Non-Confidential1

Challenges and Strategiesin

Biosimilar Product DevelopmentThe 2nd Biologics & Biosimilars Congress, Berlin, Germany, Feb 1-2, 201

Suman T. Patel, PhD

VP, Manufacturing & Quality, Epirus Biopharmaceuticals Inc

Boston, USA

Non-Confidential2

$90B+ of Biologics Will Lose Patent Protection by 2025 with 50% of Opportunity ex-US

Source: EvaluatePharma based on data pulled November, 2015Sales for Epogen and Neupogen based on actual 2012 sales; All other products based on 2018 or 2020 forecasted sales

2008 2013 2020 2025

$3B+ $65B+ $26B+

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EPIRUS Biosimilar Development

Our vision at EPIRUS:

– To build a sustainable, profitable, pure-play biosimilar business to improve patient access to important, cost-effective medicines worldwide

– To advance our pipeline through strategic partnerships

Targeted pipeline of autoimmune or rare disease therapies, including BOW015 (infliximab), BOW050 (adalimumab), BOW070 (tocilizumab), BOW080 (eculizumab) BOW090(ustekinumab) and BOW100 (golimumab)

Our goal is to advance trial science as well as to demonstrate biosimilarity

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Focused Biosimilar Pipeline Targeting ~$30B in Reference Product Sales

*BOW015 launched in its first market in collaboration with Sun Pharma under the trade name Infimab™ in India; additional near-term filings targeted for select accessible markets; Remicade is a registered trademark of Johnson and Johnson; Humira is a registered trademark of AbbVie; Actemra is a registered trademark of Chugai Seiyaku Kabushiki Kaisha Corp., a member of the Roche Group; Stelara is owned and marketed by Centocor Ortho Biotech Inc, a wholly owned subsidiary of Johnson & Johnson; Simponi is marketed by Janssen Biotech Inc; Solir is is a registered trademark of Alexion Pharmaceuticals, Inc.

Comparability

~18 Mo

Pre-Clinical

~6 Mo

Clinical

~18 Mo

Anticipated

FilingCandidate

Originator (Sponsor, Expiry1, Est. Opp2)

BOW015

Infliximab

AccessibleMarkets*

Remicade®

(Janssen, EU: 2015, US: 2018, $2.1–$3.2B)BOW015

Infliximab

Global

BOW050

Adalimumab

Global

Humira®

(AbbVie, US: 2016, EU: 2018, $3.8–$5.8B)

BOW070

Tocilizumab

Global

Actemra®

(Roche, 2019, $0.5–$0.7B)

BOW090

Ustekinumab

Global

Stelara®

(Janssen, US: 2023, EU: 2024, $0.8–$1.3B)

BOW100

Golimumab

Global

Simponi®

(Janssen, 2024, $0.8–$1.2B)

BOW080

Eculizumab

Global

Soliris®

(Alexion, EU: 2020;US: 2021, $1.3–$2.0B)

Comparability / CTA Global

Comparability / CTA Global

Comparability Global

Filings*

*Launched in first market in Nov ’14

Rare

D

ise

as

eA

uto

imm

un

e

2020

Global

Global

2015

2017

2018

2019

2021

2022

1. Ark Patent Intelligence and other public databases 2. Assumes 40% price discount, 40-60% biosimilar penetration

Global

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Biologics are Larger & More Complex Than

Small Molecules in Structure and Process

Small molecule

Lipitor®

atorvastatin

560 g/mol

1X

55

Isolate and identify the genetic

code of the protein.

Genetic code is inserted into

living cells.

Cells are carefully selected

and cultured.

Protein is isolated through a

sequence of purification processes.

The protein is packaged, after

ensuring sterility and stability, for

use by doctors and patients.

(Not to scale)Structure

Protein

Epogen®

epoetin alfa

18,396.1 g/mol

>30X

Glycoprotein

HUMIRA®

adalimumab

144,190 g/mol

>250X

Process

1

2

3

4

5

Lipitor, Epogen and Humira are registered trademarks of Pfizer, Amgen and Abbvie respectively

Non-Confidential6

Development of Biosimilars

Different Than New Chemical Entities

Example Hurdles – NMEs

Endpoint selection

Patient recruitment

Scale validation

Efficacy in representative population

Superior to competitor

In Vitro

Value

TimePreclinical P1 P2 P3 Approval

NME

Physicochemical

characterization at cell line

selection and at final

process lock down is where

the game is won or lost

Phase 1 data confirms

biosimilarity and

success at 90%

Phase 3 data follows biosimilar

characterization and Phase 1

bioequivalence

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Biosimilar Product Development Challenges &

Strategies

7

Biosimilar

Product

Development

Physico-Chemical/

Biochemical

Similarity

Biological

Similarity

IP Landscape

Innovator’s

Life Cycle Management

Strategies

COGsPD Platforms

Manufacturing/Supply

RegulationsProduct Design

Specification

Guide

Development Strategy/Plan/Execution

Product Qualification

(Similarity Assessment)

Totality of Evidence

Target Product Profile

Non-Confidential8

Stepwise Approach for Biosimilar Development

Complements Known Product Attributes

Adapted from Partha Roy, ACR 2015

Quality

Preclinical/PK

Clinical

Known Attributes

Needed Information

Cross reference

Cross reference

Integrated Similarity Assessment Exercise

Product-specific Quality, Safety, and Efficacy

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Clinical Trials Are Not the Source of the Most Robust Evidence for Comparability of Biosimilars

1. McCamish M and Woollett G. Clinical Pharmacol Ther. 2013;93 4:315–317.

2. Weise M, et al. Blood. 2012;120:5111-5117

• Clinical trials

• Evaluate residual uncertainties

related to safety, immunogenicity

and/or efficacy1

• Provide complementary information to

characterization studies2

• Biological and physiochemical

characterization studies

• Provide the most sensitive and

robust evidence for establishing

comparability1

• Determine the type and amount of

nonclinical and clinical data required2

Analytics

Process

Development

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Analytical Considerations

Non-Confidential11

Similarity (and Comparability) Assessment

Strategy

Physicochemical Analysis Method

pH, Osmolality Compendial Methods

Appearance, Color, Clarity Compendial Methods

Molecular Weight CE-SDS (± Reduction)

SEC with MALS, Intact MS

Amino Acid Sequence Peptide Mapping with LC-MS/MS

Intact MS with Deglycosylation

N-Terminal Heterogeneity Peptide Mapping with LC-MS/MS

Edman Degradation

Ion-Exchange Chromatography

Spectrophotometric Properties Circular Dichroism (CD)

UV Derivative Spectroscopy

Thermal Stability Differential Scanning Calorimetry

Chemical Stability Fluorescence Denaturation

Disulfide Bond Arrangement Non-Reducing Peptide Mapping

with LC-MS/MS

Aggregation and Reversible Self-

Association

SEC with UV

Dynamic Light Scattering (DLS)

Glycosylation N-Linked Glycan Analysis

Intact MS ± Deglycosylation

Deamidation Peptide Mapping with LC-MS/MS

Oxidation Peptide Mapping with LC-MS/MS

O-Glycation Peptide Mapping with LC-MS/MS

Fluorescence & Spectroscopy

Phosphorylation Peptide Mapping with LC-MS/MS

In vitro Biochemical Analysis Method

TNF-α Binding ELISA, Octet or Biacore

Fc Binding ELISA, Octet or Biacore

(FcRn, FcγRI, FcγRIIA, FcγRIIB,

FcγRIIIA (V, F), C1q)

In vitro Biological Analysis Method

Biological Potency Biological Potency Assay

Immunological Function Cell-Based Assay (ADCC, CDC,

Apoptosis)

11

Similarity Assessment*

Attribute Statistically Determined

Acceptance Criteria

Critical Quality Attributes

(e.g., Content, Potency,

Safety)

Tier 1 Equivalence

Quality Range

(e.g., Secondary Function

Assays)

Tier 2 Acceptable Limits

Other Structural Attributes:

Descriptive/Graphic Data

Tier 3 Side-by-Side Comparison

*On Assessment of Analytical Similarity in Biosimilar Studies

Shein-Chung Chow, Drug Des 2014, 3:3 (Editorial-Open Access)

Non-Confidential12

Cell Line Selection through Locked

Process

Cell line selected

and locked cell culture process

500–

1000

clonal

cell lines

100–200

clones; batch

culture

15–30

clones; fed

batch

Target BindingAggregation

Carbohydrate

Charge

Heterogeneity

Growth,

TiterFc Functional

Assays

Cell Culture DevelopmentCell Line Generation

Range finding in Bioreactors to

determine parameters that

influence product quality

Bioreactor fed batch combines

clone selection with process

development

Analytical Support

4–6 clones;

BRX fed

batch

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Biosimilarity Assessments To Date?

Similarity

Assessment*

Candidate

Biosimilar

Attribute Conform to

Acceptance

Criteria?

Critical Quality

Attributes

(e.g., Content,

Potency, Safety)

Quality Range

(e.g., Glycan Profile,

Purity (SEC purity,

CEx Profile – Acidic

species, Secondary

Function Assays –

ADCC, CDC)

Other Structural

Attributes:

Descriptive/Graphic

Data

1. Fingerprint similarity

2. PD/PK

3. Clinical trial –Primary indication, size of the trial

4. Extrapolations (multiple trials?)

5. Substitution/

interchangeability

Totality of the Evidence

(Stepwise Approach)

1 5

*Source of RMP and number of lots for similarity assessment?

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Clinical Considerations

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Generating Clinical Evidence to Alleviate Concerns About Biosimilars will Enable Uptake

21%

21%

33%

14%

11%

Clinician Concerns Regarding Biosimilars

Indication Extrapolation

Switching

Efficacy, Safety, and Immunogenicity

Traceability of AEs

Requirement for post-market studies

Amgen Informal HCP Survey, ACR 2015

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What Goals Are Realistic for Biosimilar Clinical Development?

Evidence Required to Demonstrate

Equivalent Potency and to Eliminate Uncertainty

Costly and Delayed Evidence Generation

without Added Value to Patients or Prescribers

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Regulatory Landscape

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FDA Guidance

As a scientific matter, a comparative clinical study will be necessary to support

a demonstration of biosimilarity if there is residual uncertainty about whether

there are clinically meaningful differences between the proposed product and

the reference product based on structural and functional characterization,

animal testing, human PK and PD data, and clinical immunogenicity

assessment. A sponsor should provide a scientific justification if it believes that

a comparative clinical study is not necessary.

Section 351(i) of the PHS Act defines biosimilarity to mean “that the biological

product is highly similar to the reference product notwithstanding minor

differences in clinically inactive components” and that “there are

no clinically meaningful differences between the biological product and

the reference product in terms of the safety, purity, and potency of the

product.”

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Biosimilar Guidelines Provide Framework For

Establishing Similarity

19

EU – CHMP/437/04 Rev 1,

23 Oct 2014

• Aim of clinical studies is to

address slight differences in

physicochemical structure,

function or preclinical assays

• In specific circumstances

"confirmatory" trial may not be

necessary if physicochemical,

biologic activity/potency and PK,

PD support similar efficacy

US – Scientific Considerations in

Demonstrating Biosimilarity April 2015

• Stepwise approach to demonstrating

similarity

• Finger print-like analyses algorithm

may allow more selective animal or

clinical testing

• Conduct comparative human PK/ PD

studies and compare immunogenicity

• If residual uncertainty then consider

what additional data may be needed

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More Regulatory Refinement Coming

20

Guidance Status

Interchangeability

FDA only regulatory body recognizing interchangeability

status

No overarching guidance; many US states passing own laws

related to substitution of biosimilars at the retail pharmacy

level

No guidance from EMA, interchangeability and substitution

are up to country member states

Naming

FDA released proposed guidance on biologic naming in

August 2015

FDA proposed that all biologics—both reference products and

biosimilars—will share a core drug substance name and also

a new “FDA-designated suffix” that is unique for each product

Final guidance expected this year

Labeling Issues No current guidance on whether label should state it has not

been deemed biosimilar for all indications and that it is not

interchangeable

Non-Confidential21

Case Studies: Comparability vs Biosimilarity

Post Approval Changes & Comparability Assessment

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Innovators: Post-Approval Changes

Schiestl et al. 2011 Nature Biotechnology 29 (4)

Non-Confidential23

What does ‘Fingerprint Identity’ Mean in a Changing

World?

Drug

Events listed in the EPAR documents

Record

Starting in

Manufacturing

process changes

per year

(average for this

group 1.4 /yr)

Deletion of

Manufacturing

sites

Addition of

Manufacturing

sites

Change to the

manufacturing

process of active

substance

Change to the

manufacturing

process of

finished product

or medicinal

product

Humira 0 3 13 8 Oct 2003 2.0

Enbrel 9 3 12 9 Nov 2000 1.6

Remicade 2 1 32 9 Feb 2000 2.9

Neulasta 2 0 15 3 Jun 2003 1.7

Mabthera 2 4 8 8 Oct 1998 1.0

Avastin 2 3 6 2 Jun 2005 0.9

Herceptin 0 4 19 1 May 2001 1.6

Lucentis 0 2 1 1 Apr 2007 0.3

Synagis 1 3 11 0 Apr 2000 0.8

Avonex 1 8 11 10 Aug 1997 1.3

Stelara 0 2 2 2 Oct 2009 0.9

Xolair 1 3 8 4 Feb 2006 1.5

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Case Studies: Comparability vs Biosimilar

Biosimilars

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Biosimilarity Assessments To Date?

Similarity

Assessment*

Candidate

Biosimilar

Attribute Conform to

Acceptance

Criteria?

Critical Quality

Attributes

(e.g., Content,

Potency, Safety)

Quality Range

(e.g., Glycan Profile,

Purity (SEC purity,

CEx Profile – Acidic

species, Secondary

Function Assays –

ADCC, CDC)

Other Structural

Attributes:

Descriptive/Graphic

Data

1. Fingerprint similarity

2. PD/PK

3. Clinical trial –Primary indication, size of the trial

4. Extrapolations (multiple trials?)

5. Substitution/

interchangeability

Totality of the Evidence

(Stepwise Approach)

1 5

*Source of RMP and number of lots for similarity assessment?

Non-Confidential26

Questions?