Biosimilars - BioRiver

Comprehensive structural and physicochemical comparability<br />

of <strong>Biosimilars</strong><br />

Martin Blüggel<br />

COO & Executive Vice President<br />

Protein Services<br />

martin.blueggel@protagen.de<br />

Protagen AG<br />

Otto-Hahn-Str. 15<br />

44227 Dortmund<br />

+49 231 9742 6300<br />

www.protagen.de

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Agenda<br />

• Introduction to Protagen AG<br />

• Biosimilar Comparability<br />

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Protagen AG – Facts and Location<br />

Private stock corporation<br />

Established in 1997<br />

49 Employees<br />

1500 m² modern laboratory space<br />

Technology Center Dortmund<br />

Germany<br />

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Protagen AG – Two Business Units<br />

PROTAGEN PROTEIN SERVICES | IT'S A MATTER OF TRUST<br />

Protein Characterization<br />

• GMP certified since 2006<br />

• Complete protein characterization and release testing<br />

• Glycosylation & post-translational modification analysis<br />

• Product & process related impurity profiling<br />

• Bioassay development and validation<br />

Biopharmaceuticals<br />

• ICH Q6B<br />

• Stability and release testing<br />

• Comparability analysis<br />

• New biological entities (NBE`s)<br />

• <strong>Biosimilars</strong><br />

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Protagen AG – Spectrum of Analytical Methods<br />

Analytical Method Description<br />

Mass Spectrometry<br />

Gel Electrophoresis<br />

Bioassay<br />

Amino Acid Analysis<br />

Spectroscopic assay<br />

Chromatography<br />

• Peptide Map to confirm identity of proteins<br />

• De novo sequencing mAB<br />

• N- and C-terminal sequencing of entire proteins<br />

• Site-specific PTM characterization<br />

• Structural analysis (Disulfide-Linkages, Glycosylation-sites, …)<br />

• Glycan analysis<br />

• Determination of total molecular weight<br />

• Quantitative analysis of complex protein mixtures<br />

• Sophisticated data quality control and evaluation<br />

• Continuous improvement of algorithms for data analysis<br />

• In-house software-development<br />

• High resolutions protein separation 1D up to 30cm, 2D up to 40x30 cm (16x12in)<br />

• Reducing / non reducing PAGE, IEF<br />

• Western blotting: antibody selection and validation via UNIchip ®<br />

• Cell-based bioassays<br />

• ELISA: antibody selection and validation via UNIchip ®<br />

• Standard and time resolved analysis<br />

• Modified amino acids (Hydroxyproline, Norleucine…)<br />

• Determination of extinction coefficient<br />

• Quantification<br />

• Fluorescence-scans<br />

• RP, IEX, SEC – HPLC/UPLC*<br />

• Glycan analysis: RP/NP HPLC with fluorescence labeling<br />

.HPAEC PAD detector label-free<br />

Protein characterization according to ICH Q6B and CHMP<br />

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Protein Analytical Services<br />

Therapeutic proteins successfully analyzed in-house are:<br />

• NBE, eg. Antibodies<br />

• Recombinant monoclonal IgG-Type<br />

• Polyclonal IgG<br />

• Fusion Proteins<br />

• Fc-constructs<br />

• Fab-fragments<br />

• Marketed Biopharmaceuticals, e.g.<br />

Originator<br />

Active Ingredient Analyzed by Protagen<br />

AG<br />

Avastin Bevacizumab Innovator<br />

Betaseron Interferon beta-1b Biosimilar<br />

Copaxone Glatiramer acetate Biosimilar<br />

Enbrel Etanercept Innovator, Biosimilar<br />

Epogen, Eprex Erythropoietin Innovator, Biosimilar<br />

Erbitux Cetuximab Innovator<br />

Herceptin Trastuzumab Innovator<br />

Humira Adalimumab Innovator, Biosimilar<br />

Hirudin Innovator<br />

Neupogen Filgrastim Innovator, Biosimilar<br />

Nutropin Somatropin Biosimilar<br />

Remicade Infliximab Innovator, Biosimilar<br />

Rituxan Rituximab Innovator, Biosimilar<br />

Tysabri Natalizumab Innovator<br />

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Agenda<br />

• Introduction to Protagen AG<br />

• Biosimilar Comparability<br />

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What are BioSimilars?<br />

Generic Drugs<br />

Patent<br />

Aspirin ASS<br />

Expiry<br />

The same !<br />

Acesal<br />

Alka-Seltzer<br />

Aspirin<br />

Godamed<br />

Herz-ASS<br />

Miniasal<br />

Togal-ASS<br />

ASS ratiopharm<br />

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Biosimilar Definition<br />

“A biosimilar is a copy version of an already<br />

authorized biological medicinal product with<br />

demonstrated similarity in physicochemical<br />

characteristics, efficacy and safety, based on<br />

a comprehensive comparability exercise.”<br />

Working Party on Similar Biological (Biosimilar) Medicinal Products (BMWP)<br />

of the Committee for Medicinal Products for Human Use (CHMP), EMA<br />

Martina Weise et al.<br />

Nature Biotechnology 29 (8) August 2011

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What are BioSimilars?<br />

Aspirin<br />

<strong>Biosimilars</strong><br />

Patent<br />

Enbrel Etanercept<br />

Expiry<br />

The same ?<br />

Merck & Co<br />

(Hanwha)<br />

Protalix<br />

Biotherapeutics<br />

Avesthagen<br />

Hospira<br />

(Celltrion)<br />

LG-LS<br />

Mycenax<br />

….<br />

� It is difficult to show similarity due to large and complex structure<br />

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What are <strong>Biosimilars</strong>?<br />

<strong>Biosimilars</strong><br />

similar ?<br />

How similar is similar ?<br />

The two are the similar if<br />

• They have a similar covalent structure<br />

• The similar folding<br />

• The similar mixture of isoforms<br />

• The same efficacy<br />

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Benefit on Early Detailed Characterization<br />

[…] a reduction in the data requirements is possible for biosimilars, the prelicensing<br />

data package is nevertheless substantial. Similarity in physicochemical<br />

characteristics is a prerequisite for a possible reduction in nonclinical and clinical<br />

data requirements.<br />

The amount of possible data reduction depends on how well the molecule can<br />

be characterized by state-of-the-art analytical methods, on observed or<br />

potential differences between the biosimilar and the reference product, and the<br />

clinical experience gained with the reference product and/or the substance class […].<br />

Working Party on Similar Biological (Biosimilar) Medicinal Products (BMWP)<br />

of the Committee for Medicinal Products for Human Use (CHMP), EMA<br />

Martina Weise et al.<br />

Nature Biotechnology 29 (8) August 2011

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Best Practice Comparability Study - Binocrit<br />

„Superimposable quality characteristics were demonstrated for a ‘biosimilar’ epoetin.“ [1]<br />

CZE<br />

MALDI<br />

IEF<br />

[1] Nature Biotechnology 29 (8) August 2011<br />

[2] EJHPPractice 15 2009/2; C Brockmeyer and A Seidel, Sandoz

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Case Study – Approval for Clinical Phase III<br />

Peptide map MS PTMs: Methionine oxidation<br />

Batch 1:<br />

Batch 2:<br />

Batch 3:<br />

Analytical principle: EIC (extracted ion chromatograms)<br />

*EIC: Extracted ion chromatogram<br />

M131ox M131<br />

M131ox / M131: ~equal<br />

M131ox / M131 : low / high<br />

M131ox: ~100%<br />

Batch to batch consistency needs to be improved<br />

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Evaluation of Comparability: Not a biosimilar !<br />

An IEF-Western blot analysis of EPO “Not a biosimilar” marketed around<br />

the world shows:<br />

From: Park SS et al, J Pharm Sci 2008, September 9<br />

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• Making it even a bit more complicated: The originators change too!<br />

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Evaluation of Comparability: Marketed Product<br />

A comparison of different pre- and post change batches of Rituxan/<br />

Mabthera shows:<br />

Schiestl et al., Nature Biotechnology, Vol 29, No 4 April 2011<br />

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Evaluation of Comparability: Marketed Product<br />

• How to handle the change of the quality profile of an originator during<br />

development of a biosimilar?<br />

Quality<br />

specifications<br />

Time<br />

Begin of<br />

Development<br />

Originator<br />

Safety and<br />

efficacy have<br />

to be similar<br />

Still similar? � Quality range for<br />

comparability<br />

Biosimilar<br />

Marketing<br />

Authorization<br />

Similar through<br />

lifecycle?<br />

Concept published by Mark Mc Camish and Gillian Woolett mABs 3:2, 209-217, March/April 2011 © Landes Bioscience<br />

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Questions for Discussion<br />

Structural Comparability<br />

• “How similar is similar ?” “Case by Case?”<br />

• FDA vs EMA Process – Harmonization – “Interchangeable” Discussion ?<br />

• CHO Genome public available and Product developments with e.g. glyco engineered Cell Lines<br />

How to achieve “Superimposable” Profile for these products?<br />

Economics<br />

• Dozens of Biosimilar candidates per blockbuster are on the way, while only few have reached clinical<br />

phase (EMA). Will similarity be an competitive advantage?<br />

• Will Biosimilar-Patents work out?<br />

• Will Asia play a similar role as in Generics ? Korea/India/China?<br />

(or When will it play this role?)<br />

Mindset<br />

Change from Innovation-Originator via Biobetter to Biosimilar in BigPharma !<br />

Need for Mindset change: “Biosimilar Development” differs from “NBE Development or Generics<br />

Development”. How can we speedup the process ?<br />

Regional<br />

• How can NRW position it self in the Biosimilar Landscape ?<br />

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Contact<br />

Protagen AG<br />

Otto-Hahn-Str. 15<br />

44227 Dortmund<br />

Germany<br />

T + 49 231 9742 6300<br />

F + 49 231 9742 6301<br />

info@protagen.de<br />

www.protagen.de<br />

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