Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. METHODS: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. FINDINGS: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. INTERPRETATION: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. FUNDING: Gossamer Bio.

Randomised clinical trial: a phase 1b study of GB004, an oral HIF-1α stabiliser, for treatment of ulcerative colitis.

BACKGROUND: Epithelial barrier dysfunction contributes to a dysregulated intestinal immune response in ulcerative colitis (UC). GB004 is an orally administered, small molecule, gut-targeted stabiliser of hypoxia-inducible factor-1α, a transcription factor with protective roles at the epithelial layer of the inflamed gut. AIMS: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of GB004 in patients with active UC. METHODS: This double-blind, placebo-controlled study randomised patients 2:1 to receive an oral solution of GB004 120 mg or placebo once daily for 28 days. Eligible patients had a Robarts Histopathology Index score ≥4 with neutrophils in the epithelium, total Mayo Clinic score 3-12, Mayo Clinic endoscopic subscore ≥1, and blood in the stool, despite treatment with 5-aminosalicylates, corticosteroids or immunosuppressants. RESULTS: Thirty-four patients were randomised. GB004 120 mg for 28 days was generally well-tolerated. Adverse events occurred in 27.3% (3/11) and 39.1% (9/23) of patients in the placebo and GB004 groups respectively. Nausea and dysgeusia were most commonly reported in the GB004 group (0% for placebo and 21.7% [5/23] and 13.0% [3/23] respectively for GB004). There were no treatment-related serious adverse events or deaths. GB004 exhibited minimal accumulation, with higher colonic concentrations relative to plasma. Exploratory pharmacodynamic and efficacy analyses demonstrated GB004 target engagement and numerically higher proportions of patients achieving improvement in multiple measures of disease activity, respectively, at day 28 for GB004 compared to placebo. CONCLUSION: Results from this phase 1b trial support evaluation of the full therapeutic potential of GB004 for the treatment of UC. A phase 2 study (NCT04556383) is ongoing. Clinicaltrials.gov NCT03860896.

RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. METHODS: We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. RESULTS: At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. CONCLUSIONS: In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473.

Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis.

BACKGROUND: Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. METHODS: We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. The primary outcome was clinical remission (Mayo Clinic score ≤2, with no subscore >1) at 8 weeks. RESULTS: The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Clinical response (decrease in Mayo Clinic score of ≥3 points and ≥30% and decrease in rectal-bleeding subscore of ≥1 point or a subscore ≤1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The most common adverse events overall were anemia and headache. CONCLUSIONS: In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.).

Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study.

OBJECTIVE: Interferon-γ-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC. DESIGN: In this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS-936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure-response relationship and histological improvement. RESULTS: 109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS-936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108-235 µg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events. CONCLUSIONS: Anti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose-response studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00656890.

Longterm safety and efficacy of abatacept through 5 years of treatment in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitor therapy.

OBJECTIVE: To evaluate abatacept safety and efficacy over 5 years in patients with rheumatoid arthritis (RA) who had inadequate response to anti-tumor necrosis factor (TNF) therapy in the ATTAIN trial. METHODS: Patients completing the 6-month, double-blind (DB) placebo-controlled period were eligible to enter the longterm extension (LTE), where all patients received abatacept every 4 weeks (∼10 mg/kg, according to weight range). Safety, efficacy, physical function, and health-related quality of life were monitored throughout. RESULTS: In total, 317 patients (218 DB abatacept, 99 DB placebo) entered the LTE; 150 (47.3%) completed it. Overall incidences of serious adverse events, infections, serious infections, malignant neoplasms, and autoimmune events did not increase during the LTE versus the DB period. American College of Rheumatology responses with abatacept at Month 6 were maintained over 5 years. At Year 5, among patients who received abatacept for 5 years and had available data, 38/103 (36.9%) achieved low disease activity as defined by the 28-joint Disease Activity Score (DAS28)/C-reactive protein (CRP); 23/103 (22.3%) achieved DAS28/CRP-defined remission. Health Assessment Questionnaire response was achieved by 62.5% of patients remaining on treatment at Year 5; mean improvements from baseline in physical component summary and mental component summary scores were 7.34 and 6.42, respectively. High proportions of patients maintained efficacy and physical function benefits or improved their disease state at each timepoint throughout the LTE, if remaining on abatacept treatment. CONCLUSION: Safety remained consistent, and abatacept efficacy was maintained from 6 months to 5 years, demonstrating the benefits of switching to abatacept in this difficult-to-treat population of patients with RA previously failing anti-TNF therapy.

Abatacept for Crohn's disease and ulcerative colitis.

BACKGROUND & AIMS: The efficacy of abatacept, a selective costimulation modulator, in Crohn's disease (CD) and ulcerative colitis (UC) is unknown. METHODS: Four placebo-controlled trials evaluated the efficacy and safety of abatacept as induction (IP) and maintenance (MP) therapy in adults with active, moderate-to-severe CD (CD-IP; CD-MP) and UC (UC-IP1; UC-MP). In CD-IP and UC-IP1, 451 patients with CD and 490 patients with UC were randomized to abatacept 30, 10, or 3 mg/kg (according to body weight) or placebo, and dosed at weeks 0, 2, 4, and 8. In MP, 90 patients with CD and 131 patients with UC who responded to abatacept at week 12 in the induction trials were randomized to abatacept 10 mg/kg or placebo every 4 weeks through week 52. RESULTS: In CD-IP, 17.2%, 10.2%, and 15.5% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at weeks 8 and 12, vs 14.4% receiving placebo (P = .611, P = .311, and P = .812, respectively). In UC-IP1, 21.4%, 19.0%, and 20.3% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at week 12, vs 29.5% receiving placebo (P = .124, P = .043, and P = .158, respectively). In CD-MP, 23.8% vs 11.1% of abatacept vs placebo patients were in remission at week 52. In UC-MP, 12.5% vs 14.1% of patients receiving abatacept vs placebo were in remission at week 52. Safety generally was comparable between groups. CONCLUSIONS: The studies showed that abatacept is not efficacious for the treatment of moderate-to-severe CD or UC.

Abatacept in subjects who switch from intravenous to subcutaneous therapy: results from the phase IIIb ATTUNE study.

OBJECTIVE: To assess safety, immunogenicity and efficacy in rheumatoid arthritis (RA) patients switched from long-term intravenous to subcutaneous (SC) abatacept. METHODS: In this phase IIIb, open-label, single-arm trial, patients who completed ≥4 years of intravenous abatacept (in long-term extensions of two phase III studies) were enrolled to receive SC abatacept (125 mg/week). The primary objective was safety during the first 3 months after switching from intravenous therapy. RESULTS: 123 patients entered the study (mean Disease Activity Score 28 (based on C reactive protein) and HAQ-DI of 3.4 and 0.94, respectively). At month 3, 120 (97.6%) patients were continuing to receive SC abatacept; no patients discontinued due to lack of efficacy. Adverse events (AEs) were reported in 49 (39.8%) patients through month 3. One patient (0.8%) discontinued due to an AE and one patient (0.8%) experienced a serious AE. Two (1.6%) patients had SC injection site reactions (erythema, pain), both with mild intensity. Clinical efficacy was maintained throughout. Limited impact on immunogenicity was observed when switching routes of administration. CONCLUSION: These data demonstrate that patients can switch from long-term monthly intravenous abatacept to a weekly fixed dose of 125 mg SC abatacept with no increased safety concerns. This study further supports SC abatacept as an alternative treatment option for patients with RA.

Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial.

OBJECTIVE: To evaluate abatacept treatment over 3 years in patients with rheumatoid arthritis (RA) refractory to methotrexate (MTX). METHODS: Patients randomised to abatacept or placebo (+MTX) during the 1-year double-blind period of the Abatacept in Inadequate responders to Methotrexate (AIM) trial received open-label abatacept (+MTX) in the long-term extension (LTE). Safety was assessed for patients who received ≥ 1 dose of abatacept, regardless of randomisation group. Efficacy was assessed for patients randomised to abatacept who entered the LTE. RESULTS: 433 and 219 patients were randomised and treated with abatacept or placebo, respectively; 378 and 161 entered the LTE. At year 3, 440/539 patients were ongoing. No unexpected safety events were observed in the LTE. By year 3, incidence rates of adverse event and serious adverse events were 249.8/100 and 15.1/100 patient-years, respectively. Incidence rates were generally stable over time. At year 3, 84.8%, 63.4% and 37.5% of patients achieved American College of Rheumatology (ACR) criteria of 20, 50 and 70, respectively, compared with 82.3%, 54.3% and 32.4% of patients at year 1. Mean changes in Genant-modified Sharp scores were reduced progressively over 3 years, with significantly greater inhibition during year 3 compared with year 2 (p=0.022 for total score). CONCLUSION: In MTX-inadequate responders with RA, abatacept provided consistent safety and sustained efficacy over 3 years. The data suggest an increasing inhibitory disease-modifying effect on radiographic progression.

Clinical response and tolerability to abatacept in patients with rheumatoid arthritis previously treated with infliximab or abatacept: open-label extension of the ATTEST Study.

OBJECTIVE: To assess the efficacy and safety of abatacept in biological-naive patients with rheumatoid arthritis and an inadequate response to methotrexate treated in the long-term extension (LTE) of the ATTEST trial. METHODS: Patients randomly assigned to abatacept, placebo or infliximab completing the 1-year double-blind period were eligible to receive abatacept ∼10 mg/kg in the open-label LTE. Efficacy to year 2 is presented for patients randomly assigned to abatacept or infliximab who switched to open-label abatacept. Safety data are presented for all patients entering LTE regardless of double-blind treatment. RESULTS: Of 431 patients randomly assigned, 79.8% remained on abatacept at year 2. At years 1 and 2, 19.7% and 26.1% of abatacept and 13.3% and 28.6% of infliximab-to-abatacept patients achieved disease activity score 28-defined remission (<2.6). Safety with abatacept during the cumulative study period was consistent with the double-blind experience, with no increase in adverse event incidence following the switch to abatacept. CONCLUSION: In methotrexate-inadequate responders, abatacept efficacy was maintained over 2 years. For infliximab-to-abatacept patients, efficacy improvements were seen in year 2 after patients switched to abatacept. Switching directly from infliximab to abatacept was well tolerated. These data demonstrate that abatacept provides sustained responses and consistent safety, suggesting that switching from infliximab to abatacept is a viable treatment option.

A model for harmonizing flow cytometry in clinical trials.

Complexities in sample handling, instrument setup and data analysis are barriers to the effective use of flow cytometry to monitor immunological parameters in clinical trials. The novel use of a central laboratory may help mitigate these issues.

Targeting lymphocyte co-stimulation: from bench to bedside.

T and B lymphocytes are central regulators and effectors of immune responses and are believed to have a key role in many autoimmune diseases. Targeting the activation or effector function of lymphocytes is a potentially effective approach to treat autoimmunity. Typically, T-cell activation occurs after engagement of the T-cell receptor with its cognate peptide-major histocompatibility complex (signal 1) and subsequent engagement of co-stimulatory molecules (signal 2). This "second signal" contributes to T-cell activation by promoting proliferation, survival, and effector function. In general, activation in the absence of co-stimulation leads to a reduced immune response, anergy, or even tolerance. B-cell activation similarly requires co-stimulation for the development of complete effector function. The most potent co-stimulatory molecules identified to date are CD28 for T-cells and CD40 for B-cells. Both molecules are recognized for their potential as immune modulators; however, thus far neither molecule has been successfully targeted directly for the treatment of autoimmune disease. The only current therapy to target either of these pathways is cytotoxic T-lymphocyte antigen-4 (CTLA-4-Ig), which indirectly blocks CD28 signaling and has proven efficacy in rheumatoid arthritis and juvenile idiopathic arthritis patients. In addition to CD28 and CD40, an array of other co-stimulatory as well as inhibitory pathways has recently been identified and scientists are just beginning to understand how these different signaling pathways interact to regulate lymphocyte activation. In the more than two decades since the discovery of the first co-stimulatory molecule, the full clinical potential of these pathways is yet to be realized. In this review, we will primarily focus on CD28 and CD40 which are the most clinically validated co-stimulatory pathways, and briefly summarize and discuss some of the other T-cell co-stimulatory molecules.

Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study.

OBJECTIVE: To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years in patients with rheumatoid arthritis. METHODS: Patients were randomized to abatacept 10 or 2 mg/kg or placebo, plus MTX. Patients completing the 1-year, double-blind period entered the longterm extension, where all patients received a fixed dose of abatacept ~10 mg/kg. We describe safety analyses for all patients who received at least 1 dose of abatacept and efficacy analyses for the original ~10 mg/kg abatacept-treated group, over 5 years. RESULTS: Of the 235 abatacept- or placebo-treated patients completing the double-blind period, 219 entered the longterm extension; 130 (59.4%) were continuing at Year 5. No unexpected safety events were observed during the longterm extension compared with the double-blind period. Incidence rates of adverse events (AE) and serious AE were 489.7 and 20.0/100 patient-years in Year 1 versus 374.9 and 18.9/100 patient-years in the cumulative period, respectively. Using exploratory analyses, improvements observed at Year 1 in the 10 mg/kg group were maintained at Year 5, as assessed by ACR responses (ACR20=77.1% vs 82.7%; ACR50=53.0% vs 65.4%; ACR70=28.9% vs 40.4% at Years 1 and 5, respectively) and disease activity (Low Disease Activity State=48.2% vs 58.5%; Disease Activity Score-28-defined remission=25.3% vs 45.3% at Years 1 and 5, respectively). CONCLUSION: Abatacept maintained the efficacy observed at Year 1 over 5 years of treatment, and demonstrated consistent safety and tolerability. These data, along with relatively high retention rates, support the longterm clinical benefit provided by selective T cell costimulation modulation. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; clinical trial registration number: NCT00254293.

Evaluation of immunogenicity of the T cell costimulation modulator abatacept in patients treated for rheumatoid arthritis.

OBJECTIVE: The immunogenicity of abatacept, a selective costimulation modulator, administered intravenously, was assessed across Phase II and III trials in patients with rheumatoid arthritis (RA). METHODS: Two direct-format enzyme-linked immunosorbent assays evaluated antibody responses [whole abatacept molecule (CTLA-4 and Ig portion) and CTLA-4 portion only (Assay A)] in the Phase II trials. During the Phase III trials and 2-year open-label periods, a similar, but more sensitive, Assay B was employed. Serum samples collected prestudy, during treatment, and 56 and/or 85 days following the last dose were evaluated. Seropositive samples with anti-CTLA-4 reactivity and sufficiently low drug levels were further characterized for neutralizing activity (cell-based bioassay). RESULTS: A total of 2237 patients with both pre- and post-baseline serum samples were eligible for assessment. Of these, 62 (2.8%) patients demonstrated an anti-abatacept or anti-CTLA-4 response, determined using either Assay A or B. Using the more sensitive Assay B, 60 of 1990 patients (3.0%) demonstrated an antibody response to the whole abatacept molecule (n = 41, 2.1%) or the CTLA-4 portion (n = 19, 1.0%). Of the 1764 RA patients evaluated in the Phase III studies, 203 discontinued therapy and had sera collected 56 and/or 85 days after discontinuation. Patients who discontinued had a higher incidence of immunogenicity versus patients who did not discontinue (7.4% vs 2.6%, respectively). Of 20 patients positive for anti-CTLA-4 reactivity, 13 were eligible for assessment with the neutralization bioassay. Of these, 8 patients exhibited neutralizing activity. Seroconversion occurred with no adverse safety outcomes or effect on pharmacokinetic parameters. No consistent pattern was observed between antibody response and loss of efficacy (American College of Rheumatology 20 and Health Assessment Questionnaire responses). CONCLUSION: Abatacept was associated with a low incidence of immunogenicity in patients with RA and lacked any adverse sequelae.

Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthritis.

OBJECTIVE: Abatacept, a soluble selective costimulation modulator, selectively modulates T cell activation via the CD80/CD86:CD28 costimulation pathway. Data from a Phase II trial showed efficacy in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate when treated with abatacept (10 mg/kg or 2 mg/kg). To determine the mechanism of action of abatacept, we analyzed changes in the serum levels of inflammatory biomarkers in the patients enrolled in this trial. RESULTS: Following 12 months' treatment, serum levels of interleukin 6 (IL-6), soluble IL-2 receptor, C-reactive protein, soluble E-selectin, and soluble intercellular adhesion molecule-1 were significantly lower in patients receiving abatacept 10 mg/kg versus placebo. Smaller reductions in tumor necrosis factor-a and rheumatoid factor were also observed in the abatacept 10 mg/kg group compared with the placebo group. Although there was no evidence for efficacy of the 2 mg/kg dose, small reductions in inflammatory biomarkers at this dosage support the biologic effect of this therapy. CONCLUSION: These findings reveal the antiinflammatory and immunomodulatory effects of abatacept in patients with RA, and are consistent with the concept that modulating T cell activation improves clinical signs and symptoms and inhibits the progression of structural damage. These data suggest that selective modulation of the CD80/CD86:CD28 pathway with abatacept may affect several inflammatory cell types and cytokines that are involved in the proinflammatory cascade.

Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition.

BACKGROUND: A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy. METHODS: Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed. RESULTS: After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group. CONCLUSIONS: Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.

Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA-4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy. METHODS: This was a 12-month, multicenter, randomized, double-blind, placebo-controlled study. A total of 339 patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept (n = 115), 2 mg/kg abatacept (n = 105), or placebo (n = 119). This report focuses on the results observed at month 12 of a phase IIb trial. RESULTS: A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 1 year compared with patients who received placebo (62.6% versus 36.1%; P < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; P < 0.001) and ACR70 responses (20.9% versus 7.6%; P = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire scores compared with patients who received placebo (49.6% versus 27.7%; P < 0.001). Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission (Disease Activity Score in 28 joints of <2.6) compared with placebo at 1 year (34.8% versus 10.1%; P < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted. CONCLUSION: Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. Abatacept in combination with MTX has the potential to play an important role in future RA therapy.

Mesenteric B cells centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell subsets.

Inflammatory bowel disease reflects an aberrant mucosal CD4+ T cell response to commensal enteric bacteria. In addition to regulatory T cell subsets, recent studies have revealed a protective role of B cells in murine CD4+ T cell colitis, but the relationship of their action to T cell immunoregulation is unknown. Here we report that mesenteric lymph node (MLN) B cells protect mice from colitis induced by Galphai2-/- CD4+ T cells. Protection required the transfer of both B cells and CD8alpha+ T cells; neither cell type alone was sufficient to inhibit CD4+ T cell-mediated colitis. Similar results were also observed in colitis induced by CD4+CD45RBhi T cells. Immunoregulation was associated with localization of B cells and expansion of CD4-CD8- CD3+NK1.1+ T cells in the secondary lymphoid compartment, as well as expansion of CD4+CD8alpha+ T cells in the intestinal intraepithelial compartment. MLN B cells from Galphai2-/- mice were deficient in a phenotypic subset and failed to provide cotransfer colitis protection. These findings indicate that protective action of B cells is a selective trait of MLN B cells acquired through a Galphai2-dependent developmental process and link B cells with the formation of regulatory T cells associated with mucosal immune homeostasis.