frequency was similar in both groups but there were less discontinuations due to adverse events (3.8% vs 9.5%), serious adverse events (1.6% vs 4.9%)serious infections (0% vs 47%), as well as fewer local injection site reactions (4.1% vs 10.4%) with abatacept. Overall, in the AMPLE study, subcutaneous abatacept demonstrated similar clinical efficacy and inhibition of radiographic progression to adalimumab.

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Safety

Abatacept was well tolerated in the two phase 3 trials previously discussed. In the study in patients who did not respond adequately to MTX, the overall incidence of adverse events in abatacept-treated patients (87.3%) was similar to that in placebo recipients (84%). However, there was a higher, but not statistically significant, incidence of prespecified serious infections among abatacept-treated patients compared with those who received placebo (2.5% vs 0.9%, respectively). Compared with placebo recipients, the incidence of infusion reactions was higher in the abatacept-treated group (acute, 8.8% vs 4.1%; peri-infusional, 24.5% vs 16.9%). In the study in patients who had an inadequate response to anti-TNFα therapy, the overall incidence of adverse events and peri-infusional adverse events was 79.5% and 5.0%, respectively, in the abatacept group and 71.4% and 3.0%, respectively, in the placebo group. The incidence of serious infections was 2.3% in each group. However, in the study in patients who were on etanercept but still had active RA, more of the combination abatacept and etanercept group experienced serious adverse events at 1 year than patients receiving placebo and etanercept (16.5% vs 2.8%), with 3.5% vs 0% experiencing serious infections.

The Abatacept Study of Safety in Use with other Rheumatoid Arthritis Therapies (ASSURE) was a 1-year study designed to evaluate the safety of abatacept when used in combination with one or more DMARDs or biologic therapies. This comprehensive trial studied 1456 patients receiving one or more nonbiologic and/or biologic DMARDs, who were randomized in a 2:1 ratio to receive abatacept (approximately 10 mg/kg) or placebo. Of the 959 patients assigned to receive abatacept, 89.2% received nonbiologic RA therapy and 10.7% received background biologic RA therapy during the trial. Of the patients assigned to the placebo group, 86.5% received nonbiologic therapy and 13.3% received background biologic therapy. MTX was the most frequently (~80%) used nonbiologic DMARD.

In the subgroup of patients receiving background nonbiologic DMARDs, the overall incidences of adverse events in abatacept- and placebo-treated patients were similar (89.7% and 86.1%, respectively), as were the rates of discontinuation due to adverse events (5.0% and 4.3%, respectively) (Table 16-1). In these patients, headache was the most common adverse event (20.3% of abatacept-treated patients and 13.9% of those who received placebo). Total serious adverse events occurred at similar rates in the abatacept and the placebo subgroups (11.7% and 12.2%, respectively), while discontinuations due to serious adverse events were more frequent in the abatacept plus nonbiologic DMARD patients (2.1% and 1.2%, respectively).

Among patients receiving biologic DMARDS, total adverse events were more frequent in the abatacept subgroup compared with those in the placebo subgroup (95.1% vs 89.1%), as were discontinuations due to adverse events (8.7% vs 3.1%). In these patients receiving background biologic therapy, headache was the most common adverse event and was reported more frequently in those receiving abatacept than in those receiving placebo (20.4% vs 15.6%). Total serious adverse events were more frequent in patients receiving abatacept plus biologic therapy than in those receiving placebo (22.3% vs 12.5%), as were discontinuations due to serious adverse events (4.9% vs 3.1%). Interestingly, in the small subgroup of patients receiving background anakinra (13 and 10 patients in the abatacept and placebo groups), the frequencies of total serious adverse events were 15.4% and 20.0%, respectively.

Considering the overall incidence of severe or very severe infections among all abatacept- and placebo-treated patients, <4% of patients in either treatment group had a severe or very severe infection; however, serious infections occurred more frequently in the abatacept group (2.9% vs 1.9% in the placebo group). In the majority of patients, the serious infections were treatable and did not result in discontinuation of treatment. All of the serious infections in abatacept-treated patients were bacterial in origin. There were no fatalities due to infection and there were no infections attributed to an opportunistic microorganism during this 1-year study. No cases of TB were observed in the randomized studies but isolated cases have been observed in long-term observational studies.

The overall incidence of neoplasms (benign, malignant unspecified) was 3.5% among all abatacept-treated patients and all placebo-treated patients. Neoplasms reported as serious adverse events occurred in 1.5% of abatacept-treated patients and in 1.0% of placebo-treated patients. Skin carcinomas (primarily basal cell or squamous cell) were the most frequently reported.

While the ASSURE study documented a greater rate of serious infections in patients treated with TNF inhibitors and abatacept, the comparative efficacy of these biologics was unknown until recently.

Enlarge 

Dosage and Administration

Intravenous Administration

In adults, abatacept should be administered as a 30-minute IV infusion at the weight-appropriate dose as shown in Table 16-2. Following the initial administration, abatacept should be given at 2 and 4 weeks after the first infusion, then every 4 weeks thereafter. When reconstituting the lyophilized powder, only the silicone-free syringe supplied with each vial should be used to avoid the development of translucent particles in the solution. Abatacept should not be infused concomitantly in the same IV line with other agents.

Pediatric patients weighing <75 kg should receive 10 mg/kg IV based on the patient’s body weight. Pediatric patients weighing ≥75 kg should be administered abatacept following the adult IV dosing regimen, not to exceed a maximum dose of 1000 mg.

Subcutaneous Treatment

After a single abatacept IV infusion loading dose (as per body weight categories above), 125 mg of abatacept administered by an SC injection should be given within a day, followed by 125 mg SC once a week. Patients who are unable to receive an infusion may initiate weekly injections of SC abatacept without an IV loading dose. Patients transitioning from IV abatacept therapy to SC abatacept should administer the first SC dose instead of the next scheduled IV dose.

Enlarge