abatacept, co-stimulation modulator, methotrexate, rheumatoid arthritis, t cell, tumor necrosis factor antagonist
M Cohen. Abatacept In Focus. The Internet Journal of Rheumatology. 2006 Volume 3 Number 1.
There have been considerable advances in the treatment of rheumatoid arthritis. However, many patients are found to be refractory to traditional disease-modifying antirheumatic drugs and the newer anti-cytokine therapies.
Agents such as abatacept and rituximab now offer exciting new options for patients, including those who, until recently, had limited treatment options.
Randomized, multinational, double-blind, placebo-controlled trials have assessed the efficacy and safety of abatacept in patients with active RA, who are methotrexate (MTX) and tumor necrosis factor (TNF) antagonist inadequate responders.
Results from these trials have shown that abatacept provides significant clinical and health-related quality of life benefits in both MTX and TNF antagonist inadequate responders. Abatacept also slowed the progression of structural damage compared with placebo/MTX alone. In addition to these clinical benefits, a fixed dose of abatacept has demonstrated a consistent safety and tolerability profile.
Longer-term data will be necessary to confirm the observations seen to date.
Rheumatoid arthritis (RA) treatment is entering a new era, targeting the immunopathology of the disease with increased specificity and selectivity beyond that observed with traditional disease-modifying antirheumatic drugs (DMARDs). Several new agents have proven to be effective in many patients who previously demonstrated an inadequate or failing response to traditional DMARDs, such as methotrexate (MTX).
Of the currently approved biologic therapies, the majority target pro-inflammatory cytokines involved in the downstream processes of the RA immune cascade. These include the tumor necrosis factor (TNF) antagonists, etanercept,1 infliximab2 and adalimumab,3 and the interleukin (IL)-1 antagonist, anakinra.4 These agents, often used in combination with the non-biologic DMARD, MTX, have helped deliver improvements in signs and symptoms of the disease, including radiographic outcomes, as well as improvements in health-related quality of life (HRQoL).5
Despite the efficacy of agents such as TNF antagonists, approximately 20–40% of patients may not respond to anti-cytokine therapy.6 Other patients may lose their response to treatment over time; in some patients, this is due to the formation of antibodies against the biologic agent.7, 8 Patients who are refractory to MTX and/or anti-cytokine agents had limited options until recently. However, the investigation of earlier events in RA immunopathogenesis as potential therapeutic targets, has led to developments in the RA armamentarium.
This review will give an overview of the two newest biologic agents approved for the treatment of RA, with focus on the first-in-class therapy, abatacept.
New therapeutic targets
Rheumatoid arthritis is a complex autoimmune disease, involving multiple immune pathways and cell types.9 The immunopathology of RA involves activated T cells, which mediate immune processes within the synovium, resulting in the release of cytokines, autoantibodies and other inflammatory mediators from macrophages, T cells and B cells.10 These, in turn, stimulate the downstream release of further inflammatory mediators resulting in the direct attack upon joint structures by macrophage- and fibroblast-like synoviocytes and other cells.10 In order to become fully activated, a T cell must not only recognize an antigen that has been processed and presented by an antigen presenting cell (APC), but also receive a co-stimulatory signal.11 One of the best characterized co-stimulatory pathways is the engagement of CD80/CD86 on APCs with CD28 on T cells.11 Another co-stimulatory pathway involves the CD40 ligand, in which T cells interact with B cells via the CD40:CD40L pathway, thereby facilitating B-cell activation and the production of autoantibodies.12 T-cell activation is also downregulated by co-stimulatory pathways. The CD28-mediated T-cell activation is downregulated by expression of endogenous cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4),13 which binds to CD80/CD86 with a much higher affinity than CD28.14
The elucidation of RA immunopathology has led to the development of novel forms of therapy, two of which have recently been approved for the treatment of RA. These are Rituxan® (rituximab) (Genentech Incorporated, San Francisco, CA) – a genetically engineered chimeric anti-CD20 monoclonal antibody that depletes B cells,15 and ORENCIA®(abatacept) (Bristol-Myers Squibb, Princeton, NJ) – a soluble human fusion protein that selectively modulates T-cell co-stimulation (Figure 1).
IL=interleukin; TNF-?=tumor necrosis factor-?; RF=rheumatoid factor; IL-6R=interleukin-6 receptor
Rituximab, in combination with MTX, is indicated to reduce signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF antagonists.15 It is also approved for non-Hodgkin's lymphoma.15 The Phase IIb DANCER (
Abatacept is the first RA therapy to be approved for the treatment of RA in patients with an inadequate response to either traditional DMARDs such as MTX or biologic DMARDs such as TNF antagonists. As such, the focus of this review will center on the clinical effectiveness, safety and dosing of abatacept treatments for patients in this previously limited treatment group.
Abatacept is the first in a new class of agents that selectively modulates the CD80/CD86:CD28 pathway of T-cell co-stimulation.18 It is a soluble, recombinant, fully-human fusion protein, comprising the extracellular domain of CTLA-4 linked to the Fc (hinge, CH2 and CH3 domains) portion of immunoglobulin G1.
Abatacept acts by binding to CD80/CD86 on APCs and preventing its interaction with CD28 on T cells.18 Whereas most RA therapies target one specific cytokine or molecule involved at the end stages of RA immunopathology,9 the novel mechanism of action of abatacept – acting at the level of the T cell – provides the potential to impact multiple downstream events. This has been demonstrated by reductions in multiple inflammatory biomarkers following treatment with abatacept in patients with active RA and an inadequate response to MTX or TNF antagonists.19 By selectively modulating the CD80/CD86:CD28 pathway,18abatacept may allow other co-stimulatory pathways to remain largely intact due to the fact there are other possible co-stimulation pathways.20
In the US, abatacept is indicated for reducing signs and symptoms, inducing a major clinical response, slowing the progression of structural damage and improving physical function, in adult patients with moderate-to-severely active RA who have had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists.19Abatacept may be used as monotherapy or concomitantly with non-biologic DMARDs, but is not recommended for use concomitantly with TNF antagonists or anakinra.21
Efficacy of abatacept in clinical studies
Several randomized, multinational, double-blind, placebo-controlled trials in patients with active RA have assessed the efficacy and safety of abatacept in patients with an inadequate response to MTX,22,23,24 and in those with an inadequate response to TNF antagonists (Table 1).25
A pilot, dose-finding, double-blind, placebo-controlled trial conducted in patients with RA treated unsuccessfully with at least one DMARD, demonstrated the safety and tolerability of abatacept monotherapy, and indicated a dose-dependent efficacy.26 Subsequently, a 12-month, randomized, double-blind, placebo-controlled, Phase IIb trial of abatacept plus MTX in patients with RA refractory to MTX therapy demonstrated significant improvements in the signs and symptoms of RA, physical function and HRQoL over 1 year.23Across Phase III clinical trials, a fixed dose of abatacept, determined according to weight range, was administered over a 30-minute infusion at Weeks 0, 2 and 4, and then every 4 weeks thereafter.19
*All patients treated with 10 mg/kg abatacept during OL phase.
DB=double-blind; OL=open-label; IV=intravenous; RA=rheumatoid arthritis; DMARD=disease-modifying antirheumatic drug; N/A=not applicable; SC=subcutaneous; MTX=methotrexate; AIM=
Eligible patients completing the double-blind periods of the AIM and ATTAIN trials were entered into the corresponding long-term extension (LTE) phase of each trial where data continue to be collected.
In addition to efficacy benefits and tolerability, one outcome that influences patients' satisfaction with treatment is quality of life.28Patients with RA experience significant levels of fatigue, a symptom that correlates with work dysfunction and the overall health status of patients.29, 30 In the AIM and ATTAIN trials,24, 25 abatacept was shown to provide clinically meaningful and statistically significant improvements in HRQoL and physical function, in addition to improvements in other patient-reported measures such as fatigue.30, 31 Moreover, abatacept demonstrated both clinically meaningful and statistically significant improvements in all eight subscales of the Short Form (SF)-36, in both patients with an inadequate response to MTX,22and in those with an inadequate response to TNF antagonists.25(Figure 2a and b)
Kremer et al. N Eng J Med 2003;349(20):1907–1915. Copyright© 2003 Massachusetts Medical Society. All rights reserved.
CTLA-4=cytotoxic T-lymphocyte-associated antigen-4
Genovese et al. N Eng J Med 2005;353(11):1114–1123. Copyright© 2005 Massachusetts Medical Society. All rights reserved.
Safety and tolerability of abatacept in clinical studies
Evidence of sustained safety and tolerability are of key importance when making treatment decisions for RA, since it is a chronic condition requiring long-term therapy. Given the structure and mechanism of action of abatacept, the rates and types of infection, in addition to evidence of immunogenicity and autoimmunity, are also of relevance.
An integrated assessment of safety data from five double-blind abatacept clinical trials comprising approximately 2000 patients19 has demonstrated that abatacept is generally safe and well tolerated when combined with non-biologic background therapy.19The most commonly reported adverse events (AEs) (occurring in ≥10% of abatacept-treated patients) were headache, upper respiratory tract infection, nasopharyngitis and nausea; the most commonly reported serious AEs (SAEs) were serious infections and malignancies.19Table 3 presents AEs occurring in ≥3% of all patients and in ≥1% in abatacept-treated patients.
Infections were reported in 54% of abatacept-treated patients and 48% of placebo-treated patients.19The most commonly reported infections (reported in 5–13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza and bronchitis. Serious infections were reported in 3% of patients treated with abatacept and 2% of patients given placebo. The most common (<1%) serious infections reported with abatacept were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis and acute pyelonephritis.19The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1%), bronchitis and herpes zoster (both <1%). The most frequent infections resulting in discontinuation were pneumonia, localized infection and bronchitis (all <1%).19
In placebo-controlled trials (involving 1955 patients treated with abatacept for a median of 12 months), the overall frequencies of malignancies were similar in the abatacept- and placebo-treated patients (1.3% and 1.1%, respectively).19However, more cases of lung cancer were observed in abatacept-treated patients than placebo-treated patients (4 patients, <1% versus 0, respectively). In the cumulative abatacept clinical trials (placebo-controlled and uncontrolled, open-label), a total of eight cases of lung cancer (0.21 cases per 100 patient–years) and four cases of lymphoma (0.10 cases per 100 patient–years) were observed in 2688 patients (3827 patient–years).19The potential role of abatacept in the development of malignancies in humans is unknown19 and long-term studies will be necessary to evaluate this risk.
The incidence rates of serious infection, serious pneumonia, neoplasms and malignancies did not appear to increase over the double-blind period of these studies.19
Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion; assessed in Phase III trials only) were more common in the abatacept-treated patients than the placebo recipients (9% vs 6%, respectively). The most frequently reported infusion-related events (1–2%) were dizziness, headache and hypertension.19Less than 1% of abatacept-treated patients discontinued due to an acute infusion-related event.19Of 2688 patients treated with abatacept in the double-blind and open-label clinical trial phases, there were two cases of anaphylaxis or anaphylactoid reactions.
Events potentially associated with drug hypersensitivity were reported in less than 0.6% of abatacept-treated patients and generally occurred within 24 hours of infusion.19
Due to the lack of data regarding the use of biologic therapies in combination with other treatments, the ASSURE (
Recent advances in the understanding of the immunopathology that underlies RA allowed the development of new therapeutic agents including the recently approved therapies abatacept and rituximab. Abatacept is approved for use in MTX and TNF antagonist inadequate responders – providing significant clinical and HRQoL benefits in both populations and slowing radiographic progression in MTX inadequate responders. From the available clinical trials, a fixed dose of abatacept has demonstrated a consistent safety and tolerability profile in patients with active RA and an inadequate response to MTX,24and in those with an inadequate response to TNF antagonists.25 Longer-term observations will be required to confirm the data available to date.
The author would like to thank Elizabeth Burtally, PhD, Medicus International, for her editorial assistance. Editorial support was funded by Bristol-Myers Squibb.