Antiviral Activity and Pharmacokinetics of the Hepatitis B Virus (HBV) Capsid Assembly Modulator GLS4 in Patients With Chronic HBV Infection

Wang²,

Wei

et al. 2021

Front. Pharmacol.

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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

Section: Discussioncontrasting

confidence: 63%

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

Wang²,

Wei

et al. 2021

Front. Pharmacol.

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“…Overall, safety and tolerability of HOT-3010 and reference Humira ® (AbbVie) were reported in this study; all AEs were mild to moderate with no severe AEs observed, indicating good tolerance of these products (Fleischmann et al, 2019; Zhang et al, 2020 ).…”

Section: Discussionsupporting

confidence: 55%

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of HOT-3010 to Adalimumab Among Healthy Chinese Male Subjects

Chen

et al. 2021

Front. Pharmacol.

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Objective: This study explored the bioequivalence of a proposed biosimilar HOT-3010 vs. its reference product (adalimumab) among healthy Chinese male subjects. The study also investigated the tolerance, immunogenicity, and pharmacokinetics (PK).Methods: A randomized, double-blind, two-arm, parallel study was performed to examine the bioequivalence of HOT-3010 (40 mg) with that of adalimumab (Humira®, AbbVie) as a reference drug. The study subjects were followed up for 71 days.Results: PK properties exhibited by HOT-3010 (N = 66) and adalimumab (N = 68) groups were similar. The 90% confidence intervals of the ratios for Cmax, AUC0-t, and AUC0∞ were observed to be in the range 80–125% on comparing the two groups. For anti-drug antibodies (ADA), the number of subjects found to be positive in the HOT-3010 group and adalimumab group were 29 (43.94%) and 32 (47.06%), whereas 27 (40.91%) and 27 (39.71%) subjects were found to be positive for NAb, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were recorded in 32 subjects each in both the groups, respectively.Conclusion: The PK characteristics and immunogenicity exhibited by HOT-3010 were similar to that of the reference product, adalimumab. The safety profiles were similar in both the treatment groups with mild-moderate adverse effects.

“…TQ-A3334 was eliminated quickly at the initial stage and slowly in the low concentration stage, resulting in a considerably slow decline in TQ-A3334 concentrations at the low concentration stage. When a longer time range for PK parameter calculation is included (e.g., extending from 0-144 h to 0-672 h), the calculated t 1/2 will be longer [20]. A longer t 1/2 and a large difference of t 1/2 were observed in this study.…”

Section: Discussionmentioning

confidence: 58%

Safety, pharmacokinetics and pharmacodynamics of TQ-A3334, an oral toll-like receptor 7 agonist in healthy individuals

Expert Opinion on Investigational Drugs

et al. 2021

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Background & Aims: TQ-A3334, a selective, oral toll-like receptor (TLR)-7 agonist, is being developed to treat chronic hepatitis B (CHB). This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TQ-A3334 in healthy participants. Research design and methods:The effects of a single-ascending dose of TQ-A3334 (0.2-1.8 mg) combined with food (1.2 mg) were evaluated in 48 healthy participants. Results: No serious adverse events or discontinuations occurred in the study. The most common adverse reactions were lymphocyte count decreased and headache, which were generally consistent with IFN-α exposure and the mechanism of action of a TLR7 agonist. TQ-A3334 was rapidly absorbed, with a time to maximum plasma concentration of 0.42-0.5 h. Systemic exposure (C max and AUC) to TQ-A3334 increased with a slight saturation proportion to dose. Food reduced the exposure of TQ-A3334. The concentrations of MCP-1, ISG-15, MX-1, and OAS-1 were observed to be slightly dose-dependent, ranging from 1.0 to 1.8 mg TQ-A3334. Conclusions: Oral doses of 0.2-1.8 mg appeared to be safe and tolerated. PD activity was seen at doses ranging from 1.0 to 1.8 mg, indicating its possible future use to treat CHB. Trial Registration: The trial is registered at the Chinese Clinical Trial website (http://www.chinadrug trials.org.cn/index.html # CTR20182248).