Pharmaceuticals in Developing and Emerging

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• Pharmaceuticals in Developing and Emerging
  Economies Production, Innovation, and Access to
  Medicines in the wake of TRIPS
• Co-sponsored by the University of Hyderabad,
  India and Deakin University, Australia.
• Friday 17 September 2010 - Sunday 19 September
  2010
• Venue University of Hyderabad, India
• Day 2 Saturday 18 September
• 14.00 16.00 Conference Hall
• Panel 2 Biosimilars/biogenerics in Developing
  Countries Challenges and Opportunities
• Panel Convenor Professor Mohamed Eldawy (Tanta
  University, Egypt)

2
Panel 2 Biosimilars/biogenerics in Developing
Countries Challenges and Opportunities

• Panel Convenor Professor Mohamed Eldawy (Tanta
  University, Egypt)
• Participants
• ? Professor Mohamed A Eldawy (Tanta University,
  Egypt)
• ? Dr Sriram Akundi V. (Biocon, Bangalore)
• ? Dr Krishna Ella (Bharat Biotech, Hyderabad)
• ? Dr Wael Mohamed Ebied (SEDICO Pharmaceutical
  Co., Egypt)
• The Panel will
• present the perspectives of all
  stakeholders on the issue
• examine the status of North-South and
  South-South collaboration in this therapeutic
  arena
• discuss lessons to be learned from
  Indian and other South Countries' home grown
  biotechnology
• explore the road forward .

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An overview of , Production, Technology
Transfer, IPRs, Regulatory and pharmaco-economic
aspects of Biosimilars/Bigenerics/FoPs/FoBs.

• Biotech-enabled Healthcare Products for
  Management, Prevention and Diagnosis of Human
  and Animal Diseases.
• Include Therapeutic APIs, Vaccines/Sera,
  Diagnostics and Devices
• Macromolecules of elaborate structure v simple
  chemicals/small molecules
• Molecular wt Aspirin 180 versus hu
  insulin 5808 Da.
• Small molecules B.E pathway very well
  defined-interchangeability/ Substitution Brand
  by generic.

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An overview of , Production, Technology
Transfer, IPRs, Regulatory and pharmaco-economic
aspects of Biosimilars/Bigenerics/FoPs/FoBs,
(continued.)

• Biologics Eq pathway in the making Guidelines
  - ??? Re interchangeability biogeneric term is
  not used, rather Biosmilar / 2nd generation / FoP
  / FoB Biosimilars are Different Issues of
  Sameness and Identity
• Include Proteins and NA fragments, None-protein
  Biologics, mAbs and Vaccines.
• GE Tissues/cells are categorized by Regulatory
  Authorities as DEVICES.
• Produced in living organisms( Prokaryotes such as
  GE Bacteria and Eukaryotes such as GE
  Yeasts/Transgenic plants animals "Pharming" ).
• i.e not via simple chemical synthesis.

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Production in GE Bacteria/Yeast/CHO
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Production in GE Bacteria/Yeast/CHODifferent
manufacturers may have different processes
START
END
Typical Protein Production Process
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Production in GE Bacteria/Yeast/CHO

• Develop host cell
• Establish a cell bank
• Protein production
• Purification
• Formulation
• Handling and Storage
• Analysis

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EMA FDA Guidelines

• EMA
• Similar biological medicinal products, Oct 2005
• Similar biological medicinal products containing
  biotechnology-derived proteins as active
  substance Quality Issues, Feb 2006
• Manufacturing process, comparability to reference
• Suitability of analytical method, physicochemical
  properties, biological activity, purity and
  impurities, specification

• FDA
• 77 FDA approved protein drugs
• 66/77 are recombinant proteins

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Points to consider

• Can a new manufacturer produce a biosimilar that
  is similar enough/essentially similar/the same
  as/identical to the original biopharmaceutical to
  be considered the same?
• How can the level of similarity/sameness be
  established?
• Are there risks associated with currently
  undetectable differences?
• How similar is similar enough?
• Biosimilars are different?

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Production in GE Plants

• Source (Lengridge W 2000).

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Production in GE Plants IPRs TT

• Dynamics of global disclosure through patent and
  journal publications for plant made
  biopharmaceutical products
• Examining the relationships between invention
  disclosure type in industry and trends, Industry
  using plant-made pharmaceuticals as a
  single-sector model for the biopharmaceutical
  industry.
• Harry Thangaraj, et al, nature biotechnology
  volume 27 number 7 july 2009

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Production in GE Plants IPRs TT
Relative contribution of industry and academia to
PMP patent and journal disclosures. Research
contribution to patents (a) and journal
disclosures (b).
(a)- Unknown 9 - Industrial-academia
Collaboration 6 - Industry 27 Academia 58 -
( G Y R NB ) (b)-Unknown 1 -
Industrial-academia Collaboration 8 - Industry
5 - Academia 86
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Production in GE Plants Potential advantages

• Oral administration of a plant-derived vaccine
  in the context of a heterologous primer/booster
  strategy, considering that oral boosting in
  systemically vaccinated individuals by passes the
  issue of inducing oral tolerance
• Minimal downstream processing, considering
  that this would represent a major revolution in
  pharmaceutical production whose downstream
  processing contributes up to 80 of manufacturing
  costs
• Enabling the participation of less developed
  countries in pharmaceutical production, with an
  emphasis on addressing local health issues.

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Production in GE Animals

• Production of Recombinant Therapeutic Proteins in
  the Milk of Transgenic Animals Somatic Cell
  Nuclear Transfer

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Production in GE Animals
16
Production in GE Animals
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Production in GE Animals

• Timeline associated with the creation of a herd
  of transgenic goats producing recombinant
  proteins in their milk.

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Production in GE Animals
Schematic representation of the process used to
purify ATryn from the milk of transgenic goats.
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Pharmacoeconomics
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Pharmacoeconomics
Revenue Forecast for Biogenerics.
Source (Wilkie D 2004)
21
Market Authorizations 2001-2006
.
Source Gary Walsh, Nature Biotechnology Volume
24 Number 7 July 2006
22
The First Biogeneric
FDA EMEA TGA, (MR, EU, OECD) Litigation
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Market Authorizations 2001-2006
Source Gary Walsh, Nature Biotechnology Volume
24 Number 7 July 2006
24
Market Authorizations 2007-2010
Source Gary Walsh, Nature Biotechnology Volume
28 Number 9 September 2010
25
Market Authorizations 2007-2010
Source Gary Walsh, Nature Biotechnology Volume
28 Number 9 September 2010
26
Market Authorizations 2007-2010

• Total is the total number of biopharmaceuticals
  approved in (a) the EU and in (b) the US each
  year.
• NBE is the number of biopharmaceutical entities
  genuinely new to the indicated region, approved
  in that region each year.
• Of the 23 NBEs recorded for Europe, 5 of those
  products had gained approval in the USA before
  2006.

Source Gary Walsh, Nature Biotechnology Volume
28 Number 9 September 2010
27
Market Authorizations 2007-2010

• New antibody approvals
• Half (13 of 25) of the genuinely new
  biopharmaceuticals to come on the market in the
  period under review are antibodies. 2009 was a
  particularly
• noteworthy year in this context, with seven mAb
  products coming on the market for the first time
  in the United States and/or the European Union.
• Four of those productsArzerra, Ilaris
  (canakinumab Novartis, Basel), Simponi
  (golimumab Centocor) and Stelara
  (ustekinumabCentocor) are fully human products.
  These join just two previously approved fully
  human antibodies (Vectibix, approved in 2006, and
  Humira, approved in 2000).

Source Gary Walsh, Nature Biotechnology Volume
28 Number 9 September 2010
28
Market Authorizations 2007-2010
The first bispecific mAb
- Structure of Removab, the first bispecific
antibody to achieve approval. (Source Fresenius
Biotech, Munich. - Currently, European
regulators through the Committee for Human
Medicinal Products (CHMP) Biosimilar Medicinal
Products Working Party are updating guidelines
specific for EPO products, follicle-stimulating
hormone (FSH follitropin alfa), interferon-ß
and, perhaps most notably, mAb-based products.
Source Gary Walsh, Nature Biotechnology Volume
28 Number 9 September 2010
29
Market Authorizations 2007-2010
Source Gary Walsh, Nature Biotechnology Volume
28 Number 9 September 2010
30
Market Authorizations 2007-2010

• The ten top-selling biopharmaceutical products in
  2009
• Biosimilars and reformulated products enter a
  marketplace where significant product competition
  already exists.
• - The approval of eight (mainly biosimilar)
  erythropoietins (EPOs), joining five previously
  approved EPOs in a 10 billion annual market.
• - Six (biosimilar) filgrastim-based products
  approved joining three previously approved via
  the traditional US (BLA) pathway.
• - Sales of all biologics totaled 94 billion by
  2007 ( the fastest growing segment of the 600
  billion pharmaceutical industry).
• - therapeutic proteins (excluding antibodies)
  sales amounted to 61 billion in 2009, mAbs sales
  were 38 billion3, yielding an overall 2009
  global biopharmaceuticals market value of 99
  billion. The total biopharmaceuticals global 2009
  market is about 100 billion.

Source Gary Walsh, Nature Biotechnology Volume
28 Number 9 September 2010
31
Intellectual property, technology transfer and
manufacture of biosimilar HPV vaccines in India
Source Swathi Padmanabhan, Tahir Amin, Nature
Biotechnology Volume 28 Number 7 July 2010
32
North-South and S-S CollaborationEvolving RD
for emerging markets MNCs In Asia
Source NRDD (VolUME 9 JUNE 2010
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South-South entrepreneurial collaboration in
health biotech
Source Halla Thorsteinsdóttir et al, nature
biotechnology volume 28 number 5 MAY 2010
34
South-South entrepreneurial collaboration in
health biotech
Source Halla Thorsteinsdóttir et al, nature
biotechnology volume 28 number 5 MAY 2010
35
South-South entrepreneurial collaboration in
health biotech
Source Halla Thorsteinsdóttir et al, nature
biotechnology volume 28 number 5 MAY 2010
36
South-South entrepreneurial collaboration in
health biotech
Source Halla Thorsteinsdóttir et al, nature
biotechnology volume 28 number 5 MAY 2010
37
South-South entrepreneurial collaboration in
health biotech
Source Halla Thorsteinsdóttir et al, nature
biotechnology volume 28 number 5 MAY 2010
38
South-South entrepreneurial collaboration in
health biotech
Source Halla Thorsteinsdóttir et al, nature
biotechnology volume 28 number 5 MAY 2010
39
Other N-S S-S collaboration in health biotech

• Fraunhofer- Cinnavex IFN for MS (Iran).
• Getz Peg IFN(Pakistan) Academia - UAE finance
• Indian cases. Proteins mAbs TNFs, India's
  Cipla sets sights on Biosimilar Avastin,
  Herceptin and Enbrel (2009 sales 17 bilion)
• Killugudi Jayaraman Nature Biotechnology 28,
  883 - 884 (2010)
• Spinout from UK Academia (patent free),
  Polytherics, Germany, Egypt( PegIFN)

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India home grown industry

• Indias billion dollar biotech - Shantha timeline
• 1992 Varaprasad attends immunization conference
  in Geneva forms hepatitis B vaccine idea
• 1993 Shantha Biotechnics is born, staff works out
  of Osmania University
• 1994 Shantha Biotechnics moves to Centre for
  Cellular and Molecular Biology
• 1995 Oman invests 1.2 million in equity Shantha
  moves into own facility
• 1997 Shanvac-B, launched (first recombinant
  health product manufactured in India)
• 1998 Shantha sells 22 million doses of ShanvacB

Source Justin Chakma et al,
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India home grown industry

• Indias billion dollar biotech - Shantha timeline
• 1999 Peerreviewed comparative study validates
  quality of ShanvacB (Abraham, P. et al.Vaccine
  17, 11251129 (1999)
• 2000 Morgan Stanley and State Bank of Indian
  Mutual Fund invest 10 million in equity
• 2002 Shantha introduces first bio-therapeutic
  product, Interferon a 2b, onto the market Shantha
  receives WHO pre-qualification for Shanvac-B
• 2005 Shantha introduces Shantetra, first
  combination vaccine (diphtheria, pertussis,
  tetanus, and hepatitis B) onto market
• 2007 Merieux Alliance picks up 60 stake in
  Shantha, which it later expands to 80
• 2009 Shantha wins a 340 million contract from
  UNICEF for pentavalent vaccines
• 2009 Sanofi Aventis acquires an 80 controlling
  stake valuing the firm at 784 million
• N.B Concern of Ind Gov re Foreign Investment
  impact on Access to HCPs.

Source Justin Chakma et al,
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Global health or global wealth?

• There is not an inevitable trade-off between
  global health and global wealth.
• Both goals can be pursued in parallel.
• Concerted action
• better tailor existing measures (PPPs, AMCs,
  patent pools and priority review vouchers)
• New entrepreneurial support mechanisms, Such as
  orphan drug-like legislation in emerging
  economies, the Global Health Accelerator

Source Rahim Rezaie Peter A Singer - nature
biotechnology volume 28 number 9 september 2010
43
45 million initiative to support development of
affordable healthcare products

• A 45 million partnership between the Wellcome
  Trust and the Department of Biotechnology,
  Government of India, is unveiled today to support
  the development of innovative healthcare products
  at affordable costs.

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• Working of the WHO resolutions.

WHA59.24 Public health, innovation,
essential health research and intellectual
property rights towards a global strategy and
plan of action WHA60.30 Public health,
innovation and intellectual property WHA61.21
Global strategy and plan of action on public
health, innovation and intellectual
property WHA63.28 Establishment of a
consultative expert working group on research and
development financing and coordination. EB126/15
Viral Hepatitis A63/15 Viral
hepatitis THE DISEASES
AND BURDEN PREVIOUS
HEALTH ASSEMBLY ACTION AND SECRETARIAT ACTIVITIES
OPPORTUNITIES FOR
PREVENTION AND CONTROL
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• Global burden of HCV.

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• Global burden of HCV and other viruses.

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????? Thank You
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Prof. M. A. Eldawy, Comment re Prof Maged, Dec
17th, 2008, CU Centennial