s perspective and position - Roche

Roche – an innovator’s perspective and
position on biosimilars
Pat Yang
Head of Global Technical Operations

This presentation contains certain forward-looking statements. These forward-looking statements
may be identified by words such as ‘believes’, ‘expects’, ‘anticipates’, ‘projects’, ‘intends’, ‘should’,
‘seeks’, ‘estimates’, ‘future’ or similar expressions or by discussion of, among other things, strategy,
goals, plans or intentions. Various factors may cause actual results to differ materially in the future
from those reflected in forward-looking statements contained in this presentation, among others:
1 pricing and product initiatives of competitors;
2 legislative and regulatory developments and economic conditions;
3 delay or inability in obtaining regulatory approvals or bringing products to market;
4 fluctuations in currency exchange rates and general financial market conditions;
5 uncertainties in the discovery, development or marketing of new products or new uses of existing products,
including without limitation negative results of clinical trials or research projects, unexpected side-effects of
pipeline or marketed products;
6 increased government pricing pressures;
7 interruptions in production;
8 loss of or inability to obtain adequate protection for intellectual property rights;
9 litigation;
10 loss of key executives or other employees; and
11 adverse publicity and news coverage.
Any statements regarding earnings per share growth is not a profit forecast and should not be interpreted to mean
that Roche’s earnings or earnings per share for this year or any subsequent period will necessarily match or
exceed the historical published earnings or earnings per share of Roche.
For marketed products discussed in this presentation, please see full prescribing information on our website –
www.roche.com
All mentioned trademarks are legally protected
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Roche: Leading Innovator in Biotech
Biologics as proportion
of Pharma sales
67%
H1 2010
Biologics
Roche: Leader in Biotech
• 67% of Pharma sales from
biotech products
• Approx. 85% of Diagnostics
sales related to biotech
products
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Roche: Long primary patent protection of our key
biologics
Product
Avastin
Lucentis
Rituxan/ MabThera
Herceptin
Pegasys
US
2019
2019
2018
2019
2018
Key EU countries
similar
marketed by Novartis
earlier
earlier
similar
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Biosimilar / Intended Copies / Biobetter
• Biosimilar (EMA / WHO definition)
– generally applies to products that have been shown to be similar to the reference
product in appropriate comparative, head to head quality, non-clinical and clinical
studies
• Intended Copies of biological products (ICBPs)
– copies of already licensed biological products that have not met the regulatory
criteria for biosimilars
• Biobetter
– intended to be better or superior to the innovator product with marked differences in
clinical efficacy, safety and/or convenience.
– Biobetters are NMEs and should go through the full development and approval
process
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Similarity and comparability are two distinct concepts
Only quality data combined with preclinical and clinical experience
provide the full picture
Release tests
Extended
characterisation
Process
The Process is the Product
End-product
controls
In-process
controls
Adapted from Koslowski S, Swann P. Advanced Drug Delivery Reviews 2006; 58: 707–722
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Current Perspectives on Biosimilars
• US: recent healthcare legislation creates a pathway for biosimilars
– FDA in the process of developing guidelines
– The data exclusivity provided under the US Healthcare reform bill has many
manufacturers reassessing whether or not to follow the “biobetter” route and/or
initiate independent clinical trials
• EU: guidelines for monoclonal antibody biosimilars are in development
• Rest of the world: the new WHO guidance is setting the standard for the approval in
developing markets
• Roche position
– Monitor and respond to the changing landscape
– Product life cycle management
– Fully committed to innovation
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Biosimilar Regulatory Framework Comparison
Key Insight
Similarity
concept
Concept created by
EU
Principle of EU
followed by WHO
(main difference is
WHO have not
issued product
specific nonclinical
or clinical
guidelines)
Substitution
Decided at member
state level in EU
Not addressed in
WHO guidance
Extrapolation
across
indications
Ok if justified both
in the EU and in the
WHO guidance
Immunogenicity
Needs to be
studied in human
pre and post
approval in EU and
according to WHO
guideline.
Unique INN;
pharmacovigilance
required
INN is independent
from the regulatory
pathway used for
approval
PV is needed for all
products in EU and
according to WHO
guideline.
WHO specific EMA specific Guidance common to both agencies
Countries adopting EMA and/or WHO guidance
will have a robust biosimilar approval pathway
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High complexity of monoclonal antibodies
Each monoclonal antibody is unique
atorvastatin
Molecular weight
= 558 Daltons
0 amino acids
Interferon-alpha
Molecular weight
= 19,625 Daltons
~165 amino acids
Source: http://www.path.cam.ac.uk/~mrc7/mikeimages.html
Antibody (IgG)
Molecular weight
= 150,000 Daltons
~1,300 amino acids
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Monoclonal antibodies
Structurally much more complex than other proteins
• Complexity: considerably more complex than currently developed
biosimilars
• Biological activity: glycosylation patterns are critical - small differences have
been shown to correlate to changes in biological activity
• Predictability: multi-functionality (both binding and immune effector
functions) coupled with an often limited understanding of
structure-function relationship will limit predictability of
in vitro data
• Extrapolation: complexity and diversity of the mechanisms of action will
be of particular challenge for indications and line
extensions
10

Biologic manufacturing is complex
Biosimilars will always be different from the original
Human
gene
Even if a biosimilar uses the
same human gene as its
innovator
DNA
Vector
Cloning into
DNA vector
Transfer into
host cell
Bacterial or
mammalian cell
produces protein
It will differ in other parts
of the process
Fermentation
Different process = different product
Formulation
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Reditux: an intended copy, not a proven biosimilar
• Same amino acid sequence
• Host cell protein content much higher
• Content of aggregates not comparable
• Glycosylation not comparable
• Effector function not comparable
• Charge distribution not comparable
• Clinical (PK/PD) published data - 17 patients
Different manufacturing means:
• Different drug
• Different safety/efficacy profile?
AUFS @ 280 nm
160
120
80
40
0
Reditux
Rituxan Ref Mat
Reditux and Rituxan
0 10 20 30 40 50
Time (minutes)
Comparison by Cation Exchange Chromatography
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Monoclonal antibodies have complex and diverse
mechanisms of action: Rituxan as an example
CDC
complement binds to Fc --> cell lysis
Complement
Target cell
Apoptosis
FcγRIII
FcγRI/II/III
NK cell
MΦ
ADCC
Fcg Receptor binds
to Fc --> cell lysis
ADCC
Phagocytosis
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Several business and execution risks exist in the
biosimilar business for new entrants
Market prospects uncertain
• Uncertainty over the US
• Rate of uptake?
Marketing challenges
• Brand development
• Need to build physician awareness
BIOSIMILARS
Biosimilars
Large investments required
• Development capabilities and
infrastructure required
• CAPEX for manufacturing plant at risk
• Post approval safety and risk
management programs
Defense tactics
• Brand loyalty
• 2nd generation products
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Physicians require significant trial data from
biosimilars
Physicians were asked to indicate the level of clinical trial data they require to begin prescribing
biosimilars.
Source: Decision Resources, 2010
Percentage of Physicians Requiring Trial
Data in Each Category
Efficacy versus reference
biologic
(i.e., head to head or noninferiority)
Immunogenicity
Pre-marketing safety
U.S. physicians
French physicians
German physicians
35
41
51
57
50
56
73
74
72
0 25 50 75 100
Percentage of physicians
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Biosimilars: Slower erosion expected
100%
0%
Biosimilars vs. Small Molecules
erosion (illustrative)
Time
Biologic
(e.g. EPO)
Small molecule injectable
(e.g. Primaxin)
Small molecule oral
Physician biosimilar acceptance
takes time
– Duration of experience with
individual biosimilars
– Increasing numbers of
biosimilars
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Market penetration of biosimilars in Europe
Biosimilars market share
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
EPO Value Share
G-CSF Value Share
EPO Volume Share
G-CSF Volume Share
Source: IMS MIDAS Sales in PADDS
Biosimilars (EPO, G-CSF) in Western Europe
Q4/2007 Q1/2008 Q2/2008 Q3/2008 Q4/2008 Q1/2009 Q2/2009 Q3/2009 Q4/2009 Q1/2010 Q2/2010
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Our large molecule strategy
• Leverage our expertise in Research and Development
– Novel therapeutics and 2nd generation products
– New devices
– New formulations
• Regulatory
– Advocate appropriate regulatory standards for biosimilar pathways
– Recommend substitution does not apply to biosimilar products
– Continue to work with global Health authorities and WHO to help shape the
forthcoming pathways
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Managing franchises
Adding benefits to key medicines; developing better
ones
Anti-CD20
oncology
Anti-HER2
Antiangiogenesis
Actemra
MabThera/Rituxan MabT/Rituxan s.c.
Herceptin Herceptin s.c.
Avastin
Actemra
GA101
T-DM1
pertuzumab
anti-PIGF anti-EGFL7
anti-NRP1
Actemra s.c.
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T-DM1 as an example for next generation antibodies
Target expression: HER2
Monoclonal antibody: Trastuzumab
Cytotoxic agent: DM1
Highly potent cytotoxic agent
Linker: MCC
Systemically stable
Antibody-drug conjugate (ADC)
T‐DM1
average drug : antibody ratio ≅ 3.5:1
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Outlook
• The regulatory environment is evolving
• Complex biologics are unique products and difficult to replicate
• Full development requirements for monoclonal antibodies expected
• Biosimilars likely to perform as branded products in the market
• Current evidence suggests slow biosimilar uptake
Roche will continue to advance the standard of care through innovation
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We Innovate Healthcare
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