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Long-term Efficacy, Safety, and Immunogenicity of the Infliximab (IFX) Biosimilar, PF-06438179/GP1111, in Patients with Rheumatoid Arthritis After Switching from Reference IFX or Continuing Biosimilar Therapy: Week 54-78 Data From a Randomized, Double-Blind, Phase III Trial.

ABSTRACT: OBJECTIVE:Our objective was to evaluate the long-term efficacy, safety, and immunogenicity of the infliximab biosimilar, PF-06438179/GP1111 (PF-SZ-IFX), in patients with rheumatoid arthritis (RA) who continued biosimilar treatment throughout 78 weeks or who switched from reference infliximab (Remicade®) sourced from the EU (IFX-EU) at week 30 or week 54 in the REFLECTIONS B537-02 study. METHODS:In this phase III, double-blind, active-controlled study, patients with moderate-to-severe active RA were initially randomized to PF-SZ-IFX or IFX-EU, each with methotrexate (treatment period [TP] 1; N?=?650). At week 30, patients receiving PF-SZ-IFX continued PF-SZ-IFX; patients receiving IFX-EU were re-randomized to continue IFX-EU or switch to PF-SZ-IFX (TP2; n?=?566). From weeks 54 to 78, all patients received open-label treatment with PF-SZ-IFX (TP3; n?=?505). Efficacy, safety, and immunogenicity data were analyzed during TP3. RESULTS:Efficacy was sustained and comparable across groups at week 78, with American College of Rheumatology criteria for???20% clinical improvement response rates of 75.9% (biosimilar group), 77.8% (week 30 switch group), and 68.3% (week 54 switch group). The incidence of treatment-emergent adverse events was 28.9%, 29.4%, and 30.2%, respectively. The proportion of patients who were antidrug antibody (ADA) positive and neutralizing antibody positive (as a percentage of ADA-positive patients) was stable and comparable between groups. CONCLUSIONS:Results to week 78 continue to support the efficacy, safety, and immunogenicity of PF-SZ-IFX in patients with moderate-to-severe active RA. There were no clinically meaningful differences between groups, independent of a single treatment transition from IFX-EU to PF-SZ-IFX at week 30 or week 54. TRIAL REGISTRATION NUMBER:NCT02222493.

SUBMITTER: Cohen SB

PROVIDER: S-EPMC7113200 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Project description:Background/objectiveREFLECTIONS B538-02 is a randomized, double-blind comparative study of the adalimumab (ADL) biosimilar PF-06410293, (ADL-PF), and reference ADL sourced from the European Union (ADL-EU) in patients with active RA. Therapeutic equivalence was demonstrated based on ACR20 responses at week 12 (primary endpoint). We report long-term safety, immunogenicity, and efficacy of ADL-PF in patients who continued ADL-PF treatment throughout 78 weeks or who switched from ADL-EU to ADL-PF at week 26 or week 52.MethodsEligible patients (2010 ACR/EULAR RA diagnosis criteria for ≥ 4 months; inadequate response to MTX, ≤ 2 doses non-ADL biologic), stratified by geographic regions were initially randomized (1:1) in treatment period 1 (TP1) to ADL-PF or ADL-EU (40 mg subcutaneously, biweekly), both with MTX (10-25 mg/week). At week 26 (start of TP2), patients receiving ADL-EU were re-randomized to remain on ADL-EU or transition to ADL-PF for 26 weeks. At week 52 (start of TP3), all patients received open-label treatment with ADL-PF for 26 weeks and were followed after last treatment dose to week 92. To evaluate maintenance of response after switching or remaining on ADL-PF, ACR20, DAS28-4(CRP), and other measures of clinical response/remission were assessed through week 78 as secondary endpoints. Three groups were evaluated: biosimilar, week 26 switch, and week 52 switch.ResultsOverall, 507 patients participated in TP3. ACR20 response rates at week 52 were 88.4%, 88.2%, and 87.6% for the biosimilar, week 26, and week 52 switch groups, respectively. ACR20 response rates and DAS28-4(CRP) scores were sustained and comparable across groups in TP3. Incidence of treatment-emergent adverse events (AEs) during TP3 and follow-up was 42.6% (biosimilar), 37.0% (week 26 switch), and 50.8% (week 52 switch); 3 (0.6%) patients (all week 52 switch) reported treatment-related serious AEs. ADL-PF was generally well tolerated, with a comparable safety profile across groups. Overall, incidences of patients with anti-drug antibodies in TP3 and follow-up were comparable among groups (46.1%, 46.5%, and 54.2%, respectively).ConclusionsThere were no clinically meaningful differences in safety, immunogenicity, and efficacy for patients who were maintained on ADL-PF for 78 weeks and those who had switched from ADL-EU at week 26 or week 52.Trial registrationClinicalTrials.gov , 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.

Dataset Information

Long-term Efficacy, Safety, and Immunogenicity of the Infliximab (IFX) Biosimilar, PF-06438179/GP1111, in Patients with Rheumatoid Arthritis After Switching from Reference IFX or Continuing Biosimilar Therapy: Week 54-78 Data From a Randomized, Double-Blind, Phase III Trial.

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