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Thomas Fuerst, Ph.D.

Director

2014 Biomanufacturing

Technology Summit

June 13, 2014

IBBR

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IBBR: Mission and Objectives

IBBR’s Mission: To conduct groundbreaking biomolecular and measurement

science research to generate innovative technologies and

solutions for medical and public health applications. IBBR is

committed to providing an exceptional environment for

specialized training and to mentoring tomorrow's biotechnology

workforce.

IBBR’s Research Focus Areas:

• Measurement Sciences

• Disease Pathways and BiomolecularTargets

• Biomolecular Engineering

• Structural Vaccinology

• Next Generation Protein Therapeutics

• Bio-sensors and Diagnostic Tools

IndustryPartnerships

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Biologics Pipeline - US and EU

Reference = 133

Biosimilars = 588

Biobetters = 434

• biosimilars = 588

• biobetters = 434

• total pipeline products (biosimilars + biobetters) = 1022

• ref. products = 133

• total product entries = 1155

Reference: BioPharma 4/14

Note, this study only covers recombinant proteins and a few

other protein products. Vaccines, blood-derived, cultured cells and tissues and other types of biologics are not included!

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Top 10 Major Biosimilars and Biobetters Currently Under Development

Product/Type Main categoryManufacturing

PlatformMechanism/Target

Sales

(US$billions)Biosimilars Biobetters

Humira

adalimumab

Anti-

inflammatoryCHO inhibits TNF-α $9.27 13 7

Remicade

infliximab

Anti-

inflammatoryMurine Myeloma inhibits TNF-α $8.90 9 9

Enbrel

etanercept

Anti-

inflammatoryCHO

inhibits TNF-α$7.87 21 8

Rituxan

rituximab

Anti-cancer CHO

targets

phosphoprotein

CD20 on B

lymphocytes

$7.29 30 17

Herceptin

trastuzumab

Anti-cancer CHOtargets the

HER2/neu (erbB2)

receptor

$6.40 24 12

Lantus

insulin glargineAnti-diabetic E.coli

absorption of

insulin$6.40 5 2

Avastin

bevacizumab

Anti-cancerCHO inhibits VEGF $6.26 14 9

Neulasta

pegfilgrastimNeutropenia E.coli

stimulates

neutrophils $4.10 14 9

Epogen/Procrit

epoetin alfaTreat anemia CHO

stimulates

erythropoiesis $3.73 69 26

Lucentis

ranibizumab

Anti-

angiogenicE.coli inhibits VEGF-A $3.72 2 2

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FDA Requirements for Biosimilars

A sponsor should include:

Structural analysis: Using state-of-the-art technology display primary and higher order

structures, post-translational modifications, and chemical modifications.

Functional assays: Appropriate studies including: bioassays, biological assays, binding

assays and enzyme kinetics. The functional assays performed should be comparative “so

they can provide evidence of similarity, or reveal differences...”

Animal data: Include toxicity studies, PK/PD measurements, and immunogenicity studies.

Human clinical studies: Include PK/PD measurements, immunogenicity results, safety and

efficacy data. Studies should demonstrate that the proposed product has neither decreased

nor increased activity compared to the reference product.

References: FDA Guidance for Industry; Scientific Considerations in demonstrating Biosimilarity to a Reference Product. Feb 2012 Amgen; Biologics and Biosimilars An Overview

Physicochemical Biophysical Bioassay

Correlate Structure/Function

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• EPO is a cytokine (34kDa) used to treat anemia in a

variety of conditions.

• Variations in the manufacturing process of EPO

biosimilars have been linked to serious side

effects in patients.

• EPO is highly glycosylated and sialylated, ~40% of total MW.

o Can affect stability, PK, PD, and immunogenic properties.

o Can cause issues with immunogenicity and comparability.

o Has been found to affect potency.

• There are 69 biosimilars currently in development for EPO.

Erythropoietin (EPO) Manufacturing Challenges due to Post Translational Modifications

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A Case Study: Comparison of Content and Potency of the Four EPO Products

• Eprex (RP), Dynepo (RP), Binocrit (Biosimilar), and Retacrit (Biosimilar)

were found to differ in content, isoform profiles and potency.

• Using a validated mouse assay, the potency of the four EPO products

was assessed in vivo.

o Binocrit and Retacrit had a slightly higher potency than declared on

the package.

o The potency of Eprex was higher than label claim (129%), whereas

the potency of Dynepo was lower than label claim (78%).

• Both SEC and ELISA data showed approximately two-fold higher protein

concentrations in Dynepo compared to the other products, suggesting

that low potency of Dynepo was due to lower specific activity.

Vera Brinks & Andrea Hawe & Abdul H. H. Basmeleh & Liliana Joachin-Rodriguez & Rob Haselberg & Govert W. Somsen & Wim Jiskoot & Huub Schellekens. Quality of Original and Biosimilar Epoetin Products. Pharm Res (2011) 28:386–393

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Vera Brinks & Andrea Hawe & Abdul H. H. Basmeleh & Liliana Joachin-Rodriguez & Rob Haselberg & Govert W. Somsen & Wim Jiskoot & Huub Schellekens. Quality of Original and Biosimilar Epoetin Products. Pharm Res (2011) 28:386–393

(Reference Product)

(Reference Product)

(Biosimilar)

(Biosimilar)

A Case Study: Isoform Distribution of Four EPO Products

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Correlation Gaps in Structure/Function Assays

Physicochemical Biophysical Bioassay• Generally

qualitative or can be made quantitative

• Highly accurate/precise

• Tight release specifications

• Generally low accuracy/precision

• Generally wide release specifications

1. What is relative weight of analytics vs. bioassays in predicting clinical outcomes?

• In some cases, can measure differences in analytics but not in the corresponding bioassay.

• In other cases, see no differences in analytics but differences in bioassays.

• In yet other cases, clinical outcomes are unrelated to analytics or bioassays.

2. How can we measure physicochemical attributes in situ/in vivo (e.g., protein interacts with or modifies the drug in bloodstream, immune response)?

How can we do this faster, better, and less expensive to lower health care costs while improving/maintaining safety and consistent clinical outcomes?