what defined success in the first 10 years of biosimilars commercial activities? What will define such in the next 10 years?

1. applied strategic
10 years experience in biosimilars: launch
to the future. What matters most?
Presentation by Dr Richard Littlewood
9 March 2016
8th Biosimilars Congregation
applied strategic 1

2. Note
• This is a copy for distribution of a presentation made by Dr. Richard Littlewood
reflecting on 10 years of experience in biosimilars, predicting what matters most for
the future.
applied strategic 2

3. Analytics
What we all know? Definition of similarity concept for
biologic medicines defined a new market for biosimilars
applied strategic 3
Preclinical
PK/PD
Clinical
Trials
Process
development
Source: McCamish 2011, CMHP/437/04
Biological
Characterization
Physiochemical
Characterization
“A company may choose to
develop a new biological medicinal
product claimed to be “similar” to a
reference medicinal product”
CHMP/437/04

4. What do we expect? Rapid growth to $35B global market
for biosimilars, predicted by observers
applied strategic 4
Biosimilars global sales
[2013-2020, $B]
60%
CAGR
Biosimilars
Biologics
175
285
2013 2020
Source: Merck Serono 2014, Blackstone & Joseph 2013, EGA 2015, Evaluate Group 2014

5. When did it start? Radical regulatory affairs innovation by
EMEA, 2004 and key guidance launched biosimilars
applied strategic Source: applied strategic analysis EMA
Legal progress
Regulatory progress
2001 2002 2003 2004 2005 2006
Directive 2003/63/EC
“Annex I” biosimilars
recognition
Directive
2004/27/EC
published
Directive
2004/27/EC
in law
First
biosimilar
approved
Product
guidelines
hGh, insulin,
EPO, G-CSF
Comparability
guidelines
Quality, non-
clinical,
clinical
guidelines

6. Where did it start? In Europe work started pre-2000;
alternative biologics versions were marketed in LATAM also
applied strategic 6
Europe
1998: Start development of
Binocrit® (epoetin alfa)
Mexico
1999: launch of Bioyetin
(epoetin alfa)
Source: applied strategic analysis

7. What is the impact? Early product launches in Europe
highlight commercial and patient access success
applied strategic 7
• Launch of biosimilar Epoetin alfa
in Europe
• 5 year healthcare cumulative
savings to Germany, €0.6B
• Typically 35% cost reduction
• 255,000 patient-years exposure
Biosimilar Epoetin Alfa
Launch 2007
Commercial & patient access
success
Source: applied strategic analysis

8. What is the impact? A relatively small set of biosimilar
products are currently marketed
applied strategic 8
Omnitrope
Silapo
EpoHexal
Binocrit
Abseamed
Tevagrastim
Ratiograstim
Biograstim
Retracrit
Nivestim
Remsima
Ovaleap
Inflectra
Grastofil
Bemfola
Accofil
Abasaglar
Benepali
Zarzio
FilgrastimHexal
20162006 2011
Source: GaBI, Biosimilars approved in Europe 2016
European product approvals

9. What is the impact? Few companies own a majority of the
assets: market looks an oligopoly…
applied strategic 9
Omnitrope
Silapo
EpoHexal
Binocrit
Abseamed
Tevagrastim
Ratiograstim
Biograstim
Retracrit
Nivestim
Remsima
Ovaleap
Inflectra
Grastofil
Bemfola
Accofil
Abasaglar
Benepali
Zarzio
FilgrastimHexal
20162006 2011
Source: GaBI, Biosimilars approved in Europe 2016
European product approvals
Assets owned by companies with
portfolio of biosimiars

10. What is the future? Patent expiry, freedom to operate for
many biologics defines a $B expansion of opportunity
Monoclonal antibodies approved/ under review in EU/ US
[Patent expiry]
applied strategic 10
Oncology
Non-
oncology
17
32
<2020 >2020
Source: applied strategic analysis
• 49 monoclonal antibody
products have potential for
biosimilar launch
• Launch of biosimilar
versions of these products
represents a step change
in opportunity size
Potential value $20-30B
Expiry of
patent, year

11. What is the future? New biosimilar products – based on
antibodies – imply increasing manufacturing complexity
applied strategic 11
Trade Name (INN) Originator Approval date
Tysabri® (Natalizumab) Biogen Idec 2004
Lucentis® (Ranibizumab) Roche/ Novartis 2006
Cimzia® (Certolizumab) UCB 2009
Stelara® (Ustekinumab) Johnson & Johnson 2009
Eylea® (Aflibercept) Bayer/ Regeneron 2011
Zaltrap® (Aflibercept) Sanofi/ Regeneron 2012
Prolia®/Xgeva® (Denosumab) Amgen 2011
Benlysta® (Belimumab) GlaxoSmithKline 2011
Soliris® (Eculizumab) Alexion 2007, 2011
Source: applied strategic analysis
• Future products with potential to be biosimilars are based on antibodies
• Greater manufacturing complexity, defining a special capability need

12. What is the future? Success with biosimilars is driving
increasing simplicity in evidence needed for approval
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“a confirmatory clinical trial may
not be necessary”
EMA 2014
“waiving clinical trials may be
accomplishable for biosimilar
rhG-CSF”
EMA 2015
“pre-licensing safety study,
immunogenicity assessment
waived?
EMA 2015
“PK PD results may make a
comparative efficacy study
unnecessary”
FDA 2015
Source: applied strategic analysis

13. What is the future? A broad range of competitors now are
present: partners are a major part of the business
applied strategic 13
Merck Serono, Merck
Pfizer, Daiichi-Sankyo
Boehringer Ingelheim,
Biogen Idec
Baxter, Lilly, Amgen
Sandoz, Teva
Hospira, Mylan
STADA, Dr. Reddy’s,
actavis. Cipla, Gedeon
Richter
Fujifilm
Samsung
GE Healthcare
Celltrion
Innovative
companies
Generics
manufacturers Others
Biocon
Lonza
Formycon
Patheon
Intas
IBA Bioton
Zydus
Broughton
Zydus
Wockhardt
CMC
Rentschler
Key partners: supporting development, contract development, manufacturers
Competitors: Commercializing biosimilar products
Source: applied strategic analysis

14. What drives success? First commercial phase. Success
factors: protein characterization, regulatory affairs
applied strategic 14
Development Clinical Regulatory Launch Commercial
Cell line to product
development; protein
characterization;
comparability
Agency relationships,
strategic leadership;
pathway interpretation
Tender management,
pricing strategy.
Customer awareness
Customer awareness,
defending against
restrictions;
Policy management
Success Factors for Biosimilar Competition: First Commercial Phase
(2006-2016)

15. What drives success? Next 10 years Success factors:
commercial power, speed to market
applied strategic 15
Development Clinical Regulatory Launch Commercial
Complex protein
manufacture
R&D partnerships
Capability to deliver
clinical studies rapidly
Marketing & Sales
power
Race to market
Success Factors for Biosimilar Competition: Second Commercial Phase
(2017-2027)

16. Speaker profile
Dr. Richard Littlewood
• Richard is the founder of the strategy firm
applied strategic
• is a physician with clinical practice experience
and a management consultant who has worked
for 15 years addressing strategic and operational
issues in health, pharma
• He is a UK GMC registered physician, has an
MA from Trinity College, Cambridge and is a
graduate of the Sloan Masters management
program at London Business School.
• Richard pioneered on biosimilars strategy and
has extensive experience in many developed
and emerging markets.
16
[applied strategic founder]
Dr. Richard Littlewood
• Adviser to global pharmaceutical companies
involved in biosimilar development in Europe,
USA and emerging markets since 2006
[Conflicts]