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Biotechnology and Drug Discovery- A Shifting Paradigm for

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Biotechnology and Drug Discovery- A Shifting Paradigm for India Prasanta K Ghosh President Cadila Pharmaceuticals Limited Ahmedabad Lecture delivered at Calcutta ... – PowerPoint PPT presentation

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Title: Biotechnology and Drug Discovery- A Shifting Paradigm for


1
Biotechnology and Drug Discovery- A Shifting
Paradigm for India
Prasanta K Ghosh President Cadila Pharmaceuticals
Limited Ahmedabad Lecture delivered at Calcutta
University Department of Chemical Technology
Friday,November 10,2006
2
Bio-Pharma Industry- A Multi-disciplinary Arena
Biochemistry Chemistry
RD
Biophysics Mathematics
Marketing Specialists
Marketing
Molecular Biology
Biotechnology Management
Pharmacy Clinical Practices
Bio- informatics
Legal, IPR Regulatory Aspects
Microbiology Cell Biology
Application Production
Chemical, Biochemical Engg. Instrumentation
Pharmacology Physiology
3
DRUG DISCOVERY PLAN Requires at the minimum
  • High scientific skills
  • Plenty of resources
  • A Team Leader and a Team with high order of
    skills
  • and determined motivation
  • High throughput screening methods through
    techniques in
  • - Genomics
  • - Proteomics
  • - Strong Organic chemistry
  • - Bioinfomatics skills

Contd..
4
DRUG DISCOVERY PLAN Requires at the minimum
  • AFTER IDENTIFYING THE DRUG.
  • Models for testing Toxicity and Efficacy
  • - In vitro Models
  • - In vivo Models
  • Production modules for enough testing materials
    under
  • cGMP condition
  • - Physiochemical characterization
  • - Immunological characterization
  • - Biological characterization
  • Clinical trial outfits
  • Manufacturing implements

Contd..
5
DRUG DISCOVERY PLAN Requires at the minimum
  • At the Regulatory level, Marketing level
    Societal acceptance level
  • Knowledgeable Regulatory Body with protective but
  • cautious approach
  • To obtain steady and time bound Regulatory
    approvals
  • Marketing Infrastructure
  • Societal attitude towards Biotech products
  • All these requirements are never optimal at one
    place or even in one country
  • Optimization is required through deliberate
    government intervention to ease the process and
    to catalyze alliance among governments,
    companies,institutions and public friendly NGOs

6
A GREAT TIME FOR CHANGES THROUGH BIOTECHNOLOGY
  • INDIA
  • Land frontier of over 3 million sq.kms
  • Coast limit of 7500 kms.
  • Population of 1.1 billion
  • One of largest country having diverse and plenty
    full genetic diversity
  • Location is unique to create economic influence
    in the region
  • Growing economic strength has attracted world
    attention .
  • Indias priorities economic growth to provide
    better quality of life for all
  • Stability is necessary to keep the pace up.

7
GLOBAL ECONOMIC ENVIRONMENT
  • Globalization is presently accepted everywhere
    for bringing industrial
  • reforms and economic benefits
  • Trade is becoming seamless across the countries
    and efficient ones
  • are creating more wealth
  • Socialist world stands transformed and has
    welcome globalization
  • Unfortunately religious fundamentalism and
    terrorism are on the
  • rise to obstruct the process of globalization
  • Our relationship with large and small adjoining
    neighbours is crucial
  • for sustainance and growth of economy.ST
    through biotechnology
  • alliance can create good relation among
    neighbors
  • Societies will reform to pave the paths that are
    beneficial to all
  • At the bottom line human beings must survive and
    prosper

8

Indian scenario in Biotechnology
  • Biotech industry ranked 2 globally by number of
    units
  • Will be the leading industry by 2020
  • India considered in world's TOP 11 biotech
    powers
  • The industry has grown by 74 in the last 2
    years
  • Estd. 200 biotech Cos - more than Japan or Korea
  • By 2010, to generate 5 billion and one million
    jobs
  • Largest no. of US-FDA-approved plants outside USA

9
Pharma market segmentation

BIO-PHARMA SHARE- 2001
PHARMACEUTICAL Uses Active Pharmaceutical
Ingredient Chemically synthesized
BIO-PHARMA SHARE- 2025
BIOPHARMACEUTICAL Use of microbes or rDNA
products made by living modified organisms to
produce natural or modified products
  • 30 drugs in the market 2005 are of Biotech
    origin 50 anticipated by 2010 rising to 65 by
    2025

10
INTERNATIONAL TREND IN DRUG RESEARCH THEIR
RELEVANCE IN INDIAN SCENARIO
11
To discover block busters for plenty of profits
To drive discovery to anticipate usage for longer
duration
To provide better quality of life with increased
longevity
To provide relief to the sufferings
To create healthy society
12
TOWARDS HEALTH FOR ALLWHAT IS
RELEVANT FOR INDIA
Diseases marked in red color indicate indicate
high class global research activities being
carried out
  • To Prevent Communicable diseases
  • Respiratory infection MMR, Influenza, TB,
    Meningococcal meningitis, Diphtheria,
    Chickenpox, Whooping cough etc
  • Intestinal infection Diarrhoea,Typhoid,
    Cholera, Viral hepatitis, Polio, Worms
    etc
  • Arthropod born infection Malaria, Filaria,
    Dengue, Chickengunya etc
  • Zoonotic diseases Yellow fever, JE,
    Brucellosis, Plague,Salmonellosis, Typhus,
    Q Fever etc
  • Others Tetanus, Leprosy, AIDS, STD

How shall we benefit ourselves unless we develop
our strong in-house RD program?
13
TOWARDS HEALTH FOR ALL
  • 2. To Prevent Non-Communicable diseases
    conditions
  • Hyper tension ,
  • Diabetes,
  • Cancer,
  • Rheumatic heart disease,
  • CHD,
  • Stroke,
  • Parkinson's disease,
  • Genetic disorder,
  • Kidney disorder,
  • Gonadal dysfunction ,
  • Rheumatoid Osteoarthritis,
  • Mental health improvement,
  • Nutrition

How shall we benefit from global research unless
we develop our RD programs?
14
HARD FACTS OF BIOTECH RESEARCH EXPENDITURE
15
Hard Facts of Drug Development
New Entity
Cost
  • Lead or Target (Clinical Candidate)
  • Animal Model Testing
  • Toxicity, Efficacy
  • Phase I Pre-Clinical (toxicity)
  • Phase II (efficacy)
  • Phase III (efficacy)
  • NDA (new drug application)
  • 190-240 M 2-10,000
  • 80-120 M 100
  • 60-120 M 20
  • 50-150 M 3
  • 150-250 M 2
  • 20 M 1

16
Expense-Success Rate of Drug Development 20
Out of 2000 to 10,000 nos. screened!!!
  • Candidate Drug
  • Phase I
  • Phase II
  • Phase III
  • 1/20 drugs entering Phase I hit market
  • Most drugs fail due to adverse side effects in a
    portion of treated population

17
Biotech Drug Discovery Evolution
18
Drug Discovery-Post Genomic Era
Target Identification Target Validation Lead
Identification Lead Optimization
In vitro Validation In vivo Validation
Phase I Phase II Phase III Regulatory Approvals
Marketing Approvals
Number of Targets gt 5000
19
Rational Drug Discovery Development (Schematic)
Identify disease
Find a drug effective against disease
protein (2-5 years)
Isolate protein involved in disease (2-5 years)
Scale-up
Preclinical testing (1-3 years)
Human clinical trials (2-10 years)
File IND
Formulation
File NDA
FDA approval (2-3 years)
20
Biopharmaceuticals discoveryGenomes to Targets
to Products Diagnostics

21

Target universe post genomics
Gene Targets for small molecular drugs 10,000
  • Potential target within human genome
  • Addressable by small molecules (47 enzymes, 30
    GPCRs, 7 channels, 4 transporters, 4 NHRs, 1
    integrins 1 DNA)

Targets for protein therapeutics 1,800 genes
Addressable by protein therapeutics 10,000
genes
Druggable 3,000 genes
Drug targets 600-1500 genes
Expression focused target genes (siRNA
anti-sense therapies) 2,300 genes
Disease modifying 4,500 genes
Source Drug Discovery Today, Aug 2005 Nature
Reviews 1 727-230, 2002

22
Combinatorial Chemistry Small molecules
  • By correctly identifying molecular building
    blocks, based on certain parameters, we can
    create very large numbers of different molecules
    very quickly.
  • Usually involves selecting a general scaffold
    molecule, and synthesizing sets of compounds
    which can be tested for activity optimization .

23
Virtual Screening
  • Build a computational model of activity for a
    particular target
  • Use model to score compounds from virtual or
    real libraries
  • Use scores to decide which to make, or pass
    through a real screen

24
Benefits of Computational Modeling
  • We may want to screen
  • All of a companys in-house compounds
  • A compound collection that could be purchased
  • A potential combinatorial chemistry library, to
    see if it is worth making, and if so which to
    make
  • A Model may evolve with prediction of how well
    each molecule will bind,based on, say a score
    assigned for each molecule
  • Decide which molecules to be synthesized for real
    screening

25
Basis of Computational Modeling
  • Machine Learning Methods
  • e.g. Neural nets, Bayesian nets, Kahonen nets
  • Train with compounds of known activity
  • Predict activity of unknown compounds
  • Scoring methods
  • Profile compounds based on properties related to
    target
  • Fast Docking
  • Rapidly dock 3D representations of molecules
    into 3D representations of proteins, and score
    according to how well they bind

26
High Throughput Screening
  • Drug companies now have millions of samples of
    chemical compounds
  • High-throughput screening can test 1,00,000
    compounds a day for activity against a protein
    target
  • Maybe tens of thousands of these compounds will
    show some activity for the target protein
  • The chemist needs to intelligently select the 2 -
    3 classes of compounds that show the most promise
    for becoming APIs ,to follow-up

27
What do we do next after identifying lead
compound/s ?
Required to generate in-vitro and in-vivo
efficacy and toxicity data.
28
A.D.M.E. Models
  • Traditionally, animals were used for pre-human
    testing. Animal tests are expensive, time
    consuming and ethically undesirable in certain
    situations.
  • ADME (Absorption, Distribution, Metabolism,
    Excretion) techniques help model how the drug is
    likely to act in the body
  • These methods can be experimental (in vitro)
    using cellular tissue, or in silico, using
    computational models

29
Pharmacogenetics- Impact on Drug Discovery
  • Quantitative traits
  • How effective is a drug?
  • How serious are side effects?
  • How many loci/alleles control trait?
  • Population variation
  • How frequent is a polymorphism?
  • How many different polymorphisms are present?
  • Are particular combinations of loci/alleles
    common?

30
Benefits of Pharmacogenomic Profiling of
Population and Candidate Drug
  • Where do you find the next profitable drug?
  • The 19/20 drugs that failed AFTER phase 1, but
    are still efficacious!
  • How do you decrease the cost of clinical trials?
  • Dont enroll people of the wrong genotype!

31
Challenges Facing the Rational Drug Discovery...
  • Huge increase in the volume of information
  • Genomics High-throughput screening
  • How do we use it to make better decisions
    (earlier)
  • Immature technology and informatics
  • Experimental hardware is changing rapidly
  • Computing needs to meet complex, changing
    analysis needs
  • Fuzzy science
  • Even our understanding of the underlying science
    is constantly changing

32

How India can leverage More efforts? More
resources? More effective planning? More
of all of these? Newer innovative efforts?

33

Development of a new drug- Schematic

34

FUTURISTIC BIOPHARMA SCENARIO Deploying Various
Techniques
Matured
Developed
Babyhood

35

PLATFORMS FOR PROTEIN PRODUCTION

From various published sources
Above information from various published sources
36
Transgenic Biopharmaceuticals in Clinicals
37
PHARMING OF FARMACEUTICALS

PHARMING OF FARMACEUTICALS

38

LIFESTOCK AS BIOREACTORS

39

INDIA SHOULD MOVE TOWARDS ALTERNATIVE PLATFORMS
  • Cell culture platform not suitable for making
    drugs affordable
  • Companies using cell-culture platform are fast
    moving to Transgenics
  • (e.g. Centocor and JJ - Remicade Reopro
    using transgenic goats Amgen,. GSK)
  • India does not have its transgenic technology
    for protein production
  • New developments in transgenic technology has
    high potential
  • (cloned transgenics enables selection of 100
    female offspring)
  • Transgenic tech. could boost animal husbandry
    and farm sector too
  • Transgenic technology would provide alternative
    proprietary route
  • for manufacturing molecules having patented
    production method


40

HOW PRODUCTS PORTFOLIO COULD BE CREATED?
Biopharmaceuticals are typically covered by two
classes of patents Product Patents covers the
molecule and formulation composition Process
Patents covers production / manufacturing
processes Example Epogen (EPO / Procrit
Epoetin alfa) Product Patent expired 2004
Process Patent expiration 2014 Companies with
alternative, novel protein production
technologies will be able to overcome existing
process patents and will have the freedom to
manufacture generic biopharmaceuticals whose
product patents expire

41

CONCLUDING REMARKS
  • To choose diseases conditions to treat
    Indians to become more healthy
  • To choose develop platforms that are unique for
    biotech drugs
  • To create organizational infrastructure so that
    bench workers remain young.
  • To keep a watch on Patent expiry of effective
    drugs
  • Stupendous reward for new drug development and
    application group
  • To create highly knowledgeable regulatory
    authorities
  • To liberally allocate funds for RD and product
    commercialization
  • To promote alliance institutions, industries,
    and inter-governmental bodies.
  • To have time bound plan for product/process
    development.


42

Radical Re-designing of Indian RD necessary to
make a global impact
Multifaceted International RD has a big basket
requiring very large investment

Thank you
Sources of all pictures gratefully acknowledged
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