Module 9 2024

03/09/2024

Biosimilars: Comparative Immunogenicity

• Historical data cannot be used for comparing different products but existing knowledge of the immunogenicity of the reference product is useful for the risk assessment and for designing immunogenicity studies • Head-to-head studies using clinically relevant patient population, same assay format & sampling strategy based on dosing schedule • 1-assay approach employing biosimilar as the antigen for sample testing (both treatment arms) – but sponsors need to demonstrate assay suitability to detect ADA towards reference product and biosimilar (antigenic equivalence, PC selection, drug tolerance, …)

• Should demonstrate similar antibody incidence, titers, neutralisation, kinetics of development

• The consequences of ADA also must be compared (impact on PK, PD, efficacy, safety)

Expectation: clinical consequences with biosimilar are not worse than those observed with the reference product

• Data assessed in context of totality of evidence

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Gene Therapy Modalities

Gene therapy products: additional challenges due to unique risks 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 product: pre-existing ADA ( → reduced efficacy) and/or treatment-induced ( → risk of cross-reacting with endogenous counterpart). Mitigation strategies & Immunogenicity monitoring include: • AAV capsid and transgene cassette 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 monitoring (follow-up)

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