Development of Biosimilar Drugs, Opportunities and Challenges · About Biosimilar Drugs A...
Transcript of Development of Biosimilar Drugs, Opportunities and Challenges · About Biosimilar Drugs A...
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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
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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
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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”
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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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