China Approves Its First Biosimilar, Henlius' Rituximab

Regulators in China have approved the country’s first ever biosimilar, a rituximab product referencing Rituxan. The product, HLX01, was developed by Henlius, and will be primarily used in the treatment of non-Hodgkin lymphoma.

China’s regulatory agency created national guidelines for developing and evaluating biosimilars in 2015, with principles and requirements consistent with those used by the FDA and the European Medicines Agency. While China currently has a bevy of biosimilars undergoing research (with approximately 200 biosimilar clinical trial applications approved to date), the rituximab product is the first to earn the regulator’s clearance.

Approval of HLX01 was based on a data package that included a 3-way similarity assessment of 12 batches of the biosimilar, 15 batches of Chinese-licensed reference rituximab (which is manufactured in Germany and then packaged, labeled, and sold in China), and 7 batches of EU-licensed rituximab. A report on this assessment was published last week in mAbs.¹

The primary structure of the rituximab molecules was investigated using intact, reduced, and deglycosylated mass analyses; reduced peptide mapping; measurement of free thiol groups; and disulfide linkage mapping. The molecules were found to have highly similar primary structures. Higher-order structures were also characterized using multiple techniques, all of which revealed the higher-order structure of the biosimilar to be highly similar to those of the 2 reference products.

An assessment of charge variants showed that the biosimilar has a similar charge variant profile compared with both reference rituximabs, with the exception of a slightly higher level of basic variants representing more unprocessed heavy chain C-terminal lysine, which does not affect the efficacy or safety of an antibody product.

The biosimilar also demonstrated the same levels of purity as the reference rituximab products and was found to possess slightly lower levels of aggregates and fragments than the reference products.

HLX01 was also shown to have the same glycosylation site, occupancy, and glycans as the reference rituximab products. The relative G0F content was higher in HLX01, resulting in lower relative content of galactose-contained glycans versus the reference rituximab products. The investigators write that the difference in galactose, however, would not cause notable changes in the molecules’ activities.

Biological functions of the biosimilar, including antibody-dependent cell-mediated cytotoxicity, Fc receptor binding, CD20 binding, complement-dependent cytotoxicity, and apoptosis were similar to those of the reference products for all tested batches.

HLX01 and its reference products also demonstrated good stability and consistent degradation behaviors under forced degradation conditions.

Taken together, write the investigators, these data show that HLX01 is highly similar to both the Chinese- and EU-licensed rituximab reference products. Furthermore, they write, the regulatory requirements that were applied in the analysis of HLX01 will set a precedent for analytical similarity assessments of biosimilars in China going forward.

Reference

1. Xu Y, Xie L, Zhang E, et al. Physicochemical and functional assessments demonstrating analytical similarity between rituximab biosimilar HLX01 and the MabThera [published online February 22, 2019]. mAbs. doi: 10.1080/19420862.2019.1578147.