Biosimilar medicines and patient safety: making an informed decision

1. Biosimilar medicines and patient safety: making an informed decision European Health Forum Gastein – EHFG 2005 Kurt Pfister PFC Pharma Focus AG Volketswil/Zürich - Switzerland

2. Agenda • Synthetic versus biotechnology-derived Medicinal Products – the difference • The risks – for originator as well as “generic” companies • Biological Medicinal Product – off-patent and now? • Impact of the different nature of the medicinal products on the marketing authorization process • Cautious approach of the regulatory bodies • Summary Remarks

3. Synthetic versus biotechnology-derived Medicinal Products – the difference The synthetic medicinal product Production

4. Synthetic versus biotechnology-derived Medicinal Products – the difference The synthetic Medicinal Product Product Aspirin Penicillin • simple • small • easily characterized • clean

5. Synthetic versus biotechnology-derived Medicinal Products – the difference The medicinal product from a biotechnology-derived protein Production Gene transfer Source of production site Production site

6. Synthetic versus biotechnology-derived Medicinal Products – the difference Prof. Florian Wurm, 10. Reg. Forum 2005

7. Synthetic versus biotechnology-derived Medicinal Products – the difference Biotech-Wirkstoffe werden eher gebraut als chemisch konstruiert. In riesigen Fermentern schwimmen Kulturen genetisch veränderter Bakterien in Nährlösung. Aus dieser Biosuppe werden die Wirkstoffe extrahiert und gereinigt. Sie bestehen aus Proteinen, die auch natürlich vorkommen - oder ähneln diesen zumindest.

8. Synthetic versus biotechnology-derived Medicinal Products – the difference The medicinal product from a biotechnology-derived protein Product • Production site complex • Product very large • Heterogeneity in structure • Difficult to characterize • Difficult to clean Factor VIIII Fred Hutchinson Cancer Research Center

9. Number of Amino Acids Molecular Weight (Dalton) Product - - 32 191 165 2332 Chemically-Based Propranolol Aspirin Calcitonin Hu Growth Hormone Erythropoietin Factor VIII 259 180 4,500 22,000 ca. 30,000 ca. 264,000 Biologic Synthetic versus biotechnology-derived Medicinal Products – the difference Difference in complexity

10. Synthetic versus biotechnology-derived Medicinal Products – the difference Difference in complexity

11. Synthetic versus biotechnology-derived Medicinal Products – the difference Difference in post-translational modification Ram Sasisekharan, MIT, FDA Public Workshop, September 14 & 15, 2004

12. Synthetic versus biotechnology-derived Medicinal Products – the difference Change of the production site and system expl. Erythropoetin Schellekens, H., Biosimilar Epoetins: How Similar Are They? Eur. J. of Hosp. Scien., Mar 04, 43-47

13. Synthetic versus biotechnology-derived Medicinal Products – the difference Ob bei zwei biotechnischen Prozessen wirklich Gleichwertiges herauskommt, haben sogar deren Erfinder nicht immer im Griff.

14. The risk – for originator as well as “generic” companies

15. The risk – difference in efficacy Impact of small structural differences on bioavailability Site of Carbohydrate Linkage – Opioid Glycopeptide (Elmagbari et al.) JPET 311:290-297, 2004

16. The risk – difference in efficacy Impact of small structural differences on tissue distribution Biodistribution of Radiolabeled Glycoforms in Mice* Tissue Form 1 Form 2 Form 3 Form 4 Blood 100% 108% 103% 217% Liver 100% 51% 13% 4% Lungs 100% 22% 56% 289% Bone Marrow --- ---  --- * Neoglycopeptides (derived from fibrinogen, thyroglobulin) 25 minutes post-dose, cpm  108 gm tissue Gupta and Surolia. 1994Glycoconjugate Journal

17. The risk – difference in safety The event, which changed perception

18. The risk – difference in safety ... the observation Bennett C.NJM, 2004; 351, 1403

19. The risk – difference in safety ... and the analysis Bennett C.NJM, 2004; 351, 1403

20. Synthetic versus biotechnology-derived Medicinal Products – the difference „The process makes the product“ Any change in the production may change the product Any change in the product may change the efficacy and safety

21. Brand Active Substances Marketer Approval 1999: $ Mio Epogen Epoetin alfa Amgen 1989 1760.0 Procrit Epoetin alfa Ortho 1990 1505.0 Neupogen Filgrastim Amgen 1991 1260.0 Humulin human Insulin Eli Lilly 1992 1088.0 Intron A Interferon alfa-2b Schering 1986 650.0 Engerix-B Hepatitis B vaccine, Biogen 1989 540.0 Ceredase Alglucerase Schering 1991 500.0 Cerezyme Imiglucerase Genzyme 1991 479.0 Betaseron Interferon beta-1b Eli Lilly 1993 413.0 Kogenate Antihemophilic factor Centocor 1993 403.4 Biological Medicinal Product – off-patent and now? Quelle: Arthur D. Little, USA 1999

22. Biological Medicinal Product – off-patent and now? •  Sales of biopharmaceutical markt coming off-patent appox. 12 billion USD • USA 45% EU 30% Japan 20% • Assumption Biosimilar-Penetration 10 bis 15%: 2 billion USD

23. Biological Medicinal Product – off-patent and now?

24. Biological Medicinal Product – off-patent and now? Why are the first “biosimilars“ not yet on the market?

25. Impact of the different nature of the medicinal products on the marketing authorization process Approval process synthetic medicinal product Efficacy Pharmaceutical Quality Bioavailablity Safety

26. Impact of the different nature of the medicinal products on the marketing authorization Pharmazeutische Qualität Sicherheit Wirksamkeit Substitution Approval process synthetic „generic“ Pharmazeutische Qualität Bioäquivalenz Innovator product Generic product

27. Impact of the different nature of the medicinal products on the marketing authorization Pharmazeutische Qualität Sicherheit Wirksamkeit Substitution Approval process „biosimilar“ Pharmazeutische Qualität Bioäquivalenz Sicherheit Wirksamkeit Innovator product Biosimilar

28. Cautious approach of the regulatory bodies Biogenerics Biosimilars Follow on Protein (FOP) Follow on Biologics (FOB)

29. Cautious approach of the regulatory bodies No specific guidelines on biosimilars „FDA Guidance concerning demonstration of comparability of human biological products, including therapeutic biologically derived products“ (April 1996)

30. Revision of Directive 2001/83 (Entering into Force Nov' 2005) Overarching Guideline on Similar Biological Medicinal Products  Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues General:Applies to all Biosimilars Quality  Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Nonclinical & Clinical Issues [comments due Oct ‘05] Nonclinical& Clinical Specific:Product data requirements Recombinant Human Erythropoietin Recombinant HumanG-CSF Recombinant HumanInsulin Recombinant Human Growth Hormone Annexes Cautious approach of the regulatory bodies

31. Cautious approach of the regulatory bodies 3 Biosimilars Reaction expected 3. / 4.Q 2005 Human Growth Hormone INF-alpha Produkt ???

32. In Summary original *****similar? Complexity of production of biologicals Complexity of structure of biologicals Not identical, but similar (how much?) Risk Substitution ?