A Phase I Clinical Study Comparing the Tolerance, Immunogenicity, and Pharmacokinetics of Proposed Biosimilar BAT1806 and Reference Tocilizumab in Healthy Chinese Men

Abstract

Objective: The study aimed to explore the bioequivalence of a proposed biosimilar BAT1806 to its reference products marketed in the EU and US (RoActemra-EU and Actemra-US) among healthy Chinese men. The tolerance, immunogenicity, and pharmacokinetics (PK) of the three drugs were also investigated.Methods: In this randomized, double-blind, single-dose, three-arm, parallel study, a single-dose of 4 mg/kg of the reference products, or the biosimilar was administered to the participants. The participants were followed up for 57 days, and PK, immunogenicity, and tolerance evaluations were completed during this period.Results: The PK parameters were similar in all three groups: BAT1806 (n = 45), RoActemra-EU (n = 42), and Actemra-US (n = 42). The 90% confidence intervals (CIs) for the ratios of Cmax, AUC0–t and AUC0–∞ were 86.90–104.41% for BAT1806 vs. RoActemra-EU, 91.70–106.15% for BAT1806 vs Actemra-US, and 90.04–105.53% for Actemra-US vs RoActemra-EU. For all comparisons, the 90% CIs for the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit of 80.00–125.00%. The intersubject variability ranged from 14.5% to 21.5%, which was considerably low. Among the participants, 19 (42.2%), 10 (23.8%), and 12 (28.6%) from the BAT1806, RoActemra-EU, and Actemra-US groups were, respectively, found to be positive for anti-drug antibodies, while 14 (31.1%), nine (21.4%), and 12 (28.6%) were positive for neutralizing antibodies. Nevertheless, these antibodies did not affect the drug concentrations, and the outcomes in the bioequivalence tests were similar after sensitivity analysis. Treatment-related and treatment-emergent adverse events (TEAEs) were recorded in 27, 34, and 32 participants in the BAT1806, RoActemra-EU, and Actemra-US groups, respectively. The most common treatment-related adverse events observed were a decrease in neutrophil, and white blood cell counts.Conclusion: The PK characteristics of BAT1806 were similar to those of the reference products, RoActemra-EU and Actemra-US. Both BAT1806 and the reference products exhibited low intersubject variability and similar safety profiles.Clinical trial registration number:http://www.chinadrugtrials.org.cn/index.html, CTR20180039; https://clinicaltrials.gov/NCT03606876

A phase I study comparing the pharmacokinetics and safety of HS628 (tocilizumab biosimilar) and reference tocilizumab in healthy male subjects

“…A total of 4 (10.00%) and 3 (8.11%) subjects tested positive for treatment-induced ADA throughout the study for the test and reference groups, respectively. The total rate of ADA positivity in the present study was lower than that reported in other tocilizumab biosimilar studies, [13][14][15] on account of the different immunogenicity assessment period (28 days vs. 48 or 57 days). Due to the limited number of ADA-positive subjects, subgroup analysis of bioequivalence and safety for ADA-positive subjects was not feasible, thus the effect of the immunogenic responses on PK and safety could not be assessed.…”

“…PK parameters generated from the present study were compared with those reported in the literature (Table 4). 13,15 The study dosage was 4 mg/kg in both the present study and literature 1 13 ; however, it was 8 mg/kg in literature 2. 15 AUC 0– t , AUC 0–∞ , and C max in the present study were slightly lower than the equivalent parameters reported in literature 1, which may be attributed to the different metabolic characteristics of the study population, or the different detection methods used for tocilizumab.…”

“…Three clinical studies have been conducted to explore the bioequivalence of other tocilizumab biosimilars in recent years, in which the PK similarity of tocilizumab biosimilars have been exhibited. 13 , 14 , 15 The objective of this phase I study was to evaluate the PK similarity of the proposed biosimilar HS628 compared with the reference tocilizumab (Actemra®) in healthy Chinese male subjects. The study also aimed to demonstrate similar safety and immunogenicity profiles of HS628 to the reference tocilizumab in this population of subjects.…”

Demonstration of Physicochemical and Functional Similarity of the Biosimilar BAT1806/BIIB800 to Reference Tocilizumab

“…High mannose glycans have the potential to change the PK of a protein (i.e., by increasing the rate of drug clearance), therefore, having lower amounts of high mannose in the biosimilar could increase the relative half-life of the product. However, the quantitative change we observed was small (in the order of 1–2%) and no meaningful impact was anticipated, which was confirmed by non-clinical and clinical studies that demonstrated equivalent PK of BAT1806/BIIB800 in a comparative PK study [ 12 ], and similar trough serum concentrations in a phase III trial in patients with RA [ 13 ]. Therefore, differences observed in high mannose content can be considered clinically non-meaningful.…”

“…Clinical similarity of BAT1806/BIIB800 compared with TCZ was demonstrated in published phase I and III studies [ 12 , 13 ]. Here we present the physicochemical, structural and biological characterization of BAT1806/BIIB800 using a comprehensive comparability exercise applying a multitude of analytical techniques and in vitro assays to determine its similarity with China-, EU- and US-sourced TCZ.…”