SB8, an approved bevacizumab biosimilar based on totality of evidence: scientific justification of extrapolation.

SB8 is a biosimilar of bevacizumab based on its similarity demonstrated by physicochemical, functional, non-clinical and clinical studies. Supported by the concept of extrapolation, SB8 was authorized and is used in a similar manner across all types of tumors as reference bevacizumab. Furthermore, SB8 offers convenience with prolonged stability compared with reference bevacizumab in diluted form. Although a biosimilar must demonstrate biosimilarity to a reference product with the 'totality of evidence' in a stringent regulatory process for marketing authorization, some concerns remain among healthcare practitioners, particularly about extrapolation. This review summarizes the concepts of the totality of evidence and extrapolation in biosimilar development and the role of bevacizumab biosimilars in the management of metastatic colorectal cancer as an extrapolated indication.

A phase I, randomized, single-dose pharmacokinetic study comparing sb8 (bevacizumab biosimilar) with reference bevacizumab in healthy volunteers.

PURPOSE: To compare pharmacokinetics, safety, tolerability, and immunogenicity between SB8, a bevacizumab biosimilar, and the European Union (EU) and United States (US) reference products (bevacizumab-EU, bevacizumab-US). METHODS: In this randomized, double-blind, parallel-group, and single-dose study, healthy volunteers were randomized to receive a 3 mg/kg dose of SB8, bevacizumab-EU, or bevacizumab-US via intravenous infusion. Primary endpoints were area under the concentration-time curve from time zero to infinity (AUCinf) and to the last quantifiable concentration (AUClast), and maximum observed serum concentration (Cmax). Bioequivalence was achieved if 90% confidence intervals (CIs) for the ratios of the geometric least squares means (LSMeans) of primary endpoints were within the predefined bioequivalence margins of 80.00-125.00%. Safety and immunogenicity were also investigated. RESULTS: The 90% CIs for the geometric LSMean ratios of AUCinf, AUClast and Cmax were all within the prespecified bioequivalence margins. Geometric LSMean ratios for SB8/bevacizumab-EU, SB8/bevacizumab-US and bevacizumab-EU/bevacizumab-US were 88.01%, 88.48% and 100.54% for AUCinf, 88.65%, 89.08% and 100.49% for AUClast and 99.59%, 101.15% and 101.56% for Cmax, respectively. Incidence of treatment-emergent adverse events (TEAEs) across treatment groups was comparable (SB8: 50.0%, bevacizumab-EU: 37.5%, bevacizumab-US: 53.8%). Most TEAEs were mild and considered as not related to the study drug. No deaths or treatment discontinuations due to adverse events occurred. Incidence of anti-drug antibodies was also comparable between all groups and no neutralizing antibodies were detected. CONCLUSION: This study demonstrated pharmacokinetic bioequivalence and similar safety and immunogenicity profiles of SB8 to both reference products, bevacizumab-EU and bevacizumab-US, and of bevacizumab-EU to bevacizumab-US. CLINICALTRIALS. GOV IDENTIFIER: NCT02453672 (submitted date); EudraCT number: 2015-001,026-41.

Evaluation of the Physico-Chemical and Biological Stability of SB8 (Aybintio), a Proposed Biosimilar to Bevacizumab, Under Ambient and In-Use Conditions.

INTRODUCTION: No stability data of SB8 (proposed biosimilar to bevacizumab) are available for opened vials at 2-8 °C or for unopened vials stored outside of this range. Furthermore, limited stability data are available for dilutions. Stability of unopened vials of SB8 at ambient temperature and in-use stability for opened vials as well as diluted SB8 in infusion bags were evaluated. METHODS: SB8 stability was assessed in three scenarios in the absence of light: unopened 100-mg vials 36 months after manufacture stored at 30 ± 2 °C with 65 ± 5% relative humidity for 1 month, opened 100-mg and 400-mg vials stored at 5 ± 3 °C for 72 h and diluted (1.4 mg/ml or 16.5 mg/ml in 100 ml 0.9% NaCl polyolefin bags) stored for 45 days at 5 ± 3 °C and then 3 days at 30 ± 2 °C; the United Kingdom's National Health Service protocol was used for the study design after dilution. Physicochemical stability (appearance, pH, protein concentration, size-exclusion high-performance liquid chromatography, non-reducing capillary electrophoresis-sodium dodecyl sulfate, imaged capillary isoelectric focusing), biological activity [vascular endothelial growth factor (VEGF) neutralization assay, VEGF binding assay] and potential safety impact properties (subvisible particulates, submicronic aggregation by dynamic light scattering) were determined. RESULTS: All stability-indicating criteria including those for biological activity were met for both unopened vials at ambient condition and for in-use conditions of opened vials as well as both dilutions. No noteworthy changes in terms of physicochemical stability, biological activity and properties with a potential safety impact occurred. CONCLUSION: Under the studied aspetic extreme conditions, SB8 was stable. Our data may support advanced SB8 preparation and may help prevent SB8 wastage because of exceptional temperature excursions or unused product. Sterility assurance is the responsibility of the user and is of utmost importance when opened or diluted SB8 is not immediately used.