pharmaceuticals and biotechnology hirzun mohd yusof, phd manager sime darby technology centre
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Pharmaceuticals and Biotechnology Hirzun Mohd Yusof, PhD Manager Sime Darby Technology Centre. Biotechnology Definition. OLD: Recombinant genetic engineering...using biological processes to develop products - PowerPoint PPT PresentationTRANSCRIPT
Pharmaceuticals and Biotechnology
Hirzun Mohd Yusof, PhDManager
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
•TrangenicPlants •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 Structure1970: First enzyme discovered to cut DNA molecules at a
specific site1971: First complete synthesis of a gene1972: First time DNA fragments linked1976: First NIH research guidelines1980: Oil-eating microbes patented by Exxon1982: First recombinant DNA vaccine for livestock1983: First whole plant grown from biotechnology1986: First genetically engineered vaccine for humans: Hep
BFirst 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 developmentTransform and enhance value creation of the agriculture sector through biotechnology.
Thrust 2 : Healthcare biotechnology developmentCapitalise on the strengths of biodiversity to commercialise discoveries in natural products as well as position Malaysia in bio-generics market.
Thrust 3 : Industrial biotechnology developmentEnsure growth oppurtunities in the application of advanced bio-processing and bio-manufacturing technologies.
Thrust 4 : R&D and technology acquisitionEstablish 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 developmentApply 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 developmentCreate 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 positioningEstablish 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 commitmentEstablish 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 WaveThe 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$100 billion by 2010
• The annual growth rate is established at 15% and some clusters such as monoclonal antibodies have an even higher growth rate (25%)
• Therapeutic proteins (e.g. growth factors, hormones, antibodies) represent the major part of biopharmaceutical sales
Market PotentialGrowth of the therapeutic protein market
Source: ADL Survey, 2004; market forecasts from Datamonitor, IMS, DSM and PhRMA , 2002 -2004
• Therapeutic proteins are currently manufactured via one or two methods:
– Mammalian cell culture (CHO cells): >60% of marketed products
– Bacteria culture: >30% of marketed products
• The industry recognizes that there will be a shortfall risk in protein manufacturing capacities over the next 5 years:
– Over 350 biotech products are currently in late-stage development for 200 serious diseases
– A significant number of major biopharmaceutical products will be coming off patent
• It is estimated that up to 4 times the current protein production capacity will be needed to satisfy demand by 2010
– Manufacturing facilities using traditional technologies require significant upfront investments and long construction and validation times
Market potentialDemand for protein production capacity
Source: ADL Survey, 2004; market forecasts from Datamonitor, IMS, BSM and PhRMA , 2002 -2004
• Demand for medium-sized production batches (up to 10 kilograms per year) will be among the fastest growing:
There is a great opportunity over the next 5 years for new entrants with competitive protein production technologies to
capture significant market share
Market potentialOpportunities for new entrants
Dr Ulrich Steiner
Worldwide Contract Manufacturing Market
US$ 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 potentialContract manufacturing market
Contract ManufacturingGeographical 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
Market 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 ofsome new analytical methods that are assisting in the standardization ofbiological 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 ExchangeDiafiltration
3rdChromatography
Buffer ExchangeDiafiltration
UFConcentration
2ndChromatography
Buffer ExchangeDiafiltration (UF)
Buffer Exch.1stChromatography
Liquid VialProduct
LyophilizedProduct
Fill/Finish
MicrofiltrationCentrifugation
Transfer to Receive Tank
UFConcentration
Refolding
IB Dissolution
IB Wash
Centrifugation
IEX
Tank Fusion
UFClarif.
ColumnCleavage
DilutionDiafilt.
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
COMPETITIVE ADVANTAGES
SUPERIORITY OVER ALTERNATIVE SYSTEMS
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)
Product Class 2000 Spend in $ billions
acting on central nervous system &sense organs
$6.0
affecting neoplasms, endocrinesystem & metabolic diseases
$5.0
acting on cardiovascular system $4.1
acting on infective & parasiticdiseases
$3.6
biologicals $2.4
acting on respiratory system $1.5
acting on digestive or genito-urinarysystem
$0.9
acting on the skin $0.2
diagnostic agents $0.2
vitamins and nutrients $0.1
other human use $1.7
Parexel’s Pharmaceutical Sourcebook2000
$25.7
Target Types Therapeutic area Example Targets
Kinase Cancer; cardiovascular;inflammation; CNS; anti-infectives etc.
MAPK eg Erk1/Erk2, JNK and p38 -mitogen induced cell cycle progressionthrough G1 phase, regulation ofembryonic development; cellmovement, apoptosis, cell & neuronaldifferentiation.
Phosphatase Cancer; cardiovascular;CNS; diabetes etc
Polymerase/Nuclease/Helicase
Cancer; anti-viral; anti-bacterial; immunology etc.
Protease Cardiovascualr; cancer;CNS; inflammation; anti-viral etc
Activation by cleavage of peptides andproteins involved in regulation of statusof cell, e.g metalloproteinase, tumornecrosis factor; caspases andapoptosis
Ion Channel CNS; inflammation;asthma; cancer;cardiovascular; depression
GPCR CNS; Cardiovascular;cancer; inflammation;asthma; metabolism
Activated G protein interacts withadenylate cyclase causing cAMPstimulation,cAMP binds to for e.g. PKAsubunits, these subunits phosphorylatetargets in cytoplasm & nucleus such asCREB to increase activation oftranscription
Nucleic acid/ProteinBinding
Cancer; hormone therapy;
Transporters/Nuclearreceptors/Protein binding
Cancer; antimicrobial;cardiovascular
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 synthesisCombinatorial chemistryNatural 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
LeadOptimization
ProfilingScreens
ADME-TOX
ClinicalTrials
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 USNatural 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 RussiaOver 25 000 unique diverse and rare natural & related compounds.
Microsource / MSDI US30,000 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 USNovel libraries of compounds isolated from plants for drug discovery
SPECS and Biospecs Netherlands800+ 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 million2008E: USD 1,655 milliom2002-2007: 20%
Three major areas:
SNP DiscoverySNP GenotypingDiagnostics
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 likelyDrug acts on therapy
Most likelyDrug 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 throughputscreen
Lead compound
Clinical trial
Diagnosis/Therapy
Chemical
Natural
Combinatorial
Proteomics
Genomics
SNP applications> 7 years
SNP applications2-4 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)