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Public PLANNING FOR SUCCESS: A CMC STRATEGY FOR BIOSIMILARS Louise Angell Lead Scientist 10th Biosimilars & Follow-On Biologics Congregation 9 th May 2017 Copyright @ 2017 Covance. All rights Reserved

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    PLANNING FOR SUCCESS: A CMC STRATEGY FOR BIOSIMILARS

    Louise Angell Lead Scientist 10th Biosimilars & Follow-On Biologics Congregation 9th May 2017

    Copyright @ 2017 Covance. All rights Reserved

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    Overview

    Covance history with Biosimilars Importance of CMC What is required for successful Biosimilar development? Building a CMC Biosimilar strategy How to de-risk a Biosimilar drug development program (case study)

    Planning for Success: A CMC Strategy - London - May 2017

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    Animal studies Toxicology PK/PD

    Phase I / Phase III PK/PD Immunogenicity Efficacy (Similarity)

    Pharmacovigilance Patient reported outcomes

    Regulatory Strategy

    BioA: PK and Immunogenicity (ADA, NAb)

    Biomarkers

    Consultancy Value communications

    Input into clinical endpoints Policy re-imbursement advice

    CMA

    CMC

    Preclinical

    Clinical

    BioA

    Regulatory

    Structural and

    functional testing Continuous testing

    multiple batches Stability

    Batch release testing

    CMC: Analytical characterisation

    Covance History with Biosimilars

    Pre-clinical Phase I Clinical

    Phase III Clinical

    Pre-registration Market

    CCLS

    3 Planning for Success: A CMC Strategy - London - May 2017

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    Importance of CMC Pre-clinical phase Clinical phase

    Analytic (physiochemical, structural and bioanalytical) In vitro functional (binding)

    In vivo functional PK/PD (animal)

    Toxicology

    PK Efficacy Safety

    PK = Pharmacokinetics PD = Pharmacodynamics

    Amount of CMC data required

    Novel biologic development

    program

    Biosimilar development program timeline

    Science driven; end in mind; Extensive innovator characterisation to minimize downstream risk

    4 Planning for Success: A CMC Strategy - London - May 2017

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    Our history with Biosimilars Importance of CMC What is required for successful Biosimilar development? Building a CMC Biosimilar strategy How to de-risk a Biosimilar drug development program (case study)

    Planning for Success: A CMC Strategy - London - May 2017

    Overview

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    Know the Target Product Profile (TPP)

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    Indications and Usage Dosage and Administration Dosage Forms and Strengths Contraindications Warnings and Precautions Adverse Reactions Drug Interactions Use in Specific Populations Drug Abuse and Dependence Overdosage Description Clinical Pharmacology Nonclinical Toxicology Clinical Studies References How supplied, Storage and Handling Patient Counselling Information

    Safety, efficacy and quality of Innovator and Biosimilar must have no meaningful clinical difference

    Image approved for use at Covance

    Planning for Success: A CMC Strategy - London - May 2017

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    Understand Mechanism of Action (MOA)

    Understanding MOA of product, and the clinical relevance of any observed structural differences, enables the design of an initial control strategy to monitor and control residual risk Confirmation of identical amino acid sequence Assessment of post-translational modifications

    including glycosylation (high mannose, afucosylation)

    Product degradation (denature/ aggregation/ oxidation or deamidation)

    Product related impurities, sequence variants Process related impurities eg Host Cell Protein

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    Image approved for use at Covance

    Planning for Success: A CMC Strategy - London - May 2017

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    Identify and Control Critical Quality Attributes (CQA)

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    Analytical and Manufacturing Controls

    Assess and control risk

    TPP

    MOA CQA

    BIOSIMILARS DO NOT GET MORE SIMILAR DURING THE DRUG DEVELOPMENT PROCESS

    Planning for Success: A CMC Strategy - London - May 2017

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    Our history with Biosimilars Importance of CMC What is required for successful Biosimilar development? Building a CMC Biosimilar strategy How to de-risk a Biosimilar drug development program (case study)

    Planning for Success: A CMC Strategy - London - May 2017

    Overview

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    Covance Biosimilar Strategy

    Assess Target Product Profile Determine Mechanism of Action Define Critical Quality Attributes Obtain Innovator Product and develop methods to support CQA

    6-12

    mon

    ths

    Pre-clinical phase Clinical phase

    Amount of CMC data required

    Planning for Success: A CMC Strategy - London - May 2017

    Continual Biosimilarity Assessment

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    Analytical Master File

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    Innovator 3

    Covance has developed Analytical Master Files

    Scientific rationale using TPP, MOA to justify CQA selection

    Portfolio of Developed Methods

    Extensive early characterization of Innovator

    Risk-minimized, accelerated development approach

    INNOVATOR SPECIFIC CMC ANALYTICAL SOLUTION MASTER

    FILE

    Planning for Success: A CMC Strategy - London - May 2017

    Image approved for use at Covance

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    Our history with Biosimilars Importance of CMC What is required for successful Biosimilar development? Building a CMC Biosimilar strategy How to de-risk a Biosimilar drug development program (case study)

    Planning for Success: A CMC Strategy - London - May 2017

    Overview

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    Herceptin Mechanism of Action Her2 Binding and ADCC via FcRIII

    *Shields, RL et al, J Biol Chem 2002; 277: 26733-40

    Herceptin binds to HER2 receptor on target cell surface, and inhibits cell proliferation by blocking receptor dimerisation and hence downsteam signaling

    NK cell binding to Herceptin Fc via FcRIII triggers degranulation and cell death

    Lack of Fucose on Human IgG1 N-Linked oligosaccharide improves Binding to Human FcRIII and Antibody-dependent Cellular Cytotoxicity (ADCC)*

    Quantification of % core glycan afucosylation (and % glycan occupancy and high mannose levels)

    Covance Image

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    Planning for Success: A CMC Strategy - London - May 2017

    Herceptin Is a registered trademark of Genentech Inc

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    Case Study: A Biosimilar Solution

    A biotechnology company Developed a Herceptin Biosimilar Ready to progress into clinical phase Structural characterisation and pre-clinical

    assessment complete, with no significant difference from the innovator identified

    Unexpected observation; limited in vitro ADCC activity

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    CLIENT THE CHALLENGES

    Early in Biosimilar development phase

    Link structure to function

    Extensive structural characterisation

    CQA

    RISK BASED CMC STRATEGY

    Client Biosimilar did not demonstrate the expected biological activity

    Client unable to progress to clinical studies

    18 month addition to Biosimilar development program

    Image approved for use at Covance Herceptin Is a registered trademark of Genentech Inc

    Planning for Success: A CMC Strategy - London - May 2017

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    Understanding Critical Quality Attributes

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    Planning for Success: A CMC Strategy - London - May 2017

    Attribute CQA Method

    Identity Intact mass LC-MS

    Identity Amino Acid Sequence Peptide map by LC-MS

    Identity Glycosylation LC-MS

    2 and 3 structure Di-sulphide bonding LC-MS

    Purity Monomer, HMWs SE-HPLC

    Purity Deamidation Peptide map

    Purity Methionine Oxidation Peptide map

    Purity Charge Distribution iCE

    Potency Concentration UV-A280

    Potency Fc Effector function Biacore

    Potency Fab binding Cell based Bioassay

    Potency ADCC Cell based Bioassay

    Image approved for use at Covance

    Data: Covance

    Sheet1

    AttributeCQAMethodState of Art TechnologyOrthoganol

    IdentityIntact massLC-MSUPLC-UV-QTOF

    IdentityAmino Acid SequencePeptide map by LC-MSUPLC-UV/FLR-QTOF Tryptic Peptide map with UPLC,Edman sequencing

    IdentityGlycosylationLC-MSUPLC-FLR-QTOF N-Glycan detection by MALDI-MS

    2 and 3 structureDi-sulphide bondingLC-MSCD

    PurityMonomer, HMWsSE-HPLCHPLC/UPLC

    PurityDeamidationPeptide map

    PurityMethionine OxidationPeptide map

    PurityCharge DistributioniCE

    PotencyConcentrationUV-A280

    PotencyFc Effector functionBiacore

    PotencyFab bindingCell based BioassayBiacore

    PotencyADCCCell based Bioassay-

    Sheet2

    Sheet3

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    Proliferation Inhibition Assay

    BT474 - Her2 receptor expressing breast cancer cell line

    BT474 assay measures Fab binding to Her2

    Herceptin serially diluted and added to BT474 cells

    Herceptin Binds Her2 receptor and inhibits proliferation of cells

    Measured as a function of adenosine triphoshate (ATP) concentration (via luciferase luminescence)

    Relative Potency (Biological Activity) is calculated against a known standard

    BT474 Cells

    Data: Covance

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    Planning for Success: A CMC Strategy - London - May 2017

    Herceptin Is a registered trademark of Genentech Inc

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    x axis

    10 100 1000 100005.8e6

    6.8e6

    7.8e6

    8.8e6

    9.8e6

    1.08e7

    1.18e7

    Graph#2

    4-P Fit: y = (A - D)/( 1 + (x/C)^B ) + D: A B C D Rel. Pot.Plot#1 (EU-Her: Concentration vs MeanValue) 1.2e+07 2.07 387 6.36e+06 1Plot#2 (US_Her: Concentration vs MeanValue) 1.2e+07 2.07 371 6.36e+06 1.04Plot#3 (TRS0020: Concentration vs MeanValue) 1.2e+07 2.07 384 6.36e+06 1.01

    __________Curve Fit Option - Fixed Weight ValuePLA (Std. Curve: Plot#1) Degrees of Freedom: parallel = 24 free = 18 non-parallel = 6R^2 = 0.991 F-stat = 0.618 F-prob = 0.97

    Relative Potency Assessment by Proliferation Inhibition

    Shows that the biological activity (binding to Her2) was the same for each product; within 70 130% criteria

    Research grade Trastuzumab

    EU Herceptin

    Log mAb Concentration (ng/mL)

    Rel

    ativ

    e Lu

    min

    esce

    nce

    Uni

    ts

    US Herceptin

    Data: Covance

    Sample Mean Relative Potency, % (versus EU Innovator control)

    US Innovator 100 RG Trastuzumab 90

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    Planning for Success: A CMC Strategy - London - May 2017

    Herceptin Is a registered trademark of Genentech Inc

    Data: Covance

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    Antibody Dependent Cell Cytotoxicity (ADCC) Assessment

    Herceptin serially diluted and added to SKBR3 cells (which express Her2) and NK cells (enriched from PBMCs)

    Herceptin binds Her2 receptor on SKBR3 cells (Fab) and FcRIII on NK cells (Fc)

    NK cells release cytokines to lyse SKBR3 cells

    Relative Potency (Biological Activity) is calculated against a known standard

    Measure release of Lactate Dehydrogenase (LDH) as function of cell lysis

    SKBR 3 Cells

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    Planning for Success: A CMC Strategy - London - May 2017

    Herceptin Is a registered trademark of Genentech Inc

    Data: Covance

    Data: Covance

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    Relative Potency Assessment by ADCC

    RG Trastuzumab significantly less potent in terms of ADCC function

    Consistent with the MS based structural characterisation and differences in afucosylation level

    Research grade Trastuzumab with less core glycan afucosylation

    Herceptin EU and US

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    Planning for Success: A CMC Strategy - London - May 2017

    Herceptin Is a registered trademark of Genentech Inc

    Data: Covance

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    Typical Fc-glycans of humanized IgG biopharmaceuticals

    G0

    G0F

    Man5

    G2F

    G1

    G1F

    G2FS1

    G2FS2

    Galactose Sialic acid

    N-Acetylglucosamine (GlcNAc) Mannose Fucose

    G2

    Absence of the N-glycan core-fucose (afucosylation) can result in increased binding affinity of antibodies to FcRIII and enhance ADCC

    Covance image

    Covance Image

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    Planning for Success: A CMC Strategy - London - May 2017

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    Intact Mass Herceptin Mass Spectra [M+52H]52+

    USA Herceptin

    Research Grade Innovator

    EU Herceptin

    Protein ion current is shared between multiple charge states, [M+nH]n+ (typical of electrospray ionisation)

    Glycan profile is defined at each charge state

    C H 3

    C H 3

    C

    H 2

    C H 2

    C C

    C C

    N N

    N N

    Covance Image

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    Planning for Success: A CMC Strategy - London - May 2017

    Herceptin Is a registered trademark of Genentech Inc

    All data: Covance

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    Intact Mass Herceptin Deconvoluted MS data (MaxEnt1)

    USA Herceptin

    G0/G0F

    2G0F G0F/G1F

    2G1F & G0F/G2F

    G1F/G2F

    2G2F

    Deconvolution converts MS data to a zero charge mass scale (Da)

    Permits characterisation and comparison of glycan profiles (pairing of glycosylated heavy chains)

    Mass accuracy in 150 kDa range typically within 60 ppm

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    Planning for Success: A CMC Strategy - London - May 2017

    Sample Mean Relative

    Potency % (versus EU Innovator)

    N-Glycan Core Afucosylation % (excl. high mannose)

    EU Herceptin N/A 14.7 (10.4) US Herceptin 94 10.2 (8.15)

    RG Trastuzumab 45 4.35 (2.55)

    Herceptin Is a registered trademark of Genentech Inc

    Data: Covance

    Data: Covance

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    Summary slide

    Successful Biosimilar

    Development

    TPP

    MoA

    CQA

    Control

    Characterise and compare

    molecules

    Understand structural effects on biological

    activity

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    Apply early and robust CMC testing to maximise success of a biosimilar development program

    A better understanding of the product leads to a higher predictability of the outcome

    Planning for Success: A CMC Strategy - London - May 2017

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    About Us Covance Inc., headquartered in Princeton, NJ, USA, is the drug development business of Laboratory Corporation of America Holdings (LabCorp). COVANCE is a registered trademark and the marketing name for Covance Inc. and its subsidiaries around the world

    Planning for Success: A CMC Strategy - London - May 2017

    PLANNING FOR SUCCESS: A CMC STRATEGY FOR BIOSIMILARSOverviewSlide Number 3Importance of CMCOverviewKnow the Target Product Profile (TPP)Understand Mechanism of Action (MOA)Identify and Control Critical Quality Attributes (CQA)OverviewCovance Biosimilar StrategyAnalytical Master FileOverviewSlide Number 13Case Study: A Biosimilar Solution Understanding Critical Quality AttributesSlide Number 16Slide Number 17Antibody Dependent Cell Cytotoxicity (ADCC) AssessmentRelative Potency Assessment by ADCCTypical Fc-glycans of humanized IgG biopharmaceuticalsSlide Number 21Intact Mass HerceptinDeconvoluted MS data (MaxEnt1)Summary slideSlide Number 24