Tuesday, 19 November, 2013 Latin America Biotherapeutic Conference Day 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. 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. 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. – 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. How advanced were biosimilar regulatory pathways before 2010?
Biosimilar
pathways
Law in place
Biosimilar
pathways under
development
Courtesy Dr. Fermín Ruíz de Ernechun

6. LATAM Biosimilar Regulation 2013
Regulation in Place
Regulation drafted or under review
No specific regulation
Courtesy Dr. Fermín Ruíz de Ernechun

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. 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. 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.

11. 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)

12. Examples of Approved Biosimilars:
Protein Chemical Mediators
Schneider C. Ann Rheum Dis 2013;72:315-318

13. 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.

14. Lymphoma with CD20-expressing lymphocytes
and treatment with anti-CD20 antibodies
CM Pereira et al. Indian J Pathol Microbiol 2011;54:388-390

15. 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

16. Inflammation Out of Control
Rheumatoid arthritis
Psoriasis

17. Role of TNFα in Inflammation:
Therapeutic Strategies
http://www.medwave.cl

18. DESGIN OF BIOSIMILAR mABs/Cepts BY
REVERSE ENGENEERING
Innovator mAB/Cept
DNA constructs: Genes
McCamish & Woollett. mAbs 3: 209-217, 2011.

19. 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.

20. Folding and Glycosylation:
The Rope and the Knots

21. 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

22. 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.

24. 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.

25. True Biosimilar: Celltrion (Hospira) Infliximab

26. Annals of the Rheumatic Diseases 2013;72:1613-1620
✔
✔
✔
✔
✔

27. 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;

28. 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

29. 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.

30. 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.