14. Dr. Thomas Kirchlechner - Sandoz Biopharmaceuticals Development

1 Moscow / Thomas Kirchlechner, May 2013
Challenges of biosimilar product development
and experience gained
IFPMA/AIPM Biotherapeutic Medicines Regulatory Workshop
Moscow, 15-16 May 2013
Dr. Thomas Kirchlechner
Sandoz Biopharmaceuticals Development, Austria

Agenda
Introduction to biosimilars
Future of biosimilars
How are biosimilars developed?
Sandoz experience

Biologics have revolutionized modern medicine –
and will continue to do so
Today / future
Human
genome
Stem-cell
research
Gene therapy
1990s to today
Leading
biotech brands
emerge
1950s
DNA molecule
decoded
Genetic code
cracked
1960s
Basic
biotechnology
enabled
1970s
 Offer real hope for many unmet needs, particularly complex
diseases
 Bind to specific targets within the body – simply not possible
with other medicines
 Contribute significantly to improved survival rates, enhanced
longevity, and better quality of life
Source: Company websites and annual reports
Note: All trademarks, logos and pictures are the property of the respective owner
Commercial
biotech firms
founded
1980s
®
®
®

By 2016, 7 of the top 10 pharmaceuticals
worldwide will be biologics1
Product Type
2016 Rev.
(USD bn)
2011 Rev.
(USD bn)
1. HUMIRA® Biologic 11.2 8.3
2. ENBREL® Biologic 7.5 7.9
3. RITUXAN® Biologic 7.4 7.1
4. AVASTIN® Biologic 7.2 6.0
5. REMICADE® Biologic 7.0 7.2
6. SERETIDE®/ADVAIR® Respiratory / device 6.8 8.1
7. HERCEPTIN® Biologic 6.3 5.9
8. REVLIMID® Small molecule 5.9 3.2
9. CRESTOR® Small molecule 5.8 7.1
10. LANTUS® Biologic 5.5 5.5
1
Source: Evaluate Pharma March 20 2012, vaccines excluded
Note: All trademarks are the property of their respective owners.

What is a biosimilar (or follow-on biologic)?
• A biologic approved via a stringent
regulatory pathway demonstrating
comparability
Overview
• Successor to a biologic medicine that
has lost exclusivity
• Not a simple generic due to complexity:
size, structure and manufacturing
Regulatory
definition
Comparability
approach
• Highly analogous structure
(via robust analytical characterization)
• Comparable quality, safety and
efficacy (via clinical trials)
Description
140
120
100
80
60
40
20
0
Min
mAU
Zarzio®
Neupogen®
GCSF Peptide Mapping
Determination of Receptor Binding:
Surface plasmon resonance spectroscopy
Rigorous analytical
characterization
Association rate Dissociation rate
0 200 400 600 800 1000 1200 1400
rel.response(RU)
time (s)
80
60
40
20
0
-20
Association rate
0 200 400 600 800 1000 1200 1400
rel.response(RU)
time (s)
80
60
40
20
0
-20
Batch 1
Batch 2
Batch 3
Batch 4
Batch 5
Batch 6
Batch 7

protein proteinProtein
(no sugars)
Monoclonal antibody
~150 kDa
Glycoprotein
(with sugars)
MammalianBacteria, Yeast
calcitonin
~3.5 kDa
epoetin
~30 kDa
somatropin
~22 kDa
Peptide
filgrastim
~19 kDa
Aspirin
0.18kDa
1x 19x 105x 122x 170x 833x
Biologics are more complex than small
molecules…

…and are produced from living organisms
Modify host cells
(e.g., bacteria,
mammalian yeast) to
produce recombinant
proteins
Extract, refold,
purify
(downstream) –
generate drug
substance
Formulate to
stable finished
drug product
(vial, syringe,
cartridge)
Grow cells
under controlled
conditions
(fermentation)
.

Access to biologics is a growing issue around
the world
Almost one-quarter of 46 European countries do not
provide access to biologics for arthritis1
Canadian children with juvenile idiopathic arthritis may
not receive "standard" care because pediatric coverage
for biologic drugs is limited and inconsistent3
Cancer patients twice as likely as general population
to go bankrupt a year after their diagnosis2
Only 50% of severe RA patients receive biologics
across EU5, US and Japan4
1
EULAR 2012: Annual Congress of the European League Against Rheumatism
2
Cancer diagnosis as a risk factor for personal bankruptcy, ASCO 2011
3
Access to biologic therapies in Canada for children with juvenile idiopathic arthritis. J.Rheum, September 2012
4
Stakeholder Insight: Rheumatoid Arthritis DMHC2592/ Published 09/2010

Biosimilar guidelines and regulations are being
developed worldwide
EU Biosimilars legal
framework established
US Health Care Reform enacted
March 2010, includes Biosimilars
Japan final guideline
released on March 4,
2009
Australia has adopted EU guidelines,
no separate pathway will be
established
Canada final guideline on
SEBs released in March
2010
WHO released final
guidance in April 2010
Taiwan
Malaysia
Argentinia
Columbia
Turkey
Venezuela
Mexico
Brazil
Saudi-Arabia
South Korea
Singapore

Agenda
Sandoz experience

Significant time, resources and expertise
required for developing biosimilars
Time &
Investment
Clinical Trials
• Significant expense (USD 75 - 250m)
• Long time to develop (7-8 years)
• Confirm comparable efficacy and safety
• Support extrapolation across indications & commercial success
• Speed of patient recruitment / trial execution
Key challenges
Technical
Development
• Achieving molecule profile highly comparable to
originator
• Developing high yielding manufacturing process

Purification process
development
Bioprocess development
Recombinant cell line development
Drug product
development
PK/PD
Preclinical
Biological
characterization
Physicochemical
characterization
Clinical
Reference
product variability
Process
development
Analytics
3. Confirmation
of biosimilarityBiological variability
2. Target directed
development
Target range
1. Target definition
Biosimilar mAbs must be systematically
engineered to match the reference product

Pre-clinical and clinical development of
biosimilars
Pre-clinical
Phase III
(confirmatory)
Characteristics
Phase I
(PK/PD)
Avg Time
Abbreviated pre-clinical program
Demonstration of PK/PD equivalence in a sensitive
population - can be healthy volunteers
No phase II dose finding studies are needed
Demonstration of similar efficacy & safety, usually
in one indication
Post approval
trials
Continue to follow the product, generate
additional data
6 – 12
months
9 – 12
months
2 – 4 yrs
Variable
1
4
2
3

Agenda
Sandoz experience

Structure: High resolution, orthogonality and
redundancy in analytical characterization provide full
understanding
Proteins can be well characterized at least up
to the complexity of monoclonal antibodies
 Primary structure determined from recombinant DNA
sequence and fully accessible to analytical verification
 Set of orthogonal analytical methods available to
characterize the identity and amount of related
variants with high sensitivity
 Glycosylation profile can be comprehensively
determined with regard to identity and content of
individual glycans with high sensitivity
 Accurate and relevant bioassays for pivotal biological
functions available
Attributes:
 Primary structure
 Mass
 Disulfide bridging
 Free cysteines
 Thioether bridging
 Higher order
structure
 N- and C-terminal
heterogeneity
 Glycosylation
(isoforms, sialic
acids, NGNA,
fucosylation, alpha
gal, site specific)
 Glycation
 Fragmentation
 Oxidation
 Deamidation
 Aggregation
Methods e.g.:
 MS (ESI, MALDI-
TOF/TOF, MS/MS)
 Peptide mapping
 Ellman‘s
 CGE
 SDS-PAGE
 CD
 H-D exchange
 FT-IR
 HPLC
 HPAEC
 IEF
 2AB NP-HPLC
 SE-HPLC
 FFF
 AUC
 DLS
 MALLS

Originators have changed their biologics
manufacturing processes multiple times after approval
Source: C Schneider, Ann Rheum Dis March 2013 Vol 72 No 3
Number of changes in the manufacturing process after approval for monoclonal antibodies (mAbs)/cepts authorised in rheumatological
indications (A). Products in order of date of approval in Europe (from MabThera, authorised on 2 June 1998 for the initial authorisation in oncology,
to Benlysta, licensed on 13 July 2011)
Changes include e.g.
• Change in the supplier of
a cell culture media
• New purification methods
• New manufacturing sites

0,0
0,4
0,8
1,2
1,6
2,0
08.2007 12.2008 05.2010 09.2011
Expiry Date
Unfucosylated G0
[% of glycans]
60
80
100
120
140
08.2007 12.2008 05.2010 09.2011
Expiry Date
ADCC Potency
[% of reference]
Post-
Shift
Pre-Shift
Pre-Shift
Post-
Shift
 Monitoring batches of an approved mAb revealed a shift in
quality
 Shift in glycosylation (structure) pattern results in different
potency in cell-based assays (function)
 Indication of a change in the manufacturing process
 Sandoz observed such shifts in several original products
Originator variability is the basis for the
biosimilarity goal posts...
Schiestl, M. et al., Nature Biotechnology 29,
310-312, 2011)

0 2 4 6 8
0
100
200
300
400
500
600
700
ADCC(%ofReference)
bG0-F [rel. %]
Variability of
reference product
Variability observed during
cell line development
Very narrow
goalposts for
biosimilar
Biologically possible variability
...and these goal posts are very
narrow

Originator manufacturing changes over time are the
basis for biosimilarity goal posts
A biosimilar product can be as similar to its reference product,...
..as that reference product is to itself over its lifetime due to process
changes
Originator
Process OLD
Biosimilar
Goal posts
for a given
parameter
Originator
Process NEW
Originator product changes
are basis for biosimilars and
justify:
– extrapolation across
indications
– interchangeability
• Manufacturing process changes are tightly regulated (see ICH Q5E)
• Change of quality attributes only acceptable if they do not alter safety/efficacy
• To demonstrate biosimilarity, it is therefore acceptable to use upper and lower
limit of pre- and post-shift material
• However, biosimilar release specification should be as tight as current
reference product specification

Quality attributes can be influenced at all stages
of cell line and process development...
Quality
Cell line
■ Host cell line.
■ Transfection/amplification pool
■ Genetic “set up” of production cell line (clone).
Process
■ Growth medium composition.
■ Culture conditions (pH, T, aeration,...)
■ USP type (batch, fed batch, perfusion,...)
■ USP regime (duration, fed type, perfusion rate..)
■ Culture history (genetic stability, process stability..)
■ Individual DSP steps
■ Hold times
■ Storage (buffer, container, conditions..)
1
2

Example for Quality by Design:
Attention to detail is essential...
High resolution identification and
quantification of major (G0,G1,G2)
and minor glycan structures
(down to a level of 0.1 rel.%)
Characterization of mAb glycosylation heterogeneity
Targeting ADCC activity and fucosylation by clone selection
2x
Originators Parental
Cells
Pool 18 Pool 16 Clone 19
0
2
4
6
8
10
bG0(-F)[%]
0 2 4 6 8
0
100
200
300
400
500
600
700
ADCC(%ofReference)
bG0-F [rel. %]

Source: Mike Doherty, Global Head Regulatory Affairs, Roche Pharmaceuticals, at Roche Investor Day 2010, March 18, 2010, see
http://www.roche.com/investors/ir_agenda/rid_2010.htm?track=8 and www.roche.com/irp100318_md.pdf
...and follow-on biologics not fulfilling these high
standards are not biosimilars and will not be approved
in EU
 Higher host cell protein content
 Content of aggregates not comparable
 Charge distribution not comparable
 Glycosylation not comparable
 ADCC effector function not comparable
 Clinical data: Only PK/PD study in 17
patients

Isoelectric focusing gels
“Non-Comparable biologics” – not approved in
highly regulated markets – are NOT biosimilars
Sample E IA IB IIA IIB IIIA IIIB IV V VII VIII E
Brockmeyer C & Seidl A et al. Eur J Hosp Pharm Pract 2009;15:34–40Schellekens H et al. Eur J Hosp Pharm Pract 2004;3:43–7
Approved biosimilar in EU
Sample 1 2 3 4
NO difference to originator
Alternative biologics ≠biosimilar
NOT similar to Reference E
Novartis/Sandoz does not represent all these approaches

Biosimilars must match originators across
multiple quality attributes
Post translat. modif. e.g.:
•NP-HPLC-(MS) N-glycans
•AEX N-glycans
•MALDI-TOF N-glycans
•HPAEC-PAD N-glycans
•MALDI-TOF O-glycans
•HPAEC-PAD sialic acids
•RP-HPLC sialic acids
Primary structure e.g.:
•LC-MS intact mass
•LC-MS subunits
•Peptide mapping
Higher order structure e.g.:
•NMR
•CD spectroscopy
•FT-IR
Impurities e.g.:
•CEX, cIEF acidic/basic variants
•LC glycation
•Peptide mapping deamidation,
•oxidation, mutation, glycation
•SEC/FFF/AUC aggregation
Combination of attributes e.g.:
•MVDA, mathematical algorithms
Biological activity e.g.:
•Binding assay
•ADCC assay
•CDC assay
For monoclonal antibodies typically > 40 different methodologies are applied,
analyzing more than 100 different quality attributes

Examples of clinical experience with
biosimilars
 Clinical studies started more than 12 years ago
 Product evaluated for 84 months in clinical phase III study
 ~ 35.000.000 patient days of safe use (2005-today)
 Evaluated in multiple studies with >5000 patients overall
Somatropin (Human Growth Hormone):
Filgrastim (Granulocyte-Colony Stimulating Factor/G-CSF):
Epoetin alfa (Erythropoietin/Epo):

Agenda
Sandoz experience

Source: IMS, NHS
UK G-CSF volume growth
Percent change vs. previous year
Sept. 2008
biosimilars
approved by
EMA
 G-CSF prevents hospital re-admission
due to infection
 More physicians start G-CSF treatment
earlier (primary prophylaxis) due to
more affordable cost
2010200920082007 2011
Biosimilar expand patient access already today

• Today, biologics can be thoroughly understood both structurally and
functionally
• Biosimilars can be created with product attributes that fall within the
variability of the original products – “highly similar”
• Clinical trials confirm similarity - de novo proof of efficacy not
necessary
• Many years experience have shown that EMA approved biosimilars
are as safe and effective as the original products
• Biosimilars are broadening patient access and improving affordability
already today
Conclusions
2013 © All rights reserved. All trademarks are the property of their respective owners.

Thank you!

14. Dr. Thomas Kirchlechner - Sandoz Biopharmaceuticals Development

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