Pharmaceuticals and Biotechnology

gooseliverΒιοτεχνολογία

22 Οκτ 2013 (πριν από 3 χρόνια και 10 μήνες)

107 εμφανίσεις


Pharmaceuticals and Biotechnology


Hirzun Mohd Yusof, PhD

Manager

Sime Darby Technology Centre

Biotechnology Definition


OLD:
Recombinant genetic engineering...using biological processes
to develop products



NEW:

Use of biological processes to solve problems or make useful
products. Life sciences…biology/chemistry technology affecting
discovery and development of products for:



Human healthcare (therapeutics, diagnostics, drug delivery, cell
and gene therapy…even moving toward some devices and
drug/device combinations)


Wellness…not just sickness


Agriculture (food, feed, fibers, transgenics)


Environment (bio
-
remediation)


Bio
-
based industrial processes and efficiency


Bio
-
based energy

Supply (reagents, biologicals)



All driven by a new set of enabling technology (genomics,
combinatorial chemistry, SNPs, proteomics, etc.)


Source: Burrill and Company

Biotech industry?

Biotechnology

Genes and proteins

Human

Agricultural


Trangenic
Plants


Animals


Drug
development


Gene surgery


Genetic
testing

Microbes


Alcohol


Mining


Waste
management

Chemicals


Extracts


Oils


Pharma
-
intermediaries


Nutraceuticals

“Spare parts”


Tissue
regeneration


Growing
organs

Development is evolutionary…

1953: Watson and Crick DNA Structure

1970: First enzyme discovered to cut DNA molecules at a
specific site

1971: First complete synthesis of a gene

1972: First time DNA fragments linked

1976: First NIH research guidelines

1980: Oil
-
eating microbes patented by Exxon

1982: First recombinant DNA vaccine for livestock

1983: First whole plant grown from biotechnology

1986: First genetically engineered vaccine for humans: Hep
B


First anticancer drug through biotech: interferon

1990: First food product from biotech approved: modified
yeast



Development is evolutionary…

1994: First FDA approval for food product

1997: First weed & insect resistant crops developed


First cloned animal: Hello Dolly!

2000: First complete plant genome mapped


108.9 million acres of biotech crops grown in 13
countries

2004: First genetically modified pet: the GloFish

2004: About 25% of all prescription products on market since
2000 are from biotechnology


The Human Genome & Biotechnology


“A milestone in biology unlike any other.”


“The HGP could fundamentally restructure the nation’s
$1.3 trillion healthcare industry in the next 20
-
30 years:
PwC/Russ Coile


June 26, 2000; 5
-
years ahead of schedule


A short 50 years after the discovery of DNA by Watson
and Crick in 1953


30,000
-
40,000 genes not the 100
-
120,000 thought earlier


Five times as many as in baker’s yeast


About twice as many as that needed to grow a worm or
fly!


Bananas share about ½ our genome while mice share
90%!


BUT, each single human gene can make 10 proteins vs. a
worm or fly’s genes making just one or two.


PM’s Support of Biotechnology


“…. Biotechnology has great potential in Malaysia and it
could be a catalyst for new growth areas in the country’s
economy as well as a source of new wealth and income for
the people, Biotech is useful in many areas


agriculture,
livestock farming, herbal industry and traditional and
modern medicine.”





YAB Prime Minister of Malaysia Dato’ Seri Abdullah Badawi

at the luncheon meeting with top CEO’s of US Biotechnology firms

during BIO 2004 Convention and Exhibition,

9 June 2004 in San Francisco, California

Malaysia Biotechnology Focus Area

HEALTHCARE

INDUSTRIAL

AGROBIOTECHNOLOGY

Diagnostics

Vaccines

Drug Discovery

Wellness

Bio
-
generics

Alternative protein production

Enzyme & industrial chemical

Bio
-
energy

Plant

Natural Products

Marine

Animal

Source: CEO/President MIGHT’s presentation in Sarawak BioSymposium, March 2005

Nine Policy Thrusts


Thrust 1 : Agriculture biotechnology development

Transform and enhance value creation of the agriculture sector through
biotechnology.


Thrust 2 : Healthcare biotechnology development

Capitalise on the strengths of biodiversity to commercialise discoveries in
natural products as well as position Malaysia in bio
-
generics market.


Thrust 3 : Industrial biotechnology development

Ensure growth oppurtunities in the application of advanced bio
-
processing and
bio
-
manufacturing technologies.


Thrust 4 : R&D and technology acquisition

Establish Centres of Excellence, in existing or new institutions, to bring together
multidisciplinary research teams in co
-
ordinated research and commercialisation
initiatives. Accelerate technology development via strategic acquisitions.


Thrust 5 : Human capital development

Build the nation's biotech human resource capability in line with market needs
through special schemes, programmes and training.

Nine Policy Thrusts…continue


Thrust 6 : Financial infrastucture development

Apply competitive "lab to market" funding and incentives to promote committed
participation by academia, the private sector as well as government
-
linked
companies. Implement sufficient exit mechanism for investments in biotech.


Thrust 7 : Legislative and regulatory framework development

Create an enabling environment through continuos reviews of the country's
regulatory framework and procedures in line with global standards and best
practices. Develop a strong intellectual property protection regime to support
R&D and commercialisation efforts.


Thrust 8 : Strategic positioning

Establish a global marketing strategy to build brand recognition for Malaysian
biotech and benchmark progress. Establish Malaysia as centre for Contract
Research Organisations and Contract Manufacturing Organisations.


Thrust 9 : Government commitment

Establish a dedicated and professional implementation agency overseeing the
development of Malaysia's biotech industry, under the aegis of the Prime Minister
and relevant government ministries.





Malaysia Biotechnology Corporation

BIOPHARMACEUTICAL

Biological based therapeutics


Biologically derived material that possess the ability
to heal or to cure human illness


Traditionally extracted from human cadaver or other
sources


Currently replaced by biotechnological methods
through revolution in genetic engineering

Protein drugs have emerged from the
shadows to become, in the last 20 years,
significant products in the arsenal
against illnesses.


While conventionally made proteins are
considerable, proteins resulting from the
biotechnology revolution drive future
growth of the protein drug industry.



The Biotech Wave


In

the

last

5

years,

168

biopharmaceutical

products

obtained

marketing

approval

in

major

markets
.

In

the

next

5

years,

It

is

anticipated

that

an

additional

82

to

137

new

biopharmaceutical

products

will

be

marketed


The

aggregate

sales

of

biopharmaceuticals

amounted

to

US
$
23

billion

in

2002

and

US
$
38

billion

in

2003
.

It

is

forecasted

to

reach

US
$
100

billion

by

2010


The

annual

growth

rate

is

established

at

15
%

and

some

clusters

such

as

monoclonal

antibodies

have

an

even

higher

growth

rate

(
25
%
)


Therapeutic

proteins

(e
.
g
.

growth

factors,

hormones,

antibodies)

represent

the

major

part

of

biopharmaceutical

sales

Market Potential

Growth of the therapeutic protein market

Source: ADL Survey, 2004; market forecasts from Datamonitor, IMS, DSM and PhRMA , 2002
-
2004


Therapeutic

proteins

are

currently

manufactured

via

one

or

two

methods
:


Mammalian

cell

culture

(CHO

cells)
:

>
60
%

of

marketed

products


Bacteria

culture
:

>
30
%

of

marketed

products


The

industry

recognizes

that

there

will

be

a

shortfall

risk

in

protein

manufacturing

capacities

over

the

next

5

years
:


Over

350

biotech

products

are

currently

in

late
-
stage

development

for

200

serious

diseases


A

significant

number

of

major

biopharmaceutical

products

will

be

coming

off

patent


It

is

estimated

that

up

to

4

times

the

current

protein

production

capacity

will

be

needed

to

satisfy

demand

by

2010


Manufacturing

facilities

using

traditional

technologies

require

significant

upfront

investments

and

long

construction

and

validation

times

Market potential

Demand for protein production capacity

Source: ADL Survey, 2004; market forecasts from Datamonitor, IMS, BSM and PhRMA , 2002
-
2004


Demand

for

medium
-
sized

production

batches

(up

to

10

kilograms

per

year)

will

be

among

the

fastest

growing
:








There is a great opportunity over the next 5 years for new
entrants with competitive protein production technologies to
capture significant market share

Market potential

Opportunities for new entrants

Dr Ulrich Steiner

Worldwide Contract Manufacturing Market


US$ MM


Protein Drugs (Final products)

38,000


Annual growth

15%



Outsourcing Ratio

15%


Contract Manufacturing

900

2004

2014 (Forecasts)


US$ MM



Protein Drugs (Final products)

175,000




Outsourcing Ratio

30%


Contract Manufacturing

10,500

Market potential

Contract manufacturing market

Contract Manufacturing

Geographical Breakdown
(2014 forecasts):


Europe

30%

North America

40%

Asia

30%


(>US$ 3,100 MM)

Contract manufacturing of biopharmaceuticals
will be one of the fastest growing industrial
sectors in the next 10 years:


Significant market size and rapid growth


Modest start
-
up investments


Relatively low risk (cf. drug discovery)

Generic Biological Drugs


Biological products are approaching the end of their
market exclusivity with over $10 billion in 2000 sales
coming off patent over the next five years


Generic biologic products represent a significant
opportunity and anticipate progress on this cutting
edge of technology




-
Coan & Ellis, Generic Biologics: The next Frontier, ABN Amro Report

BRAND
NAME

GENERIC NAME

SOURCES

2001 GLOBAL SALES,
US$ MILLION

U.S. PATENT
EXPIRATION

Epogen or
Procrit

Epoetin alfa

Amgen, Johnson &
Johnson, and Sankyo

$5,772

2004

Novolin

Human insulin

Novo Nordisk

1,829

2005

Neupogen

Filgrastim

Amgen and Roche

1,533

2006

Humulin

Human insulin

Eli Lilly

1,061

2001

Avonex

Interferon beta
-
1a

Biogen

972

2003

Intron A

Interferon alpha
-
2b

Schering
-
Plough

700

2002

Cerezyme
or
Ceredase

Alglucerase

Genzyme

570

2001

Humatrope

Somatropin

Eli Lilly

311

2003

Activase

Alteplase

Genentech,
Boehringer Ingelheim,
Mitsubishi, and
Kyowa Hakko Kogyo

276

2005

Nutropin

Somatropin

Genentech

250

2003

Protropin

Somatrem

Genentech

250

2005

TOTAL

$13,524

M
arket potential

Generic biopharmaceuticals market

Generic Biotechnology Feasibility


Numerous arguments why generic biotechnology products would not be feasible.


interrelated concerns over safety and immunogenicity


science’s ability to manufacture and measure such products


process
dependant


Since those early reservations, there has been a combination of technological
advances, (e.g., in vitro/biochemical and analytical assays).


Examples of

some new analytical methods that are assisting in the standardization of

biological products are:



MALDI
-
TOF Spectroscopy



Reflectometric Interference Spectroscopy



Capillary electrochromatography



Signal Transduction Fingerprinting



Bioinformatics, including Microarray Technology and pharmacogenomics.


Company

Marketed Products

Products in development

Bharat Biotech

(Hyderabad, India)

Hepatitis B

Streptokinase, VEGF

Dr Reddy’s Labs
(Hyderabad, India)

G
-
CSF

EPO, IFN
-
Beta, hGH, tPA, IFN
-
gamma

Dragon (Vancouver)

EPO

TPO, G
-
CSF, insulin, hepatits B

GeneMedix

(New Market, UK)

GM
-
CSF

IFN
-
alpha
-
2b, EPO, insulin, IFN
-
gamma, IL
-
2

LG Chem

(Seoul, S. Korea)

EPO, hGH, IFN
-
alpha
-
2a, IFN

gamma, GM
-
CSF, hepatitis B

Rhein Biotech (now
acquired by Berna)

Hepatits B, IFN
-
alpha, IL
-
2

EPO, G
-
CSF,

Shantha
(Hyderabad, India)

Hepatitis B

IFN
-
alpha, insulin, GM
-
CSF, G
-
CSF,
streptokinase, tPA, EPO, hGH

Companies involve in generic biologics


Lyophilization

Bulk Filtration

Seed Fermentation

Drop Tank

Main Fermentation

Feed Media 2

Feed Media 1

Buffer Exchange

Diafiltration

3rd

Chromatography

Buffer Exchange

Diafiltration

UF

Concentration

2nd

Chromatography

Buffer Exchange

Diafiltration (UF)

Buffer Exch.

1stChromatography

Liquid Vial

Product

Lyophilized

Product

Fill/Finish

Microfiltration

Centrifugation

Transfer to

Receive Tank

UF

Concentration

Refolding

IB Dissolution

IB Wash

Centrifugation


IEX

Tank

Fusion

UF

Clarif.

Column

Cleavage

Dilution

Diafilt.

UF

Holding Tank

Homogenization

Dilution

Cell Paste

Typical Process Flow of Biopharmaceutical Production

Micro
-
organisms

(bacteria & yeasts systems)


No


No


< 100 kg

Transgenic Plants Systems

(tobacco, corn, alfalfa, potatoes)


Yes


No/Yes


> 100 kg

Cell Culture

(CHO cells)


Yes


Yes


< 100 kg

Transgenic Animal Systems

(cattle, goat, rabbit milk,

chicken eggs, pig semen)


Yes


Yes


> 100 kg

Compatibility with
Complex Proteins

Glycosylation

Scale

C
OMPETITIVE
A
DVANTAGES

S
UPERIORITY
O
VER
A
LTERNATIVE
S
YSTEMS

Companies active in Animal Transgenesis:



Mammary gland


Milk


GTC Biotherapeutics
(
recombinant form of human antithrombin
-

Market Authorization Application EMEA)

, BioProtein, Pharming
(
recombinant human C1 inhibitor


Phase III)

, Nexia
Biotechnologies



Bone marrow

blood


Hematech


Kirin
(human polyclonal antibody)



Chicken ovary


eggs


Avigenics
(lead product schedule for Phase II in 2005),

Tranxenogen, Vivalis + 10 others



Seminal vesicle


semen


TGN Biotech

Challenges for the future….drug from
transgenic animal

DRUG DISCOVERY

Drug Discovery

Diseases
-
defects in
cellular communication &
control

Mediated by post
-
translational modification
e.g.phosphorylation, acetylation

Idea for targets

Drug Discovery Process

Viral infections

Osteoporosis

Neurological

Diabetes

Obesity

Cancer

Cardiovascular

Respiratory

Amplification &expansion
-

cascades
of phosphorylation events: signal
transduction pathways.

Aberrations linked to disease

Company
-
financed R&D by Product Class,

Estimated 2000 (US only)

Drug Targets

Human genome 22,300 genes

Addressable by protein
therapeutics ~10,000 genes

Target for small molecular
drugs ~10,000 genes

Disease modifying ~ 4,500 genes

Additional targets for
antisense and siRNA
therapies ~2,100 genes

Druggable ~3,000 genes

Additional targets for
protein therapeutics
~1,800 genes

Target universe

post genomics

Source: Drug Discovery Today, Aug 2005

Potential target within human genome:


addressable by small molecules (enzymes, GPCR, channels and NHRs)


addressable by protein therapeutics (membrane proteins and soluble factors)

What is screening?

A Drug Discovery technique where a number of chemical
substances are tested for their ability to interact with
specific proteins (targets) that are believed to be
important in disease states

Source of compounds:



Chemical synthesis


Combinatorial chemistry


Natural compound (plant,microbial, marine

organisms)


The phases of discovery & development
of a new drug


Identify
disease
area

Target
Selection

Target
Validation

Assay

Development

Hit

Identification

Lead

Optimization

Profiling

Screens

ADME
-
TOX


Clinical

Trials


Market

Over the past ten years, expectation has been raised with high
-
throughput screening…results of high
-
throughput screening has
been dissapointing….



…Steve Carney, Editor Drug Discovery Today, Aug 2005

Clinical trial to drug

Potential lead compound

Characterization and structure

elucidation of active compound

Process flow of discovery of new compound from nature

Microbial culture collection

Bioassay screening for

bioactive compound

Plant extracts

List of companies involved in natural compound libraries

Company

Location

Library Type


Albany Molecular


US

Natural products libraries include over 100,000 samples of
extracts derived from nature.


Analyticon

Discovery



Germany


MEGAbolite® libraries consist of pure structurally
elucidated natural compounds.


Cerylid


Australia


Natural products library of over 600,000 extracts from more
than 60,000 biotic samples. available through partnerships
only.



Interbioscreen


Russia

Over 25 000 unique diverse and rare natural & related
compounds.



Microsource / MSDI


US

30,000 extracts of more than 12,000 specimens from the
Amazon. A 720 compound/ 9 plate


collection of pure natural
products and derivatives

Moscow MedChem Labs


Russia

Library of natural compound is now about 200 compounds



Sequoia Sciences


US

Novel libraries of compounds isolated from plants for drug
discovery



SPECS and Biospecs


Netherlands

800+ isolated natural products or derivatives from plants,
fungi, bacteria, sea organisms, etc. (purity >80%).

TimTec

US

True natural product

(240
-
compound) and natural product
-
derived(1600
-
compound) libraries;2500 plants available from
stock for extraction, 9000 plants available for collection

Pharmacogenomics…in drug discovery

The use of genomics approaches to elucidate
drug response:



Via DNA: genetic approach
(pharmacogenetics).


Via RNA: expression profiling.


Via Protein: Proteomics.

Pharmacogenomics Market

World wide market size and
growth


2003 : USD 670 million

2008E: USD 1,655 milliom

2002
-
2007: 20%

Three major areas:


SNP Discovery

SNP Genotyping

Diagnostics

In 2003:

Human Genome contains many variations or polymorphisms

No two human genomes are identical

SNP

(Single Nucleotide Polymorphism)

Every individual has ~0.1% of the
genome that is different. In
average, every 1Kb has a SNP
can be used as a marker on the
genome.

Applications of the SNP Analysis



Disease gene hunting



Prognostics / diagnostics of genetic risks



Pharmacogenomics and drug discovery



Personalized medicine

GENE X

GENE Y

%

%

Normal Population

Patient Population

SNP & Disease Gene ID

%

Population

A

Population B

Most likely

Drug acts on

therapy

Most likely

Drug has no efficacy

Drug treatment

Choose other drug

SNP and
Drug Response Evaluation





Genetic basis for individual differences in

drug absorption and metabolism

For example:

A drug is safe for 70% of
people,

ineffective for 25%,

harmful for 5%

Genetic Variation

Polymorphisms vary

across populations

Target ID

Drug screen

High throughput

screen

Lead

compound

Clinical

trial

Diagnosis/

Therapy

Chemical


Natural

Combinatorial

Proteomics


Genomics


SNP applications

> 7 years

SNP applications

2
-
4 years

SNP and Drug Development

Advantages to the pharmaceutical industry:



Increase efficiency of target and lead discovery


Reduce timelines and costs of clinical trials


Product differentiation in the market place





Trends in Biotechnology 19, 491
-
496 (2001).

Personalized medicine


Advantages to patients and clinicians:


Higher probability of desired outcome with a drug


Low probability of side effects


Preventive strategies


Focused therapies


Reduce costs


Better health and better healthcare



Trends in Biotechnology 19, 491
-
496 (2001).

Personalized medicine

SNP or DNA/Protein marker discovery


Access to patient populations


Genotyping costs & Technology development


Computational methodologies

Marker utilization in practice


Assay platform development


Large scale data & knowledge management


Ethical, legal, & social considerations


Physicians & patients education



Trends in Biotechnology 19, 491
-
496 (2001).

Challenges to Personalized Medicine

Conclusion: Malaysia’s aspiration in biotechnology vs
regulatory Issues


Challenges:



IP regulatory



Generic/Biosimilar biopharmaceutical???



New technologies (biopharmaceutical from transgenics)???



cGTP
-

Good Tissue Practice (tissue replacement, tissue engineering,
cell and tissue banking)???



Pharmacogenomics (ethical issues, diagnostics, pre
-
disposition
screening)