A Randomized, Phase I Pharmacokinetic Study Comparing SB2 and Infliximab Reference Product (Remicade®) in Healthy Subjects

Abstract

ObjectiveSB2, a biosimilar to infliximab reference product (INF), has an identical amino acid sequence and similar physicochemical functional properties to its reference product. The primary objective of this study is to demonstrate pharmacokinetic (PK) bioequivalence between SB2 and EU-sourced INF (EU-INF), between SB2 and US-sourced INF (US-INF), and between EU-INF and US-INF.MethodsThis study was a randomized, single-blind, three-arm, parallel group study in 159 healthy subjects. All subjects received a single 5 mg/kg intravenous infusion of study drug and then were observed for 10 weeks to study PK, safety and immunogenicity. The primary PK parameters were area under the concentration-time curve (AUC) from time zero to infinity (AUCinf), AUC from time zero to the last quantifiable concentration (AUClast) and maximum concentration (Cmax). Bioequivalence for the primary PK parameters was to be concluded using an analysis of variance (ANOVA) if the 90 % confidence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the treatments compared were completely contained within the pre-defined equivalence margin, 0.8–1.25.ResultsAll of the 90 % CIs for the geometric LSMean ratios of primary PK parameters for each comparison were within the pre-defined equivalence margin. The proportion of subjects who experienced treatment-emergent adverse events was comparable between treatments. The incidences of anti-drug antibodies between the three treatments were comparable.ConclusionThis study demonstrated biosimilarity of SB2 to its marketed reference products of infliximab in terms of PK equivalence in healthy subjects. SB2 was generally well tolerated and showed comparable safety and immunogenicity profiles to the reference products (ClinicalTrials.gov Identifier: NCT01922336).

Assessment of Bezlotoxumab Immunogenicity

“…Although not directly studied, the risk of immunogenicity following a second dose in participants with CDI is also thought to be low because no treatment‐emergent ADA‐positive participants were observed in phase 3, and 1013 were categorized as negative. For drugs that are immunogenic, it is not uncommon to observe ADA following a single dose, particularly if the half‐life is in the multiweek range, as the drug remains systemically available to elicit a response from the immune system for a considerable amount of time . Bezlotoxumab has an elimination half‐life of approximately 19 days and, therefore, after a 10‐mg/kg dose, remains systemically available for several months and thus is also available to elicit a response from the immune system; for reference, at 180 days postdose, the mean bezlotoxumab concentration was ∼1 µg/mL.…”

“…For drugs that are immunogenic, it is not uncommon to observe ADA following a single dose, particularly if the half-life is in the multiweek range, as the drug remains systemically available to elicit a response from the immune system for a considerable amount of time. 16,17 Bezlotoxumab has an elimination half-life of approximately 19 days and, therefore, after a 10-mg/kg dose, remains systemically available for several months and thus is also available to elicit a response from the immune system; for reference, at 180 days postdose, the mean bezlotoxumab concentration was ß1 µg/mL. The absence of treatment-emergent ADA in the phase 3 single-dose data set is expected to be a robust predictor of a low immunogenicity risk for bezlotoxumab in CDI patients, even following a second dose.…”

A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy

“…SB2 has undergone the stepwise process described above; SB2 was shown to be similar on the molecular level and bioequivalent in normal human subjects in a phase I PK study,14 all compared with the infliximab reference product (INF). This study now reports the primary results of the phase III study—to demonstrate clinical equivalence in patients with moderate to severe RA despite MTX treatment, compared with INF.…”

Biosimilars in Dermatology – theory becomes reality

“…Nevertheless, most clinical trials with currently available biosimilars have been trials with rheumatoid arthritis and ankylosing spondylitis . Table shows the available clinical study data for approved biosimilars as well as other biosimilars that are expected shortly on the market . It is conceivable that rheumatic diseases have been chosen because anti‐TNFα compounds are used more frequently by rheumatologists than by dermatologists.…”