Adalimumab Biosimilar (Henlius Biotech)

The primary objective of this randomized, double‐blind, parallel‐controlled study (from December 2016 to October 2018) was to evaluate pharmacokinetic (PK) equivalence of adalimumab biosimilar HLX03 and reference adalimumab in healthy volunteers, and to assess safety, and immunogenicity of HLX03. The primary PK endpoints were maximum observed plasma concentration (Cmax) and area under the concentration curve from time zero to the last quantifiable concentration (AUC0–t). Equivalence was determined if the 90% confidence interval (CI) of geometric least square mean ratio between the two treatment groups were within the predefined range of 80%–125%. Safety and immunogenicity were monitored during the study. Healthy Chinese males (N = 220) were randomized 1:1 to receive a single subcutaneous 40 mg dose of HLX03 or China (CN)‐sourced adalimumab. The ratios of the geometric mean of Cmax and AUC0–t were 102.2% and 105.7%, respectively, with corresponding 90% CIs falling in the predefined margins, which demonstrated PK equivalence between HLX03 and CN‐adalimumab. The incidence of treatment‐emergent adverse events (TEAEs) was similar in the two groups (73.8% and 66.0% in the HLX03 and CN‐adalimumab groups, respectively). Grade 3–4 TEAEs were reported in 7.5% and 5.7% of participants, respectively. The incidences of participants with antidrug antibodies (HLX03: 96.2%; CN‐adalimumab: 93.4%) or neutralizing antibodies (HLX03: 40.6%, CN‐adalimumab: 41.4%) were comparable between groups. This study demonstrated PK bioequivalence between HLX03 and CN‐adalimumab, with similar safety and immunogenicity profiles. These data support further clinical development of HLX03 as an adalimumab biosimilar.

Quality by design (QbD) is an efficient but challenging approach for the development of biosimilar due to the complex relationship among process, quality, and efficacy. Here, the analytical similarity of adalimumab biosimilar HLX03 to Humira® was successfully established following a QbD quality study. Quality target product profile (QTPP) of HLX03 was first generated according to the public available information and initial characterization of 3 batches of Humira®. The critical quality attributes (CQAs) were then identified through risk assessment according to impact of each quality attribute on efficacy and safety. The anticipated range for each CQA was derived from similarity acceptance range and/or the corresponding regulatory guidelines. Finally, a panel of advanced and orthogonal physicochemical and functional tests and comparison of 6 batches of HLX03 and 10 batches of the reference standard demonstrated high similarity of HLX03 to Humira®, except for slightly lower percentage of high mannosylated glycans (%HM) in HLX03 which had no effect on FcγRIII binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity in human peripheral blood mononuclear cell (PBMC). All above demonstrated the feasibility and efficiency of QbD-based similarity assessment of a biosimilar monoclonal antibody (mAb).