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A Comparative Study to Assess the Efficacy, Safety, and Immunogenicity of YLB113 and the Etanercept Reference Product for the Treatment of Patients with Rheumatoid Arthritis.

ABSTRACT: INTRODUCTION:YLB113 is a biosimilar of the reference product (RP), etanercept, under development for treatment of patients with moderate-to-severe rheumatoid arthritis (RA) and other approved indications. A phase 3 study was conducted in Europe, Japan, and India to compare the efficacy, safety, and immunogenicity of YLB113 with the RP over a treatment period of 52 weeks. METHODS:Overall, 528 patients with moderate-to-severe RA receiving concomitant methotrexate were randomized to receive a once-weekly, subcutaneous dose of 50 mg YLB113 or the RP. The primary endpoint was ACR20 response rate at week 24, with similarity confirmed if the 95% confidence interval (CI) for YLB113 and the RP was within the range of - 15 to 15%. Safety and immunogenicity endpoints were assessed to week 52. RESULTS:Based on the European analysis, in the full analysis set, ACR20 response at week 24 was 83.3% and 88.5% for YLB113 and the RP, respectively. Responses were within the predefined clinical equivalence margin. The sensitivity analysis in the per protocol set revealed a similar proportion of subjects exhibiting ACR20 response at week 24 between groups, with a difference of - 5.1% (95% CI - 11.07 to 0.81). The incidence of treatment-emergent adverse events was comparable between groups, and the incidence of antidrug antibody development to week 24 favored YLB113 (0.8 vs. 8.3%). CONCLUSIONS:This study demonstrated biosimilarity of YLB113 to the RP regarding efficacy, safety, and immunogenicity in patients with moderate-to-severe RA. Based on the same mechanism of action, biosimilarity could be extrapolated to other therapeutic indications approved for etanercept. TRIAL REGISTRATION:EudraCT Number: 2015-002,809-12.

SUBMITTER: Yamanaka H

PROVIDER: S-EPMC7021908 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundABP 710 is being developed as a biosimilar to infliximab reference product (RP). Analytical similarity and pharmacokinetic equivalence between the two have been previously demonstrated. Here we report results from a comparative clinical study that evaluated the efficacy and safety of ABP 710 relative to the RP in patients with rheumatoid arthritis (RA).MethodsIn this multicenter, randomized, double-blind, 50-week equivalence study, patients with moderate to severe active RA despite methotrexate received 3-mg/kg infusions of ABP 710 or RP at predetermined intervals based on initial randomization and then with re-randomization at week 22. The primary endpoint was response difference (RD) of ACR20 at week 22, with clinical equivalence evaluated based on 90% CI of - 15%, 15%. Secondary endpoints included Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP), ACR20, ACR50, and ACR70 across time, as well as safety and immunogenicity assessments.ResultsA total of 558 patients were randomized for the initial treatment (ABP 710 n = 279; RP n = 279). The estimated RD of ACR20 at week 22 was 9.37% with 90% CI (2.67%, 15.96%). The lower bound was within the pre-specified criteria, thus confirming non-inferiority; the upper bound exceeded the pre-specified criteria by 0.96% such that superiority could not be ruled out statistically. In a post hoc analysis with adjustment for random imbalance in baseline factors, the CI of RD was narrowed (0.75%, 13.62%). Changes from baseline in DAS28-CRP as well as ACR20, ACR50, and ACR70 response rates across time and hybrid ACR evaluations were similar for the initial and initial/re-randomized treatment groups. Adverse events and incidence of anti-drug antibodies were similar between treatment groups.ConclusionsThese efficacy and safety results support similarity with no clinically meaningful differences between ABP 710 and infliximab RP. Although we were unable to statistically confirm non-superiority, post hoc analysis was supportive of non-superiority. DAS28-CRP, ACR20, ACR50, ACR70, and hybrid ACR evaluations over the entire study were consistently comparable as were safety and immunogenicity.Trial registrationClinicalTrials.gov. Identifier: NCT02937701. Registered August 30, 2016.

Project description:BackgroundSandoz etanercept (SDZ ETN; GP2015) is an etanercept biosimilar with equivalent efficacy and comparable safety and immunogenicity to reference etanercept (ETN) in patients with moderate-to-severe chronic plaque-type psoriasis.MethodsEQUIRA was a phase III, double-blind study conducted in patients with moderate-to-severe rheumatoid arthritis and inadequate response to disease-modifying anti-rheumatic drugs. Eligible patients were randomized 1:1 to receive subcutaneous 50 mg SDZ ETN or ETN, once-weekly, for 24 weeks. At week 24, patients with at least moderate EULAR response in the SDZ ETN group continued SDZ ETN treatment, and those in the ETN group were switched to receive 50 mg SDZ ETN, for up to 48 weeks. Patients received concomitant methotrexate at a stable dose (10-25 mg/week) and folic acid (≥ 5 mg/week). Equivalence between SDZ ETN and ETN for change from baseline in disease activity score including 28 joint count C-reactive protein (DAS28-CRP) at week 24 (primary endpoint) and comparable safety and immunogenicity profile of SDZ ETN and ETN have previously been demonstrated at week 24. Herein, we present the 48-week results of the study after a single switch from ETN to its biosimilar at week 24.ResultsThe least squares mean (standard error) change in DAS28-CRP from baseline up to week 48 was comparable between "continued SDZ ETN" (- 2.90 [0.12], n = 148) and "switched to SDZ ETN" (- 2.78 [0.13], n = 131) groups. The proportion of patients achieving EULAR good/moderate responses based on DAS28-erythrocyte sedimentation rate and ACR20/50/70 response rates were comparable between the two groups. The proportion of patients with at least one treatment-emergent adverse event was 42.9% in the "continued SDZ ETN" and 38.0% in the "switched to SDZ ETN" groups. Serious adverse events occurred in 4 patients in each of the two groups. After week 24, none of the patients in the switched group developed anti-drug antibodies (ADAs), while 4 patients in the continued SDZ ETN group had single-event, very low titer, non-neutralizing ADAs detected.ConclusionsThe 48-week results from the EQUIRA study demonstrate that switch from ETN to SDZ ETN in patients with moderate-to-severe rheumatoid arthritis does not impact the efficacy, safety, or immunogenicity of etanercept.Trial registrationEudraCT number 2012-002009-23 , Registered 19 April 2012-prospectively registered.

Project description:ObjectivesThe aims were to demonstrate pharmacokinetic (PK) similarity between DRL_RI, a proposed rituximab biosimilar, and two reference innovator products (Rituxan® [RTX-US] and MabThera® [RTX-EU]) and compare their pharmacodynamics (PD), efficacy, safety, and immunogenicity in rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX)-based therapy and no prior biologic administration.MethodsIn this randomized, double-blind, parallel-group study, 276 patients with moderate-to-severe active RA were randomized to receive DRL_RI, RTX-US, or RTX-EU on days 1 and 15. The primary PK end points included area under the concentration-time curve from time 0 to 336 h after first infusion (AUC0-14 days, first infusion), AUC from day 1 through week 16 (AUC0-∞, entire course), and AUC from time 0 to time of last quantifiable concentration after the second dose (AUC0-t, second infusion). Secondary end points included other PK parameters, such as maximum concentration (Cmax), time to Cmax after each infusion, terminal half-life, systemic clearance, and volume of distribution after the second infusion; PD parameters and efficacy until week 24; safety and immunogenicity at week 24 and 52; and B cell recovery until week 52. AUC from time 0 to time of last quantifiable concentration after the first dose and over the entire course from day 1 through week 16 (AUC0-t, entire course) was analyzed as an exploratory end point.ResultsThe 91% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the primary end point of AUC0-∞, entire course were within the bioequivalence limits of 80-125% for all comparisons: DRL_RI versus RTX-US 100.37% (92.30-109.14), DRL_RI versus RTX-EU 93.58% (85.98-101.85), and RTX-US versus RTX-EU 93.24% (85.62-101.54). PD outcomes (peripheral blood B-cell depletion and mean change in Disease Activity Score [28 joints]-C-reactive protein), efficacy, safety, and immunogenicity were also comparable between DRL_RI and the reference products.ConclusionDRL_RI, a proposed biosimilar, demonstrated three-way PK similarity with RTX-EU and RTX-US, the reference innovator products, with comparable efficacy, PD, safety, and immunogenicity.Clinical trials registration numberClinicalTrials.gov identifier: NCT02296775.

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A Comparative Study to Assess the Efficacy, Safety, and Immunogenicity of YLB113 and the Etanercept Reference Product for the Treatment of Patients with Rheumatoid Arthritis.

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