1. WHAT IS A BIOSIMILAR? Philip D. Home, DM, DPhil Professor of Diabetes Medicine Newcastle University Consultant Diabetologist Newcastle Diabetes Centre Newcastle-Upon-Tyne, United Kingdom

2. Biosimilar Medications Nature and Definition Biopharmaceuticals (“biological medications”; “biologic[al]s”) Biological medical products derived from cell culture/fermentation processes producing target therapeutic proteins First example was recombinant human insulin (Eli Lilly, 1980) Other examples: cytokines, monoclonal antibodies, growth hormone Biosimilars (“follow-on biologics”) Biopharmaceuticals intended to be a clinically equivalent end product to another existing biopharmaceutical Available clinical products include epoetin alfa, growth hormone, insulin “A new biological product similar to an already authorized medicine…similar but not identical to the biological reference medicine”

3. What Biosimilars Are Currently Approved in Europe? Biosimilars were first introduced in Europe in 2006 Currently there are 16 biosimilars approved in Europe, across 5 product types – Growth hormone (somatropin) – EPO (epoetin alfa, zeta) – G-CSF (filgrastim) – Monoclonal antibody TNF (infliximab) – FSH (follitropin alfa) – Insulin glargine EMA. European Public Assessment Reports; 2014.

4. Differences Between Development of New Generics and New Biosimilar Medications Classic GenericsBiosimilars Manufacturing Chemical synthesis Simple fermentation Standard analytics Genetically modified cell lines Complex fermentation Complex purification process Formulation Complex analytical characterization Preclinical (tissue/animal) Generally none In vitro/in vivo bioassay Toxicity studies Local tolerance studies PK/PD studies Clinical Generally a bioavailability study PK/PD studies Clinical efficacy/tolerability/safety studies Postmarketing surveillance McCamish M, et al. MAbs. 2011;3:209-217.

5. Biosimilar Medications: Why Many May Be Different From the Standard Product Biopharmaceuticals are complex products Host cell for manufacturing may be different Extraction from bioreactor may be different Purification is complex and may be different Postfermentation processing may be different Formulation may be different Accordingly Antigenicity may be different—different degradation products Bioavailability may vary—formulation differences Storage stability may vary Differences in administration devices add another dimension

6. Challenges With Biosimilar Insulins Biosimilar insulins may come with several challenges Assurances of close bioequivalence Manufacturing expertise and batch-to-batch variability Product metabolism and stability PD/PK comparability Clinical efficacy and clinical safety Toxicologic and immunogenicity issues Heinemann L, et al. Diabetes Obes Metab. 2015;17:911-918.

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