1. The role of biosimilars in BMT Dr Bronwen Shaw Chief Medical Officer, Anthony Nolan Consultant in haematopoietic cell transplantation, Royal Marsden

2. Overview What are biosimilars Which biosimilars are relevant to BMT Why are there concerns How are these regulated What is the data (are the concerns justified?) Conclusions

3. Definitions Biological medicine: –Is a medicine whose active substance is made by or derived from a living organism Biopharmaceutical: –A drug created by means of biotechnology, especially genetic engineering Examples: insulin, erythropoietin, GCSF

4. Why do we have biosimilars The patents of several biopharmaceuticals have expired or they are about to expire New agents can be developed Pressure to reduce healthcare expenditure and increase patient access to treatment will drive the development of cheaper biosimilars

5. Definitions Biosimilars (follow on biologics): –The World Health Organisation (WHO) defines biosimilars or Similar Biotherapeutic Products (SBPs) as ‘a biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product (RBP)’ –RBP: Filgrastrim/ Lenograstim

6. Which biosimilars are relevant to BMT Erythropoetin –Anaemia GCSF –Neutropaenia –Mobilisation Auto –Mobilisation Allo

7. Why are there concerns? Lack of understanding of biosimilars Lack of regulation Highly financially driven healthcare decisions Protecting healthy volunteers

8. Why are there concerns? Biologics are structurally complex medicines Slight changes in their manufacture can cause undetected changes in the biological composition of the product These changes can in turn affect the safety and effectiveness of the product in patients.

9. Why are biopharmaceuticals different? High molecular weight Complex three-dimensional structure Complex manufacturing process Produced by living organisms; therefore often heterogeneous Difficult to characterize completely by physico-chemical analytical methods or bioassays Dependence of biological activity on reproducibility of the production process, in-house standards, and maintenance of cold-chain integrity Inherent risk of immunogenicity Crommelin DJA, et al. Int J Pharm. 2003;266:3-16.

10. Manufacturing process Complex –Develop host cell –Establish a cell bank –Protein production –Purification –Analysis –Formulation –Storage and handling Proprietary

11. Manufacturing process Cheddar cheese and red wine from different manufactures are unique (e.g. in flavor or texture) But they may be treated as the same (generic equivalent) and be assigned the same generic product name

12. Immunogenicity Johnson & Johnson made a change in the manufacturing process for its EPREX product –marketed for a decade with no evidence of immunogenicity problems. The change caused a serious adverse reaction in a small number of patients –Pure red cell aplasia due to antibody production (triggered by the EPREX) This was resolved by a costly and lengthy process

13. Biosimilar Epoetins: Gaps in Quality and Potential Safety Biosimilar versions of epoetins have been available in developing countries for many years and are widely used for economic reasons Despite limited data on the efficacy and safety of biosimilar epoetins, they are prescribed under the assumption that they have similar safety and efficacy profiles as the original product. The aim of this study was –systematically evaluate the quality of biosimilar epoetins –report the potential implications of the results for product efficacy and patient safety European Journal of Hospital Pharmacists, 2005;11, science issue 1, 11-17

14. Methods - Epoetin biosimilar samples Biosimilar epoetin samples were procured from pharmacies in 13 countries (31 samples) Samples were tested against the European quality specifications for epoetin alfa Analysed at 3 labs in the USA: –Physical characteristics –Activity –Impurities (Bacterial endotoxin)

15. Conclusions from this study Several of the biosimilar epoetins tested were found to be inconsistent in quality and potency –26/31 did not conform to all European specifications for epoetin alfa –22/31 samples contained additional forms (basic isoforms), which can reduce clinical efficacy –2 samples were contaminated with impurities (bacterial endotoxin), which poses a risk to patient safety –17/31 samples contained > 2% aggregates, which can influence the immunogenicity profile of the product These results indicate that the biosimilar epoetins tested are not similar to innovator epoetin alfa (Eprex R ) Physicians and Patients cannot assume that the safety and efficacy of these products are similar to innovator epoetin because they receive marketing authorization.

16. Regulations If there are strict licensing criteria some of these problems should not arise European Medicines agency (EMEA) guideline in 2006 on how to obtain a licence for a biosimilar: –the main requirement for the manufacturer is to prove ‘comparability’ for the primary indication with a licensed product (which must already be licensed on the basis of a full registration dossier) –the comparability exercise includes non-clinical and clinical requirements –If a license is granted efficacy for other indications can be extrapolated

17. Regulations FDA –Affordable Care Act, signed into law by President Obama on March 23, 2010, amends the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product –Under the BPCI Act, a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product –No biosimilar is yet FDA approved

18. GCSF Two RBP of recombinant G-CSF are available internationally –Granocyte (Lenograstim) and Neupogen (Filgrastim) Primary indication: Chemotherapy induced neutropenia Other indications: post BMT, mobilisation, Congenital neutropenia, Cyclical neutropenia, HIV Both agents are licensed for mobilisation of HSC in normal donors in the European Union (EU) Neupogen used for normal donor mobilisation in the USA, but is not licensed indications in the product insert and in view of this the US Food and Drug Administration (FDA) continues to require close study and oversight of long- term safety

19. GCSF 3 drugs approved by the EMEA in EU: Met criteria required Nivestim/Ratiograstim/Zarzio No data on mobilisation in normal donors Limited safety data No long term follow up 1 has a post marketing study (5 yr follow up) –Several others available Less easy to find regulatory data

20. Biosimilar GCSF: clinical data Mobilisation for Autologous transplants –Several studies show equal CD34 yields, similar days to neutrophil recovery post transplant (Publicover A, 2010; Lefrère F, 2011; Ferro HH, 2009) –No difference in failure rate –No obvious difference in side effects (though not the primary outcome) Mobilisation for Allogeneic transplants –No published data –Some ongoing studies

21. Conclusions Biosimilars may: –Reduce costs –Increase availability globally –Be equally efficacious –Some caution should be exercised due to: Manufacturing process Variable regulations Extrapolated indications Limited safety data Lack of long term safety data

22. Recommendations Emerging evidence for equal efficacy in autologous mobilisation Regulatory process important for each agent Manufacturer/pharmacy recommendations –Prescribe by specific name –No direct substitution –Only one agent to be given during a course of treatment

23. Recommendations Small amounts of short term safety data (in some settings) No long term safety data in any setting yet Risk/benefit in donors different to in patients Professional Societies (EBMT/WMDA) are urging ‘caution’ in normal donors –Registration studies –Post marketing safety studies