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The New England Journal of Medicine Oct 2020Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with abatacept, a T-cell... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with abatacept, a T-cell costimulation modulator, in patients with rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (DMARDs) are unclear.
METHODS
In this 24-week, phase 3, double-blind, controlled trial, we randomly assigned patients in a 1:1 ratio to receive oral upadacitinib (15 mg once daily) or intravenous abatacept, each in combination with stable synthetic DMARDs. The primary end point was the change from baseline in the composite Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP; range, 0 to 9.4, with higher scores indicating more disease activity) at week 12, assessed for noninferiority. Key secondary end points at week 12 were the superiority of upadacitinib over abatacept in the change from baseline in the DAS28-CRP and the percentage of patients having clinical remission according to a DAS28-CRP of less than 2.6.
RESULTS
A total of 303 patients received upadacitinib, and 309 patients received abatacept. From baseline DAS28-CRP values of 5.70 in the upadacitinib group and 5.88 in the abatacept group, the mean change at week 12 was -2.52 and -2.00, respectively (difference, -0.52 points; 95% confidence interval [CI], -0.69 to -0.35; P<0.001 for noninferiority; P<0.001 for superiority). The percentage of patients having remission was 30.0% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P<0.001 for superiority). During the treatment period, one death, one nonfatal stroke, and two venous thromboembolic events occurred in the upadacitinib group, and more patients in the upadacitinib group than in the abatacept group had elevated hepatic aminotransferase levels.
CONCLUSIONS
In patients with rheumatoid arthritis refractory to biologic DMARDs, upadacitinib was superior to abatacept in the change from baseline in the DAS28-CRP and the achievement of remission at week 12 but was associated with more serious adverse events. Longer and larger trials are required in order to determine the effect and safety of upadacitinib in patients with rheumatoid arthritis. (Funded by AbbVie; SELECT-CHOICE Clinicaltrials.gov number, NCT03086343.).
Topics: Abatacept; Administration, Oral; Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Double-Blind Method; Drug Tolerance; Female; Heterocyclic Compounds, 3-Ring; Humans; Inducible T-Cell Co-Stimulator Protein; Infusions, Intravenous; Intention to Treat Analysis; Janus Kinase Inhibitors; Male; Middle Aged; Remission Induction
PubMed: 33053283
DOI: 10.1056/NEJMoa2008250 -
Journal of Clinical Oncology : Official... Jun 2021Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.
METHODS
ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).
RESULTS
In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) ( = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, < .001), and the SGFS was better (97.7% 58.7%, < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.
CONCLUSION
Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
Topics: Abatacept; Adolescent; Adult; Aged; Child; Cyclosporine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Tacrolimus; Young Adult
PubMed: 33449816
DOI: 10.1200/JCO.20.01086 -
Expert Review of Clinical Immunology Apr 2019Rheumatoid arthritis (RA) is a complex disease in which different mechanisms are involved. Studies suggest a key role for aberrant pathways of T-cell activation in the... (Review)
Review
Rheumatoid arthritis (RA) is a complex disease in which different mechanisms are involved. Studies suggest a key role for aberrant pathways of T-cell activation in the initiation and perpetuation of disease. Abatacept is a fusion protein composed of the Fc region of the immunoglobulin G1 (IgG1) fused to the extracellular domain of cytotoxic T lymphocyte-associated antigen (CTLA4). It has the ability to modulate T-cell activation by interfering with co-stimulation of these cells, a necessary step to become activated. This suggests that abatacept may play a role in the progression and/or even the initiation of RA. Areas covered: a review of the different studies carried out during clinical development of abatacept was performed. Both formulations, intravenous (IV) and subcutaneous (SC), showed a similar and consistent efficacy and safety profile. Abatacept was effective both in RA patients not responding to methotrexate (MTX) and to tumor necrosis factor (TNF) inhibitors. Expert commentary: abatacept, with its unique mechanism of action, proved to be a useful therapeutic alternative in RA, also having an acceptable safety profile. Evidence points out that abatacept may be able to alter the RA disease course. Ongoing studies will clarify this issue.
Topics: Abatacept; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Expert Testimony; Humans; Lymphocyte Activation; Recombinant Fusion Proteins; T-Lymphocytes; Treatment Outcome
PubMed: 30730220
DOI: 10.1080/1744666X.2019.1579642 -
Drugs Jul 2017The biological DMARD (bDMARD) abatacept (Orencia), a recombinant fusion protein, selectively modulates a co-stimulatory signal necessary for T-cell activation. In the... (Review)
Review
The biological DMARD (bDMARD) abatacept (Orencia), a recombinant fusion protein, selectively modulates a co-stimulatory signal necessary for T-cell activation. In the EU, abatacept is approved for use in patients with highly active and progressive rheumatoid arthritis (RA) not previously treated with methotrexate. Abatacept is also approved for the treatment of moderate to severe active RA in patients with an inadequate response to previous therapy with at least one conventional DMARD (cDMARD), including methotrexate or a TNF inhibitor. In phase III trials, beneficial effects on RA signs and symptoms, disease activity, structural damage progression and physical function were seen with intravenous (IV) or subcutaneous (SC) abatacept regimens, including abatacept plus methotrexate in methotrexate-naive patients with early RA and poor prognostic factors, and abatacept plus methotrexate or other cDMARDs in patients with inadequate response to methotrexate or TNF inhibitors. Benefits were generally maintained during longer-term follow-up. Absolute drug-free remission rates following withdrawal of all RA treatments were significantly higher with abatacept plus methotrexate than with methotrexate alone. Both IV and SC abatacept were generally well tolerated, with low rates of immunogenicity. Current evidence therefore suggests that abatacept is a useful treatment option for patients with RA.
Topics: Abatacept; Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Immunoconjugates; Methotrexate; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 28608166
DOI: 10.1007/s40265-017-0775-4 -
Diabetes Care May 2023Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.
RESEARCH DESIGN AND METHODS
We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests.
RESULTS
A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline.
CONCLUSIONS
Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.
Topics: Humans; Abatacept; Diabetes Mellitus, Type 1; Immunosuppressive Agents; T-Lymphocytes, Regulatory; Glucose
PubMed: 36920087
DOI: 10.2337/dc22-2200 -
Nihon Rinsho. Japanese Journal of... Jun 2016Abatacept (ABT) is a recombinant fusion protein comprising the extracellular domain of human CTLA4, which inhibits the activation of T cells. Several clinical trials... (Review)
Review
Abatacept (ABT) is a recombinant fusion protein comprising the extracellular domain of human CTLA4, which inhibits the activation of T cells. Several clinical trials have provided evidence of efficacy and safety of ABT in the patients with rheumatoid athritis (RA) with various clinical characteristics such as MTX inadequate responders (IR), TNF inhibitor-IR. Moreover, indirect comparison of ABT to other biologics reported in Cochrane review revealed that ABT has better safety profile in serious adverse events and serious infection Thus the features of ABT in the treatment of RA have gradually become apparent and knowledge of these features is helpful for better use of biologics. In this review we will discuss the efficacy and safety of ABT in the management of RA.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; CTLA-4 Antigen; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; Humans; Lymphocyte Activation; Methotrexate; Molecular Targeted Therapy; Product Surveillance, Postmarketing; T-Lymphocytes
PubMed: 27311187
DOI: No ID Found -
Journal For Immunotherapy of Cancer Apr 2022Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain....
Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.
Topics: Abatacept; Adult; Humans; Immune Checkpoint Inhibitors; Male; Myocarditis; Nitriles; Pyrazoles; Pyrimidines
PubMed: 35383117
DOI: 10.1136/jitc-2022-004699 -
Paediatric Drugs Dec 2020Juvenile idiopathic arthritis (JIA) encompasses several forms of chronic inflammatory arthritis of unknown etiology presenting in children < 16 years of age, with a... (Review)
Review
Juvenile idiopathic arthritis (JIA) encompasses several forms of chronic inflammatory arthritis of unknown etiology presenting in children < 16 years of age, with a minimum symptom duration of 6 weeks. Approximately half of affected children have polyarticular-course JIA (pJIA), a functional concept related to several clinically and genetically heterogeneous JIA categories (systemic, extended oligoarthritis, polyarticular rheumatoid factor-positive or rheumatoid factor-negative, enthesitis-related arthritis, and psoriatic arthritis), which has as its defining feature the involvement of five or more joints during the disease course. Chronic inflammation and joint damage lead to the manifestations of JIA such as pain, limitation of motion, and loss of physical function, all of which negatively impact patients' quality of life. The American College of Rheumatology recommends initial treatment with a conventional synthetic disease-modifying antirheumatic drug (csDMARD), such as methotrexate (MTX) and, in patients with pJIA who have an inadequate response or intolerance to MTX, the use of a biologic DMARD (bDMARD) such as a tumor necrosis factor inhibitor, abatacept, or tocilizumab. Abatacept selectively modulates the CD80/CD86:CD28 co-stimulatory signal required for full T cell activation, and thus has a distinct mechanism of action upstream of that of other currently available bDMARD treatments for rheumatic diseases. To enable physicians to make informed treatment decisions, it is important to review available data for the existing therapeutic agents. Here, we summarize the current evidence from phase III pivotal trials of intravenous (IV) and subcutaneous (SC) abatacept and from an ongoing registry of patients with JIA treated with abatacept. In the pivotal trials for IV and SC abatacept, either with or without MTX, both formulations demonstrated clinical efficacy, with a high proportion of patients achieving stringent clinical responses, as well as improvements in patient-reported outcomes and a favorable safety profile, particularly with regard to infections.
Topics: Abatacept; Adolescent; Antirheumatic Agents; Arthritis, Juvenile; Child; Humans
PubMed: 33029724
DOI: 10.1007/s40272-020-00422-2 -
Current Opinion in Rheumatology May 2018The purpose of this review is to summarize the current knowledge concerning the mechanisms of action of Abatacept in patients with rheumatoid arthritis. (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to summarize the current knowledge concerning the mechanisms of action of Abatacept in patients with rheumatoid arthritis.
RECENT FINDINGS
Abatacept (CTLA-4Ig) represents a soluble, recombinant, fully humanized fusion protein, comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1. Abatacept binds to the costimulatory molecules CD80 and CD86 on antigen-presenting cells (APC), thereby blocking interaction with CD28 on T cells. In humans, Abatacept treatment was shown to be effective in patients with various autoinflammatory diseases including rheumatoid arthritis. Although the prevention of T-cell activation by interfering with signaling via CD28 still represents the main mechanism of action Abatacept acts on additional cell populations including regulatory T cells (Treg), monocytes/macrophages, osteoclasts, and B cells.
SUMMARY
Effects of Abatacept on other cell populations besides T cells have to be taken into account and might represent a valuable contribution to the therapeutic success.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Leukocytes, Mononuclear; Macrophages
PubMed: 29401118
DOI: 10.1097/BOR.0000000000000491 -
Inflammopharmacology Jun 2022To examine the effectiveness of Janus-kinase inhibitors (JAKis) or abatacept (ABA) in patients with rheumatoid arthritis-interstitial lung disease (RA-ILD).
OBJECTIVES
To examine the effectiveness of Janus-kinase inhibitors (JAKis) or abatacept (ABA) in patients with rheumatoid arthritis-interstitial lung disease (RA-ILD).
METHODS
Patients with RA-ILD receiving JAKis or ABA were retrospectively evaluated at baseline and after 18 months of treatment. A computer-aided method (CaM) was used to assess the extent of high-resolution computed tomography (HRCT) fibrosis percentage. According to HRCT fibrosis changes, patients were classified as "worsened" (progression of 15% or more), "stable" (changes within 15%) or "improved" (reduction of 15% or more). Correlations between RA characteristics and JAKis or ABA responses were studied using a multivariate regression model.
RESULTS
Seventy-five patients (69.3% women) were evaluated, 31 received a JAKi while 44 received ABA. In the JAKis group, five patients (16.1%) showed RA-ILD progression, 20 patients (64.5%) were considered stable, and six patients (19.4%) demonstrated RA-ILD improvement. In the ABA group, five patients (11.3%) showed RA-ILD progression, 32 patients (72.7%) were stable, and seven patients (16.0%) demonstrated RA-ILD improvement. In both groups, the percentage of current smokers was different between those classified as "worsened" and those classified as "improved/stable" (p = 0.01). In multivariate regression analysis, current smoking habit (p = 0.0051) and concomitant methotrexate treatment (p = 0.0078) were the two variables related to RA-ILD progression in ABA-treated patients, whereas in JAKis-treated patients, the only RA-ILD progression-related variable was disease duration of RA (p < 0.001).
CONCLUSIONS
Treatment with JAKis or ABA was related to stability or improvement of RA-ILD in 83.9% and 88.6% of patients, respectively. RA duration is the only variable associated with worsening RA-ILD in JAKis-treated patients.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Fibrosis; Humans; Janus Kinase Inhibitors; Lung Diseases, Interstitial; Male; Retrospective Studies
PubMed: 35462572
DOI: 10.1007/s10787-022-00936-w