DRUG DISCOVERY PLAN Requires at the minimum

whipmellificiumBiotechnology

Feb 20, 2013 (4 years and 7 months ago)

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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 University

Department of Chemical Technology

Friday,November 10,2006


Bio
-
Pharma Industry
-

A Multi
-
disciplinary Arena

Biochemistry

&

Chemistry

Microbiology &

Cell Biology

Pharmacology

&

Physiology

Molecular


Biology


Biophysics &

Mathematics


Biotechnology

Management

Chemical,

Biochemical Engg.

& Instrumentation


Pharmacy &

Clinical Practices


Legal, IPR &

Regulatory Aspects

Bio
-

informatics

Marketing

Specialists

R&D

Application & Production

Marketing

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












Biotech industry ranked #2 globally by number of units


Will be the leading industry by 2020



India considered

in
world's
TOP
1
1
biotech powers



The industry
has

grown

by 74% in the last 2 years



Estd. 200
biotech
Co
s

-

more
than Japan or Korea



By 2010, to generate $5 billion
and one
million jobs



Largest no. of US
-
FDA
-
approved plants outside USA


Indian scenario in Biotechnology






PHARMACEUTICAL



Uses Active Pharmaceutical Ingredient


Chemically synthesized

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









Pharma market segmentation

BIO
-
PHARMA SHARE
-

2025

BIO
-
PHARMA SHARE
-

2001

INTERNATIONAL TREND IN DRUG RESEARCH

&


THEIR RELEVANCE IN INDIAN SCENARIO

DRIVING FORCES FOR DRUG DISCOVERY
0
1
2
3
4
5
6
Service providly philosophy
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


TOWARDS HEALTH FOR ALL:WHAT IS RELEVANT FOR INDIA

1.
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









Diseases marked in red color indicate indicate high class global research activities being carried out

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


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

Hard Facts of Drug Development

Cost

New Entity


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

Expense
-
Success Rate of Drug Development


20 Out of 2000 to 10,000 nos. screened!!!

Discovery

Pre
-
clinical

Phase I

Phase II

Phase III

Registration

Total

190
-
240

80
-
120

60
-
120

50
-
150

150
-
250

20

550
-
900

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

Phase I

Phase II

Phase III

Regulatory Approvals

Marketing Approvals

Number of Targets > 5000

Identify disease

Isolate protein

involved in

disease (2
-
5 years)

Find a drug effective

against disease protein

(2
-
5 years)

Preclinical testing

(1
-
3 years)

Formulation

Human clinical trials

(2
-
10 years)

Scale
-
up

FDA approval

(2
-
3 years)

Rational Drug Discovery & Development (Schematic)





Biopharmaceuticals discovery:Genomes to Targets to Products & Diagnostics


Target discovery

( For New Chemical Entities)

Genes

DNA
-
diagnostics

Gene therapy

Biotherapeutics

Vaccines

Proteins

Genomics













Addressable
by protein
therapeutics
~10,000 genes

Gene Targets for
small molecular
drugs ~10,000

Disease
modifying ~
4,500 genes

Expression focused
target genes (siRNA &
anti
-
sense therapies)
~2,300 genes

Druggable
~3,000 genes

Targets for

protein
therapeutics
~1,800 genes

Target universe

post genomics

Potential target within
human genome:



Addressable by
small
molecules

(47% enzymes,
30% GPCRs, 7% channels,
4% transporters, 4% NHRs,
1% integrins & 1% DNA)

Source:

Drug Discovery Today, Aug 2005

Nature Reviews 1: 727
-
230, 2002

Drug targets
600
-
1500 genes


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

.

Combinatorial Chemistry: Small molecules


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

Virtual Screening


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

Benefits 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”

3
D

representations

of

molecules

into

3
D

representations

of

proteins,

and

score

according

to

how

well

they

bind

Basis of Computational Modeling


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

High Throughput Screening

What do we do next after identifying lead compound/s ?



Required to generate in
-
vitro and in
-
vivo



efficacy and toxicity data.


Traditionally,

animals

were

used

for

pre
-
human

testing
.

Animal

tests

are

expensive,

time

consuming

and

ethically

undesirable

in

certain

situations
.



ADME

(
A
bsorption,

D
istribution,

M
etabolism,

E
xcretion)

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

A.D.M.E. Models


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?

Pharmacogenetics
-

Impact on Drug Discovery


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!

Benefits of Pharmacogenomic Profiling of
Population and Candidate Drug


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


Challenges Facing the Rational Drug Discovery...














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?

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














Development of a new drug
-

Schematic


Identify
disease
area

Target
Selection

Target
Validation

Assay

Development

Hit

Identification

Lead

Optimization

Profiling

Screens

ADME
-
TOX


Clinical

Trials


Market













FUTURISTIC BIOPHARMA SCENARIO

Deploying Various Techniques

Transgenic Chick/Egg/Cow

Infancy


Microbial products

Mammalian Cell culture

Insect cell culture


Transgenic animals


Transgenic plants

Gene Therapy/DNA vaccine


Cell Therapies


Matured

Babyhood

Developed













PLATFORMS FOR PROTEIN PRODUCTION

Host system

E. coli

Yeast

Insect Cell

Mammalian
Cells

Transgenic
Plants

Transgenic
animals

Time to Engineer

(gene
-
to
-
protein)

+

++

+++

+++

3 months

++++

4 months

+++++

0.5


2 years

Capital
Investment

$ 0.2
-
0.5M / m
3

$ 0.2
-
0.5M/m
3

Not
available


$2
-
3 M/ m
3

$ 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

No. of Products
approved

34

11

2

14

NONE>15 in
Develop

NONE>60 in
Development

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 (non
-
Hodgkin)

Large Scale Biology

(Tobaco)

Phase III

C1
-
esterase
inhibitor

Phase
-
III
On Fast Track

Pharming

(Rabbits)

Gastric Lipase

Meristem
Therapeutics

(Corn)

Phase II

a
-
1
-
a湴楴特灳楮

偨慳e
-
䥉 捯m灬整p

偐L
therapeutic

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)

Phase I

MM
-
093

Phase
-
I

Merimack

TGEV vaccine

ProdiGene

(Corn)

Phase I

Factor
-
IX

Phase
-
I

HemoCare
(Pigs)






PHARMING OF
FARMACEUTICALS

Company
Plant used
Product
Indication
Clinical Stage
Meristem Therapeutics
Maize
Gastric lipase
Cystic fibrosis
Phase 2
Maize
Lactoferrin
Gastrointestinal disorders
Phase 1
Planet Biotechnology
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
Arizona State Univ.
Potato
Vaccine
E.Coli
Phase 1
Potato
Vaccine
Hepatitis "B"
Phase 1
Potato / Tobacco
Vaccine
Norwark virus
Phase 1
Ventria Biosciences
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
Protalix

Glucocerebrosidase
Gaucher's disease
Phase 1
D.Yusibov and others
Spinach
Vaccine
Rabies
Phase 2
Epicyte / Monsanto
Maize
Antibody
Cancer
Phase 3








PHARMING OF
FARMACEUTICALS













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.
[b]
Average total production from 2 lactations per
year.












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.















Radical Re
-
designing of Indian R&D

necessary to make a global impact

Multifaceted International R&D has a big
basket requiring very large investment

Thank you

Sources of all pictures gratefully acknowledged