A randomized controlled trial comparing PF-06438179/GP1111 (an infliximab biosimilar) and infliximab reference product for treatment of moderate to severe active rheumatoid arthritis despite methotrexate therapy

Abstract

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.

Keywords: Biosimilar; Dose escalation; Infliximab; PF-06438179/GP1111; Rheumatoid arthritis.

Conflict of interest statement

Ethics approval and consent to participate

This study was conducted in compliance with the provisions of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines, and it was reviewed and approved by an institutional review board or independent ethics committee(s) at each of the participating investigational sites. All patients provided informed consent prior to undergoing any screening procedures.

Consent for publication

Not applicable.

Competing interests

SBC has received consulting fees from Amgen, Boehringer-Ingelheim, Coherus, Merck, Pfizer, and Sandoz and has received research grants from Amgen, Boehringer-Ingelheim, Coherus, Merck, and Pfizer. RA has received honoraria and research grants from Pfizer. HK has received consulting fees, speaking fees, and/or honoraria from AbbVie GK, Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Novartis Pharma K.K., Pfizer Japan Inc., and Sanofi K.K. and has received research grants from AbbVie GK, Astellas Pharma Inc., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Mitsubishi Tanabe Pharma, and Takeda Pharmaceutical Co. Ltd. SCR has received research grants and consulting fees, speaking fees, and/or honoraria from Pfizer Inc. TH has no competing interests to disclose. KS and SS are employees of Hexal AG, a Sandoz company. MIR, RP, and KLS are full-time employees of and declare having stock holdings and/or stock options from Pfizer Inc. SYH and CI were employees of and had stock holdings and/or stock options from Pfizer Inc. at the time of the study.

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Figures

Fig. 1

Study design. aA sample size of approximately 614 patients was planned for enrollment; the actual number of patients randomized was 650. bIntravenous PF-06438179/GP1111 or infliximab-EU 3 mg/kg was given as an induction regimen at weeks 0, 2, and 6, followed by maintenance treatment with a 3 mg/kg dose starting at week 14 and continuing every 8 weeks thereafter. Dose escalation to 5 mg/kg PF-06438179/GP1111 or infliximab-EU was permitted at or after week 14 for patients with inadequate RA response. EOT End of treatment, Infliximab-EU Infliximab sourced from the European Union, RA Rheumatoid arthritis

Fig. 2

Efficacy of PF-06438179/GP1111 and infliximab-EU. a Difference (95% CI) in week 14 ACR20 response between PF-06438179/GP1111 and infliximab-EU using NRI and symmetric equivalence margin. b Difference (90% CI) in week 14 ACR20 response between PF-06438179/GP1111 and infliximab-EU using NRI and asymmetric margin. c ACR20, ACR50, and ACR70 response rates by visit (ITT population). d Mean (± SE) change from baseline in DAS28-CRP by visit (ITT population). e Mean (± SE) change from baseline in HAQ-DI by visit (ITT population). ACR20/50/70 American College of Rheumatology criteria for ≥ 20%/50%/70% clinical improvement, DAS28-CRP Disease Activity Score in 28 joints, four components based on C-reactive protein, HAQ-DI Health Assessment Questionnaire Disability Index; Infliximab-EU Infliximab sourced from the European Union, ITT Intention to treat, NRI Nonresponder imputation, PP Per protocol

Fig. 3

ADA and NAb incidence by study visit (safety population). a ADA incidence. b NAb incidence. aADA-positive and ADA-negative test results were defined as ADA titer ≥ 1.30 and < 1.30, respectively. Overall, a patient who tested positive was defined as having at least one postdose positive sample during the 30-week treatment period, regardless of predose ADA status. bNAb-positive and NAb-negative results were defined as NAb titer ≥ 0.70 and < 0.70, respectively. Incidences of NAb-positive patients are expressed as percentages of ADA-positive patients. ADA Antidrug antibody; Infliximab-EU Infliximab sourced from the European Union, NAb, Neutralizing antibody