AB0195 PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATION OF A PROPOSED BIOSIMILAR MSB11456 VERSUS BOTH THE US-LICENSED AND EU-APPROVED TOCILIZUMAB: RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, SINGLE-DOSE TRIAL IN HEALTHY ADULTS
Authors: C. Schwabe, C. Wynne, A. Illes, M. Ullmann, E. Vincent, V. Ghori, C. Petit-Frere, A. S. Racault, I. Morin
Journal: Annals of the Rheumatic Diseases (2021)

Background: Tocilizumab, a biologic disease-modifying antirheumatic drug, is a recombinant humanized monoclonal immunoglobulin G1 antibody against the interleukin-6 receptor (IL-6R). MSB11456 is a proposed biosimilar to the US-licensed tocilizumab and EU-approved tocilizumab. Prior to initiation of its clinical development program, MSB11456 was considered highly similar to the reference products based on extensive in vitro pharmacological testing and functional activity assays. Objectives: This double-blind, parallel-group phase I study ( NCT03282851 ) assessed the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of MSB11456 to US-licensed and EU-approved tocilizumab and provided data on the similarity of safety profiles and immunogenicity of MSB11456 and the reference products in healthy adult subjects. Methods: Healthy adult volunteers were randomized to receive a single 162 mg subcutaneous injection of MSB11456, US-licensed tocilizumab, or EU-approved tocilizumab. Samples for PK/PD and immunogenicity analysis were taken predose, up to 29 days postdose, and at the end of study visit (day 48). Primary endpoint PK parameters were natural log transformed and analyzed using analysis of covariance (ANCOVA) methods; results were then transformed back to the original scale. Secondary PD analysis measured serum soluble IL-6R and serum C reactive protein (sCRP) parameters, and data were analyzed using a method similar to that for PK data. Safety data were collected throughout the study and analyzed descriptively. Results: 685 subjects were randomized and treated. Results of the primary PK analysis demonstrated bioequivalence between MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products, since all corresponding 90% confidence intervals (CIs) for the geometric least squares mean (LSM) ratios were within the predefined 80.00% to 125.00% equivalence margin (Table 1). PD analyses also demonstrated equivalence of MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products. Safety, tolerability and immunogenicity were also comparable between treatments. The incidence of tocilizumab-specific neutralizing antibodies was low (&lt;3% for all three products). Conclusion: PK and PD equivalence of MSB11456, US-licensed tocilizumab, and EU-approved tocilizumab were demonstrated with comparable immunogenicity, safety, and tolerability for the three products. This study adds to the totality of evidence in support of MSB11456 as a proposed biosimilar to tocilizumab. Table 1. Results of primary PK analysis Parameter Treatment n Ratio of geometric LSMs (%) 90% CI of ratio MSB11456 vs US-licensed tocilizumab AUC 0–∞ MSB11456 194 106.16 96.80, 116.43 US-licensed tocilizumab 190 AUC 0–t MSB11456 230 104.15 93.58, 115.90 US-licensed tocilizumab 226 C max MSB11456 230 104.45 95.05, 114.77 US-licensed tocilizumab 226 MSB11456 vs EU-tocilizumab AUC 0–∞ MSB11456 194 104.03 94.96, 113.96 EU-approved tocilizumab 200 AUC 0–t MSB11456 230 94.78 85.15, 105.50 EU-approved tocilizumab 224 C max MSB11456 230 94.83 86.28, 104.22 EU-approved tocilizumab 224 US-licensed vs EU-approved tocilizumab AUC 0–∞ US-licensed tocilizumab 190 97.99 89.40, 107.41 EU-approved tocilizumab 200 AUC 0–t US-licensed tocilizumab 226 91.01 81.71, 101.36 EU-approved tocilizumab 224 C max US-licensed tocilizumab 226 90.79 82.57, 99.84 EU-approved tocilizumab 224 AUC, area under the serum concentration-time curve (µg·h/mL); AUC 0–∞ , AUC from time zero to infinity; AUC 0–t , AUC from time zero to the time of the last quantifiable concentration; C max , maximum concentration (µg/mL) Acknowledgements: Medical writing support was provided by Caroline Spencer and Dr Sue Chambers (Rx Communications, Mold, UK), funded by Fresenius Kabi SwissBioSim. Disclosure of Interests: Christian Schwabe: None declared, Chris Wynne: None declared, Andras Illes Employee of: Fresenius Kabi SwissBioSim, Martin Ullmann Employee of: Fresenius Kabi SwissBioSim, Emmanuelle Vincent Employee of: Fresenius Kabi SwissBioSim, Vishal Ghori Employee of: Fresenius Kabi SwissBioSim, Corinne Petit-Frere Employee of: Biosimilars, Fresenius Kabi SwissBioSim, Anne-Sophie Racault Employee of: Fresenius Kabi SwissBioSim, Isabelle Morin Employee of: Former employee of Fresenius Kabi SwissBioSim