1 Dr Gilberto Castañeda Hernández - CINVESTAV


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Tuesday, 19 November, 2013
Latin America Biotherapeutic Conference Day 1

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1 Dr Gilberto Castañeda Hernández - CINVESTAV

  1. 1. Key Note Address: Clinical Pharmacology of Biotechnological Medicines: Why Biosimilars Are Not Generics Gilberto Castañeda-Hernández, Ph.D. Departamento de Farmacología Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional México, D.F.
  2. 2. Statement of Possible Conflicts of Interest • I am a Senior Investigator at the Center for Research and Advanced Studies of the National Polytechnic Institute in Mexico. • I have given lectures and participated in studies sponsored by: Abbvie, Amgen, Astra-Zeneca, Bayer, Concordia, Grünenthal, Janssen, Lilly, Liomont, Medix, MSD, Novartis, Pfizer, Roche, Sanofi, Sandoz, Senosiain, Silanes, Sophia, UCB. • I am neither in the payroll nor posses shares of any of these companies.
  3. 3. Size matters!!!! Molecular Weights in Daltons Conventional Drugs Non-proteic nature Biotechnological Medicines Proteins Aspirin 180 Adrenaline 183 Diclofenac 296 Paroxetine 329 Ketorolac 376 Atorvastatin 558 Levofloxacin 740 Tacrolimus 804 Paclitaxel 854 Insulin 5,800 Filgrastim 18,800 Interferon alpha 19,625 Somatropin 22,000 Erythropoietin 30,400 Rituximab 145,000 Trastuzumab 146,000 Infliximab 149,000 Bevacizumab 149,000 Innovator/Generic Innovator/Biosimilar
  4. 4. – It should be recognised that, by definition, similar biological medicinal products are not generic medicinal products, since it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers ...the generic approach is not suitable for the licensing of SBPs since 197biotherapeutic products usually consist of relatively large and complex entities that are difficult 198to characterize... even minor differences in the manufacturing process may affect the pharmacokinetics, pharmacodynamics, efficacy and/or safety of biotherapeutic products Los medicamentos biotecnológicos innovadores podrán ser referencia para los medicamentos biotecnológicos no innovadores, a los cuales se les denominará biocomparables. La forma de identificación de estos productos será determinada en las disposiciones reglamentarias.
  5. 5. How advanced were biosimilar regulatory pathways before 2010? Biosimilar pathways Law in place Biosimilar pathways under development Courtesy Dr. Fermín Ruíz de Ernechun
  6. 6. LATAM Biosimilar Regulation 2013 Regulation in Place Regulation drafted or under review No specific regulation Courtesy Dr. Fermín Ruíz de Ernechun
  7. 7. Bioequivalence of Generic and Innovator Products Bioequivalence of the generic with the innovator can be concluded from plasma concentration against time curves, as the active molecule in both products is identical.
  8. 8. sciencephoto.com Biotech Products are Glycoproteins. Peptidic chains Sugars Martin Schiestl, Thomas Stangler, Claudia Torella, Tadej Čepeljnik, Hansjörg Toll & Roger Grau Same brand (innovator) batch-to-batch changes in glycosylation: Not identical molecules, as determined by capillary electrophoresis. But similar biological activity. Darbopoetin α Rituximab Etanercept Conclusion: Some, but not all, changes in glycosylation are acceptable. Biosimilarity (similar biological activity) must be demonstrated.
  9. 9. Although very similar in terms of sequences and modifications, a mass difference observed by LC-MS intact mass measurements indicated that they were not identical. Comprehensive glycosylation profiling confirmed that the proportion of individual glycans was different between the biosimilar and the innovator, although the number and identity of glycans were the same.
  10. 10. Biotech Medicines: Produced by Living Cells Recombinant technologies Protein Chemical Mediators (MW: 5,000 - 50,000 Daltons): • Insulin • Erythropoietin • Filgrastim • Somatropin Anti-Proteins (MW ≈ 150,000 Daltons): • Soluble Receptors (Cept’s) • Monoclonal Antibodies (mAB’s)
  11. 11. Examples of Approved Biosimilars: Protein Chemical Mediators Schneider C. Ann Rheum Dis 2013;72:315-318
  12. 12. The Other Biotechnological Therapeutic Products: Monoclonal Antibodies (mABs) and Soluble Receptors (Cepts) Real hope for patients with chronic-degenerative diseases such as Cancer, Arthritis, Psoriasis, etc.
  13. 13. Lymphoma with CD20-expressing lymphocytes and treatment with anti-CD20 antibodies CM Pereira et al. Indian J Pathol Microbiol 2011;54:388-390
  14. 14. Trastuzumab and HER-2 Positive Breast Cancer HER-2: Human Epidermal Growth Factor Receptor 2 Trastuzumab (mAB) Selctivaley targets the extracellular domain of the HER-2 protein http://www.bccancer.bc.ca/HPI/Nursing/Education/breastcancer/treatmentoptions/systemic.htm#herceptin
  15. 15. Inflammation Out of Control Rheumatoid arthritis Psoriasis
  16. 16. Role of TNFα in Inflammation: Therapeutic Strategies http://www.medwave.cl
  17. 17. DESGIN OF BIOSIMILAR mABs/Cepts BY REVERSE ENGENEERING Innovator mAB/Cept DNA constructs: Genes McCamish & Woollett. mAbs 3: 209-217, 2011.
  18. 18. Post-Transcription Processes: Glycosylation, Folding and Affinity McCamish & Woollett. mAbs 3: 209-217, 2011. Berger et al. Adv Biochem Engin/Biotechnol 2011 Epub ahead of print.
  19. 19. Folding and Glycosylation: The Rope and the Knots
  20. 20. Immunogenicity Y Product A Y Product B Y Anti-antibody Less immunogenic Longer half-life Less risk of reactions More immunogenic Shorter half-life Increased risk of reactions
  21. 21. WARNING!!! 1. Despite recognizing a same ligand (antigen), potency and immunogenicity can differ between innovator and biosimilar mABs/Cepts. 2. Innovator’s data cannot be directly extrapolated to a non-innovator produced by a different process. 3. Identical bioavailability, efficacy and safety cannot be guaranteed. 4. Hence, a biosimilar must generate its own efficacy and safety data in well designed, statistically sound comparative clinical studies. 5. Equivalence, or at least non-inferiority must be demonstrated.
  22. 22. Types of Biotechnological Medicines: Definitions1-3 • Innovator: Generated by original research. Protected by a patent. • Biosimilar: Non-innovator product highly similar to the innovator that complies with national regulations consistent with WHO guidelines. • Intended Copy: Non-innovator product licensed without biosimilar regulation in some countries. Approval before biosimilar regulation was enacted. 1. Thomas Dörner, Vibeke Strand, Gilberto Castañeda-Hernández, Gianfranaco, Ferraccioli; John D. Isaacs;Tore K. Kvien, Emilio Martín-Mola, Thomas Mittendorf, Josef S. Smolen, Gerd R. Burmester. The role of biosimilars in the treatment of rheumatic diseases. Ann Rheum Dis 2013;72:322-328 2. Morton A. Scheinberg and Valderilio F. Azevedo. Biosimilars in Rheumatology: Perspectives and Concerns, Rheumatology (Oxford) Epub ahead of print, 2013. 3. H. Mellstedt. Antineoplasic biosimilars – the same rules as for cytotoxic generics cannot be applied. Ann Oncol 2013;24(Suppl 5):v23-v28.
  23. 23. True Biosimilar: Celltrion (Hospira) Infliximab
  24. 24. Annals of the Rheumatic Diseases 2013;72:1613-1620 ✔ ✔ ✔ ✔ ✔
  25. 25. Intended Copies of mABs and Cepts Licensed Without Biosimilar Regulation Drug Manufacturer Intended Copy Examples of countries where it is marketed Rituximab Dr. Reddy Laboratories (India) Reditux India Peru Ecuador Chile Paraguay Probiomed (Mexico) Kikuzubam Mexico Shanghai CP Goujian (China) Yisaipu Etanar Etart China Colombia Mexico Probiomed (Mexico) Infinitam Mexico Etanercept Dörner et al. Ann Rheum Dis 2013; 72: 322-328, Cofepris 2012; Scheinberg and Azevedo, Rheumatology (Oxford) Epub ahead of print, 2013;
  26. 26. Safety Issues with Rituximab Intended Copy Anaphylactic Reactions with Rituximab There are two rituximab products in Mexico. Analysis of the cases showed that adverse reactions occurred after the switch of one product for the other. Comunicado 04/04/2012 http://www.cofepris.gob.mx/AZ/Paginas/Farmacovigilancia/Comunicados.aspx
  27. 27. Conclusions (1) 1. For conventional drug products (small molecules), bioequivalence between generic and innovator products can be established from plasma concentration versus time curves. The same molecule is being determined. 2. Biosimilars, however, are not generics. Not identical with regard to the innovator. 3. Thorough molecular characterization, as well as comparative preclinical and clinical studies documenting efficacy and safety are required.
  28. 28. Conclusions (2) 4. Biosimilars must produce their own clinical data. Extrapolation from innovator’s results is not possible. THEY CANNOT BE IDENTICAL. 5. Biosimilars, but not intended copies, are welcome, as they reduce costs and increase access.