Transcript DRUG DISCOVERY PLAN Requires at the minimum

Biotechnology and Drug DiscoveryA 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
Bio-Pharma Industry- A Multi-disciplinary Arena
Marketing
Marketing
Specialists
Biochemistry
&
Chemistry
R&D
Biophysics &
Mathematics
Molecular
Biology
Pharmacy &
Clinical Practices
Legal, IPR &
Regulatory Aspects
Biotechnology
Management
Bioinformatics
Application & Production
Chemical,
Biochemical Engg.
& Instrumentation
Pharmacology
&
Physiology
Microbiology &
Cell Biology
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…..
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..
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 NGO’s
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 .
• India’s priorities: economic growth to provide better quality of life for all
•Stability is necessary to keep the pace up.
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.S&T 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
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
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
INTERNATIONAL TREND IN DRUG RESEARCH
&
THEIR RELEVANCE IN INDIAN SCENARIO
DRIVING FORCES FOR DRUG DISCOVERY
Profit Philosophy
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
0
1
2
3
4
Service providly philosophy
5
6
TOWARDS HEALTH FOR ALL:WHAT IS RELEVANT FOR INDIA
Diseases marked in red color indicate indicate high class global research activities being carried out
1. To Prevent Communicable diseases
•Respiratory infection :
MMR, Influenza, TB, Meningococcal
meningitis, Diphtheria, Chickenpox,
Whooping cough etc
• Intestinal
Diarrhoea,Typhoid, Cholera, Viral
hepatitis, Polio, Worms etc
infection :
• 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 R&D program?
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 R&D programs?
HARD FACTS OF BIOTECH RESEARCH
EXPENDITURE
Hard Facts of Drug Development
• Lead or Target (Clinical
Candidate)
• Animal Model Testing
New Entity
Cost
• $190-240 M
2-10,000
• $80-120 M
100
• $60-120 M
20
• $50-150 M
• $150-250 M
3
2
• $20 M
1
– Toxicity, Efficacy
• Phase I Pre-Clinical
(toxicity)
• Phase II (efficacy)
• Phase III (efficacy)
• NDA (new drug
application)
Expense-Success Rate of Drug Development
20 Out of 2000 to 10,000 nos. screened!!!
• Candidate Drug
• 1/20 drugs entering
Phase I hit market
• Most drugs fail due to
adverse side effects in a
portion of treated
population
• Phase I
• Phase II
• Phase III
20
550-900
150-250
60-120
50-150
80-120
190-240
Discovery
Preclinical
Phase I
Phase II
Phase III
Registration
Total
Biotech Drug Discovery Evolution
 rDNA Technology
 Gene Silencing /
Regulation
 Genomics
 Proteomics
 Structural Biology
 Pharmacogenomics
Rational Drug Design
Drug Discovery-Post Genomic Era
Target Identification
Target Validation
Lead Identification
Lead Optimization
In vitro Validation
In vivo Validation
Marketing Approvals
Phase I
Phase II
Phase III
Regulatory Approvals
Number of Targets > 5000
Rational Drug Discovery & Development (Schematic)
Identify disease
Isolate protein
involved in
disease (2-5 years)
Find a drug effective
against disease protein
(2-5 years)
Scale-up
Preclinical testing
(1-3 years)
Human clinical trials
(2-10 years)
Formulation
FDA approval
(2-3 years)
Biopharmaceuticals discovery:Genomes to Targets to Products & Diagnostics
Genomics
Gene therapy
Vaccines
Genes
DNA-diagnostics
Proteins
Biotherapeutics
Target discovery
( For New Chemical Entities)
Target universe –post genomics
Gene Targets for
small molecular
drugs ~10,000
Targets for
protein
therapeutics
~1,800 genes
Addressable
by protein
therapeutics
~10,000 genes
Expression focused
target genes (siRNA &
anti-sense therapies)
~2,300 genes
Potential target within
human genome:
Druggable
~3,000 genes
Drug targets
600-1500 genes
• Addressable by small
molecules (47% enzymes,
30% GPCRs, 7% channels,
4% transporters, 4% NHRs,
1% integrins & 1% DNA)
Disease
modifying ~
4,500 genes
Source: Drug Discovery Today, Aug 2005
Nature Reviews 1: 727-230, 2002
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 .
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
Benefits of Computational Modeling
• We may want to screen:
– All of a company’s 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
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
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
What do we do next after identifying lead compound/s ?
Required to generate in-vitro and in-vivo
efficacy and toxicity data.
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
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?
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?
– Don’t enroll people of the “wrong” genotype!
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
How India can leverage: More efforts? More resources? More effective
planning? More of all of these? Newer innovative efforts?
Can we have
more
successes?
At least 2-4 N C Es / Yr.
Can we have
some block
busters?
How?
More drugs should have blockbuster
potential if R&D is rightly structured.
Higher Success rate in Clinical Research
need to be achieved.
How reduce
marketing
time?
Target:Market introduction time from
15-20 yrs to <7 years. Policy change?
Development of a new drug- Schematic
Identify
disease
area
Target
Selection
Target
Validation
Assay
Hit
Development Identification
Lead
Optimization
Profiling
Screens
ADMETOX
Clinical
Trials
Market
FUTURISTIC BIOPHARMA SCENARIO
Deploying Various Techniques
Matured
Microbial
products
Developed
Mammalian Cell culture
Insect cell culture
Transgenic animals
Transgenic plants
Gene Therapy/DNA vaccine
Cell Therapies
Infancy
Transgenic Chick/Egg/Cow
Babyhood
PLATFORMS FOR PROTEIN PRODUCTION
Host system
E. coli
Time to Engineer
(gene-to-protein)
Yeast
+
Insect Cell
++
+++
Mammalian
Cells
+++
3 months
Transgenic
Plants
++++
4 months
Transgenic
animals
+++++
0.5 – 2 years
Capital
Investment
$ 0.2-0.5M / m3
$ 0.2-0.5M/m3
Not
available
$2-3 M/ m3
$ 10/m2
$0.5-1 M
$ Cost / gram raw
material
5 - 25
5 - 25
Not
available
150
0.05
1-2
Expression level
1-5 g/L
1-5 g/L
1-5 g/L
0.1 – 3 g/L
5 g/ Kg Leaf
2-35 g/L Milk
Cost to produce
1.0 gram protein
++
$50-100/g
++
$300-500/g
+++
$500-1000/g
+++
$500-5000/g
+
$10-12/g
+
$1-4/g
Product
localization
Secretion
periplasmic
Intra-cell/
Secreted
Secreted
Secreted
Secreted only
by Moss
Secreted in Milk
Protein folding
Refolding
required
Refolding (at
times)
Correct
folding
Correct
folding
Correct folding
Correct folding
N / O-linked
glycosylation
No Metabolic
Engineering in
progress
High mannose
GluNAc
Simple,
No Sialation
Complex
Plant-specific
gly-cosylation
knocked out
Similar to that
in Human
proteins
Safety concerns
Endotoxins
(pyrogens)
Low
Viruses
Viruses
Allergens
BSE, TSE,
prions,virus
NONE>15 in
Develop
NONE>60 in
Development
No. of Products
approved
34
11
2
14
From various published sources
Above information from various published sources
Transgenic Biopharmaceuticals in Clinicals
Plant-derived Biopharmaceuticals
Animal-derived Biopharmaceuticals
Product
Company
(Host used)
Stage
Product
Company (Host
used)
Stage
Anticaries
antibody
Monsanto (Corn)
Phase III
Antithrombin
-III
Approved in EU
Phase-III US
GTC
(Goat)
scFv (nonHodgkin)
Large Scale Biology
(Tobaco)
Phase III
C1-esterase
inhibitor
Phase-III
On Fast Track
Pharming
(Rabbits)
Gastric Lipase
Meristem
Therapeutics
(Corn)
Phase II
a-1antitrypsin
Phase-II complete
PPL
Newcastle
Disease Poultry
Vaccine
DOW Agriscience
(Non-nicotine
Tobacco)
Approved
in USA
ABX-IL-8
MAB
Phase-II
Abgenix
(Mice)
Antitumor
antibody
Monsanto
(Corn)
Phase I
MDX-CD4
MAB
Phase-II
Medarex
(Mice)
Anti-HSV
antibody
Epicyte &
Monsanto
(Corn & Soybean)
ProdiGene
(Corn)
Phase I
MM-093
Phase-I
Merimack
Phase I
Factor-IX
Phase-I
HemoCare
(Pigs)
TGEV vaccine
therapeutic
PHARMING
PHARMING OF
OF
FARMACEUTICALS
FARMACEUTICALS
Company
Meristem Therapeutics
Plant used
Product
Indication
Clinical Stage
Maize
Gastric lipase
Cystic fibrosis
Phase 2
Maize
Lactoferrin
Gastrointestinal disorders
Phase 1
Corn
slgA
Prevention of tooth decay
Phase 2
Tobacco
ICAM1
receptor for common cold
Phase 1
Prodigene
Maize
Lt-B vaccine
Traveller's diarrhoea
Phase 2
LSBC (in Ch.11
Tobacco
scFv
Non-Hodgkin's Lymphoma
Phase 3
Tobacco
Vaccine
Feline Parvovirus
Phase 3
Potato
Vaccine
E.Coli
Phase 1
Potato
Vaccine
Hepatitis "B"
Phase 1
Potato / Tobacco
Vaccine
Norwark virus
Phase 1
Rice
Lactoferrin
Undisclosed
Undisclosed
Rice
Lysozyme
Undisclosed
Undisclosed
Biolex
Lemna
Interferon Alpha
Hepatitis "B" & "C" & CML
Phase 1
Cobento Biotech AS
Aribidopsis
Intrinsic Factor
Vitamin B12 deficiency
Phase 2 / 3
Dow Agrisciences
Non nicotine tobacco
Vaccine
Newcastle disease -Poultry
USDA Approved
Glucocerebrosidase
Gaucher's disease
Phase 1
Planet Biotechnology
Arizona State Univ.
Ventria Biosciences
Protalix
D.Yusibov and others
Spinach
Vaccine
Rabies
Phase 2
Epicyte / Monsanto
Maize
Antibody
Cancer
Phase 3
LIFESTOCK AS BIOREACTORS
Rabbit
Pig
Sheep
Goat
Gestation time, months
1
4
5
5
Age at sexual maturity (months)
5
6
8
8
Induced lactation in prepubertal founder females
–
–
9
9
Natural lactation in founder females
7
16
18
18
Induced lactation in prepubertal daughters
–
–
22
22
Natural lactation in daughters
15
28
31
31
Number of offspring
8
10
1–2
1–2
Annual milk yield, l
5(a)
300(b)
500
800
Raw recombinant protein per female per year, kg
0.02
1.5
2.5
4
[a]
Average total production from 2–3 lactations per year.
year.
[b]
Average total production from 2 lactati
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 J&J - 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
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
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 R&D and product commercialization
• To promote alliance : institutions, industries, and inter-governmental
bodies.
• To have time bound plan for product/process development.
Multifaceted International R&D has a big
basket requiring very large investment
Sources of all pictures gratefully acknowledged
Radical Re-designing of Indian R&D
necessary to make a global impact
Thank you