Biosimilars Knowledge Connect Webinar 4th November 2013

www.BiosimilarsKnowledgeConnect.com

Copyright © 2013 Quintiles

The Biosimilars Investigator Network

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

The purpose of the Biosimilars Knowledge Connect program is to:

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

Biosimilars Knowledge Connect The story so far...

740+ investigators registered to date across all regions

Quarterly newsletters

Slide resource deck offered to all who register

42 respondents to the Biosimilars Knowledge Connect Community survey (Q1 2013)

65% of survey responders rating the website as ‘helpful’ or ‘very valuable’

Localized investigator guides • Re-designed Biosimilars Knowledge for Europe, Asia and the Connect website including: Americas > Biosimilars study update section > Congress update section > Variety of resource libraries including video, newsletters and written resources

Biosimilars Knowledge Connect program factsheet

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

Agenda Topic Regulatory Update: Focus on US/EU requirements

Presenter Dr Kamali Chance, Senior Director Head of Global Biosimilars Regulatory Strategy

Q&A Global Biosimilar Development and impact on clinical practice Q&A Closing remarks

Time 20 Minutes

5 Minutes

Dr John Patava, Senior Director Head of Biosimilars Intelligence and Capabilities

20 Minutes

5 Minutes

Biosimilars: Focus on US/EU Requirements

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

Copyright © 2013 Quintiles

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

6

What are Biologics/Biosimilars?

7

Terminology Terminology

Synonyms

Definition • 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

Biologic Product

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

8

Innovator Biologics

All trademarks mentioned herein are the property of their respective owners 9

Biosimilar ≠ Generic

Small molecule

Biological medicine

 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

Generics

Biosimilars

Source: J. Mascaro: Regulatory evaluation of therapeutic biological medicines, Aug 15, 2007 10

2012/2013 Global Clinical Use of Biosimilars and Alternative Biologics Country

Companies

Marketed Marketed alternative biosimilars/followbiologics on biologics

USA

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

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

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

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 11

2012/2013 Global Clinical Use of Biosimilars and Alternative Biologics 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, EPObeta

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

S. Korea

Epogen, hGH, EPO, LG Lifescience, Daewoong, Dong-A , Celltrion, EGFR, GCSF, IFN Boryung Group, CJ (CheilJedang), Genexine, alpha2A, follitropin, infliximab, EPO-alpha, Hanlim Pharm hCG

EPO

Source: Datamonitor strategic analysis pipeline trends December 2011; ADIS, EvaluatePharma and PharmaProjects May 2013 12

Pathway to the Market: US and EU Biosimilar Development

13

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.

14

Biosimilar regulations in EU and USA: different stages of development • The EU pioneered the development of biosimilar regulations • US overarching guidelines issued

Product Class monoclonal antibodies: non-clinical and clinical issues

Product Class Specific Guideline: Erythropoietin (revised)

EMEA Legislative Pathway

2004

2005

EMEA Regulatory Guidance [Overarching Guideline] under revision

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

2006

2007

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

Product Class Immunogenicity assessment of monoclonal antibodies

Guidelines under revision: Follicle stimulating hormone, Interferon-beta

2008

2009

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

2010

2011

PHS Act amended to allow the approval of biosimilars

Draft revisions to overarching guidelines and nonclinical and clinical guidelines

2012

2013

Overarching Draft Guidelines on biosimilars

Europe

USA

-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.

15

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

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 nonhuman primates, FDA/EMA generally do not require an in vivo non-clinical study unless it is absolutely needed

Non-clinical animal testing

16

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.

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.

Pediatric studies

17

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

18

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 19

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

20

Immunogenicity: Risk Factors that Can Affect Immunogenic Response Patient Related

Product Related

• Underlying disease

• Manufacturing process

• Immune status

• Varying glycosylation

• Concomitant medications

• Degradation products

• Genetics

• Formulation

• Age

• Structural homology

• Dosing schedule

• Post translational modifications

• Route of administration

• Chemical modifications

• Previous exposure to related

• Impurities from host cells

proteins

• Stability

21

Biosimilar Product Development If US or EU only

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

22

Biosimilar Product Development If both for US and EU

• 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

23

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 24

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 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

Source: EvaluatePharma 2012, GaBI, FierceBiotech, GenNews

Introduction of biosimilar products drives down cost of biological medicines

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 UK filgrastim volume growth percent change vs. previous year

November 2008 biosimilar approved

-2 2007

17 13

• 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

-5 2008

2009

2010

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

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

Planning biosimilar clinical trials

Difference between originator and biosimilar development Originator Development

Biosimilar Development

Clinical Trials PK/PD Pre-Clinical

Analytical

Drug Discovery

Drug development paradigm turned upside down

Factors Influencing Biosimilars Trial Design Molecular complexity Existence of reliable biomarkers

Immunogenicity of the innovator

Factors Influencing Clinical Trial Design

Biological class Complexity of endpoints of pivotal trials for innovator

How well mechanism of action and targets of innovator have been characterized Molecular weight

Nature of the indication and patient populations Safety experience of the innovator product

Same Biosimilar Product: Different Indications 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

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%

*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

Educating and building the biosimilar sites of today and tomorrow

• 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

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

Biosimilars Knowledge Connect Webinar 4th November 2013

www.BiosimilarsKnowledgeConnect.com

Copyright © 2013 Quintiles