A randomized, double blind, single dose, comparative study of the pharmacokinetics, safety and immunogenicity of MB02 (bevacizumab biosimilar) and reference bevacizumab in healthy male volunteers

Abstract

Aims The pharmacokinetic (PK) similarity between MB02, a proposed bevacizumab biosimilar, and reference bevacizumab approved from the USA (US‐bevacizumab) and European Union (EU‐bevacizumab) was evaluated. Safety and immunogenicity were also assessed. Methods In this phase 1, randomized, double blind, single dose, parallel group study, 114 healthy male volunteers were randomized 1:1:1 to receive a 3 mg/kg intravenous dose of MB02, US‐bevacizumab or EU‐bevacizumab, and evaluated for 100 days. PK similarity between MB02 and reference bevacizumab was determined using the standard bioequivalence criteria (0.80–1.25) for the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC(0‐∞)) and the maximum observed serum concentration (Cmax). Results Baseline demographics were similar across treatment groups. All study drugs exhibited similar PK profile. The 90% confidence interval for the geometric lead square means ratios for the primary parameters AUC(0‐∞) and Cmax for MB02, US‐bevacizumab and EU‐bevacizumab were fully contained within the pre‐defined bioequivalence limits for the 3 pairwise comparisons: AUC(0‐∞) (MB02:US‐bevacizumab 0.998 [0.944 to 1.05]; MB02:EU‐bevacizumab 1.07 [1.00 to 1.14]; and US‐bevacizumab:EU‐bevacizumab 0.934 [0.884 to 0.988]) and Cmax (MB02:US‐bevacizumab 0.983 [0.897 to 1.08]; MB02:EU‐bevacizumab 1.06 [0.976 to 1.16]; and; US‐bevacizumab: EU‐bevacizumab 0.926 [0.851 to 1.01]). Treatment emergent adverse events were reported in 87 subjects (76.3%), most being mild and with comparable incidence among treatment groups. Thirty‐three subjects (28.9%) reported 56 possibly related treatment emergent adverse events with comparable incidence across treatments, the most frequent being headache (10.5%) and fatigue (3.5%). Anti‐drug antibody incidence was low and similar between treatment groups. Conclusions This study demonstrates the PK similarity and bioequivalence of MB02 to the reference bevacizumab, whether approved from USA or EU. The safety and immunogenicity profile of MB02 was shown also to be similar to the bevacizumab reference product (NCT 04238663).

A randomized, double‐blind, single‐dose study to assess bioequivalence of MB02 biosimilar after manufacturing iteration and reference bevacizumab

“…This study provided information of the interference in multiple doses with ADA/nAbs. 7 The 90% CIs for the comparability ratios of the exposure parameters were within the prespecified acceptance range of 80.00%-125.00% for the comparison of the three products and are consistent with other bevacizumab biosimilar clinical trials.…”

“…The efficacy of MB02 was tested in STELLA clinical trial. This study provided information of the interference in multiple doses with ADA/nAbs 7 …”

“…Serum samples were obtained at pre-dose, end of infusion, 2, 3, 4, 5, 6, 7, 12, and 24 h as well as Days 3,4,5,6,7,8,10,14,21,28,42,56,78, and 100 after the start of the infusion. A peripheral IV catheter was placed at admission for blood collection to avoid multiple skin punctures during stay at the Clinical Research Unit.…”

“…4,5 Firstly, MB02 has showed to be bioequivalent to reference bevacizumab in three pharmacokinetic (PK) studies conducted in healthy volunteers. 6,7 The last step in the similarity assessment was a confirmatory clinical study in a highly sensitive population (STELLA clinical trial). 8 As part of MB02 global development, an optimized drug substance manufacturing process using completely chemically defined growth and feed media was implemented.…”

“…Analytical similarity was demonstrated, including non‐clinical in vitro studies evaluating the biological activity of the antibody, followed by an extensive clinical development program as per EMA and FDA guidelines for biosimilar development 4,5 . Firstly, MB02 has showed to be bioequivalent to reference bevacizumab in three pharmacokinetic (PK) studies conducted in healthy volunteers 6,7 . The last step in the similarity assessment was a confirmatory clinical study in a highly sensitive population (STELLA clinical trial) 8…”