A pharmacokinetics study of proposed bevacizumab biosimilar MYL-1402O vs EU-bevacizumab and US-bevacizumab

Abstract

Purpose: Bevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor-specific angiogenesis in some cancers. MYL-1402O is a proposed bevacizumab biosimilar.

Methods: The primary objective of this single-center, randomized, double-blind, three-arm, parallel-group, phase 1 study in healthy male volunteers was to evaluate bioequivalence of MYL-1402O to EU and US-reference bevacizumab, and EU-reference bevacizumab to US-reference bevacizumab. The primary pharmacokinetic parameter was area under the serum concentration-time curve from 0 extrapolated to infinity (AUC_0-∞). Pharmacokinetic parameters were analyzed using general linear models of analysis of variance. Secondary endpoints included safety and tolerability.

Results: Of 111 enrolled subjects, 110 were included in the pharmacokinetic analysis (MYL-1402O, n = 37; EU-reference bevacizumab, n = 36; US-reference bevacizumab, n = 37). Bioequivalence was demonstrated between MYL-1402O and EU-reference bevacizumab, MYL-1402O and US-reference bevacizumab, and between EU- and US-reference bevacizumab where least squares mean ratios of AUC_0-∞ were close to 1, and 90% CIs were within the equivalence range (0.80-1.25). Secondary pharmacokinetic parameters (AUC from 0 to time of last quantifiable concentration [AUC_0-t], peak serum concentration [C_max], time to C_max, elimination rate constant, and elimination half-life) were also comparable, with 90% CIs for ratios of AUC_0-t and C_max within 80-125%. Treatment-emergent adverse events were similar across all three treatment groups and were consistent with clinical data for bevacizumab.

Conclusion: MYL-1402O was well tolerated and demonstrated pharmacokinetic and safety profiles similar to EU-reference bevacizumab and US-reference bevacizumab in healthy male volunteers. No new significant safety issues emerged (ClinicalTrials.gov, NCT02469987; ClinicalTrialsRegister.eu EudraCT, 2014-005621-12; June 12, 2015).

Keywords: Bioequivalence; Cancer; Monoclonal antibody; Pharmacokinetics; Phase 1.

Fig. 1

Study design: bioequivalence of MYL-1402O to EU and US-reference bevacizumab. IV, intravenous; R, randomization

Fig. 2

a Mean serum bevacizumab concentration vs time (linear scale). b Mean serum bevacizumab concentration vs time (semi-log scale). All treatments were a single intravenous dose of 1 mg kg⁻¹ in 25 mL over 90 min