A randomized phase I study comparing the pharmacokinetics of a bevacizumab (HD204) biosimilar to European Union- and United States of America-sourced bevacizumab

Martin Demarchi, Pierre Coliat, Philippe Barthelemy, Roland Schott, Meher BenAbdelghani, Michael Kim, Jocelyn Chung Shii Hii, Peggy Feyaerts, Felicia Rui Xia Ang, Marie Paule Derde, Filip Deforce, Thierry Petit, Chris Schwabe, Chris Wynne, Lisa Soyeon Park, Xavier Pivot, Martin Demarchi, Pierre Coliat, Philippe Barthelemy, Roland Schott, Meher BenAbdelghani, Michael Kim, Jocelyn Chung Shii Hii, Peggy Feyaerts, Felicia Rui Xia Ang, Marie Paule Derde, Filip Deforce, Thierry Petit, Chris Schwabe, Chris Wynne, Lisa Soyeon Park, Xavier Pivot

Abstract

Purpose: This first-in-human study was designed to evaluate the pharmacokinetic (PK) equivalence between HD204 and the European Union (EU)-sourced bevacizumab, between HD204 and the United States of America (US)-sourced bevacizumab, and between EU-sourced and US-sourced bevacizumab (NCT03390673).

Methods: In this randomized, double-blind, 3-way parallel group, single-dose comparative PK study, healthy male subjects were randomized to receive a single 1 mg/kg intravenous dose of HD204, EU-sourced bevacizumab or US-sourced bevacizumab. PK parameters were calculated using non-compartmental methods. PK equivalence was determined using the pre-defined equivalence margin of 0.8-1.25 in terms of AUC(0-∞) for the pairwise comparisons.

Findings: Baseline demographics for the 119 randomized subjects were similar across the three groups. The 90% CIs for the ratio of the geometric means of HD204 to US-sourced bevacizumab, HD204 to EU-sourced bevacizumab, and EU-sourced to US-sourced bevacizumab were all within the interval of 80% to 125% for AUC0-inf, thus demonstrating equivalency in the PK properties for all three treatment groups. Similarly, the ratio of the geometric means for AUC0-last and Cmax were all within the 80% and 125% margins, supporting the robustness of the primary findings. All other PK parameters, including the half-life (t1⁄2) clearance (CL), volume of distribution (Vd) and time of maximum concentration (tmax), were comparable. There was no difference between the 3 treatment arms in terms of vital signs, laboratory tests and adverse events. None of the subjects treated with HD204 had positive ADA results.

Implications: HD204 demonstrates equivalent pharmacokinetic profiles compared to those of both US-sourced and EU-sourced bevacizumab. (NCT03390673).

Conflict of interest statement

The authors have read the journal’s policy and have the following competing interests: Prestige BioPharma funded this study, sponsored the trial, and organized data monitoring. MK, JCSH, PF, FRXA, and LSP are employees of Prestige BioPharma. XP consults with honorarium for Prestige BioPharma. Auckland, New Zealand and Christchurch Clinical Studies Trust Ltd performed the treatment and collected the data respectively, under a convention and payment from Prestige BioPharma. CS and CW are employees of Auckland, New Zealand and Christchurch Clinical Studies Trust Ltd respectively. DICE Cro bvba performed the data monitoring and analyses, under a convention and payment from Prestige BioPharma. MPD and FD are employees of DICE Cro bvba. Prestige BioPharma owns HD201. Hoffman-La Roche, Basel, Switzerland owns the reference medical product Herceptin. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no other patents, products in development or marketed products associated with this research to declare.

Figures

Fig 1. Study design.
Fig 1. Study design.
N = number of subjects. Pharmacokinetic schedule: Prior to infusion of study drug, 45 minutes after the start of study drug infusion, at the end of infusion, at 3h, 6h, and 12h after the end of infusion, at 24h (Day 2), 48h (Day 3), 72h (Day 4), 168h (Day 8), 336h (Day 15), 504h (Day 22), 672h (Day 29), 840h (Day 36), 1008h (Day 43), 1176h (Day 50), 1512h (Day 64), 1848h (Day 78) and 1680h (Day 71).
Fig 2
Fig 2
A-B Mean ± SD bevacizumab serum concentration-time profiles. Mean (±SD) bevacizumab concentrations over time are shown for all three groups on a linear scale (upper panel) and a semi-logarithmic scale (lower panel). Time 0h = pre-dose; Time 1.5h = end of infusion. Number of subjects with serum concentrations reported at each time are provided in the source table. Notes: Mean bevacizumab concentrations = 0.0 μg/L are not plotted on the semi-logarithmic graph; the large SD on Day 22 for EU-Avastin is due to one subject with an atypical PK profile; some error bars are not shown on the semi-logarithmic graph as negative values cannot be plotted logarithmically.
Fig 3
Fig 3

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