Introduction: Biosimilar MAbs – The Challenges Ahead

Thomas Schreitmüller, Technical Regulatory Policy & Strategy BiologicsF. Hoffmann - La Roche Ltd. Basel, Switzerland

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Biological Products are Complex: Size

Biological Products are100–1,000 times larger than chemical pharmaceuticals

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Interferon‐alphaMolecular weight= 19,625 Daltons ~165 amino acids

Antibody (IgG) moleculeMolecular weight= 150,000 Daltons ~1,300 amino acids

Adapted from:M. Clarkavailable at: http://www‐immuno.path.cam.ac.uk/~mrc7/

AspirinMolecular weight = 180 Daltons

pyro-E O

D

GO

D

pyro-E • Pyroglutamyl peptidesD

D • Deamidation

O

O • Methionine oxidationG

• Glycation

Mab products are Complex: Process induced Modifications

33Adapted from: Steven Kozlowski; FDA

K

G

D

K

• C-terminal Lysine

D

G

• Glycation

• High mannose, G0, G1, G1, G2

• Sialylation

Modifications may result in approximately 108 potential variants

Antibodies have Different Mode of Actions

4Modified from: Hasmann, M. et al. (2009)

The in-vivo mode(s) of action are often incompletely understood and may differ between indications

• no endogenous counterparts of therapeutic mAbs safety concern not as serious as with e.g. rhEPO

• but immunogenicity issues with mAbs well known (anaphylaxis, seserum sickness, etc.), even for „fully human“ mAbs

• immunogenicity not only dependent on sequence

Immunogenicity is an Issue even with „fully human“ mAbs:

( humanization etc.) and glycosylation but potentially also on quality (e.g. aggregates) issue for biosimilars

• effect on efficacy to be discussed

• definition on „neutralizing Abs“ (anti-idiotypes only, or also Abs bindign to the Fc region which might inhibit immune effector functions ?)

The Pros and Cons for Biosimilar MAbs

Pro

• Structural characterization & manufacture well established

• Available potency assays

Con

• Every MAb is unique & small structural changes can have significant consequences

• Assays might not be able to discriminate differences

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• Function well established

• Safety profile well known

• Efficacy profile well established

• Functions are species specific which makes preclinical studies difficult

• Safety may differ with impurity profile

• Efficacy might not be transferable

Schneider CK, & Kalinke U. Nature Biotechnology 2008; 26: 985–990

Significant changes in originator mAbs - the MabThera®/Rituxan® case

Monitoring batches of MabThera® and Rituxan® revealed a shift in glycosylation profile and ADCC potency Manufacturing changes have not led to any differences in off target toxicity - even when Fc functions were markedly changed

0,0

0,4

0,8

1,2

1,6

2,0

08.2007 12.2008 05.2010 09.2011

Expiry Date

Unfucosylated G0[% of glycans]

60

80

100

120

140

08.2007 12.2008 05.2010 09.2011

Expiry Date

ADCC Potency[% of reference]

Post-Shift

Pre-Shift

Pre-Shift

Post-Shift

Schiestl, M. et al., Nature Biotechnology 29, 310-312, 2011)

The Race is on

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Some Thoughts:Similarity versus Comparability

• A ‘comparability’ assessment is dependant on an established manufacturing history related to preclinical and clinical experience. It applies only to biological products produced by one manufacturer

• ‘Similarity’ assessments refer to robust comparative quality-, preclinical- and clinical testing of a biological product produced by a distinct, independent manufacturingprocess establishing similarity to the originators reference biological product.

• The approach to establish similarity of a MAb copy should build upon the principles used for simpler proteins:

– Identical amino acid sequence and high similarity with regard to chemical, physical and biological characteristics should first be demonstrated in laboratory/non-clinical testing

– Clinical similarity may then be tested head-to-head– Extrapolation across endpoints, populations or diseases may be justified scientifically

Some Thoughts:Monoclonal Antibody Biosimilars Testing - General principles

Fc: effect or functions• Target cell killing• Immune activation• C’ activation• Half-life

CDR: Ligand-binding

• However, application of those principles should take into account particular properties of MAbs:– MAbs are large, structurally and fuctionally

complex proteins– Multiple features determine clinical activities– Different activities may depend on different

features – MAbs are generally used to treat serious and/or

life-threatening diseases

Adopted from EMA MAb Workshop Jul2009

Some Thoughts:Establishing a Basis to Extrapolate Benefit/Risk

• Strong CMC and non-clinical data limiting potential differences are critical– For complex molecules such as monoclonal antibodies, there will always

be differences

• Extensive high quality in vitro biological characterization studies are needed

• I i f t l ti ll d d i FIM t di• In vivo safety evaluation generally needed prior FIM studies

• Clinical head-to-head trials are necessary• Endpoints should be clinically sensitive and relevant• Generally the goal should be to demonstrate equivalence of efficacy, with margins based on science, data and clinical setting

• Transparency with regards to source and kind of pivotal data in labeling of the biosimilar MAb

Adopted from EBE – EMA MAb Workshop 24OCT2011

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l1 it was suggested to delete this last sentencelikan01, 10/18/2011

l2 added consistent with abbott's comments; for discussionlikan01, 10/18/2011

• With respect to transparency for all stakeholders as well as efficiency in biosimilar Mab development product specific guidelines may add value.

• The content could be:– Requirements for analytic assessments including effector function testing (taking into consideration MoA and

safety relevant functionalities)

Some Thoughts:Are Product specific Guidelines helpful? What to include?

– PK or PK/PD requirements specific to distinct indicated populations and molecular class– Guidance on immunogenicity studies in populations expected to exhibit different propensities for ADA

formation– Specific requirements for clinical trials to demonstate similar efficacy and safety

Adopted from EBE – EMA MAb Workshop 24OCT2011

Thank You !

WS Session Two: Biosimilar Monoclonal Antibodies and Beyond

14:00 – 14:15 Introduction: Biosimilar mAbs – The Challenges Ahead Thomas Schreitmüller, F. Hoffman – La Roche Ltd., Basel, Switzerland 14:15 – 14:40 The EU Guideline for Biosimilar Monoclonal Antibodies

Steffen Gross, Paul-Ehrlich-Institut, Langen, Germany 14:40 – 15:05 Case Studies for Biosimilar mAb Development – CMC Elements

Thomas Stangler, Sandoz, Kundl, Austria 15:05 – 15:30 Preclinical and Clinical Considerations for Biosimilar mAbs, including

Interchangeability Frank Scappoticci, Genentech, a Member of the Roche Group, South San

Francisco, CA USA

16:00 – 17:30 PANEL DISCUSSION – Questions and Answers Steffen Gross, Paul-Ehrlich-Institut, Germany Kimberly May, Merck, USA Peter Richardson, European Medicines Agency, United Kingdom Anthony Ridgway, Health Canada, Canada Frank Scappoticci, Genentech, a Member of the Roche Group, USA Emily Shacter, CDER, FDA, USA Thomas Stangler, Sandoz, Austria