Module 9 2021

22/03/2021

Biosimilars: Comparative Immunogenicity

• Historical data cannot be used for comparing different products but existing knowledge of the immunogenicity of the reference product in various patient population and in various indications is useful for designing immunogenicity studies. • Head-to-head studies using clinically relevant patient population, same assay format & sampling strategy based on dosing schedule. • Single assay employing biosimilar as the antigen for sample testing (both treatment arms). Reduce assay development work compared to two-assay testing. • Should demonstrate similar antibody incidence, titres, neutralisation, kinetics of development. • The consequences of ADA also must be compared (impact on PK, PD, efficacy, safety). Expectation: clinical consequences are not worse than those observed with the reference product. • Data assessed in context of totality of evidence. • Post-approval surveillance of immunogenicity is a key requirement for all biosimilars.

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Gene therapy modalities

Gene therapy products: additional challenges due to unique risks and concerns. Viral delivery systems: potential innate and adaptive immunity to AAV vectors (adeno- associated virus). Potential risks: • pre-existing immunity to components of AAV vector (  reduction of tissue transduction efficiency). • treatment-emergent immune response (humoral and cellular) against AAV vector components (  reduction of duration of expression of transgene protein). • immune response to transgene protein: pre-existing ADA (  reduced efficacy) and/or treatment-induced (  risk of cross-reacting with endogenous counterpart). Mitigation strategies & Immunogenicity monitoring include: • Vector engineering to minimise immunogenic sequences • Pre-existing ADA/NAb assessment as critical part of patient enrolment. • Post-dose monitoring: ADA and NAb response to the vector, ADA and NAb responses to transgene protein, cellular response to the virus • Long-term follow-up monitoring

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