Biosimilars for Doctors - Introduction

Transkriptio

1 Biosimilar Medicines 12 th EGA International Conference Biosimilars for Doctors - Introduction Pekka Kurki Finnish Medicines Agency, Fimea EMA The views and opinions expressed in the following presentation are based on the experience of the individual presenter and should not be attributed to any regulatory authority Biosimilars for doctors 2 1

2 What is a biosimilar? Biosimilar = similar biological medicinal product (EU) Current regulatory definition of a biosimilar in the EU: A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product). A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise Biosimilars for doctors 3 Comparability Similar but not the same? Biosimilars for doctors 4 2

3 Biotechnological manufacturing process pexpression Biosimilars for doctors 5 Change of the manufacturing process leads to a new version of the active substance The manufacturer has to demonstrate the comparability of the versions from the old and the new manufacturing process (ICH guideline Q5E) similar but not the same Biosimilars for doctors 6 3

4 The extent of the comparability exercise depends of the type of the change The change has an impact on in-process controls but not on the specifications of the product The change has an impact on the specifications but not on safety or efficacy An impact on safety and efficacy is possible Physicochemical& biological testing Additional (non) clinical tests The development of biosimilars is based on this scenario Biosimilars for doctors 7 Production batches of biotechnology-derived proteins are not identical Change in the manufacturing process This change was approved without any clinical data Schiestl et al, Nat Biotech Biosimilars for doctors 8 4

5 Changes of the manufacturing process are common (by 2013) Mabthera > 6 Remicade > 35 Enbrel > 20 Humira > Biosimilars for doctors 9 How to create a biosimilar? Tailoring Analysis of several batches of the reference product for key characteristics. The range of variation in these characteristics defines the target ranges for the biosimilar product Fitting The manufacturing process will be adjusted to produce a protein that fits into the desired target ranges Comparison Extensive head-to-head comparisons to the reference by physico-chemical and in vitro biological tests Confirmation Comparable pharmacokinetics Comparable efficacy and safety Biosimilars for doctors 10 5

6 Comparable efficacy and safety (biosimilar infliximab as an example) Biosimilars for doctors 11 Biosimilar infliximab 1 Clinical development (871 patients) Bioequivalence study (250 patients) for 54 weeks Parallel group design (biosimilar vs Remicade ) Ankylosing spondylitis Kinetics primary and clinical endpoints secondary Safety and efficacy study (N 606) for weeks Rheumatoid arthritis Biosimilar vs. Remicade, equivalence design Primary efficacy endpoint ACR20 Secondary endpoints (ACR50, ACR70, DAS28, ADL etc.) 1 European Public Assessment Reports: Biosimilars for doctors 12 6

7 Mean (±SD) serum concentrations (μg/ml) of infliximab vs time (h) by treatment for dose 5; PK population Biosimilars for doctors 13 Biosimilar infliximab Efficacy (ACR20 at week 30) 1 Treatment arm n/n (%) Estimate of Treatment Difference All-randomised Population 95% CI of Treatment Difference Biosimilar Remicade 184/302 (60.9) 178/304 (58.6) 0.02 (-0.06, 0.10) The primary analysis was supported by the secondary efficacy endpoints. Comparable safety profile, including immunogenicity. 1 European Public Assessment Reports: Biosimilars for doctors 14 7

8 Extrapolation of safety and efficacy (an old concept with regard to healthy individuals-patients, adultsadolescents-children, foreign data, ethnic groups, organ dysfunction, mild-severe etc) Biosimilars for doctors 15 Extrapolation of safety and efficacy Development of biosimilars Identical primary-, secondary, and tertiary structure Comparable post-translational profile Comparable in vitro functional characteristics Comparable pharmacokinetics Equivalent efficacy and comparable safety and immunogenicity Can two comparable versions of an active substance behave differently in different therapeutic indications? Have we ever seen such a case? Biosimilars for doctors 16 8

9 Situations where the safety and efficacy might differ between different therapeutic indications Different receptors involved in different indications More than one active site in the active substance (mabs) Different concomitant medications (e.g. immunosuppression) Different populations with specific safety/immunogenicity concerns Biosimilars for doctors 17 Biosimilar infliximab Therapeutic indications: Rheumatoid arthritis Crohn s disease (adults and children) Ulcerative colitis Ankylosing spondylitis Psoriasis (skin and joints) Biosimilars for doctors 18 9

10 Biosimilar infliximab: Physico-chemical analysis Main areas of investigation Amino acid sequence Higher order structure Protein isoforms Glycoforms Purity and stability A difference in the proportion of afucosylated glycoforms fucosylated afucosylated Drug Information Association Biosimilar infliximab Functional studies A difference in % of afucosylated glycoforms A difference in Fc RIIIa/bbinding A difference in ADCC (Jurkat) Impact on extrapolation? (to IBD) Biosimilars for doctors 20 10

11 Difference in ADCC PBMC NK cells Neutrophils Fc RIIIA-VV Fc RIIIA-VF Fc RIIIA-FF Fc RIIIA-VV/VF + serum Mixture of Fc Rpositive cells The difference in the ADCC-activity is not seen in more physiological conditions Biosimilars for doctors 21 Additional testing, possibly be relevant to IBD Blocking of TNFα effects on epithelial cells Suppression of cytokine secretion in epithelial cell line by blocking soluble TNFα Suppression of apoptosis in epithelial cell line cells by blocking soluble TNFα Biosimilars for doctors 22 11

12 Additional testing for possible IBD-related mechanisms Evaluation of Regulatory Macrophage Function Suppression of T cell proliferation by induced regulatory macrophages in mixed lymphocyte reaction (MLR) assay Quantitation of the induced regulatory macrophages by FACS Induced regulatory macrophage-mediated wound healing of colorectal epithelium cells The function of the biosimilar and the reference products are comparable, i.e. extrapolation to IBD is possible Biosimilars for doctors 23 Extrapolation The totality of evidence Different receptors involved in different indications Different function of one of the active sites Different concomitant medications (e.g. immunosuppression) Different populations with specific safety/immunogenicity concerns The current data indicate that extrapolation to IBD is possible Biosimilars for doctors 24 12

13 Thank you for your attention! Biosimilars for doctors 25 Extrapolation of safety and efficacy A consideration for all new medicinal products Patient group & disease With regard to maturation, age, sex, pregnancy, co-morbidities Patients with or without impaired organ function Between ethnic populations Different stages of the disease Etc REFLECTION PAPER ON THE EXTRAPOLATION OF RESULTS FROM CLINICAL STUDIES CONDUCTED OUTSIDE THE EU TO THE EU-POPULATION (CHMP/EWP/692702/08) NOTE FOR GUIDANCE ON ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN CLINICAL DATA (CPMP/ICH/289/95) NOTE FOR GUIDANCE ON CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS IN THE PAEDIATRIC POPULATION (CPMP/ICH/2711/99) Biosimilars for doctors 26 13