Biosimilars:
Market dynamics and the Roche portfolio
Mike Doherty | Global Head Regulatory Affairs
Roche Pharmaceuticals
1
High complexity of monoclonal antibodies
Each monoclonal antibody is unique
Aspirin
Interferon-alpha
Antibody (IgG)
Molecular weight
= 180 Daltons
0 amino acids
Molecular weight
= 19,625 Daltons
~165 amino acids
Molecular weight
= 150,000 Daltons
~1,300 amino acids
Source: http://www.path.cam.ac.uk/~mrc7/mikeimages.html
2
Biologic manufacturing is complex
Biosimilars will always be different from the original
Even if a biosimilar uses the
same human gene as its
innovator
Human
gene
It will differ in other parts
of the process
Transfer into
host cell
DNA
Vector
Cloning into
DNA vector
Bacterial or
mammalian cell
produces protein
Fermentation
Different process = different product
Formulation
3
Different process = different product
Exhibited differences when compared to branded product
• Same amino acid sequence
• Host cell protein content much higher
Reditux and Rituxan
160
• Content of aggregates not comparable
• Effector function not comparable
• Charge distribution not comparable
120
AUFS @ 280 nm
• Glycosylation not comparable
80
• Clinical (PK/PD) published data - 17 patients
Different manufacturing means:
•
•
Reditux
40
Different drug
Different safety/efficacy profile?
Rituxan Ref Mat
0
0
10
20
30
Time (minutes)
40
50
Comparison by Cation Exchange Chromatography
4
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
EU working on new guidance
5
Monoclonal antibodies have complex and diverse
mechanisms of action
Anti–CD20 (Rituxan) possible mechanisms of cell killing
CDC
complement binds to Fc --> cell lysis
FcgRIII
NK cell
ADCC
Fcg Receptor binds
to Fc --> cell lysis
Complement
Target cell
FcgRI/II/III
MF
Apoptosis
ADCC
Phagocytosis
6
Our large molecule strategy
Well positioned to continue to commercialise innovative
products
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
7
HGH experience serves as good starting analog
for biosimilars in the US
Omnitrope has limited market share
US Sales (%)
45%
Growth Hormone % US Sales by Product
Genotropin
40%
Humatrope
Norditropin
35%
Nutropin
Omnitrope
Saizen
30%
Serostim
Tev-Tropin
Zorbtive
25%
20%
15%
10%
5%
Omnitrope
0%
Q4,
Q1,
Q2,
Q3,
Q4,
Q1,
Q2,
Q3,
Q4,
Q1,
Q2,
Q3,
2006 2007 2007 2007 2007 2008 2008 2008 2008 2009 2009 2009
Source: IMS
Has gained a 1% market
share based on sales
8
Significant regulatory hurdles for monoclonal
biosimilars
Anticipated guidance
• full analytical characterisation with justification for differences in content
• reduced toxicology testing and comparable PK
• clinical efficacy and safety studies including immunogenicity evaluation
• unique labeling (safety labeling with independent data)
– intense scrutiny of frequency of known safety events e.g. PML
• post marketing commitments and risk management plans to evaluate frequency
of key safety signals
• interchangeability statement based on degree of similarity (safety)
• No substitution for monoclonal antibody products allowed
9
Outlook
• The regulatory environment is evolving
• Complex biologics are unique products and difficult to replicate
• Current evidence suggests slow biosimilar uptake
• Full development requirements for monoclonal antibodies expected
• Biosimilars likely to perform as branded products in the market
• Roche will continue to advance the standard of care through innovation
10