Towards biosimilar monoclonal antibodies Pros and cons

EMEA Workshop on Biosimilar Monoclonal Antibodies Christian K Schneider, MD BMWP Chairman European Medicines Agency (EMEA), UK Paul-Ehrlich-Institut, Germany Can more complex biologicals be biosimilars?

In principle, the concept of “similar biological medicinal products” applies to any biological medicine. Guideline CPMP/BWP/437/04

How much do we need to know? www.lucky-lions.com

Idea: C. Nick How much „similarity“ do we need? Christian K Schneider 2 Why „biosimilar“ (and not „biogeneric“)?

Aspirin 180 Daltons

Insulin 5 700 Daltons

MAb 150 000 Daltons

Christian K Schneider Source: Cecil Nick, Parexel 3 Why „biosimilar“ (and not „biogeneric“)?

“The process is the product. “

- Fluctuations in the manufacturing process Batch inconsistency (e.g., pH, temperature, culture media): (glycosylation spectra, aggregates)

- Changes in the manufacturing process New product? (e.g., expression system):

• „One process – one product“ paradigm

Biotechnological medicinal products are „individuals“

Biotechnological medicinal products are more than the drug substance

Small changes can have high impact

Christian K Schneider 4 Terminology that matters

Pieter Bruegel der Ältere (1525/1530-1569) Cave terminology! The Tower of Babel, 1563 » Biosimilar mAb – Similarity of active substance – Aim is to establish similarity to licensed product – Same indications (but not necessarily all)

» 2nd generation mAb – Different active substance (Humira® is not a biosimilar to Remicade®!) – Stand-alone development, might however be comparative – Can be different indications – (would these be the „follow-on“ biologicals?)

Christian K Schneider 5 Monoclonal antibodies – a success story

Reichert J et al: successes in the clinic. Nature Biotechnol.23(9): 1073 (2005) Christian K Schneider 6 Evolution of monoclonal antibodies

= murine Evolution of monoclonal antibodies („-mab“): = human

New constructs - bispecific antibodies - diabodies - single chain fragments - engineered Fc mAbs - conjugated mAbs - ... Murine mAb Chimaeric mAb Humanized mAb Fully Human mAb

„-omab“ „-iximab“ „-zumab“ „-umab“

Arcitumomab (CEA-Scan®) (Remicade®) (Herceptin®) (Humira®) (1996) (1999) (2000) (2003)

Immunogenicity

Christian K Schneider 7 We have experience!

Christian K Schneider Reichert J et al: Monoclonal antibody successes in the clinic. Nature Biotechnol.23(9): 1073 (2005) 8 Non-clinical testing: A question of relevance Central aspect: biotechnological products are species-specific.

A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies)*.

*NfG on preclinical safety evaluation of biotechnology derived pharmaceuticals (CPMP/ICH/302/95; ICH S6)

Relevant species for licensed mAbs described Christian K Schneider 9 Potency assays are available

Product Specificity Potency assay Comments Avastin Anti-VEGF anti-proliferation bioassay Assay chosen as drug () (inhibition of rhVEGF-induced substance release test proliferation of Human Umbilical based on its sensitivity Vein Endotheliae Cells (ability to detect significant HUVEC). changes in the activity), robustness, precision (relative number of viable cells, (RSD<10%) and accuracy quantified by fluorescence) (98-102%) Simulect Anti-CD25 Inhibition of binding of (Basiliximab) radiolabelled IL-2 to IL-2 receptor expressed on T- lymphocytes (and thus inhibition of lymphocyte proliferation)

Synagis Anti-RSV In vitro: RSV Comparison of different (Palivizumab) Microneutralisation Assay, RSV predecessor products with Fusion Inhibition Assay, palivizumab during BIAcore Analysis development In vivo potency: Reduction of RSV titre in the lungs of infected cotton rats Tysabri Anti-α4-integrin In vitro assay: Ability to bind (Natalizumab) α4-integrins and block its interaction with its co-receptor.

Xolair Anti-IgE Inhibition of binding: Ability of Shown to correlate to the (Omalizumab) omalizumab to inhibit binding of inhibition of release of IgE to its receptor histamine

Christian K Schneider http://www.emea.europa.eu/htms/human/epar/eparintro.htm 10 Current methodology: Increasing sensitivity

O Physicochemical characterisation, e.g. » Capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) » Mass spectrometry techniques (e.g., MALDI-TOF) » Nuclear magnetic resonance O Antigen-antibody interaction, e.g. » Surface plasmon resonance O Secondary structure detection, e.g. » Circular dichroism in near- and far-UV spectra O Combination of methodologies, e.g. » liquid chromatography combined with mass spectrometry (e.g. Beck, A. et al, J Chromatogr B Analyt Technol Biomed Life Sci. 819(2): 203-218 (2005))

Christian K Schneider 11 Licensed mAbs: Efficacy and safety

O For example: Remicade® (Infliximab) (anti-TNFα)

O Licensed indications: » Rheumatoid arthritis » Adult Crohn‘s disease » Paediatric Crohn‘s disease » Ulcerative colitis » Ankylosing spondylitis » Psoriatic arthritis » Psoriasis

http://www.emea.europa.eu/humandocs/Humans/EPAR/remicade/remicade.htm Christian K Schneider 12 Licensed mAbs: Efficacy and safety

O For example: Moderate to severe psoriasis

Before treatment After treatment

http://www.emea.europa.eu/humandocs/Humans/EPAR/remicade/remicade.htm Christian K Schneider 13 Licensed mAbs: Efficacy and safety

O Safety data in 2005:

– TREAT-Registry (only patients with Crohn‘s disease) (Crohn’s Therapy Resource Evaluation and Assessment Tool registry) O 6290 patients, 3235 of them treated with Remicade O Ca. 25.000 Infusions

– Cumulative safety data (August 1998 – August 2004): O 1.350.000 Patient years O 576.000 Patients

http://www.emea.europa.eu/humandocs/PDFs/EPAR/Remicade/EMEA-H-240-II-69-AR.pdf Christian K Schneider 14 Toward biosimilar mAbs

…and Con‘s

Christian K Schneider 15 Complexity of monoclonal antibodies

Carter PJ: Potent antibody therapeutics by design, Nature Rev Immunol 6, 343 (2006) Christian K Schneider 16 Glycosylation of mAbs

Christian K Schneider 17 Glycosylation

Christian K Schneider 18 Complexity of monoclonal antibodies

Typical antibody manufacturing process

“ t. c u d ro p e th is s s e c ro p e h “T

Carson KL. Flexibility – The guiding principle for antibody manufacturing. Christian K Schneider Nature Biotechnol 23(9): 1054 (2005) 19 Current methodology: Increasing sensitivity ? O h Physicochemical characterisation, e.g.g » Capillary electrophoresis with laser-inducedu fluorescence detection (CE-LIF) o en » Mass spectrometry techniquese (e.g., MALDI-TOF) » Nuclear magnetic resonanceiv it O Antigen-antibody interaction,s e.g. n » Surface plasmons resonancee O Secondary structure detection, e.g. se » Circular dichroisme in near- and far-UV spectra th O Combinatione of methodologies, e.g. » liquidr chromatography combined with mass spectrometry (e.g. Beck,A A. et al, J Chromatogr B Analyt Technol Biomed Life Sci. 819(2): 203-218 (2005))

Christian K Schneider 20 Biosimilar mAbs: Signs or fiction?

Are obviously approaching?!

Christian K Schneider 21 EMEA Workshop

O Philosophy: Open discussion on pros and cons of biosimilar mAbs O Possibility and feasibility O No conclusion (yet)… …but scientific evolution O Questions as a starting point O Focussed presentations, not meant to be exhaustive, but to initiate discussions. O If issues come up that are important, but do not fit to the topic of session: Move to end of workshop (where there should be time)

Christian K Schneider 22 The floor is yours!

Christian K Schneider 23