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.

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.

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

– 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.

Biosimilar

pathways

Biosimilar

pathways under

development

Law in place

How advanced were biosimilar regulatory pathways before 2010?

Courtesy Dr. Fermín Ruíz de Ernechun

LATAM Biosimilar Regulation 2013

Regulation in Place

Regulation drafted or under review

No specific regulation

Courtesy Dr. Fermín Ruíz de Ernechun

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.

Bioequivalence of Generic and Innovator Products

Same brand (innovator) batch-to-batch changes in glycosylation: Not identical molecules,

as determined by capillary electrophoresis. But similar biological activity.

Etanercept Rituximab Darbopoetin α

Biotech Products are

Glycoproteins.

Peptidic chains

Sugars

Conclusion: Some, but not all, changes in glycosylation are acceptable.

Biosimilarity (similar biological activity) must be demonstrated.

sciencephoto.com

Martin Schiestl, Thomas Stangler, Claudia Torella, Tadej Čepeljnik, Hansjörg Toll & Roger Grau

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.

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)

Schneider C. Ann Rheum Dis 2013;72:315-318

Examples of Approved Biosimilars:

Protein Chemical Mediators

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.

Lymphoma with CD20-expressing lymphocytes

and treatment with anti-CD20 antibodies

CM Pereira et al. Indian J Pathol Microbiol 2011;54:388-390

Trastuzumab and HER-2 Positive

Breast Cancer

HER-2: Human Epidermal Growth Factor Receptor 2

http://www.bccancer.bc.ca/HPI/Nursing/Education/breastcancer/treatmentoptions/systemic.htm#herceptin

Trastuzumab (mAB)

Selctivaley targets

the extracellular domain

of the HER-2

protein

Inflammation Out of Control

Rheumatoid arthritis Psoriasis

Role of TNFα in Inflammation:

Therapeutic Strategies

http://www.medwave.cl

Innovator mAB/Cept DNA constructs: Genes

DESGIN OF BIOSIMILAR mABs/Cepts BY

REVERSE ENGENEERING

McCamish & Woollett. mAbs 3: 209-217, 2011.

McCamish & Woollett. mAbs 3: 209-217, 2011.

Post-Transcription Processes:

Glycosylation, Folding and Affinity

Berger et al. Adv Biochem Engin/Biotechnol 2011 Epub ahead of print.

Folding and Glycosylation:

The Rope and the Knots

Immunogenicity

Less immunogenic

Longer half-life

Less risk of reactions

More immunogenic

Shorter half-life

Increased risk of reactions

Y Product A

Y Product B

Y Anti-antibody

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.

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.

True Biosimilar: Celltrion (Hospira) Infliximab

✔

✔ ✔

✔

✔

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

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

Etanercept Shanghai CP

Goujian (China)

Yisaipu

Etanar

Etart

China

Colombia

Mexico

Probiomed

(Mexico)

Infinitam Mexico

Dörner et al. Ann Rheum Dis 2013; 72: 322-328, Cofepris 2012; Scheinberg and Azevedo,

Rheumatology (Oxford) Epub ahead of print, 2013;

Safety Issues with Rituximab Intended Copy

Comunicado 04/04/2012 http://www.cofepris.gob.mx/AZ/Paginas/Farmacovigilancia/Comunicados.aspx

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.

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.

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.