www.3sbio.com

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Development of Biosimilar Drugs,

Opportunities and Challenges

Yingfei Wei, Ph.D.

October 28, 2011

AAPS BADG Lunch Seminar

San Mateo, CA

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About Biosimilar Drugs

A “copy” of the patent expired biological drug (protein/ppt/mAb)

Different from the generic small molecule drugs – much more complicated, never truly be “IDENTICAL” • Big size, post-translational modification

• Heterogeneous isoforms

• Immunogenicity

• Complicated manufacture process

• Injected proscription drug

Need special regulatory process & guidelines • Efficacy & safety – in vitro/in vivo tests

• Immunogenicity test

• Post-market surveillance

Need special legislation • Years of exclusivity

• Interchangeability/automatic substitution

Higher success rate, lower development cost

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Core Competencies for Biosimilar

Developers

Traditional

Generic World

Patent

Regulatory

Manufacture

Biosimilars World

Marketing

Clinical trial design

Pharmacovigilance

Biological manufacture

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0

20

40

60

80

100

15%

85%

2001 2003 2005 2006 2007 2008 2009

3%

35%

62%

2010

Biosimilars

CAGR 103%

Antibodies

CAGR 27%

Recombinant

Proteins

CAGR 10%

0

200

400

600

800

1000

2000 2001 2002 2003 2004 2005 2006 2010 2015

Large

Molecule

Drugs

CAGR 18%

Small molecule

drugs

CAGR 9%

+10%

Worldwide Market size (€B)

$255B

$680B

1. 2007 to 2010 based on forecasts Note: Biologicals from players in emerging markets, non-protein antiinfectives, vaccines, pregnancy hormones and non-protein hormones are excluded from the current analyses Source: Datamonitor; BCG

Biologics Market Growing Faster

than Small Molecule Drugs

Worldwide Market size (€B)

Market Size By Drug Type Biologics Market By Segment1

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Biosimilars Key Drivers

In in 2010, global pharma market reached $830 B. Biological drugs market exceeded $116 B (14%). Biosimilar drug sales $380M

Large number of biological drug patents expire soon (>$60B by 2015)

Increasing market demand • Aging population

• Health awareness

• Affordability and insurance coverage

Increasing healthcare cost

Increasing innovative drug R&D cost

affordable, safe, and efficacious biological drugs

Biosimilars would free up healthcare funds for new innovative drugs

Higher success rate, lower development cost

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Slower and Costly

2-3 years 1 year 2-3 years 1 year

6

Molecular Biol.

Cell Biol.

Process Deve.

Pre-

clinical Clinical

Develop.

Review

Approval Commerciali

zation

$3-8 M

Generics Biosimilars $30-100M

Innovative

Biologics

~ $1B

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Global Status

EU • EU Commission: legislative framework in 2004

• EMEA: general guidelines in 2005

• Over 10 products marketed since 2006 (hGH, EPO, GCSF, Insulin and IFN)

Australia • Guideline established in fall 2006

• Several biosimilar products approved

USA • Congress passed the new legislation in March 2010 (12 years data

exclusivity)

• FDA working on new regulatory guidelines

Japan • Guideline established in fall 2008

• The first biosimilar drug approved

India: active

China: No clear guidelines available, active discussions

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Criteria for Biosimilar Products

Non-clinical studies

• Analytical studies: biochemical/biophysical, cellular activities and characteristics, MOA

• Animal studies: pharmaco-toxicological assessment, clinically relevant activity

Clinical studies

• Comparative PK, PD

• Efficacy (> one surrogate marker)

• Safety

• Immunogenicity

• Route of administration, dosage form, strength

Clinical safety and pharmacovigilance

• Post-market monitoring

• Risk management plan

Manufacturing – Quality, safety, efficacy

Key: comparable quality, safety, and efficacy to the reference medicine

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Immunogenicity – clinically relevant

anti-drug antibody

Causes of immunogenicity - complicated • Product related

• structure, stability, etc.

• Product and process-related impurity, post-translational modification

• Route of administration, dosing regimen and schedule

• Patient related • Genetic or acquired, age

• Underlying disease and treatment

• Ab classes, affinity, specificity

Safety impact of immunogenicity • Varies from indication

• Therapeutically irrelevant or

• Life-threatening • Reduce efficacy

• Cross-reactivity to endogenous protein

• Serious general immune effects

• Alters PK, PD and activity in patients

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Immunogenicity – clinically

relevant anti-drug antibody

How to reduce immunogenicity • In-silico modeling to identify T-cell epitopes

• In-vitro cell-based assays to confirm/identify T-cell epitope

• Maintain human sequence and post-translational modification

• Reduce the impurity to the minimum level

How to test immunogenicity • Develop appropriate strategy in clinical study design

• State of art and validated screening and confirmatory assay with appropriate specificity and sensitivity

• Sufficient patient numbers and data points

• Justified timing of sampling

• Consider interference from impurity and circulating antigen

10

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Biosimilars vs Innovators

Process = product

Production cell line

Formulation

Manufacture

Route of administration

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Hurdles and Don’ts

Hurdles:

Manufacture process is complex

and expensive to achieve

“similar” quality, safety, and

efficacy profile

Uncertainty of regulatory

pathway in US, China, and many

other countries

Non-interchangeable

Conflicting interests among

regulators, original biologics

makers, insurance payers,

practitioners, and patients

Don’ts:

Don’t change primary sequence

Don’t change major process and

formulation

Don’t change the route of

delivery, dose regime and

schedule

Don’t aim at “better”, aim at

“same” or “as similar as

possible”

12

www.3sbio.com 5/23/2009, CABS Ann. Meeting

SFDA Regulatory Requirements

Marketed product outside of China • Comparable manufacture process and QA/QC standards

• Comparable biological activity in vitro and in vivo

• 1 month tox on 1 species*

• 1-2 efficacy models

• Full clinical trial

Marketed product in China • Comparable manufacture process and QA/QC standards

• Comparable biological activity

• 1 month tox on 1 species*

• 1-2 efficacy models

• Phase III trial

* Based on the comparability to the known drug, the pharmacology and toxicology study can be reduced or eliminated

www.3sbio.com 5/23/2009, CABS Ann. Meeting

Biological Drugs on the Market in

China

New generation of biological drugs

• EPO, TPO, 3SBio + many developers

• GCSF, many developers

• Enbrel (益赛普 ), CITIC, Celgen “Legacy” biological drugs

• Interferon

• hGH

• Insulin

• Interleukins

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Case Study: human erythropoietin

Biochemical Assessment of Erythropoietin Products

From Asia Versus US Epoetin alfa Manufactured by

Amgen

SUNGAE S. PARK,1 JIHEA PARK,1 JASON KO,2 LOUISE CHEN,1 DAVID MERIAGE,1 JILL CROUSE-ZEINEDDINI,3

WENDY WONG,4 BRUCE A. KERWIN2

JOURNAL OF PHARMACEUTICAL SCIENCES 2008

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21546

1Amgen Inc., Process and Product Development, Formulation and Analytical Resources Group, Thousand Oaks,

California 91320

2Amgen Inc., Process and Product Development, Analytical and Formulation Sciences Group, Seattle, Washington 98119

3Amgen Inc., Process and Product Development, Cellular Sciences Group, Thousand Oaks, California 91320

4Amgen Inc., Department of Quality Assurance, Thousand Oaks, California 91320

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Recombinant Human Erythropoietin

(rHuEPO) Sample List from Asia

Marketed

Country Trade Name Company Exp. Date HSA CHO Cell Label Conc. (IU) Lot # Container Type

USA Epogen1 Amgen August 5, 2007 Yes, 0.25% Yes 2000 P029954 Vial

USA Epogen1 Amgen February 2, 2007 Yes, 0.25% Yes 3000 P008951 Vial

USA Epogen1 Amgen January 8, 2007 Yes, 0.25% Yes 10000 P028155 Vial

Korea Eporon Dong-A February 2007 Yes Yes 4000 ED50398 Vial

Korea Eporon Dong-A March 2007 Yes Yes 4000 IU/0.4 mL PD50908 PFS

Korea Espogen LG November 2007 Yes, 2.5 mg/mL NA 2000 IU/0.5 mL EPO05017 PFS

Korea Epokine CJ March 2007 Yes Yes 4000 IU/0.4 mL 5530 PFS

China Epiao SS-Pharm November 2007 Yes, 0.25% NA 2000 20051101 Vial

China Jia Lin Hao Shandong E-Hua December 2007 Yes Yes 3000 20051203 Vial

China Ji Mai Xin Hua-Bae Pharm August 2007 Yes NA 3000 Y20050931 PFS

China Ji Mai Xin Hua-Bae Pharm September 2007 Yes NA 3000 Y20051031 PFS

China Huan Er Bo Beijing Four Rings March 2008 Yes NA 3000 IU/0.6 mL 20060305 PFS

China Huan Er Bo Beijing Four Rings February 2009 Yes NA 3000 IU/0.6 mL 20060203 PFS

China SEPO China-SPG August 2007 Yes Yes 4000 20050905 Vial

India Zyrop Imported from March 2008 Yes, 0.25% Mammalian 10000 H10-4031H01 Lyophilized

Argentina (Bio Sidus)

India Wepox Wockhardt August 2008 NA Mammalian 40000 XF10336 PFS

cell

India Shanpoietin Shantha Biotech April 2008 NA Yes 4000 EPO2206 PFS

India Shanpoietin Shantha Biotech July 2008 NA Yes 4000 EPO2806 PFS

India Epotin Imported from April 2008 Yes Yes 4000 Y20060541 PFS

China (NCPCGB)

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EPO China Market Growth

Chinese Total EPO Market in Volume and Sales (1999-2010)

17

Source: IMS Health

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

0

100

200

300

400

500

600

700

800

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

Volume (Vials in thousands)

Valu

e (R

MB

mill

ions

)

Value (RMB)

Volume (Vials)

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Chinese EPO Market Volume and Value (1999-2010)

18

3SBio Kirin Roche North China Chengdu Diao NJ Huaxin

SZ Xinpeng BJ Sihuan SD Kexing SH Clone SH Ke-hua SD Ahua

SZ Xinpeng SH Sanwei Hayao Others

Source: IMS Health

0.1 0.30.6 0.7

0.9 0.91.2

1.4

2.0

2.6

3.0

3.7

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

19

99

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

09

20

10

Via

ls (

mil

lio

ns)

3SBio

15 28

46 55 73

85 113 122

156

213

248

301

0

50

100

150

200

250

300

350

19

99

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

09

20

10

RM

B (

mil

lio

ns)

3SBio

Chinese EPO Market is Crowded

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(A) samples from China (lanes 2–9) and Korea (lanes 10–13) and (B) samples from

India (lanes 1–5).

Iso-electro-focus (IEF) Gel

*

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SDS–PAGE with Western Blot

Analysis for Aggregation

*

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Relative Denaturation - 9G8A antibody assay to detect

unfolding structure

Samples from China, Korea and India were compared to Amgen Epogen. A value of

1 indicates no difference in folding between the sample and the EPO standard

*

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Concentration

Striped bars represent the labeled concentration and solid bars

represent the concentration measured by ELISA.

*

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Conclusion

rHuEPO from Korea, China, and India were compared with the innovator product, Epoetin alfa, in vitro for molecular integrity, glycoforms, and ELISA

Some rHuEPO from Korea, India, and China contained more glyco-forms and other impurities

These data emphasize potential biochemical discrepancies resulting from different cell lines, manufacturing processes, and quality control.

These data formed the basis for a strong argument in

favor of establishing high standards of quality control in

product manufacturing and processing.

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Challenges for Biosimilars

Development

Competition Innovator

Reg

ula

tion

IP

$$

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Opportunities and Challenges

Opportunities

• Large market needs and growing affordability

• Existing manufacturing technology

• Growing understanding to biological drugs

• Competitive pricing advantage on global market

• Low risk low cost

Challenges

• Lack of clear regulatory guidance in many countries (US, China)

• Balanced legislation which protect and promote innovative drugs

• Complicated analytical techniques

• Development of manufacturing capability

• Enter the market at risk (against innovative drug and other competitors)

• No interchangeability, brand marketing required

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