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Extension Study of PF-05280586, a Potential Rituximab Biosimilar, Versus Rituximab in Subjects With Active Rheumatoid Arthritis.

ABSTRACT: OBJECTIVE:This extension study provided continued treatment to subjects with active rheumatoid arthritis who had participated for ?16 weeks in a pharmacokinetic similarity study of PF-05280586 (potential rituximab biosimilar). Objectives were to evaluate overall pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of PF-05280586 after transition from rituximab reference products to PF-05280586, and follow-up of biomarker and efficacy assessments. METHODS:Subjects were offered ?3 additional courses of treatment of PF-05280586, with or without a single transition from rituximab in Europe (rituximab-EU; MabThera) or the US (rituximab-US; Rituxan) to PF-05280586. Each course comprised 2 intravenous infusions (1,000 mg on days 1 and 15, separated by 24 weeks [± 8 weeks]). RESULTS:Of 220 subjects in the parent study, 185 were randomized and included in this study. There were no notable differences in drug concentrations between groups or across courses, with little variation in depletion of CD19+ B cells between groups, and no apparent relationship between infusion-related reactions and antidrug antibodies with or without single transition from rituximab reference products to PF-05280586. Long-term safety and tolerability of PF-05280586 was acceptable in all groups for up to 96 weeks, with a low incidence of treatment-emergent adverse events independent of single drug transition. The percentage of subjects with a low disease activity score and disease activity score remission was similar across groups for all time points, and responses were sustained until end of study. CONCLUSION:This study demonstrated acceptable safety, tolerability, and immunogenicity, with or without single transition from rituximab reference products to PF-05280586, without increased immunogenicity on single transition.

SUBMITTER: Cohen SB

PROVIDER: S-EPMC6221032 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Extension Study of PF-05280586, a Potential Rituximab Biosimilar, Versus Rituximab in Subjects With Active Rheumatoid Arthritis.

Cohen Stanley B SB Burgos-Vargas Rubén R Emery Paul P Jin Bo B Cronenberger Carol C Vázquez-Abad María-Dolores MD

Arthritis care & research 20181101 11

<h4>Objective</h4>This extension study provided continued treatment to subjects with active rheumatoid arthritis who had participated for ≥16 weeks in a pharmacokinetic similarity study of PF-05280586 (potential rituximab biosimilar). Objectives were to evaluate overall pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of PF-05280586 after transition from rituximab reference products to PF-05280586, and follow-up of biomarker and efficacy assessments.<h4>Methods</h4>Su ...[more]

PMID: 29692005

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Project description:BackgroundBiosimilars are highly similar to the licensed biologic ("reference product"), with no clinically meaningful differences in safety, purity, or potency between the two products.ObjectiveThis comparative 52-week clinical study evaluated the efficacy, safety, immunogenicity, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-05280586 (Ruxience™ [a rituximab biosimilar]) versus rituximab reference product sourced from the EU (MabThera®; rituximab-EU).Patients and methodsSubjects with CD20-positive, low-tumor-burden follicular lymphoma (LTB-FL) and an Eastern Cooperative Oncology Group performance status 0-1 were randomized (1:1) to PF-05280586 or rituximab-EU (375 mg/m2 intravenously [once weekly for 4 weeks at days 1, 8, 15, and 22]), stratified using the Follicular Lymphoma International Prognostic Index 2 classification. The primary endpoint was overall response rate (ORR) at week 26 (percentage of subjects achieving complete response [CR] or partial response [PR]). Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the difference in ORR between groups was within the prespecified margin (± 16%). Secondary endpoints included progression-free survival (PFS), CR rate, safety, immunogenicity, PK, and PD.ResultsA total of 394 subjects were randomized: PF-05280586 (n = 196) or rituximab-EU (n = 198). ORR at week 26 was 75.5% (PF-05280586) versus 70.7% (rituximab-EU), for a difference of 4.66%; 95% CI (- 4.16 to 13.47), which was entirely within the prespecified equivalence margin. Rates of CR were 29.3% (PF-05280586) versus 31.0% (rituximab-EU). Estimated 1-year PFS rates were 78.2% (95% CI 70.2-84.2) and 83.0% (95% CI 75.0-88.6) for PF-05280586 and rituximab-EU, respectively. Safety, immunogenicity, and mean serum concentrations were similar between groups.ConclusionsThe efficacy, safety, immunogenicity, PK, and PD of PF-05280586 and rituximab-EU were similar up to week 52 in subjects with previously untreated CD20-positive LTB-FL.Clinical trial registrationClinicalTrials.gov, NCT02213263 and EudraCT (2014-000132-41).

Project description:BACKGROUND:This double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira®) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10-25 mg/week). We report results for the first 26 weeks of treatment. METHODS:Patients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (-12%, 15%). Secondary efficacy endpoints to week 26 included ACR20/50/70, change from baseline Disease Activity Score based on high-sensitivity C-reactive protein [DAS28-4(CRP)], European League Against Rheumatism (EULAR) response, DAS28-4(CRP) of less than?2.6, and ACR/EULAR remission. QuantiFERON-TB testing was performed at screening and week 26. RESULTS:Patients (78.7% of whom were female and whose mean age was 52.5 years) had a mean baseline RA duration of 6.8 years. The mean baseline DAS28-4(CRP) values were 5.9 (PF-06410293) and 6.1 (adalimumab-EU). The observed week-12 ACR20 values were 68.7% (PF-06410293) and 72.7% (adalimumab-EU) in the intention-to-treat population. With non-responder imputation, the treatment difference in week-12 ACR20 was -2.98% and corresponding CIs-95% CI (-10.38%, 4.44%) and 90% CI (-9.25%, 3.28%)-were entirely contained within the equivalence margins (symmetric and asymmetric, respectively). The secondary efficacy endpoints were similar between arms. Over 26 weeks, injection-site reactions occurred in 1.7% versus 2.0%, hypersensitivity events in 4.4% versus 8.4%, pneumonia in 0.7% versus 2.0%, and opportunistic infections in 2.4% versus 1.7% in the PF-06410293 and adalimumab-EU arms, respectively. One death due to myocardial infarction occurred (adalimumab-EU arm). Rates of anti-drug antibody incidence were 44.4% (PF-06410293) and 50.5% (adalimumab-EU). CONCLUSIONS:The study results demonstrate that efficacy, safety, and immunogenicity of PF-06410293 and adalimumab-EU were similar during the first 26 weeks of treatment in patients with active RA on background MTX. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02480153 . First posted on June 24, 2015; EU Clinical Trials Register EudraCT number: 2014-000352-29 . Start date: October 27, 2014.

Project description:BACKGROUND:This double-blind, active-controlled, randomized, multinational study evaluated the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-06438179/GP1111 (IxifiTM/Zessly®), an infliximab biosimilar, vs infliximab (Remicade®) reference product sourced from the European Union (infliximab-EU) in biologic-naïve patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate therapy. This paper reports results from the initial 30-week treatment period. METHODS:Patients (N?=?650) were stratified by geographic region and randomized 1:1 to PF-06438179/GP1111 or infliximab-EU (3 mg/kg intravenous at weeks 0, 2, and 6, then every 8 weeks). Dose escalation to 5 mg/kg was allowed starting at week 14 for patients with inadequate RA response. The primary endpoint was American College of Rheumatology criteria for ??20% clinical improvement (ACR20) response at week 14. Therapeutic equivalence was declared if the two-sided 95% CI for the treatment difference was within the symmetric equivalence margin of ±?13.5%. Statistical analysis was also performed with a two-sided 90% CI using an asymmetric equivalence margin (-?12.0%, 15.0%). RESULTS:Patients (80.3% female; 79.4% seropositive) had a mean RA duration of 6.9 years, and mean baseline Disease Activity Score in 28 joints, four components based on C-reactive protein was 6.0 in both arms. Week 14 ACR20 in the intention-to-treat population was 62.7% for PF-06438179/GP1111 and 64.1% for infliximab-EU. Week 14 ACR20 using nonresponder imputation was 61.1% for PF-06438179/GP1111 and 63.5% for infliximab-EU, and the 95% (-?9.92%, 5.11%) and 90% (-?8.75%, 4.02%) CIs for the treatment difference (-?2.39%) were entirely contained within the prespecified symmetric and asymmetric equivalence margins, respectively. No differences were observed between arms for secondary efficacy endpoints. Overall postdose antidrug antibody (ADA) rates through week 30 were 48.6% and 51.2% for PF-06438179/GP1111 and infliximab-EU, respectively. Efficacy and immunogenicity were similar between treatments for patients with dose escalation (at or after week 14), as well as between treatments for patients without dose escalation. Safety profiles of PF-06438179/GP1111 and infliximab-EU were similar, with no clinically meaningful differences observed between arms, including after ADA development. Serum drug concentrations were similar between arms at each time point during the initial 30-week treatment period. CONCLUSION:PF-06438179/GP1111 and infliximab-EU demonstrated similar efficacy, safety, immunogenicity, and PK with or without dose escalation in patients with moderate to severe active RA on background methotrexate. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02222493 . Registered on 21 August 2014. EudraCT, 2013-004148-49 . Registered on 14 July 2014.

Project description:Background/objectivesABP 798 is a proposed biosimilar to the originator biologic rituximab, an anti-CD20 monoclonal antibody. This comparative clinical study evaluated the pharmacokinetics (PK), safety, and efficacy of ABP 798 versus rituximab reference product (RP) in patients with moderate-to-severe rheumatoid arthritis (RA).MethodsAdults with moderate-to-severe RA with an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs including 1 or more tumor necrosis factor inhibitor therapies (n = 311) received ABP 798, US-sourced rituximab RP (rituximab US), or EU-sourced rituximab RP (rituximab EU) (1000 mg, 2 weeks apart). At week 24, ABP 798- or rituximab EU-treated subjects received a second dose of the same treatment, while rituximab US-treated subjects transitioned to receive ABP 798. The key efficacy endpoint was DAS28-CRP change from baseline at week 24. Other efficacy endpoints included DAS28-CRP at other time points; ACR20, ACR50, and ACR70 criteria; and hybrid ACR. The rituximab RP groups were pooled for all efficacy endpoints since PK equivalence had been established between rituximab US and rituximab EU.ResultsClinical equivalence between ABP 798 and rituximab RP was established as the 90% confidence interval for DAS28-CRP change from baseline at week 24 fell within the prespecified equivalence margin (- 0.6, 0.6). Safety and immunogenicity profiles of ABP 798 were comparable across treatment groups and not affected by single transition from RP to ABP 798.ConclusionsClinical equivalence in terms of efficacy, safety, and immunogenicity was established between ABP 798 and rituximab RP in this comparative clinical trial in patients with moderate-to-severe RA. Key Points • ABP 798 provided similar efficacy as rituximab reference product (RP) in patients with moderate-severe rheumatoid arthritis. • The safety and immunogenicity profiles for ABP 798 were similar to those for the rituximab RP. • The single transition from rituximab RP to ABP 798 did not show differences in efficacy, safety, or immunogenicity.

Dataset Information

Extension Study of PF-05280586, a Potential Rituximab Biosimilar, Versus Rituximab in Subjects With Active Rheumatoid Arthritis.

Publications

Extension Study of PF-05280586, a Potential Rituximab Biosimilar, Versus Rituximab in Subjects With Active Rheumatoid Arthritis.

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