Copyright © 2013 Quintiles

Biosimilars Knowledge Connect Webinar 4th November 2013

www.BiosimilarsKnowledgeConnect.com

The Biosimilars Investigator Network

Develop and maintain a community of engaged investigators with an interest in biosimilars research

Provide investigators with a comprehensive and up to date set of resources that supports them, their staff and patients in the execution of biosimilars trials

Enable doctors with a relevant interest to gain access to latest information about regulatory processes for biosimilar registration and clinical research

The purpose of the Biosimilars Knowledge Connect program is to:

Biosimilars Knowledge Connect The story so far...

740+ investigators

registered to date across all regions

42 respondents to the

Biosimilars Knowledge Connect Community

survey (Q1 2013)

65% of survey responders rating the

website as ‘helpful’ or ‘very valuable’

Quarterly newsletters • Re-designed Biosimilars Knowledge Connect website including: > Biosimilars study update section > Congress update section > Variety of resource libraries including

video, newsletters and written resources

Localized investigator guides for Europe, Asia and the

Americas

Slide resource deck offered to all who

register

Biosimilars Knowledge Connect program factsheet

• Upcoming in 2013 Q4: > 2 KOL discussion videos > 2 Educational webinars

Agenda Topic Presenter Time

Regulatory Update: Focus on US/EU requirements

Dr Kamali Chance, Senior Director

Head of Global Biosimilars Regulatory Strategy

20 Minutes

Q & A 5 Minutes

Global Biosimilar Development and impact on clinical practice

Dr John Patava, Senior Director

Head of Biosimilars Intelligence and Capabilities

20 Minutes

Q & A 5 Minutes

Closing remarks

Copyright © 2013 Quintiles

Biosimilars: Focus on US/EU Requirements

Kamali Chance, MPH, PhD, RAC Senior Director, Head, Global Biosimilars Regulatory Strategy

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Overview

• What are biologics/biosimilars? Terminology Innovator Biologics Biosimilar ≠ Generic Approved Biosimilars and Alternative Biologics

• Pathway to Market: US and EU Biosimilar Development Definition of Biosimilarity Biosimilar Guidelines in the EU and US Generics vs. Biosimilars Biosimilars: Quality, Non-clinical and Clinical Considerations Risk Factors that Can Affect Immunogenic Response Biosimilar Product Development Extrapolation to Other Indications

• Q & A

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What are Biologics/Biosimilars?

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Terminology

Terminology Synonyms Definition

Biologic Product

• Virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except chemically synthesized polypeptides), or analogous product applicable to the prevention, treatment, or cure of a disease or condition in humans

Originator • Reference • Innovator • Comparator

• Novel biological medicine that has been patented

Biosimilar • Follow-on biologic (USA) • Bioequivalent biologic • Subsequent entry biologic

(Canada) • Biocomparable (Mexico)

• Biologic medicine with identical primary amino acid sequence to an originator medicine

• Developed with intention to be as close to originator as possible

• Demonstrated similarity in physiochemical characteristics, efficacy, and safety

Copy Biologic • Alternative biologic

• Copy of an originator medicine that has been approved in a country where no official biosimilar regulatory pathway exists or existed

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Innovator Biologics

All trademarks mentioned herein are the property of their respective owners

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Biosimilar ≠ Generic

Biosimilars

Generics Proof of quality and bioequivalence No substantial clinical data required Reference to originator’s data

Different manufacturing processes can and often do yield differences in the end product

After the quality of a biological medicine is demonstrated, some non-clinical and clinical studies are necessary

Immunogenic response cannot be predicted and therefore must be tested

Source: J. Mascaro: Regulatory evaluation of therapeutic biological medicines, Aug 15, 2007

Small molecule

Biological medicine

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2012/2013 Global Clinical Use of Biosimilars and Alternative Biologics

Country Companies Marketed

biosimilars/follow-on biologics

Marketed alternative biologics

USA

Sandoz, Momenta, Merck (Bioventures Division), Pfizer, Lilly, Janssen, Protalix, Biotherapeutics, Momenta Pharma, Hospira, Itero, Phage Biotech, Baxter, Pharmacia-Upjohn, Teva

GH, heparin, rGlucagon, Calcitonin-Salmon, hyaluronidase, G-CSF

EU

Sandoz, Hexal, Teva, Biopartners, Medice Arzneimittel Pütter , CT Arzneimittel, Ratiopharm , AstraZeneca, GSK, Novo Nordisk, Sanofi Aventis, Hospira

GH, EPO, G-CSF, somatropin hGH

Japan Sandoz, Daiichi Sankyo (Ranbaxy), JCR, Kissei, Nippon Kayaku, Nipro, Otsuka Holdings, Roche, Nektar Therapeutics

GH, G-CSF, GM-CSF, IL-2, Zenotech , EPO-kappa, IFNa

India

Bharat Biotech International, Dr. Reddy's Laboratories, Shantha Biotechnics Ltd, Wockhardt, Biocon, Intas Biopharmaceuticals, Lupin, Reliance Life Sciences, Zydus, Intas, Ranbaxy, Sanofi, CP GuoJian Pharmaceutical

GH, EPO, G-CSF, Peg-GSF, IFNa, insulin, teriparatide, mAbs, Regen-D (rhEGF), Indikina, se (strepto-kinase), Glargine, Lispro, Aspart, EPO, G-CSF, streptokinase, Rituximab, IL-2, IFNb, Etanercept

China

Beijing Tri-Prime Genetic SinoBiomed Inc., Shanghai Sunway Biotech, 3SBio Inc., Shenzhen Kexing Biotech, Amoytop Biotech Co. Ltd., CP GuoJian Pharmaceutical, GeneScience Pharmaceuticals, Simcere Pharmaceuticals, Tonghua Dongbao, Wanbang Biopharmaceuticals

GH, EPO, G-CSF, PEG-GSF, IFNa, IL-2, IL-11, insulin, Etanercept, mAbs

Source: Datamonitor strategic analysis pipeline trends December 2011; ADIS, EvaluatePharma and PharmaProjects May 2013

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Country Companies Marketed biosimilars

Marketed alternative biologics

Mexico Probiomed, SICOR Biotech UAB, Pfizer rEPO, R IFN alpha2B IFN alpha2A , rHu G-CSF, Taliglucerase alfa

Brazil

Instituto Butantan, FK Biotecnologic, Bio-Manguinhos, Novo Nordisk, Pfizer, Aspen Pharmacare, Cristália, Enzon Pharmaceuticals, Silvestre Labs

Rh insulin, rEPO-α, monoclonal antibodies, Taliglucerase alfa, PEG-IFN alpha2b, G-CSF, EPO

Israel Teva HGH, IFN alpha2B, G-CSF

Switzerland Biopartners, JW Group Rh-insulin, rhGH, EPO-beta

Canada Cangene, Biocon, Celltrion, Hospira, Roche, Nektar Therapeutics, Sandoz

hGH, R Insulin glargine, EPO-zeta, PEG-IFN alpha2A

Germany Stada, Medice Arzneimittel Pütter EPO-zeta, EPO

S. Africa Bioclones EPO

S. Korea LG Lifescience, Daewoong, Dong-A , Celltrion, Boryung Group, CJ (CheilJedang), Genexine, Hanlim Pharm

Epogen, hGH, EPO, EGFR, GCSF, IFN alpha2A, follitropin, infliximab, EPO-alpha, hCG

Source: Datamonitor strategic analysis pipeline trends December 2011; ADIS, EvaluatePharma and PharmaProjects May 2013

2012/2013 Global Clinical Use of Biosimilars and Alternative Biologics

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Pathway to the Market: US and EU Biosimilar Development

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Definition of Biosimilar/Biosimilarity

A similar biological or 'biosimilar' medicine is a biological medicine that is similar to another biological medicine that has already been authorized for use and it does not have any meaningful differences from the reference medicine in terms of quality, safety or efficacy. Article 8 of Directive 2001/83, as amended.

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…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.” Section 7002(b)(2) of the Affordable Care Act, amending section 351(i) of the PHS Act.

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-http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c -The BPCI Act appears in Title VII, subtitle A of the Patient Protection and Affordable Care Act, March 2010. -US FDA:. Guidances for industry. Quality and Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance Feb 2012.

2004 2009 2011 2006 2007 2008 2012 2010 2013 2005

EMEA Legislative Pathway

EMEA Regulatory Guidance [Overarching Guideline] under revision

Product Class Specific Guidelines: Low molecular weight heparin, recombinant Interferon-alpha

Product Class monoclonal antibodies: non-clinical and clinical issues

Guidelines under revision: Follicle stimulating hormone, Interferon-beta

Product Class Specific Guideline: Erythropoietin (revised)

Quality Guideline; Non-Clinical & Clinical Guideline (under revision )

Product Class Specific Guidelines: Insulin, G-CSF, Somatropin

Product Class Immunogenicity assessment of monoclonal antibodies

PHS Act amended to allow the approval of biosimilars

Overarching Draft Guidelines on biosimilars

Draft revisions to overarching guidelines and nonclinical and clinical guidelines

Europe USA

Biosimilar regulations in EU and USA: different stages of development

• The EU pioneered the development of biosimilar regulations • US overarching guidelines issued

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Generics vs. Biosimilars

Parameter Generics (chemical drugs) Biosimilars

Production source

Chemical synthesis

Living organisms, i.e. cultured yeast, bacteria or animal/plant cells

Active pharmaceutical ingredient

Must be identical to the reference product

Same primary amino acid sequence, the biosimilar active pharmaceutical ingredient is not identical to the reference product

Development batches One batch Generally more than three batches

Characterization Non-comparative Compared with reference product

In vitro non-clinical testing No Yes, compared with the reference product

Non-clinical animal testing No

• Comparative PK/PD (if PD marker is available) in relevant species

• One comparative repeat dose toxicity study in relevant species. If the relevant species is non- human primates, FDA/EMA generally do not require an in vivo non-clinical study unless it is absolutely needed

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Generics vs. Biosimilars

Parameter Generics (chemical drugs) Biosimilars

Clinical – Phase I study Comparative PK/PD (if PD marker available) study in healthy volunteers

Comparative PK/PD (if PD marker available) in healthy volunteers or patients – scientific justification required

Clinical – Phase III studies: safety (including immunogenicity) and efficacy

No

Comparative clinical study(ies) required against the reference product; number of studies required will depend upon the mechanism of action (MOA) for all indications. The number of studies required is assessed by regulators on a case-by-case basis

Pharmacovigilance plan Generally not required, but depends on the drug

Generally required, often mimics reference product’s requirements, but may include additional data for the biosimilar

Post-marketing studies Generally not required Often may be required for late developing adverse events.

Pediatric studies No

In the USA, pediatric studies must be addressed for a biosimilar; however, they are not required for products found to be interchangeable. Not required in the EU.

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Biosimilars: Quality

What should be characterized and compared with reference product? > Comparison of physicochemical parameters (multiple lots of reference products and

biosimilar) » Primary structures, such as amino acid sequence » Higher order structures, including secondary, tertiary, and quaternary structure

(including aggregation) » Enzymatic post-translational modifications, such as glycosylation,

phosphorylation, deamidation and oxidation, among others » N or C terminal truncations; charge variations (isoforms) » Degradants and impurities

> Stability profile

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Biosimilars: Non-clinical Studies

What should be compared with reference product? > In vitro studies – generally performed to assess any possible differences in

bioactivity - Binding to target antigen - Binding to receptors - Fab associated functions (e.g. neutralization, receptor activation or receptor

blockade) - Fc-associated functions (ADCC and CDC assays, complement activation)

> Safety pharmacology, reproduction, mutagenicity and carcinogenicity are generally not required

> In vivo studies – depend upon the need for additional information (residual uncertainty), and the availability of a relevant animal model - Generally, 28-day repeat dose toxicity study is required. If a relevant animal

model not available, determine if transgenic animals or transplant models are available.

- If the relevant animal model is a non-human primate, FDA/EMA generally do not require an in vivo non-clinical study unless it is absolutely needed

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Clinical Safety & Pharmacovigilance

Type of data required: > Comparison of type, frequency and severity of adverse events

> Assessment of anti-drug antibodies, including neutralizing antibodies (immunogenicity assessment)

> Because all differences cannot be detected pre-licensing, a risk assessment will need to be provided for late-occurring safety events seen for the innovator product

> Risk management/pharmacovigilance plan may be required:

- Any PhV measures for the reference product generally will need to be adopted for the biosimilar product

- Any differences seen for the biosimilar product will also need to be addressed

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Immunogenicity: Risk Factors that Can Affect Immunogenic Response

• Underlying disease

• Immune status

• Concomitant medications

• Genetics

• Age

• Dosing schedule

• Route of administration

• Previous exposure to related

proteins

• Manufacturing process

• Varying glycosylation

• Degradation products

• Formulation

• Structural homology

• Post translational modifications

• Chemical modifications

• Impurities from host cells

• Stability

Patient Related Product Related

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Biosimilar Product Development

Both agencies expect a step-wise development plan that can ensure similarity/comparability at each step. The reference product (active comparator) has to be sourced from the respective region. All assessments will be two-way comparability.

> Chemistry Manufacturing and Controls – Analytical comparability

> Non-clinical comparability – in vitro and in vivo (if relevant animal model is available)

> Human PK/PD (if PD biomarker is available) comparability data

> Immunogenicity comparability data

> Efficacy and Safety comparability data

If US or EU only

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Biosimilar Product Development

• Both agencies expect a step-wise development plan that can ensure similarity/comparability at each step.

• Three-way comparability for the following:

> Chemistry Manufacturing and Controls – Analytical comparability > Non-clinical comparability – in vitro and in vivo (if relevant animal model is available) > Human PK/PD (if PD biomarker is available) comparability data

• Two-way comparability for the following (reference product can come from either region):

> Immunogenicity comparability data > Efficacy and Safety comparability data

If both for US and EU

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Extrapolation to other Indications

• The mechanism of action (MOA) in each condition of use for which licensure is sought may include the following:

> The target/receptor(s) for each relevant activity/function of the product > The binding, dose/concentration response, and pattern of molecular

signaling upon engagement of target/receptor(s) > The relationship between product structure and target/receptor interactions > The location and expression of the target/receptors(s)

• The PK and bio-distribution of the product in different patient populations; PD measures may provide important information on MOA

• Differences in expected toxicities in each condition of use and patient population

• Any other factor that may affect the safety or effectiveness of the product in each condition of use and patient population for which licensure is sought

Biosimilar Medicine Development

Considerations and Impact on Clinical Practice

Dr John Patava, Director, Head of Biosimilar Intelligence and Capabilities

Annual Cost of Herceptin vs. Per capita GDP

Source: IMF, Hyundai Securities

List of major biologics by global revenues: Patent expiry products

Source: EvaluatePharma 2012, GaBI, FierceBiotech, GenNews

Brand Name Generic Name Company Revenues 2012 Patent Expiry US

Patent Expiry Ex-US

Humira adalimumab Abbott Laboratories 9,627 31/12/2016 16/4/2018

Enbrel etanercept Amgen 8,519 22/11/2028 1/2/2015

Remicade infliximab Merck & Co. 7,642 4/9/2018 13/8/2014

Rituxan rituximab Roche 7,155 1/1/2018 12/11/2013

Lantus insulin glargine Sanofi 6,378 12/2/2015 30/11/2014

Herceptin trastuzumab Roche 6,283 18/6/2019 28/7/2014

Avastin bevacizumab Roche 6,149 4/7/2019 21/1/2022

NovoLog insulin aspart Novo Nordisk 2,711 7/12/2014 31/12/2017

Tysabri natalizumab Elan 2,457 26/4/2017

Aranesp darbepoetin alfa Amgen 2,040 1/1/2024 1/1/2016

Erbitux cetuximab Bristol-Myers Squibb 1,843 13/2/2016 29/6/2014

Xolair omalizumab Roche 1,793 31/12/2018 31/12/2017

Introduction of biosimilar products drives down cost of biological medicines

Adapted with permission from Macmillan Publishers Ltd: Clin Pharmacol Ther (McCamish M and Woollett G. The state of the art in the development of biosimilars. 91(3):405–417), © 2012

Biosimilars can improve healthcare • Biosimilars can enable previously restricted therapies to become part of the accepted

standard of care • In the UK, patients have benefited from lower acquisition costs and improvements in

the practice of medicine after the approval of a filgrastim biosimilar • This has enabled the routine use of filgrastim (as a biosimilar) as a first-line treatment

for the first time

-2 -5

13

17

2007 2008 2009 2010

November 2008

biosimilar approved

Note: Zarzio® (filgrastim) is not marketed in the United States.

UK filgrastim volume growth percent change vs. previous year

• Many physicians moved filgrastim back to first-line cancer treatment because of lower biosimilars cost

• G-CSF prevents hospital readmission owing to infection

• Biosimilars are less expensive than originator biologics

• Zarzio “patient support kits” expand patient access: – Patients self-administer at home – Efficiency savings repatriated

Planning biosimilar clinical trials

Drug development paradigm turned upside down

Clinical Trials

PK/PD

Pre-Clinical

Analytical

Originator Development Biosimilar Development

Difference between originator and biosimilar development

Drug Discovery

Factors Influencing Clinical Trial

Design

Safety experience of the innovator

product

Biological class

Molecular weight

Molecular complexity

Nature of the indication and

patient populations

Complexity of endpoints of pivotal trials for innovator

How well mechanism of action and targets of innovator have been

characterized

Immunogenicity of the innovator

Existence of reliable biomarkers

Factors Influencing Biosimilars Trial Design

Same Biosimilar Product: Different Indications

Indication* Rheumatoid Arthritis Psoriasis

No. of enrolled subjects 600 300

No. of sites 115 64

No. of countries 14 8

Duration of trial 27 months 18 months

Cost 100% 40%

Biological medicines that act through inhibition of TNF-α activity are indicated for multiple clinical conditions including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis

*Two evaluations were consistent wrt to Statistical plan. Test was equivalence, Similar assumptions for margin and power.

Buy-in from regulatory agencies

• The FDA encourages sponsors and applicants to use the meetings described in this guidance to optimize product development and facilitate submission of marketing applications

• Companies can request scientific advice or protocol assistance either during the initial development of a medicinal product before submission of a marketing-authorization application or later on, during the post-authorization phase

Participating in Biosimilars Research

• Benefits of biosimilars research to patients: – Regulatory agencies have given careful consideration to patient safety in

putting together biosimilar regulatory guidelines – During clinical trials, patients have access to an active medicine, either

biosimilar or originator. There is no placebo arm – Increase affordability and accessibility to biological medicines – Enable previously restricted therapies to become part of the accepted

standard of care – Allow these medicine to be used earlier to treat patients – Enable more patients to be treated for the same drug budget, and free more

resources to be used elsewhere

Biosimilars Knowledge Connect

• Launched in October 2012, Quintiles Biosimilar Knowledge Connect seeks to: – Proactively educate investigators and site staff about biosimilars in 30

countries – Establish a global network of study sites, Biosimilar Investigator Connect – Improve site recruitment and retention – Prepare operational staff

• BiosimilarsKnowledgeConnect.com – Fact sheets, Q&A – Physician guide – Patient education tools – Learning modules – Videos of Quintiles and industry KOLs – Quarterly newsletters

Educating and building the biosimilar sites of today and tomorrow

Over 740 investigators have registered with Biosimilars Investigator Connect (Oct 2013)

Thank You For Your Participation

• Thanks to Kamali for a great summary of the regulatory pathways for biosimilar development and registration – Serves to give great confidence in the oversight of

biosimilar development • There is good evidence to suggest that biosimilar

products have a role to play in future clinical practice – Opportunity for broader access and application of

biological medicines

Copyright © 2013 Quintiles

Biosimilars Knowledge Connect Webinar 4th November 2013

www.BiosimilarsKnowledgeConnect.com