AIPPI World IP Congress 2014 Workshop Pharma 2 Biosimilar pharmaceutical products

An Industry Perspective

September 16, 2014 Masahisa Yamaguchi, PhD Department Manager Intellectual Property Dept. Chugai Pharmaceutical Co., Ltd.

About Chugai Pharmaceutical Co., Ltd.

1

Head Office: Tokyo, Japan Revenue: \423.7 billion (Dec. 31, 2013) Number of Employees: 6,872 (Dec. 31, 2013) Principal Shareholder: Roche Holding Ltd (61.56%)

Oncology 45.3%

Bone&Joint Diseases

24.5%

Renal Diseases

12.8%

Others 17.4% AVASTIN

HERCEPTIN RITUXAN XELODA NEUTROGIN/GRANOCYTE TARCEVA etc.

EPOGIN MIRCERA OXAROL RENAGEL etc. ACTEMRA /RoACTEMRA

EDIROL ALFAROL etc.

PEGASYS TAMIFLU SIGMART COPEGUS CELLCEPT etc.

RedBio-products

1. Scientific Aspects of Biologics and Biosimilars

2. Regulations and Guidelines for Biosimilars

3. Development Status of Biosimilars

Table of Content

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1. Scientific Aspects of Biologics and Biosimilars

2. Regulations and Guidelines for Biosimilars

3. Development Status of Biosimilars

Table of Content

3

Types of Pharmaceuticals

Molecular Weight

1,000 100 10,000 100,000

180 Aspirin

447 Pravastatin

5,807 Insulin

150,000 Antibody

30,000 Epoetin beta

1,202 Ciclosporin

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Chemical Products Biological Products Manufacturing

Chemical synthesis Relatively simple

manufacturing process

Biological synthesis using human DNA, bacterial or animal cell lines

Complex manufacturing process

Characteristics Small, simple, low molecular weight

Rigid and stable structure

Large, heterogeneous, high molecular weight

Flexible and labile structure

Characterization Easy to characterise and purify

Difficult to characterise and purify

Examples Conventional drugs Protein product, Antibody product

Size, Structure & Complexity

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Size

C

ompl

exity

Large molecule drug

Human growth hormone

(hGH) ~ 3,000 atoms

Car ~ 3,000 lbs

Large biological drug

IgG antibody ~ 25,000 atoms

Business jet ~ 25,000 lbs (without fuel)

Small molecule drug

Bike ~ 20 lbs

Aspirin 21 atoms

Manufacturing Process for Biologics

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Master cell line

Each stage of the complex manufacturing process confers unique properties on the resulting biologic product: The process is the product

Small Molecule Drugs and Biological Drugs

Small molecule drug Biological drug Active ingredient

Variant (active)

Variant (inactive)

Impurity (host)

Decomposed

Impurity (process)

Homogeneous Single molecule

Heterogeneous Mix. of various molecules

Active

Inactive

Even if a biosimilar developer uses the same DNA sequence as the innovator, the final biosimilar drug will differ from the reference drug:

clinical outcomes of a biosimilar drug also could differ 7

8

Similarity in Biologics

Efficacy

Safety

Reference product

Biosimilar product

Similarity

Biosimilar developers can use only a part of Quality Characteristics: intensive and detailed evaluation and comparison should be required

Immunogenicity

Quality Characteristics Physicochemical Biological Surrogate maker Pharmacokinetics Pharmacodynamics

Manufacturing Process Master cell Culture conditions Purification Formulation

Experience/Know-how Manufacturing Analysis Biological Clinical

Factors Affecting Similarity Clinical Outcomes

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Heterogeneity of EPO Products

Difference in Reditux and Rituxan

10

0

40

80

120

160

0 10 20 30 40 50

AU

FS @

280

nm

Time (minutes)

Rituxan Ref Mat

Reditux

Same amino acid sequence Host cell protein content much higher Content of aggregates not comparable Glycosylation not comparable Effector function not comparable

Different manufacturer means: Different drug Different clinical profile?

Comparison by Cation Exchange Chromatography

R. Harris (2008) presentation at Biogenerics 2008 Data source: Genentech (Matt Field, Susan Gruerman)

Reditux (Dr. Reddy) April 30, 2007

Intended copy

Scientific Aspects of Biological Drugs

Small Molecule Drugs: Possible to produce the exact copy of a reference drug Biological Drugs: Impossible to produce the exact copy of a reference drug

Complexity of the structure and 3D-conformation Heterogeneous mixtures of protein molecules with different physical, chemical and biological properties Limited scientific approaches to assess chemical and biological characteristics Variations in the manufacturing process

It is necessary for the market approval of a biosimilar to conduct clinical tests for efficacy and safety in addition to quality characteristics

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1. Scientific Aspects of Biologics and Biosimilars

2. Regulations and Guidelines for Biosimilars

3. Development Status of Biosimilars

Table of Content

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Guidelines for Biosimilars JP Guideline for ensuring quality, safety and efficacy of biosimilars (2009.3.4)

US

Draft: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (2012)

Draft: Quality considerations in Demonstrating Biosimilarity to a Reference Protein Product (2012)

Draft: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (2012)

Draft: Clinical Pharmacology Data to support a Demonstration of Biosimilarity to a reference Product (2014)

EP

[General] Similar biological medicinal products (2005.10)

[Quality issues] Similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (2006.6)

[Non-clinical, clinical issues] Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (2006.6)

[Product class specific guidelines] insulin (2006.7) revised (2012), somatropin (2006.7), G-CSG (2006.7), IFN-alpha (2009.4), LMW-heparins (2009.10), EPO (2006.7) revised (2010.9), Mab (2012.12), IFN-beta, FSH (2013.9)

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Major Features of JP/EU/US Guidelines

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JP EP US Frame-work

Single guideline covering all biotech-based drugs

An overarching GL + GLs for quality and non-clinical and clinical issues + Product class specific GLs

Draft: Scientific Considerations, Quality Considerations, Clinical Pharmacology Data

Basic concept

Evaluation by comparability studies on quality and PK/PD profiles, together with clinical data complementing the data (case-by-case and step-by-step approach)

Proof of similarity in combination of quality, non-clinical and clinical study data based on comparative studies (case-by-case)

FDA recommends a stepwise approach to assess the demonstration of biosimilarity using a totality-of-the-evidence approach.

PV

Plans for post-marketing surveillance study and risk management required at submission of application

Naming

Different nonproprietary and brand names required distinguishable from the reference drug and other biosimilar drugs

same nonproprietary name as the reference drug

No mention

Image of Data Requirements in Japan

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Not available for biosimilar developer

Quality Non-clinical

PK/PD Efficacy Safety Post- marketing

Clinical

Quality characeristics of

biosimilar (full data)

Comparability to the comparator

Comparability data required by ICH Q5E

Case-by-case Step-by-step

Depends on data until then

Process

Manufacturing

Comparative Data Independent Data

Biosimilar Naming

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WHO A different nonproprietary name from the reference drug INN of the reference product + a unique suffix (called a biological qualifier)

EP The same nonproprietary name as the reference drug

Australia A different nonproprietary name from the reference drug ABN of the reference product + a biosimilar identifier

Japan A different nonproprietary name from the reference drug JAN of the reference product + JAN biosimilar + number

Reference Product: Filgrastim (recombinant) First Biosimilar by Mochida : Filgrastim (recombinant) [filgrastim biosimilar 1] Second Biosimilar by NK: Filgrastim (recombinant) [filgrastim biosimilar 2]

For Trade name: JAN of the reference product + BS + Dosage form + company name

Reference Product: Neupogen First Biosimilar by Mochida: Filgrastim BS injection [Mochida] Second Biosimilar by NK: Filgrastim BS injection [NK]

Debates on Biosimilar Naming

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Should biosimilars go by a different nonproprietary name ? Pros:

Biologicals are scientifically different than traditional chemical drugs No two biological products made from different cell lines and/or using

different manufacturing processes are ever identical to the reference product they aim to replicate

Knowing specifically which product, and by which manufacturer it was produced that a patient received is essential to keeping medicines and patients safe

Cons: The lack of global consistency for naming of biosimilars will result in a loss of

scientific basis for naming, confusion and uncertainty for practitioners and patients and inappropriately delayed access to affordable biologicals

The current INN scheme works well within the EU and that the creation of new names/identifiers will cause confusion and constitutes a safety issue

It is not problematic to identify the biological products, which are subject to adverse reaction reports

1. Scientific Aspects of Biologics and Biosimilars

2. Regulations and Guidelines for Biosimilars

3. Development Status of Biosimilars

Table of Content

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Development Status of Biosimilars Product Biosimilar Company Reference EP US JP

Somatropin /hGH

Omnitrope Somatropin BS Sandoz (Novartis) Genotropin (Pfizer) Apr. 2006 May 2007* Jun. 2009

Valtropin BioPartners (Bioton) Humatrope (EliLilly) Apr. 2006 Apr. 2007* -

Epoetin alfa

Abseamed Medice Arzneimittel Eprex/Erypo (J&J) Aug. 2007 - -

Binocrit Sandoz (Novartis) Eprex/Erypo (J&J) Aug. 2007 - -

Epoetin alfa Hexal Hexal Eprex/Erypo (J&J) Aug. 2007 - -

Epoetin zeta Retacrit Hospira Eprex/Erypo (J&J) Dec. 2007 - -

Silapo Stada Eprex/Erypo (J&J) Dec. 2007 - -

Epoetin theta Eporatio Ratiopharm Eprex/Erypo (J&J) Oct. 2009 - -

Biopoin Teva/CT Arzneimittel Eprex/Erypo (J&J) Oct. 2009 - -

Epoetin kappa Epoetin alfa BS JCR/Kissei Espo (Kyowa-Kirin) - - Jan. 2010

Filgrastim

Biograstim CT Arzneimittel Neupogen (Amgen) Sep. 2008 - -

Filgrastim ratiopharm Ratiograstim Ratiopharm Neupogen (Amgen) Sep. 2008 - -

Tevagrastim Teva Neupogen (Amgen) Sep. 2008 Aug. 2012** -

Zarzio Sandoz (Novartis) Neupogen (Amgen) Feb. 2009 - -

Filgrastim Hexal Hexal Neupogen (Amgen) Feb. 2009 - -

Nivestim Hospira Neupogen (Amgen) Jun. 2010 - -

Filgrastim BS Fuji/Mochida Gran (Kyowa-Kirin) - - Nov. 2012

Filgrastim BS Teva/NihonKayaku Gran (Kyowa-Kirin) - - Feb. 2013

* Based on FDCA 505(b)(2), not as a Biosimilar **Based on BLA , not as a Biosimilar As of Feb. 2013 19

Current Situation of Biosimilars

Development cost Small compound drugs: over 800M USD, 8-10 years, 500-1000 patients Generics: 2-3M USD, 2-3 years, 20-50 patients Biosimilars: 75-250M USD, 6-8 years, 100-500 patients

Price

10-35% reduction in price compared to reference product in EP and JP Penetration

EU market penetration (volume) of hGH, EPO, G-CSF is 10-30% JP market penetration (volume) is slower than EP situation Substitution

Authorities in EP and JP are against biosimilar substitution

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Competitive Powers of Biosimilars

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Additional Cost for Biosimilars Production Cost Pre-clinical Clinical Post-marketing Surveillance

Biosimilar Price

Price competitiveness of Biosimilars

Reference Product Price

Generic Price

Price competitiveness of Generics

Price Reduction

=

The price difference between the reference biological product and biosimilars are small and cannot be an effective driver for penetration

0

50,000

100,000

150,000

200,000

250,000

300,000

350,00019

9019

9119

9219

9319

9419

9519

9619

9719

9819

9920

0020

0120

0220

0320

0420

0520

0620

0720

0820

0920

1020

1120

1220

1320

1420

1520

1620

1720

1820

1920

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Other biotech productBioengineered vaccineMonoclonal antibodyRecombinant product

Antibodies: Still a Market Growth Driver

Source: Evaluate Pharma

million USD)

As of 2014.07 22

Biosimilar Monoclonal Antibody

Clinical Trial Registration Approved

Infliximab Pfizer, Samsung, Reliance, Sanofi/Nichiiko

Celltrion in US (2014) , Hospira/Celltrion in EP and KR (2013), Nippon Kayaku in JP (2014),

Etanercept Sandoz, Samsung, LG Lifesciences, Reliance

Hanwha in KR Cipra in IN, Probopmed in MX, Shanghai CPG in CN and others.

Adalimumab Pfizer, Fujifilm/Kirin, Boehringer Ingelheim

Rituximab Pfizer, Sandoz, Boehringer Ingelheim, Lanbaxy, Reliance

Shanghai CPG in CN Dr Reddys (IC) in IN, Probiomed in MX (2013), Biocad in RU (2014)

Trastuzumab Pfizer, Reliance, Nippon Kayaku, Probiomed, Hanwha

Celltrion in KR, Shanghai CPG in CN

Mylan in IN (2014)

Bevacizumab

Pfizer, Reliance, Amgen/Actavis, Boehringer Ingelheim

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Unsuccessful Development of Biosimilar Antibody

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Teva halts phase III biosimilar rituximab trial (GaBI Online, 12/10/2012) Israel generics giant Teva Pharmaceutical Industries (Teva) has suspended its phase III trial of its biosimilar version (TL011) of Roches Rituxan/MabThera (rituximab). [Collaborating with Lonza]

Samsung halts biosimilar rituximab development (GaBI Online, 19/10/2012)

South Korean electronics giant Samsung has halted clinical development for the biosimilar version (SAIT101) of Roches Rituxan/MabThera (rituximab). [Collaborating with Biogen Idec]

Celltrion Drops Late-Stage Trial of Roche Rituxan Drug Copy (Bloomberg,

18/04/2013) Celltrion Inc. dropped a late-stage trial of a biosimilar version of Roche Holding AG best-selling Rituxan drug, potentially benefiting competitors such as Boehringer Ingelheim GmbH and Novartis AG.

Summary

Biological products are complex and difficult to produce exactly the same product unlike small molecule generic drugs

Generally, intensive quality data and non-clinical and clinical study data based on comparative studies are necessary for biosimilar market approvals

Current evidence suggests that biosimilars show a relatively slow market penetration

Biosimilar monoclonal antibodies are the next target and many companies including innovator companies and companies from the outside industry are trying to enter the market

Successful development of biosimilar monoclonal antibodies might require strong technical and financial power

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Thank you for your attention!

Slide Number 1About Chugai Pharmaceutical Co., Ltd.Table of ContentTable of ContentTypes of PharmaceuticalsSlide Number 6Manufacturing Process for BiologicsSmall Molecule Drugs and Biological DrugsSimilarity in BiologicsHeterogeneity of EPO ProductsDifference in Reditux and RituxanScientific Aspects of Biological DrugsTable of ContentGuidelines for BiosimilarsMajor Features of JP/EU/US GuidelinesImage of Data Requirements in JapanBiosimilar NamingDebates on Biosimilar NamingTable of ContentDevelopment Status of BiosimilarsCurrent Situation of BiosimilarsCompetitive Powers of BiosimilarsAntibodies: Still a Market Growth DriverBiosimilar Monoclonal AntibodyUnsuccessful Development of Biosimilar AntibodySummarySlide Number 27