A Phase I, Randomized, Single-Dose Study Evaluating the Biosimilarity of TAB008 to Bevacizumab in Healthy Volunteers

Abstract

Objective: This study compared the pharmacokinetics (PK), safety, and immunogenicity of the biosimilar TAB008 monoclonal antibody to bevacizumab (Avastin ® ) in normal healthy Chinese male volunteers. Methods: In this randomized, double-blind, parallel controlled study, a total of 100 healthy Chinese male subjects were randomized (1:1) to receive a single 1 mg/kg intravenous dose of TAB008 or Avastin ® over a 90-min infusion. The subjects were followed for 99 days after drug administration. Primary endpoints were bioequivalence of major pharmacokinetic parameters (AUC 0-t and AUC 0-∞ ) and maximum observed serum concentration (C max ). Secondary endpoints included safety and immunogenicity parameters. Results: The two groups of test subjects (49 subjects in the TAB008 group and 50 subjects in the Avastin ® group) were well matched in regards to all demographic and baseline characteristics. The treatment group ratios of LS geometric means for the three primary PK parameters were fully contained within the bioequivalence limits of 80.00–125.00% (90% CI was 103.66–118.33% for C max , 94.32–111.72% for AUC 0-t , and 94.69–112.23% for AUC 0-∞ ). Treatment-emergent adverse events (TEAEs) were reported for 24 (49.0%) subjects in the TAB008 group and 22 (44.0%) subjects in the Avastin ® group. TEAEs related to the study drug were reported for 19 (38.8%) subjects in the TAB008 group and 19 (38.0%) subjects in the Avastin ® group. National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 3 TEAEs were reported for 1 (2.0%) subject in the TAB008 group and 3 (6.0%) subjects in the Avastin ® group. There were no Grade 4 or 5 TEAEs or serious adverse events (SAEs) during the study. Anti-drug antibody generation was reported once only in each group, and neutralizing antibody (Nab) analysis was negative upon follow-up. Conclusion: TAB008 attained pharmacokinetic similarity to bevacizumab, and was safe and well tolerated.

A phase I, randomized, single-dose pharmacokinetic study comparing sb8 (bevacizumab biosimilar) with reference bevacizumab in healthy volunteers

“…Moreover, results confirm that bevacizumab-EU and bevacizumab-US are bioequivalent to each other, consistent with results from other phase I studies of bevacizumab biosimilars [16,17]. The PK results of this study are consistent with those of other phase I PK studies of (proposed) bevacizumab biosimilars which also demonstrated equivalence to the reference product [16][17][18][19][20][21][22][23][24][25][26]. However, direct comparisons of absolute PK parameters values between studies are generally not appropriate due to differences between the doses used (1 mg/kg, 3 mg/kg or 5 mg/kg), sample collection, and assessment methods [16][17][18][19][20][21][22][23][24][25][26].…”

A Randomized, Double-Blind, Single-Dose Study Comparing the Biosimilarity of HOT-1010 With Bevacizumab (Avastin®) in Chinese Healthy Male Subjects

“…The mean t 1/2 of HOT-1010 and Avastin ® was 14.6 d and 14.9 days, which was consistent with the results of other bevacizumab biosimilars (13.1-19.3 days) in Chinese, Indian, Caucasian and Korean healthy male subject studies (Knight et al, 2016;Zhang et al, 2018;Wang et al, 2019;Liu et al, 2020;Shin et al, 2020;Singh et al, 2020). The median T max of HOT-1010 (3.48 h) was similar to that of bevacizumab and other bevacizumab biosimilars (2.5-4.5 h) when intravenous dose ranged from 1 to 3 mg/kg (Zhang et al, 2018;Wang et al, 2019;Liu et al, 2020;Shin et al, 2020;Singh et al, 2020). HOT-1010 was well-tolerated and no safety concerns were identified, and safety profiles were similar between HOT-1010 group and Avastin ® group.…”

“…The most common TEAEs (more than 5% incidence) included increased blood triglycerides, increased alanine aminotransferase, increased aspartate aminotransferase, hyperuricemia, decreased blood fibrinogen, increased conjugated bilirubin, increased blood creatine phosphokinase and proteinuria. TEAEs reported in this study were almost expected, based on previous studies in healthy subjects and tumor patients (Genentech Inc, 2015;Liu et al, 2020;Wang et al, 2019). All subjects with TEAEs had recovered.…”

“…Although the exact mechanisms are not clear yet, these AEs of HOT-1010 should be paid more attention in the future study. Additionally, 82 subjects were found to be negative for ADA test, other studies also showed the relatively low immunogenicity of bevacizumab (Knight et al, 2016;Zhang et al, 2018;Wang et al, 2019;Liu et al, 2020;Shin et al, 2020;Singh et al, 2020), the comparison of immunogenicity still needs to be further investigated with larger sample size.…”

Phase 3 Trial of BI 695502 Plus Chemotherapy Versus Bevacizumab Reference Product Plus Chemotherapy in Patients With Advanced Nonsquamous NSCLC

“…Similar results have been reported in other studies of bevacizumab, with ADA rates of 1.4% to 2.5% reported in studies of healthy volunteers and patients with NSCLC. 27 , 28 , 33 …”