A Retrospective Analysis of the Potential Impact of Differences in Aggregates on Clinical Immunogenicity of Biosimilars and their Reference Products.

Abstract

Aggregates, in particular high molecular weight species (HMWs), have been linked to increased immunogenicity. The current understanding on the impact of HMWs is mainly based on in vitro and nonclinical studies and there are only limited data available associating differences in HMWs in marketed monoclonal antibodies (mAbs) to clinical outcomes. Biosimilars offer a unique opportunity to study the potential association between quality parameters and clinical outcomes. We performed a retrospective evaluation to investigate the association between HMW content and reported antidrug-antibody (ADA) incidence in 30 full-length biosimilar mAbs approved in the European Union and the United States. Information for HMW content and ADA incidence were collected from publicly available sources. Differences in HMW content between biosimilars and their reference products (RPs) ranged from -0.75 to 1.65% with slightly higher differences observed in antineoplastic products as compared with immunosuppressant products. The difference in the ADA incidence between the RP and the biosimilar for the programs studied ranged from -11.0 to 18.5%. No association was observed between differences in HMW content and reported ADA incidence, in neither phase I nor phase III studies. Our results show that the limited differences in the content of HMWs between marketed biosimilars and reference mAbs were not associated with differences in reported immunogenicity, determined as incidence of ADAs and neutralizing ADAs in comparative clinical studies.