Design and Implementation of Biosimilar Development

Programs

Dr. Nigel Rulewski Vice President,

Global Strategic Drug Development Quintiles

NY Pharma Forum 31st January 2012

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Established multinational bio-pharmaceutical companies Generic companies Biotech – small independent and large conglomerate backed Local, regional and global

Unprecedented Interest in Biosimilars

Downsizing for almost every major

pharmaceutical company

Major failures in late stage drug development

Products withdrawn from the market

Reduced availability of venture funding

Patent expiration of major blockbuster

products

Country Marketed Biosimilars* Companies

GH, Heparin Sandoz, Momenta, Merck (Bioventures Division), Pfizer, Lilly, J&J, Protalix, Biotherapeutics, Momenta Pharma, Hospira, Itero, Phage Biotech

GH, EPO, G-CSF, IFN alpha2B, EPO Sandoz, Teva, Biopartners, Medice Arzneimittel Pütter , CT Arzneimittel, Ratiopharm , AstraZeneca, GSK, Novo Nordisk, Sanofi Aventis

GH, G-CSF, GM-CSF, IL-2, Zenotech Sandoz, Daiichi Sankyo (Ranbaxy),

GH, EPO, G-CSF, Peg-GSF, IFNa, insulin, teriparatide, mAbs, Regen-D (rhEGF), Indikina, se (streptokinase), Glargine, Lispro, Aspart, EPO, G-CSF, Streptokinase

Bharat Biotech International, Dr. Reddy's Laboratories, Shantha Biotechnics Ltd, Wockhardt, Biocon , Intas Biopharmaceuticals, Lupin, Reliance Life Sciences

GH, EPO, G-CSF, PEG-GSF, IFNa, IL-2, IL-11, insulin Beijing Tri-Prime Genetic SinoBiomed Inc., Shanghai Sunway Biotech, 3SBio Inc., Shenzhen Kexing Biotech, Amoytop Biotech Co. Ltd., CP GuoJian Pharmaceutical, GeneScience Pharmaceuticals

Recombinant human erythropoietin, Recombinant human interferon alfa-2b, Recombinant human interferon alfa-2a, Filgramosim rHu G-CSF

Probiomed, SICOR Biotech UAB

Vaccines (Recombinant hepatitis B surface antigen, Attenuated virus, Autologous whole cell) Therapeutics (Recombinant human insulin, Recombinant erythropoietin-α, Monoclonal antibodies)

Instituto Butantan, FK Biotecnologic, Bio-Manguinhos, Novo Nordisk

HGH, IFN alpha2B, G-CSF Teva

Rh-insulin, rhGH Biopartners

hGH Cangene

EPO-zeta Stada

EPO Bioclones

Epogen, hGH, EPO, EGFR, GCSF, IFN alpha2A, follitropin LG Lifescience, Daewoong, Dong-A

US

EU

Japan

India

China

Mexico

Brazil

Israel

Switzerland

Canada

Germany

S. Africa

S. Korea

Generic Companies and Pharmemerging Players are Penetrating Markets

*GH and Heparin approved in US under FFD&C Act via 505(b)(2) pathway

Global Regulatory Guidelines for Biosimilars

Snapshot as of January 2011

Europe Pathway in place 2005

USA Guidance in development

Canada Draft guidance issued 2010

Australia Using the EU Approach 2006

Japan Final guidance issued 2009

WHO Final recommendations issued (2010)

Brazil Final guidance issued 2010

India Draft guidance issued 2011

China No specific pathway for biosimilars

Russia No specific pathway for biosimilars

ROW

Some countries are beginning to implement guidance following EMA or WHO (e.g. Malaysia, Taiwan, Korea); many others do not have the healthcare infrastructure to support complex biologics

The EMA set precedent guidance for biosimilar approvals for certain product classes in 2006, and recently followed up with draft guidance for monoclonal antibodies.

The WHO, in order to encourage regulatory harmonization across markets, also finalized guidance in 2010. Many countries are now forming their own guidance, referencing either the EMA or WHO.

Russia

China

India

Brazil

USA

Canada

Europe

Australia

Japan

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Status of Guidelines

Country Inception Approval Pathway

Argentina Sept 09 Biologic and biosimilar approval guidance

Malaysia Jul 09 Guidance for Registration of Biosimilars in Malaysia

Mexico Jun 09 Article 222 of the General Health Law

Saudi Arabia

Dec 10 Guidelines on Biosimilars Version 1.1

Singapore Apr 10 Guidance on Medicinal Product registration in Singapore

South Korea

Sept 10 Guidelines on Evaluation of Biosimilar Products

Taiwan Nov 08 Market Approval of Biosimilar Products

Turkey Aug 08 Instruction Manual on Biosimilar Medical Products

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Recent Changes to Guidelines

– US user fees will be set at the same level as innovative fee.

– US user fees may vary between $770,000 -$1.54m.

– US Biologic exclusivity requirements may be reduced from 10 to 7 years.

– EMA issued concept paper of reform of biosimilar guidelines to incorporate all they have learnt over last six years.

– EMA and FDA plan to collaborate of biosimilar development requirements and approvals.

Over View of EU Guidelines Biosimilars must demonstrate close similarity/comparability to

the innovator/originator reference product in respect of: CMC nonclinical and

clinical (efficacy & safety)

Biosimilars must be comparable to the original molecule and

the development strategy should be defined on a case by case basis as agreed by regulators.

Clinical development in stepwise fashion though pk/pd and

clinical equivalence.

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EMA Approval Requirements for Biosimilars vs Biologics The EMA guidance provides a legal framework, general requirements and guidelines to ensure quality,

safety, and efficacy of approved biosimilar products since 2005

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Reference Biologic Biosimilar

CMC Quality Studies

Non-Clinical Studies

Pharmacokinetics -- Pharmacodynamics in vitro & in vivo

Toxicology

• Single & Repeat dose toxicity

• Safety pharmacology • Reproduction toxicology

• Mutagenicity • Carcinogenicity • Immunogenicity

• Repeat dose toxicity

• Local tolerance testing • Immunogenicity

Clinical Studies

Pharmacokinetics

Pharmacodynamics

Clinical Efficacy • Each indication

• Comparative, in single indication

Clinical Tolerability • Each indication

• Comparative, in single indication

Source: www.ema.europa.edu

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Overview of a Biosimilar Clinical Development Program

Simple Overview

– Stepwise approach through Phase I and Phase III.

– Phase I pharmacokinetic comparison of Biosimilar to innovator product, to establish single dose and steady state pharmacokinetics.

– Phase III comparison of Biosimilar to innovator product to clinical endpoint.

– Phase I and III may be combined in one continuous study.

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Choice of Reference Product

– All guidelines state comparator product must be the product marketed in territory in question.

– EU and US markets are often supplied by different manufacturing sites for a particular product.

– Even when all product is made in one plant –final filling for EU and US markets may be conducted at different sites and into different containers.

– Does this mean a world wide biosimilar program has two comparator products, one from the EU and another from the USA.

– EU regulators are being very firm on need to conduct comparator trial with local product.

– How is this being dealt with in practice?

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Overview of a Biosimilar Clinical Development Program

– Pharmacokinetic comparison of Biosimilar to innovator product –single doses in healthy volunteers or patients.

– These studies are three way comparisons---Biosimilar vis US sourced innovator vis EU sourced innovator.

– Pharmacokinetic equivalence requires comparison at steady state-this may also require a three arm study.

– Multiple dose pharmacokinetic studies are conducted as standalone or as part of the large Phase III comparison with Innovator product in a combined Phase I/III Study.

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Overview of a Biosimilar Clinical Development Program

– EMA have remained firm on need to use EU marketed innovator product.

– FDA have shown signs of accepting EU product as active comparator once

pharmacokinetic equivalence has been shown between EU and US innovator products.

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Overview of a Biosimilar Clinical Development Program

Reference Indication Phase I three way comparison

Biosimilar

EU innovator

US innovator

Biosimilar

Phase III Efficacy comparison

EU innovator product?

This may all be conducted within one continuous study or as two separate standalone studies

Additional Major Indication Phase I comparison to steady state

Biosimilar

EU innovator product

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Choice of Reference Indication

– EU Guidelines suggest choice of reference indication should be based on which is the most sensitive indication.

– If mechanism of action can be shown or is believed to be the same in other indications, extrapolation /assumption of efficacy in those indications is possible.

– Even if efficacy is extrapolated to other indications, pharmacokinetic data may be needed in additional major indications.

– Will EMA and FDA agree on when efficacy can be extrapolated to other indications??

Best Selling Drugs of 2009

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Source: Evaluate Pharma, PWC Biotech Reinvented.

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Choice of Reference Indication and Extrapolation

RA Cancer Juv Arthritis

Psoriatic Arthritis

Ank Spon

Plaque Psoriasis

Crohn’s Disease/UC

Rituximab X NHL/CLL

Enbrel X X X X X

Remicade X X X X X

Humira X X X X X X

• Clearly RA is the largest indication for all four products. • RA is also the most sensitive indication, possibly with the exception of plaque psoriasis with Remicade, psoriatic arthritis with Humira- viable reference indications? • Can you extrapolate Rituximab efficacy in RA to Oncology indications? • Can you extrapolate Remicade and Humira efficacy in RA to Crohn’s or UC?

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Choice of Reference Indication and Extrapolation

Herceptin – Choice of indication is less difficult with oncology products Avastin and Herceptin. – Herceptin approved for adjuvant therapy and metastatic breast cancer (also

gastric cancer). – Adjuvant setting would require a very large sample size and a multi year trial.

– Metastatic breast cancer is the only viable indication for biosimilar work and

extrapolation should not be an issue. ORR or PFS as endpoints.

Avastin – Approved for colorectal, non small cell lung cancer, glioblastoma and metastatic

renal cell carcinoma.

– Colorectal would be the obvious choice and extrapolation should not be an issue.

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Equivalence Margins

– Small Molecule Bioequivalence based on pharmacokinetic comparisons using equivalence margins of 0.8-1.25.

– These margins may be too wide even for some small molecules i.e. anti-epileptics.

– Certainly they are two wide to demonstrate equivalent clinical efficacy.

– US Non inferiority guidelines are being utilized for determining equivalence

margins. Calculate the non inferiority margin and then make it a two sided test.

– These calculations produce margins that are much tighter, (+/- 0.15) with dramatic effects on sample size.

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Primary Efficacy Endpoints or Surrogate Endpoints

– EU Guidelines allow for provision of use of proven surrogate endpoints.

– Objective is to show similarity not prove the compound is efficacious-the innovator has already achieved this.

– Rituximab, Remicade, Enbrel and Humira will most likely use ACR 20 the primary endpoint used by innovator. None have proven validated surrogates. Some programs including DAS 28.

– Herceptin and Avastin can most likely use Overall Response Rate (ORR) to show similarity.

– No examples of use of surrogates found on Clinicaltrials.gov.

Challenges in Clinical Trials

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Little incentive for patients to participate if the innovators product is available and reimbursed

Lack of interest by investigators that are motivated by new science for publication or presentations

Health agency guidelines tend to require the use of the comparator drug authorized in their respective territory

Sample size for Phase III study can be large (N= 600 - 2,000)

Challenges in Clinical Trials

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Oncology and RA are highly competitive due to large numbers of innovative products in development

Rituximab is a particular challenge in that it is approved as second line to anti TNFs. Biosimilar trials will need to be conducted where anti TNFs are available

Site selection and trial design will be pivotal to the success of biosimilar trials

Psoriasis

RA

Competitive Landscape: Etanercept

Innovator Drug (Biobetter)* Neurokine Worldwide

Protalix Worldwide

Hisun China

Avasthagen India

Ranbaxy India

BioAssets Development Worldwide

Mycenax Worldwide Cipla

India

Shangai Celgen China (Registered)

Zenotech/Ranbaxy India

Unspecified / Other

CPGJ / Lafrancol China Colombia

Indications

Simcere China

Celgene / Abraxis US/Canada

LG Life Sciences Worldwide

EMS (Reumatocept) Brazil

AS

Merck/Hanwha Korea / Worldwide?

3SBio China

Zenotech India

Green Cross Korea

Genexine Korea

*Assumption: Could file as a novel biologic (“biobetter”) rather than a biosimilar Source: Pharma Projects, 2011; Evaluate Pharma, 2011; Nomura AEJ, May 2011; Clinicaltrials.gov; Company websites

Biosimilar Development Cost and Time

Measure Conventional Generic

Biosimilar Biologic

Development Time

3-4 years 6-8 years 10-15 years

Development Cost

<$5m $1m - $2m

• $10m - $150m • India ave $10-$20M • US ave $50-70M

$250m - $500m

Profit Margin ~20% 30% (expected)

Manufacturing Facility Cost

~ $20M • ~$ 30M for bacterial

• $200-$300M for mammalian

• ~$ 30M for bacterial

• $200-$300M for mammalian

Selling Price (vs innovator)

Up to 95% discount

• 20-50% discount • Japan 70%

innovator price

Source: Credit Suisse, Biosimilars 101, Aug 2009

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Issues in Biosimilar Development

– Lifecycle management strategies being introduced by innovators to restrict biosimilar uptake.

– Amgen awarded new composition patent on Enbrel that may block biosimilars until 2028.

– Amgen entered into multi-year supply deals with distributors for Epogen.

– Genentech developing S/C formulation of Herceptin.

– Innovator manufacturers are blocking access to product to conduct biosimilar clinical trials.

– Distributors charging higher prices for innovator product to be used in clinical trials.

Summary

1. Biosimilars offer a great opportunity – US $45 billion will lose patent protection in the next 5 years.

2. There is an unprecedented level of interest in biosimilars, drawing a large number of companies

into the field. 3. Clinical trials required are large and expensive.

4. Costs will be high but risk is relatively low (compared to NCEs).

5. Selection of territories, sites and clinical trial design will be key to the success of these programs

6. Multiple biosimilar developers may saturate the ability to conduct the required clinical trials

7. Watch clinicaltrials.gov to see what the market leaders are doing.

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Thank you

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