1

Learning Objectives

• Compare and contrast biosimilars to their reference product

and generic therapies in terms of structure, manufacturing,

regulatory pathway, and clinical properties

• Evaluate evolving policy related to prescribing, dispensing, and

maintaining pharmacovigilance with biosimilars

• Determine whether biosimilars are appropriate for select

patients with RA based on their benefits/limitations, disease-

and treatment-related factors, and patient preferences

2

What Is a Biosimilar?

• A biosimilar is a product that is highly similar to an FDA-approved

biopharmaceutical (ie, “reference product” or “biooriginator”) that will

be out of patent in 10 years and has:

– Undergone rigorous analytical and clinical assessment, in

comparison to its reference product

– Been approved by a regulatory agency according to a specific

pathway for biosimilar evaluation

• A biosimilar is highly similar to its reference product in

physicochemical characteristics, purity, potency, efficacy, and safety

www.fda.gov/Drugs/DevelopmentApprovalProcess/; Beck A, et al. Anal Chem. 2012;84:4637-46;

Dörner T, et al. Nat Rev Rheumatol. 2015;11:713-24.

Biosimilars Are Not…Second-Generation (or “Biobetter”)

• Structurally different from

originally licensed

biopharmaceutical

• Intended to improve

performance while preserving

mechanism of action

• Examples:

– Infliximab, adalimumab,

golimumab

– Filgrastim and pegfilgrastim

– Not considered to be

biosimilar

www.ispor.org/research_pdfs/48/pdffiles/PHP159.pdf; www.bioprocessintl.com/manufacturing/biosimilars/special-report-a-world-of-difference-biosimilars-and-biobetters-offer-

unique-benefits-and-risks/; Beck A, et al. Anal Chem. 2012;84:4637-46; Woodcock J, et al. Nat Rev Drug Discov. 2007;6:437-42.

Generic Drugs

• Small-molecule drugs that are

less complex than biosimilars

– Manufacturing process is

several orders of magnitude

less complex

– Regulated under different

legislation

3

• Biosimilars approved by the US FDA to treat RA include:

– Infliximab-dyyb

– Etanercept-szzs

– Adalimumab-atto

www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Current State of Biosimilars Market

http://gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe; http://www.gabionline.net/Biosimilars/General/Subsequent-entry-biologics-approved-in-Canada;

http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Japan; http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

http://gabionline.net/Biosimilars/General/Biosimilars

http://www.gabionline.net/Biosimilars/General/Biosimilars

BiosimilarReference

Drug Class Company EU Approval

Canada

Approval

Japan

Approval US Approval

Abseamed Eprex ESA Medice Arzneimittel Putter Aug-07 — — —

Binocrit Eprex ESA Sandoz (Novartis) Aug-07 — — —

Epoetin alfa Hexal Eprex/Erypo ESA Hexal (Novartis) Aug-07 — — —

Retacrit Eprex ESA Hospira Dec-07 — — —

Silapo Eprex ESA STADA Arzneimittel Dec-07 — — —

Epoetin alfa BS Espo ESA JCR Pharmaceuticals — — Jan-10 —

Biograstim Neupogen G-CSF CT Arzneimittel Sep-08 — — —

Ratiograstim Neupogen G-CSF Ratiopharm Sep-08 — — —

Tevagrastim/Filgrastim NK Neupogen G-CSF Teva/Nippon Kayaku Sep-08 — Feb-13 —

Zarzio (EU)/Filgrastim BS Injection (Japan)/Zarxio (US) Neupogen G-CSF Sandoz (Novartis) Feb-09 — Mar-14 Mar-15

Filgrastim Hexal Neupogen G-CSF Hexal (Novartis) Feb-09 — — —

Nivestim Neupogen G-CSF Hospira Jun-10 — — —

Grastofil Neupogen G-CSF Apotex/Stada Oct-13 — — —

Accofil Neupogen G-CSF Accord Healthcare Sep-14 — —

Omnitrope Genotropin hGH Sandoz (Novartis) Apr-06 Apr-09 Jun-09 —

Remsima/Inflectra Remicade TNF inhibitor Celltrion//Nippon Kayaku Sep-13 Jan-14 Jul-14 Apr-16

Benepali Enbrel TNF inhibitor Samsung Bioepis Jan-16 Aug-16 — —

Flixabi Remicade TNF inhibitor Samsung Bioepis May-16 — — —

Erelzi Enbrel TNF inhibitor Sandoz (Novartis) — — — Aug-16

Amjevita Humira TNF inhibitor Amgen — — — Sep-16

Ovaleap Gonal-f FSH Teva Sep-13 — — —

Bemfola Gonal-f FSH Finox Biotech Mar-14 — — —

Abasaglar (previously Abasria) Lantus Insulin glargine Eli Lilly/Boehringer Ingelheim Sep-14 — Dec-14 —

Insulin glargine Lantus Insulin glargine Biocon/Fujifilm Pharma — — Mar-16 —

4

CT-P13 (infliximab-dvvb)

• First TNF inhibitor (biosimilar monoclonal antibody) approved

• US FDA granted approval April 5, 2016

• Indicated for Crohn’s disease, ulcerative colitis, RA, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis

www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm

GP2015 (etanercept-szzs)

• US FDA granted approval August 30, 2016

• Indicated for RA, polyarticular JIA, ankylosing spondylitis, plaque

psoriasis, psoriatic arthritis

www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518639.htm

5

ABP501 (adalimumab-atto)

• US FDA granted approval September 23, 2016

• Indicated for RA, ankylosing spondylitis, cutaneous

psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative

colitis

www.fda.gov/newsevents/newsroom/pressannouncements/ucm522243.htm

Goals of “Stand-Alone” and

Biosimilar Development Are Different

Overview of the Regulatory Pathway and FDA’s Guidance for the Development and Approval of Biosimilar Products in the US.

www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM486171.pdf. Accessed September 7, 2016.

Overview of the Regulatory Pathway and FDA’s Guidance for the Development and Approval of Biosimilar Products in the US. http://www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM486171.pdf. Accessed September 7, 2016.

“Stand-Alone”

Development Program, 351(a)

Goal: To establish safety and

efficacy of a new product

“Abbreviated”

Development Program, 351(k)

Goal: To demonstrate biosimilarity

(or interchangeability)

Analytical

Non-clinical

Clinical Pharmacology

Clinical

Safety and Efficacy

(Phases 1, 2, 3)Clinical

Pharmacology

Non-clinical

Analytical

Additional

Clinical Studies

6

FDA Proposed Guidance on Naming

• USAN with an added random four-letter suffix, devoid of meaning,

for all biologics (including reference products) with limited

exceptions

• Filgrastim in the US (approved indications vary)

– Filgrastim (reference biologic)

– Tbo-filgrastim (not biosimilar [351(a)])

– Filgrastim-sndz (biosimilar [351(k)]

• Benefits

– Ability to differentiate products for pharmacovigilance purposes

– Common core names will group similar biologics in electronic

systems

– Having suffix for all products reduces perception that biosimilar is

inferior to reference product

www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf.

• Concerns

– Unless interchangeable biosimilar has the same suffix, it will

inhibit interchange

– Potential for errors when using four-letter suffix devoid of

meaning (alternative to represent manufacturer)

– More complex naming system increases likelihood that errors

could occur, actually harming pharmacovigilance

– Need to change name of current biologics on market creates

confusion

www.healio.com/rheumatology/psoriatic-arthritis/news/online/%7Bfd74beb9-177e-4618-8a94-

aab7cd3f77b7%7D/physician-groups-support-proposed-fda-biosimilar-naming-convention-but-also-call-for-maker-id

www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf.

7

Biosimilars Are Reverse Engineered

1. Kozlowski S. 2014 Biotechnology Technology Summit; June 13, 2014; Rockville, MD.

2. www.fda.gov/Downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf..

Biosimilar

candidateReverse Engineering

Reference

product1

Characterizereference

product

Identify

CQAs of

reference

product

Developunique cell

line andmanufacturing

process

Characterizebiosimilar

candidateand identify

CQAs

Evaluate

similarity to

reference

product

Manufacturing Biosimilars: Sources of Variation

Adapted from Mellstedt H, et al. Ann Oncol. 2008;19:411-9.

Cloning and Protein Expression

Protein Production, Purification, and Validation

Target

DNA

Source

DNA

Cloning into

DNA vector

Possibly same

gene sequence

Possibly different

vector

Transfer into host cell

Expression screening/

selection

Different cell-

expression system

Characterization

and stability

Purified bulk

drug

Different cell line,

growth media,

method of expansion

Different cell line,

growth media,

bioreactor conditions

Different operating

conditions

Different binding and

elution conditions

Different methods,

reagents, reference

standards

Purification

through

chromatography

Recovery through

filtration or

centrifugation

Cell production

in bioreactorsCell expansion

8

Demonstrating Biosimilarity: General Principles

• Clinical efficacy and safety of reference biopharmaceutical have

already been demonstrated

• Biosimilar must demonstrate no significant difference from its

reference product

– Robust analytical, toxicologic, PK/PD, and immunogenicity

studies in comparison to reference product

– Smaller comparative effectiveness clinical trial(s), which must be

conducted in patients with a disease for which the reference

product is licensed

– No need to demonstrate efficacy in all indications

• No differences in safety or efficacy are expected between an

approved biosimilar and its reference product

www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm;

Gerrard T, et al. GaBi J. 2015;4:118-24.

Biosimilars Development: A Stepwise Approach

Dörner T, et al. Nat Rev Rheumatol. 2015;11:713-24;

Dörner T, et al. Ann Rheum Dis. 2013;72:322-8; Braun J, et al. Arthritis Rheumatol. 2014;66:3538-9;

www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf.

In vitro

studiesPK/PD studies

Assess

binding to

target(s)

Assess

signal

transduction

and

functional

activity/

viability

Determine if

in vivo studies

are needed

Necessary only

if factors of

concern are

identified, eg,

new post-

translational

modification

structures

In vivo

studies

Focus of

study

depends on

the need for

additional

information

Preclinical Phase 1 Phase 3

Single-dose crossover or parallel

group designs preferred

PD markers selected on the basis

of their clinical relevance

Affinity is a key determinant of the

PK and PD profile of mAbs and

soluble receptor constructs1.32

Close reproduction of

conformational structure for

biosimilar mAbs and soluble

receptor constructs is

needed to ensure comparable

biological effect 48

Safety and

efficacy

No clinically

significant

difference in

efficacy to

reference

product

Compare

severity and

frequency of

adverse

events, in

particular for

immunogeni-

city

9

Extrapolation of Indications

• Extrapolation of data from a clinical trial of a biosimilar conducted in one

disease to support approval for additional indications for which the

reference product is already licensed

• Factors to be considered:

– Clinical experience with the reference product

– Mechanism(s) of action in each indication

– Target receptors

– Product structure and target/receptor interactions

– PK and biodistribution in different patient populations

– Differences in the safety/immunogenicity profile between indications

• Cannot extrapolate across indications in which reference product may

have different mechanisms of action (eg, rituximab in RA and lymphoma)

Weise M, et al. Blood. 2014;124:3191-6.

www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm.

Switching vs Substitution

• Switch = transition

– Patient transitioned to biosimilar, after initial treatment with

originator

– Single switch study

• Substitution = interchange

– BPCI Act of 2009 affords 1 year of exclusive marketing rights to

first biosimilar approved as being interchangeable with reference

product

– Interchange could be initiated without prescriber input

– Repeated switching study (although single switch study might

fulfill statutory requirement)

Dörner T, et al. Nat Rev Rheumatol. 2015;11:713-24.

10

BPCI Act of 2009: Interchangeability

www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/UCM216146.pdf.

Efficacy and Safety of Approved Biosimilars

• Biosimilars have been shown to be as effective as reference

products at early time points and in sustained studies

• No meaningful safety differences

Emery P, et al. Ann Rheum Dis. 2015 Jul 6. [epub ahead of print];

Yoo DH, et al. Ann Rheum Dis. 2013;72:1613-20;

Yoo DJ, et al. Arthritis Res Ther. 2016;18:82.

11

Acknowledgment of

Commercial Support

This activity is supported by an educational grant from Genentech.

Contact Information

Call (toll-free) 866 858 7434

E-mail info@med-iq.com

Please visit us online at www.Med-IQ.com for additional

activities provided by Med-IQ®.

© 2016

To receive credit, click the “Get Credit” tab at the

bottom of the Webcast for access to the evaluation,

attestation, and post-test.

Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients

or doctors.

12

Abbreviations/Acronyms

BPCI = Biologics Price Competition and Innovation

CQAs = critical quality attributes

DNA = deoxyribonucleic acid

ESA = erythropoietin-stimulating agent

EU = European Union

G-CSF = granulocyte colony-stimulating factor

FDA = Food and Drug Administration

FSH = follicle-stimulating hormone

HgH = human growth hormone

JIA = juvenile idiopathic arthritis

mAbs = monoclonal antibodies

PD = pharmacodynamic

PK = pharmacokinetic

RA = rheumatoid arthritis

TNF = tumor necrosis factor

US = United States

USAN = United States Adopted Name