Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials.
Ontology highlight
ABSTRACT:
SUBMITTER: Takeuchi T
PROVIDER: S-EPMC4445012 | biostudies-other | 2015 Mar
REPOSITORIES: biostudies-other
Similar Datasets
Project description:PURPOSE OF REVIEW:Etanercept was the first tumour necrosis factor inhibitor approved to treat rheumatoid arthritis (RA) in the United States (US) and Europe. The recent patent expiration of the etanercept originator ENBREL in Europe has facilitated the development of biosimilar products, creating the prospect of reduced treatment costs. In this article, we review the original trials for etanercept in RA to facilitate critical appraisal of biosimilar trial data. RECENT FINDINGS:Two etanercept biosimilars are currently approved in Europe and/or the US, SB4 (Benepali) and GP2015 (Erelzi), having met the pre-specified equivalence criteria for biosimilarity. Trial data demonstrates subtle differences in clinical outcomes and adverse events between the biosimilars and the reference product (RP). The development of etanercept biosimilars may reduce the financial burden of treating RA, but real-world data regarding efficacy and safety in comparison to the RP will be vital to assess for meaningful differences.
| S-EPMC6244902 | biostudies-other
Project description:ObjectivesTo evaluate oral tofacitinib versus placebo for treatment of active rheumatoid arthritis in Japanese patients with inadequate response to disease-modifying antirheumatic drugs.MethodsIn this double-blind, placebo-controlled, randomized, parallel-group, 12-week, phase 2 study (clinicaltrials.gov NCT00687193), 317 patients received tofacitinib: 1, 3, 5, 10, or 15 mg as monotherapy or placebo twice daily (BID).Primary endpointresponse rate by American College of Rheumatology (ACR) ≥ 20% improvement criteria (ACR20) at week 12.ResultsACR20 response rates: 37.7% (20/53), 67.9% (36/53), 73.1% (38/52), 84.9% (45/53), and 90.7% (49/54) with tofacitinib: 1, 3, 5, 10, and 15 mg BID, respectively, versus 15.4% (8/52) with placebo (p < 0.01; all doses). Dose-dependent ACR20 responses with tofacitinib versus placebo occurred from week 2 onward (p < 0.05). Changes from baseline in 28-joint disease activity score using erythrocyte sedimentation rate improved with tofacitinib versus placebo from week 4 (p < 0.01; all doses). Six tofacitinib patients experienced treatment-related serious adverse events (AEs). Most common treatment-emergent AEs: nasopharyngitis (10% vs 12%) and hyperlipidemia (5% vs 0%). Serum creatinine, hemoglobin, and total-, low-, and high-density lipoprotein-cholesterol levels increased with tofacitinib.ConclusionsTofacitinib produced dose-dependent ACR20 responses and reduced disease activity. The safety profile was consistent with that reported from global monotherapy trials.
| S-EPMC4819568 | biostudies-literature
Project description:Biologics, possibly in combination with a conventional disease-modifying antirheumatic drug (DMARD) - preferably methotrexate (MTX), are used in accordance with the recommendations of the international rheumatological societies. However, in clinical practice, this recommendation is often problematic, as many rheumatologists know from personal experience. The quality of life of the patient is affected mainly by drug-induced intolerances (eg, MTX). Thus, the acceptance of the patient to treatment is often so inadequate that a discontinuation of the drug is necessary. In daily practice, approximately 30% of patients with biological therapy receive no concomitant DMARD according to the register data.
| S-EPMC4440355 | biostudies-literature
Project description:BackgroundThe aim of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Patients Who Have Achieved a Stable Low Disease Activity-State study was to investigate the effect of etanercept (ETN) dose maintenance, reduction or withdrawal on patients with rheumatoid arthritis (RA) who had already achieved stable low disease activity (LDA) on ETN 50 mg+methotrexate (MTX).MethodsPatients with RA (n=91) and stable LDA with ETN 50 mg once weekly (QW)+MTX were included. After 8 weeks with unchanged treatment, 73 patients were randomised in a double-blind design to ETN 50 mg QW+MTX (ETN50), ETN 25 mg QW+MTX (ETN25) or placebo QW+MTX (PBO) for 48 weeks. Patients who flared were declared failures and treated with open-label ETN50 until week 48. The primary outcome was the proportion of patients on ETN50 versus PBO who were non-failures after 48 weeks.ResultsThe proportion of non-failure patients was significantly lower with ETN50 (52%; p=0.007) and ETN25 (44%; p=0.044) versus PBO (13%). Median time to failure was significantly shorter with PBO (6 weeks) compared with ETN50 (48 weeks; p=0.001) and ETN25 (36 weeks; p<0.001). The majority of patients who flared regained LDA with open-label ETN50 quickly. Adverse events were consistent with the known side effect profiles of these medications.ConclusionsIn patients with established RA who have achieved stable LDA on ETN50+MTX, continuing both is superior to PBO+MTX. Reduced dose ETN was also more effective than PBO in maintaining a favourable response, suggesting that a maintenance strategy with reduced dose ETN may be possible in a number of patients with established RA.Trial registration numberNCT00858780.
| S-EPMC4717401 | biostudies-literature
Project description:ObjectivePatients with rheumatoid arthritis (RA) in whom remission is achieved following combination therapy with methotrexate plus etanercept face an ongoing medication burden. This study was undertaken to investigate whether sustained remission achieved on combination therapy can be maintained with either methotrexate or etanercept monotherapy, as assessed following discontinuation of one or the other medication from the combination.MethodsOf the 371 adult patients with RA who received combination therapy with methotrexate plus etanercept, remission (defined as a Simplified Disease Activity Index [SDAI] score of ≤3.3) was sustained in 253 patients through a 24-week open-label period. These 253 patients then entered a 48-week, double-blind period and were randomized to receive either 1) methotrexate monotherapy (n = 101), 2) etanercept monotherapy (n = 101), or 3) methotrexate plus etanercept combination therapy (n = 51). Patients who subsequently experienced disease-worsening received rescue therapy with the combination regimen at the same dosages as used in the initial run-in period. The primary end point was the proportion of patients in whom SDAI-defined remission was maintained without disease-worsening at week 48 in the etanercept monotherapy group as compared to the methotrexate monotherapy group. Secondary end points included time to disease-worsening, and the proportion of patients in whom SDAI-defined remission was recaptured after initiation of rescue therapy.ResultsBaseline demographic and clinical characteristics of the RA patients were similar across the treatment groups. At week 48, SDAI-defined remission was maintained in significantly more patients in the etanercept monotherapy group than in the methotrexate monotherapy group (49.5% versus 28.7%; P = 0.004). Moreover, as a secondary end point, sustained SDAI-defined remission was achieved in significantly more patients who received combination therapy than in those who received methotrexate monotherapy (52.9% versus 28.7%; P = 0.006). Time to disease-worsening was shorter in those who received methotrexate monotherapy than in those who received etanercept monotherapy or those who received combination therapy (each P < 0.001 versus methotrexate monotherapy). Among the patients who received rescue therapy, SDAI-defined remission was recaptured in 70-80% in each treatment group. No new safety signals were reported.ConclusionThe efficacy of etanercept monotherapy was superior to that of methotrexate monotherapy and similar to that of combination therapy in maintaining remission in patients with RA. SDAI-defined remission was recaptured in most of the patients who were given rescue therapy. These data could inform decision-making when withdrawal of therapy is being considered to reduce treatment burden in patients with well-controlled RA.
| S-EPMC8251940 | biostudies-literature
Project description:ObjectiveA considerable proportion of patients with rheumatoid arthritis (RA) do not have a satisfactory response to biological therapies. We investigated the use of metabolomics approach to identify biomarkers able to anticipate the response to biologics in RA patients.MethodsDue to gender differences in metabolomic profiling, the analysis was restricted to female patients starting etanercept as the first biological treatment and having a minimum of six months' follow-up. Each patient was evaluated by the same rheumatologist before and after six months of treatment. At this time, the clinical response (good, moderate, none) was determined according to the EUropean League Against Rheumatism (EULAR) criteria, based on both erythrocyte sedimentation rate (EULAR-ESR) and C-reactive protein (EULAR-CRP). Sera collected prior and after six months of etanercept were analyzed by 1H-nuclear magnetic resonance (NMR) spectroscopy in combination with multivariate data analysis.ResultsTwenty-seven patients were enrolled: 18 had a good/moderate response and 9 were non responders according to both EULAR-ESR and EULAR-CRP after six months of etanercept. Metabolomic analysis at baseline was able to discriminate good, moderate, and non-responders with a very good predictivity (Q2 = 0.68) and an excellent sensitivity, specificity, and accuracy (100%). In good responders, we found an increase in isoleucine, leucine, valine, alanine, glutamine, tyrosine, and glucose levels and a decrease in 3-hydroxybutyrate levels after six months of treatment with etanercept with respect to baseline.ConclusionOur study confirms the potential of metabolomic analysis to predict the response to biological agents. Changes in metabolic profiles during treatment may help elucidate their mechanism of action.
| S-EPMC4641599 | biostudies-literature
Project description:IntroductionOncostatin M (OSM) has been implicated in the pathophysiology of rheumatoid arthritis (RA) through its effect on inflammation and joint damage. GSK315234 is a humanised anti-OSM Immunoglobulin G1 (IgG1) monoclonal antibody (mAb). This 3-part study examines the safety, tolerability and efficacy of GSK315234 in patients with active RA.MethodThis was a 3-part (Parts A, B and C), multicenter study. Part A and Part B were randomised, double-blind, placebo-controlled, Bayesian adaptive dose finding studies to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of single (Part A) and 3 repeat (Part B) intravenous infusions of GSK315234 in patients with active RA on a background of methotrexate (MTX). Part C was a single dose, randomised, single-blind, placebo-controlled study to assess subcutaneously administered GSK315234 to patients with active RA on a background of MTX.ResultThe primary endpoint of the study was mean change in DAS28 at Day 28 in Part A and Day 56 in Part B and C. All patients receiving at least one dose of GSK315234 were included in safety analysis. In Part A, there were statistically significant differences in DAS28 between 3 mg/kg and placebo at Day 56, 84 and 91. There was also a statistically significant difference in DAS28 between 0.3 mg/kg, 3 mg/kg and 10 mg/kg, as compared to placebo, at Day 84. Although these changes were small and occurred late, they supported progression to Part B and C to determine the therapeutic potential of GSK315234. For Part B, no significant difference was observed between 6 mg/kg and placebo. For Part C, a statistically significant difference in DAS28 was observed at Day 40, Day 84 and Day 100 between the 500 mg subcutaneous group, as compared to placebo. No significant findings were observed at any of the time points for EULAR response criteria, ACR20, ACR50 or ACR70. An exploratory analysis of clinical, pharmacokinetic and pharmacodynamics data suggests the lack of efficacy may be due to moderate binding affinity and rapid off-rate of GSK315234 as compared to the higher affinity OSM receptor causing a protein carrier effect prolonging the half life of OSM due to accumulation of the OSM/antibody complex in the serum and synovial fluid.ConclusionOur data highlighted the importance of binding affinity and off-rate effect of a mAb to fully neutralize the target and how this may influence its efficacy and potentially worsen disease activity. Using an anti-OSM mAb with high affinity should test this hypothesis and examine the potential of OSM as a therapeutic target in RA.Trial registrationClinicalTrials.gov no: NCT00674635.
| S-EPMC3978888 | biostudies-literature
Project description:OBJECTIVES:SB4 (Benepali, Brenzys) is a biosimilar of reference etanercept (ETN). In a randomised, double-blind, 52-week study, SB4 demonstrated comparable efficacy and safety to ETN in patients with rheumatoid arthritis (RA). The open-label extension period evaluated long-term efficacy, safety and immunogenicity when continuing SB4 versus switching from ETN to SB4. METHODS:In the randomised, double-blind phase, patients received weekly subcutaneous administration of 50?mg SB4 or ETN with background methotrexate for up to 52 weeks. Patients in the Czech Republic and Poland who completed the 52-week visit were enrolled in the open-label extension period and received SB4 for 48 additional weeks. Efficacy, safety and immunogenicity were assessed up to week 100. RESULTS:Of 245 patients entering the extension period, 126 continued to receive SB4 (SB4/SB4) and 119 switched to SB4 (ETN/SB4). American College of Rheumatology (ACR) response rates were sustained and comparable between SB4/SB4 and ETN/SB4 with ACR20 response rates at week 100 of 77.9% and 79.1%, respectively. Other efficacy results, including radiographic progression, were also comparable between the groups. After week 52, rates of treatment-emergent adverse events were 47.6% (SB4/SB4) and 48.7% (ETN/SB4); one patient/group developed non-neutralising antidrug antibodies. No cases of active tuberculosis or injection-site reactions were reported during the extension period. One patient (SB4/SB4) died of hepatic cancer. CONCLUSIONS:SB4 was effective and well tolerated over 2 years in patients with RA. Efficacy, safety and immunogenicity were comparable between the SB4/SB4 and ETN/SB4 groups, showing no risk associated with switching patients from ETN to SB4. TRIAL REGISTRATION NUMBER:NCT01895309; 2012-005026-30.
| S-EPMC5705842 | biostudies-literature
Project description:ObjectiveTwo randomised controlled trials, AMBITION (NCT00109408) and ADACTA (NCT01119859), showed tocilizumab (TCZ) monotherapy superior to methotrexate (MTX) and adalimumab (ADA) monotherapy, respectively, for improving rheumatoid arthritis (RA) disease activity. This study compared the benefit of TCZ versus MTX or ADA monotherapy for improving patient-reported outcomes (PROs) in patients with RA.MethodsPROs included patient global assessment (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and Short Form-36 (SF-36) physical component summary (PCS) and mental component summary (MCS) and eight domain scores. Outcomes included proportions of patients reporting changes from baseline in PRO scores ≥minimum clinically important differences (MCID) and ≥age-matched and gender-matched normative values at 24 weeks.ResultsIn AMBITION, TCZ-treated patients reported significantly greater mean improvements in HAQ (-0.7 vs -0.5), FACIT-Fatigue (8.7 vs 5.7), SF-36 PCS (9.8 vs 7.8) and five SF-36 domains at week 24 than with MTX; 45.0%-84.0% of TCZ-treated patients reported improvements ≥MCID, and 24.3%-52.1% reported scores ≥normative values across all PROs versus 39.4%-81.8% and 14.5%-45.0%, respectively, with MTX. In ADACTA, TCZ-treated patients reported significantly greater improvements in PtGA (-42.3 vs -31.8), pain (-40.1 vs -28.7), SF-36 MCS (7.9 vs 5.0) and three SF-36 domains than with ADA; 57.7%-83.3% of TCZ-treated patients reported improvements ≥MCID, and 22.1%-49.3% reported scores ≥normative values across all PROs versus 13.6%-37.8%, respectively, with ADA.ConclusionsTCZ monotherapy resulted in more patients reporting clinically meaningful PRO improvements and PRO scores ≥normative values compared with MTX or ADA monotherapy.Trial registration numbersNCT00109408 and NCT01119859; Post-results.
| S-EPMC5604726 | biostudies-literature
Project description:ObjectiveTo perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA).MethodsSafety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations.ResultsOverall, 3882 and 3016 abatacept-naïve RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept.ConclusionsAbatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected.
| S-EPMC4898160 | biostudies-literature