A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS B537-01)

Palaparthy, Ramesh; Udata, Chandrasekhar; Hua, Steven; Yin, Dong; Cai, Chun-Hua; Salts, Stephanie; Rehman, Muhammad; McClellan, Joseph E.; Xu, Meng

doi:10.1080/1744666x.2018.1446829

Cited by 24 publications

(26 citation statements)

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“…Originally developed by Pfizer, PF-06438179/GP1111 (PF-SZ-IFX) is an infliximab biosimilar that is approved in the EU [12], Japan [13], the USA [14], and Brazil [15] for all eligible indications of reference infliximab (Remicade ® ) in each region. In preclinical studies, when compared with reference infliximab, PF-SZ-IFX was shown to have an identical primary amino acid sequence and similar biologic activity, including binding to TNF and inhibition of TNFinduced cell apoptosis in vitro [16]; in studies conducted in healthy subjects, PF-SZ-IFX also exhibited similarity to reference infliximab in its pharmacokinetic, safety, and immunogenicity profiles [17].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…PF-06438179/GP1111 demonstrated similar toxicokinetic, tolerability, and antidrug antibody (ADA) responses to infliximab in a nonclinical in vivo toxicity study [ 15 ]. A phase I pharmacokinetics (PK) clinical study in healthy volunteers demonstrated similarity in PK, safety, and immunogenicity of PF-06438179/GP1111 to infliximab-US and infliximab-EU, as well as between infliximab-EU and infliximab-US reference products [ 16 ]. In the present double-blind, active-controlled, randomized, multinational study, we compared the efficacy, safety, PK, and immunogenicity of PF-06438179/GP1111 with infliximab-EU (Remicade®), each with background MTX therapy, as treatment for patients with moderate to severe active RA and inadequate response to MTX therapy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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BackgroundThis 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.MethodsPatients (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%).ResultsPatients (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.ConclusionPF-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 registrationClinicalTrials.gov, NCT02222493. Registered on 21 August 2014.EudraCT, 2013-004148-49. Registered on 14 July 2014.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1646-4) contains supplementary material, which is available to authorized users.

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“…and to outcomes of BE testing performed in the analysis. The study duration included an immunogenicity assessment with prespecified sample collections at 0 (predose), 336, 672, 1008 and 1680 hours post dose, and a PK evaluation with prespecified sample collections at 0 (predose), 8,12,24,48,72,96,120,144,168,192,264,336,504,672,840 and 1008 hours post dose, and an additional sample collection at 1680 hours post dose for facilitating the immunogenicity assessment at that time point. Both PK and immunogenicity samples were analysed at QPS, LLC (Newark, DE, USA) using validated bioanalytical procedures.…”

Section: What This Study Addsmentioning

confidence: 99%

“…While PK similarity determination with such a study design has been mostly shown to be highly efficient and informative in our experience, [5][6][7][8] there have been some complications associated with PK alterations caused by extensive immunogenicity response, especially when there was an imbalance in immunogenicity potential in terms of host-specific immunological characteristics between the test and reference groups. The impact of these complications on PK similarity determination remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

A mechanistic pharmacokinetic model with drug and antidrug antibody interplay, and its application for assessing the impact of immunogenicity response on bioequivalence testing

Liao

Udata

Yin

et al. 2020

Brit J Clinical Pharma

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Single-dose pharmacokinetic (PK) studies in healthy subjects have been the design of choice for bioequivalence determination for decades. This preference has been recently extended to PK similarity studies of proposed biosimilars. However, PK similarity studies can be complicated by the effect of immunogenicity response on drug disposition. The impact is exacerbated when there is an imbalance in hostspecific immunological characteristics of subjects between the test and reference groups. Such complications remain poorly understood. The purpose of this communication is to show that the impact of immunogenicity response on PK similarity determination can be critical, using adalimumab as an example. Methods: Data for adalimumab concentrations and immunogenicity response over 10 weeks were obtained from 133 healthy subjects receiving a 40 mg dose of Humira ® in a PK similarity study. Also, a population PK model with a mechanistic construct for delineating the interplay between adalimumab disposition and antidrug antibodies response was utilized to estimate via simulation the probability that a PK similarity study would fail in typical study settings. Results: The simulations showed that the immunogenicity response can have a profound impact on the outcome of PK similarity determination. As such, the probability of failing to achieve the similarity conclusion increased to 51.9%, from 13.8% in the absence of immunogenicity response. Conclusion: This study provides a model-based framework for better understanding of how a PK similarity study can be optimally designed and for interpretation of the outcome of PK similarity determination when the drug disposition is affected in the presence of immunogenicity response.

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A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS B537-01)

Abstract: CT.gov identifier NCT01844804.

Cited by 24 publications

References 3 publications

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

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

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

A mechanistic pharmacokinetic model with drug and antidrug antibody interplay, and its application for assessing the impact of immunogenicity response on bioequivalence testing

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