Module developed by Pfizer

November 2017

What is a biosimilar? Biosimilar Training Module I

This learning module is intended for UK healthcare professionals only. PP-GEP-GBR-0895 + Nov 2017

BROUGHT TO YOU BY

I. Introduction

II. What is a biologic?

III. What is a biosimilar?

IV. Glossary

Agenda

Introduction

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The aim of this module is to: • Provide a brief overview of what biological medicines are, the development pathway and how this is

continually evolving

• Describe the current and future landscape of biologics and how they are contributing to the advancement of the healthcare industry

• Provide an introduction to biosimilars including:

Learning Objectives

• Key definitions • Approval and regulatory pathways • Key terminology and differences to generic medicines • Current EMA guidelines

What is a biologic?

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What are biological medicines?

Biological medicines work by interacting with the body to produce a therapeutic outcome and can be tailor made to fit the

desired target

Biological medicines are comprised of:

• Proteins (hormones, enzymes, monoclonal antibodies) • Blood products • Immunological medicinal products (vaccines and sera) • Allergens • Gene and cell therapy products

Reference: European Commission. Biosimilar Medicinal Products. 2014. http://ec.europa.eu/DocsRoom/documents/8242/attachments/1/translations/en/renditions/pdf [Accessed 12 October 2017].

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The biologic discovery process: Innovation is complex

• Most biological medicines are produced by biological processes from a genetic sequence1

• They are made by living systems using biotechnology practices1: – Recombinant DNA engineering – Controlled gene expression – Antibody selection and optimisation

• Biologics are larger and more complex in structure than small molecule pharmaceutical compounds1

Biologics: important terms2

Small molecule

Biologic

Recombinant DNA2

DNA molecule constructed by joining the gene of interest with

another genetic material capable of multiplying inside host cell

(vector)

Molecular cloning2

Replication of a recombinant DNA molecule

References: 1. Schellekens H. NDT Plus. 2009;2(Suppl 1):i27–i36; 2. Russell P. Genetics. 4th ed. New York: Harper Collins; 1996:454–505.

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Biologics are complex molecules produced through a highly specialised manufacturing process1–3

Biological medicines are produced by living organisms from a genetic sequence using biotechnology

Characterisation and stability

Purified bulk drug

Cell expansion

Cell production in bioreactors

Recovery through filtration or

centrifugation

Purification through

chromatography

Different manufacturing processes and analytical characterisation/testing methods

are used by biosimilar and reference product manufacturers Adapted from Mellstedt H, et al.

Gene of interest

DNA vector

Cloning into DNA vector Transfer into host cell, expression, screening

Recombinant protein production

“Biosimilar” defined on slide 22. References: 1. Strober B, et al. J Am Acad Dermatol. 2012;66(2):317–322; 2. Kuhlmann M & Covic A. Nephrol Dial Transplant. 2006;21 (Suppl 5):v4–v8; 3. Mellstedt H, et al. Ann Oncol. 2008;19(3):411–419.

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Biologics differ from small molecule drugs1–4

• Biologics are medicinal products produced by a living organism • They are larger and more complex than chemically synthesised small

molecule drugs Small molecule

(Chemical) Biologic (Protein)

Production Chemical synthesis Typically living systems (e.g., cultured bacterial, yeast, animal or plant cells)

Characterisation May be characterised using limited physicochemical methods

Necessary to perform comprehensive structural and functional assessment

Manufacturing Can be characterised using limited physiochemical methods; typical chemical reaction equipment required

Necessary to perform comprehensive structural and functional assessment; sophisticated equipment and materials required

Administration Various routes, including oral, topical and parenteral (IM, IV, SC)

Primarily through parenteral (IM, IV, SC) delivery

Immunogenicity Mostly non-immunogenic Potentially immunogenic

References: 1. Shellekens, H et al. Lancet Oncol. 2016;17:e502–e509; 2. Strober BE, et al. J Am Acad Dermatol. 2012;66:317–322; 3. Nowicki M. Kidney Blood Press Res. 2007;30:267–72; 4. European Commission. Biosimilar Medicinal Products. 2014. http://ec.europa.eu/DocsRoom/documents/8242/attachments/1/translations/en/renditions/pdf [Accessed 12 October 2017]. CHO cell image: Public domain image of Chinese hamster ovary (CHO) cells in cell culture flask from Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Cho_cells_adherend1.jpg [Accessed 12 October 2017].

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Comparison between a biologic monoclonal antibody and an aspirin molecule

An approximately 800-fold difference in size necessitates magnifying the boxed area to clearly identify the aspirin molecule on the lower left

Aspirin Monoclonal antibody

Reference: Kozlowski et al. N Engl J Med. 2011;365:385–388.

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Heterogeneity of biological medicines

• Biological products display a certain degree of variability (micro-heterogeneity) 1

• Endogenously produced biologics are also subject to heterogeneity • Owing to micro-heterogeneity in its structure, natural biologic may

comprise several isoforms, some of which differ in electrical charge and biological activity2,3

Endogenously produced biologic

Due to heterogeneity, several glycosylation isoforms can exist

References: 1. Weise M, et al. Blood. 2012; 120(26):5111–5117; 2. Lasne F, de Ceaurriz J. Nature. 2000; 405:635; 3. Jelkmann W. J Physiol. 2011;589(6):1251–1258.

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Biologics continue to contribute to advancing healthcare

Have a successful record in treating many life-threatening and chronic diseases in multiple

therapeutic areas1

Can augment or replace the body’s endogenous growth factors, hormones, cytokines and enzymes or

remove undesirable molecules in the body1,2

Can address many unique disease targets not accessible to traditional pharmaceutical drugs2

Allow for targeted treatment, creating more opportunities for personalised medicine3,4

References: 1. Walsh G. Nat Biotechnol. 2010;28(9):917–924; 2. Morrow T, Felcone LH. Biotechnol Healthc. 2004;1(4):24–29; 3. Offit K. Hum Genet. 2011;130(1):3–14; 4. Chan IS, Ginsburg GS. Annu Rev Genomics Hum Genet. 2011;12:217–244.

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Hundreds of biologics are in the process of being discovered and developed

Recent figures on biologic development • Nearly 300 mAb products are currently in

clinical trials1

• In 2014, approximately 340 recombinant proteins (including

mAbs) were in clinical trials2

• More products are likely to gain approval over the next several years1,2

References: 1. Norman P. Monoclonal antibodies in the pipeline: a segment of major growth report – overview. Insight Pharma Reports. http://www.insightpharmareports.com/monoclonalantibodiesreport/ [Accessed 12 October 2017]; 2. Research and markets: recombinant therapeutic proteins market & pipeline analysis 2014. Business Wire. http://www.businesswire.com/news/home/20140918005437/en/ Research-Markets-Recombinant-Therapeutic-Proteins-Market-Pipeline#.VE6tBGx0yUl September 2014 [Accessed 12 October 2017].

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Biologics have advanced treatment in numerous therapeutic areas

Gastrointestinal

Crohn’s disease

Ulcerative colitis Immunology

Ankylosing spondylitis

Juvenile idiopathic arthritis

Mucositis

Multiple sclerosis

Psoriasis

Psoriatic arthritis

Rheumatoid arthritis

Haematology

Anaemia

Haemophilia

Neutropenia

PNH

Von Willebrand disease

Other

Cervical dystonia

Cosmetic changes

Dupuytren’s contracture

Fertility disorders

Hepatitis C

Impaired growth

Osteoporosis

Paget’s disease

Wet age-related macular degeneration

Oncology

Breast cancer

Cervical cancer

Colon/rectal cancer

Glioblastoma

Leukaemia

Lung cancer

Lymphoma

Ovarian cancer

SCC (head/neck)

Cardiovascular

Myocardial infarction

Diabetes

Biologics have been used to treat a range of disorders in different therapeutic areas

Respiratory

Asthma

Cystic fibrosis

Lysosomal Diseases

Fabry disease

Gaucher disease

Mucopolysaccharidoses

Pompe disease

Inherited Conditions

CAPS

Hereditary angioedema

Hunter syndrome

Turner syndrome

Reference: Walsh G. Nat Biotechnol. 2010;28(9):917–924.

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Key learning points: Biologics

1. Biologics are produced by living organisms and interact with the body to produce a therapeutic outcome

2. Biologics are larger and more complex than chemically synthesised small molecule drugs

3. Biologics have advanced treatment in numerous therapeutic areas and have become a standard therapy

4. Hundreds of biologics are in the process of being discovered and developed

What is a biosimilar?

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What is a biosimilar?

A biosimilar is a biologic medicinal product that contains a version of the active substance of an

already authorised original biologic medicinal product (reference medicinal product). Similarity to the reference medicinal product in terms of quality characteristics, biologic activity, safety and efficacy

based on a comprehensive comparability exercise needs to be established. 1

A biosimilar is not a scientific definition of the product; it is a regulatory term

Reference: 1. EMA. Procedural advice for users of the centralised procedure for similar biological medicinal products applications. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/04/WC500125166.pdf [Accessed 12 October 2017].

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What is a biosimilar?

A biosimilar is a new biologic product that is highly similar to an already approved product (the reference product) in terms of structure, function and biological

activity

A biosimilar:

• Is a biologic approved via a stringently defined regulatory pathway demonstrating comparability to a reference biologic that has lost exclusivity

• Is comparable with the selected reference product in terms of quality

• Has a highly analogous structure (via robust analytical characterisation)

• Has demonstrable comparability in quality, safety and efficacy via clinical trials

Reference: European Commission. Biosimilar medicinal products. 2014. http://ec.europa.eu/DocsRoom/documents/8242/attachments/1/translations/en/renditions/pdf [Accessed 12 October 2017].

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Biosimilars apply to biologics as generics apply to small molecule drugs

• Compared with small molecule drugs, biologics and biosimilars are1-2: • Larger • More complex • More difficult to manufacture

• They are also regulated differently

Generics Proof of quality2

Pharmacokinetic bioequivalence2 No substantial clinical data2

Small Molecule

Biologic Biosimilars Proof of quality and similarity3

Pharmacokinetic bioequivalence3 Clinical safety and efficacy data3

References: 1. Schellekens H. Nephrol Dial Transplant. 2005;20(Suppl 4):iv31–iv36; 2. Mellstedt H et al. Ann Oncol. 2008;19(3):411–419; 3. Aapro M. GaBi J. 2013;2(2):91–93.

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The EMA pioneered the biosimilar concept

2003 2004 2005 2006

Concept of similar biological medicinal

product was first introduced into

EU pharmaceutical legislation1

Legal basis for the biosimilar

approval pathway was put into

effect2

First biosimilar medicine was

approved by the European

Commission1

Legal basis for the biosimilar

approval pathway was approved1

2015

The FDA finalised guidelines for demonstrating

biosimilarity to a reference product3

References: 1. McCamish M, Woollett G. MAbs. 2011;3(2):209–217; 2. EMA. Biosimilar guidelines. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c [Accessed 12 October 2017]; 3. FDA. Biosimilarity guidances. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm290967.htm [Accessed 12 October 2017].

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Biosimilars are unique entities with specifications distinct from their reference products1–3

• Although biosimilars are developed against a reference product, they have their own specifications, which are dependent on:

• Rigorous control strategies are necessary to maintain production

consistency and to ensure that biosimilars conform to specifications

References: 1. European Medicines Agency. Specifications: test procedures and acceptance criteria for biotechnological/biological products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002824.pdf [Accessed 12 October 2017]; 2. Ryan AM. Vet Pathol. 2015;52(2):419–426; 3. Schiestl M, et al. Nat Biotechnol. 2011;29:310–312.

• The manufacturing process • Industry standards • Regulatory expectations • Data from comparisons with the reference product

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Biosimilars are unique entities with specifications distinct from their reference products1,2

Developers of biosimilars do not have access to the reference product companies’ proprietary data, including details of the manufacturing

processes used

Biosimilar developers perform an extensive analysis of the reference product

Their own biosimilar manufacturing processes are developed, using their knowledge of biopharmaceutical production and modern state-of-the-art technology

A biosimilar is produced that replicates essential features of, but is not identical to, the reference product

References: 1. Weise M, et al. Nat Biotechnol. 2011;29:690–693; 2. Ventola CL. P T. 2013;38(5):270–287.

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Biosimilar development is a multistep process

Clone the gene into the host cell using vector1-3

Identify clones that produce a protein

with target posttranslational modifications1-3

Optimise the target product profile by

iterative perfecting of process variables1

Investigate reference product quality attributes to understand

target variability1

Set similarity criteria1

Determine the primary amino

acid sequence1,2

References: 1. McCamish M, Woollett G. Clin Pharmacol Ther. 2012;91(3):405–417; 2. Kuhlmann M, Marre M. Br J Diabetes Vasc Dis. 2010;10(2):90–97; 3. Kuhlmann M, Covic A. Nephrol Dial Transplant. 2006;21(suppl 5):v4–v8.

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The amino acid sequence of a biosimilar must be identical to that of the reference product

Primary sequence is the first product attribute that must be determined and matched in the development of a biosimilar product

The reference product is studied to

determine the exact amino acid sequence and higher order structure (including

secondary structure folding)

Determining the amino acid sequence entails classical protein sequencing, de novo tandem mass spectrometry (MS/MS), peptide MS-mapping and amino-acid analysis

The amino acid sequence of a biosimilar must be identical to that of the reference product

Primary Structure

Secondary Structure

(alpha helices and beta sheets)

N

C

Leu

Tyr

Gln

Leu

Glu

Asn

Tyr

C

Reference: Greer FM. Generics and biosimilars initiative (GaBI Online). Posted: September 25, 2015. http://www.gabionline.net/layout/set/print/content/view/full/4140 [Accessed 12 October 2017].

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The goal of biosimilar development is to demonstrate that there are no clinically meaningful differences based on the totality of evidence, not to re-establish benefit1–4

Reference biologics1,2

Nonclinical

Clinical pharmacology

PK/PD

Analytical

Clinical studies

Biosimilars1–3

Nonclinical

Comparative clinical pharmacology

PK/PD

Analytical

Comparative clinical studies

Confirm safety profile and efficacy in a disease population (dose ranging is not necessary)

Development pathways

References: 1. Schneider CK, et al. Nat Biotechnol. 2012;30:1179–1185; 2. McCamish M. Presented at EMA Workshop on Biosimilars; London, UK; October 2013 http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2013/09/event_detail_000780.jsp&mid=WC0b01ac058004d5c3 [Accessed November 2017] 3. Berghout A. Biologicals. 2011;39:293–296; 4. European Commission. Biosimilar Medicinal Products. 2014. http://ec.europa.eu/DocsRoom/documents/8242/attachments/1/translations/en/renditions/pdf [Accessed 12 October 2017].

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Why do biosimilars need to be regulated differently than generics or novel biologics?

Relies on being able to provide information on the quality and bioequivalence to its reference compound; this is not possible for a biologic, so the generic

regulatory route is not appropriate3

Entire clinical development programme of the reference

product would need to be repeated

Solution2

Biosimilars concept, as pioneered in the EU, provides a tailored pathway so that not all clinical studies have to be repeated to provide a rigorous review

Regulate as generics1 Regulate as novel products2

Two choices from existing regulatory systems

References: 1. Schellekens H. Nephrol Dial Transplant. 2005;20(Suppl 4):iv31–iv36; 2. McCamish M, Woollett G. Clin Pharmacol Ther. 2012;91(3):405–417; 3. EMA Questions and answers on generic medicines. 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/11/WC500012382.pdf [Accessed 12 October 2017].

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The term generic is not used when discussing biologics

Biobetter/ second-generation

or next-generation biologic

Biologic that has been structurally and/or functionally altered to achieve an improved or different clinical performance1 • Related to an existing biologic by target or action4

Terminology: novel biologic molecular entities

Me-too biologic/ non-comparable biologic

Biological medicinal product developed on its own1–3 • Not directly compared and analysed against a

licensed reference biologic in accordance with the regulatory guidelines for biosimilars1–3

• May or may not have been compared clinically1–3

References: 1. Weise M et al. Nat Biotechnol. 2011;29(8):690-693; 2. Dörner T et al. Ann Rheum Dis. 2013;72(3):322–328; 3. Greer F. Biosimilars: the race to market continues. http://www.contractpharma.com/issues/2012-10/view_features/biosimilars-the-race-to-market-continues October 9, 2012. [Accessed 12 October 2017]; 4. Dinwoodie N. BioPharm Int. 2011;24:31–35.

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The term generic is not used when discussing biologics

Organisation Term Definition

WHO1 Similar biotherapeutic product

A biotherapeutic product similar to an already licensed reference biotherapeutic product in terms of quality, safety and efficacy

FDA1–2

(US) Biosimilar A biological product that is highly similar to a US-licensed reference biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences in safety, purity or potency of the product

EMA3 Biosimilar medicine/ similar biological medicinal product

A biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product) in the EEA

PMDA4 (Japan) Follow-on biologic

A biotechnological drug product developed to be comparable with an already approved biologic manufactured by a different company in regard to quality, safety and efficacy

Health Canada5

Subsequent entry biologic (SEB)

A biologic drug that enters the market subsequent to a version previously authorised in Canada with demonstrated similarity to the reference biologic drug; a SEB relies in part on prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to the reference biologic drug and which influences the amount and type of original data required

Terminology: Biosimilars

References: 1. Wang J, Chow SC. Pharmaceuticals. 2012;5:353–368; 2. FDA. Improving access to innovative medical therapies. Subtitle A BPCI Act;H. R. 3590–3686:sec 7002; 3. EMA. Guideline on similar biological medicinal products. 2014; 4. Ministry of Health, Labor and Welfare (MHLW). Guideline for the quality, safety and efficacy assurance of follow-on biologics. MHLW: Tokyo, Japan, 2009; 5. Minister of Public Works and Government Services Canada. Guidance for Sponsors: information and submission requirements for subsequent entry biologics (SEBs). Ottawa, Canada: Health Canada; 2010.

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Some regulatory authorities define biosimilars and generics differently

FDA3

A biological product that is highly similar to a US-licensed reference biological product, notwithstanding minor differences in clinically

inactive components, and for which there are no clinically meaningful differences in safety, purity

or potency of the product

EMA1

A biological medicinal product that contains a version of the active substance of an already

authorised original biological medicinal product (reference medicinal product) in the EEA

Biosimilar

EMA2

A medicine that is developed to be the same as a medicine that has already been authorised;

its authorisation is based on efficacy and safety data from studies on the previously authorised

medicine

Generic

FDA4

A drug that has the same dosage, safety, strength, method of administration, quality, performance and intended use as a brand

name; can be expected to have an equal effect and no differences when substituted for the

brand name product

References: 1. EMA. Guideline on similar biological medicinal products. 2014. http://ec.europa.eu/DocsRoom/documents/8242/attachments/1/translations/en/renditions/pdf [Accessed 12 October 2017]; 2. EMA. Glossary. http://www.ema.europa.eu/ema/index.jsp?curl=pages/document_library/landing/glossary.jsp&mid=&startLetter=G [Accessed 12 October 2017]; 3. Wang J, Chow SC. Pharmaceuticals. 2012;5:353–368; 4. FDA website. Glossary. http://www.fda.gov/drugs/informationondrugs/ucm079436.htm#G [Accessed 12 October 2017].

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Key learning points: Biosimilars

1. A biosimilar is a new biologic product that is highly similar to an already approved product (the reference product) in terms of structure, function and biological activity

2. The concept of a similar biological medicinal product was first introduced into EU pharmaceutical legislation in 2003, with the legal basis for their approval pathway effective in 2005; the first biosimilar was approved in 2006

3. Biotechnology-derived medicinal products, including biosimilars, are centrally reviewed by the EMA

4. The goal of biosimilar development is to demonstrate that there are no clinically meaningful differences, not to re-establish benefit

Glossary

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DNA: deoxyribonucleic acid IM: intramuscular IV: intravenous SC: subcutaneous mAb: monoclonal antibody CAPS: cryopyrin-associated periodic syndromes PNH: paroxysmal nocturnal hemoglobinuria SCC: squamous cell carcinoma TTP: thrombotic thrombocytopenic purpura PD: pharmacodynamic PK: pharmacokinetic EEA: European Economic Area FDA: Food and Drug Administration PMDA: Pharmaceuticals and Medical Devices Agency WHO: World Health Organisation.

Glossary

Questions

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Biological medicines are made by living systems: True False

Question 1

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Which of the following is not true about biologics? 1. They are larger than chemically synthesised small molecular drugs

2. They are made up of protein

3. They are administered mainly through oral delivery

4. They have the potential of being immunogenic

Question 2

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Aspirin is an example of a biologic: True False

Question 3

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Which of the following are true about biologics contribution to advancing healthcare? (select all that apply). 1. They have a successful record in treating many life-threatening diseases

2. They can augment or replace the body’s enzymes

3. They allow for targeted treatment i.e. personal medicine

4. They have not been developed for treating myocardial infarction yet

Question 4

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Which of the following is not true for biosimilars? 1. They are biologic medicinal products that contain a version of the active

substance of an already authorised original biologic medicinal product

2. Biosimilars are identical to the reference product

3. They have demonstrable comparability in efficacy to the reference products

4. They are larger than chemically synthesised small molecular drugs

Question 5

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This learning module is intended for UK healthcare professionals only. PP-GEP-GBR-0895 + Nov 2017