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Pharmaceuticals and Biotechnology Hirzun Mohd Yusof, PhD Manager Sime Darby Technology Centre

Pharmaceuticals and Biotechnology Hirzun Mohd Yusof, PhD Manager Sime Darby Technology Centre. Biotechnology Definition. OLD: Recombinant genetic engineering...using biological processes to develop products

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Pharmaceuticals and Biotechnology Hirzun Mohd Yusof, PhD Manager Sime Darby Technology Centre

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  1. Pharmaceuticals and Biotechnology Hirzun Mohd Yusof, PhD Manager Sime Darby Technology Centre

  2. 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

  3. Biotech industry? Biotechnology Genes and proteins “Spare parts” Microbes Chemicals Human Agricultural • Tissue regeneration • Growing organs • Drug development • Gene surgery • Genetic testing • TrangenicPlants • Animals • Alcohol • Mining • Waste management • Extracts • Oils • Pharma-intermediaries • Nutraceuticals

  4. 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

  5. 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

  6. 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.

  7. 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

  8. Malaysia Biotechnology Focus Area HEALTHCARE INDUSTRIAL Bio-generics Alternative protein production Enzyme & industrial chemical Bio-energy Diagnostics Vaccines Drug Discovery Wellness AGROBIOTECHNOLOGY Plant Natural Products Marine Animal Source: CEO/President MIGHT’s presentation in Sarawak BioSymposium, March 2005

  9. 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.

  10. 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

  11. BIOPHARMACEUTICAL

  12. 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

  13. The Biotech Wave 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.

  14. Market Potential Growth of the therapeutic protein market • 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 Source: ADL Survey, 2004; market forecasts from Datamonitor, IMS, DSM and PhRMA , 2002 -2004

  15. Market potential Demand for protein production capacity • 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 Source: ADL Survey, 2004; market forecasts from Datamonitor, IMS, BSM and PhRMA , 2002 -2004

  16. Market potential Opportunities for new entrants • 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 Dr Ulrich Steiner

  17. Market potential Contract manufacturing market Worldwide Contract Manufacturing Market 2004 2014 (Forecasts) 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) US$ MM Protein Drugs (Final products) 175,000 Outsourcing Ratio 30% Contract Manufacturing 10,500 US$ MM Protein Drugs (Final products) 38,000 Annual growth 15% Outsourcing Ratio 15% Contract Manufacturing 900 Contract Manufacturing Geographical Breakdown (2014 forecasts): Europe 30% North America 40% Asia 30% (>US$ 3,100 MM)

  18. 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

  19. Market potential Generic biopharmaceuticals market

  20. 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.

  21. Companies involve in generic biologics

  22. Seed Fermentation Centrifugation Buffer Exchange Diafiltration (UF) IB Wash 2nd Chromatography Feed Media 1 IB Dissolution Buffer Exchange Diafiltration Feed Media 2 3rd Chromatography Main Fermentation IEX Dilution Diafilt. UF Buffer Exchange Diafiltration Drop Tank Refolding UF Concentration Centrifugation Microfiltration UF Clarif. Column Cleavage Tank Fusion Bulk Filtration Cell Paste UF Concentration Lyophilization Fill/Finish Dilution Transfer to Receive Tank Lyophilized Product Liquid Vial Product Homogenization Buffer Exch. 1stChromatography Holding Tank Typical Process Flow of Biopharmaceutical Production

  23. COMPETITIVE ADVANTAGES SUPERIORITY OVER ALTERNATIVE SYSTEMS Compatibility with Complex Proteins Glycosylation Scale

  24. Companies active in Animal Transgenesis: Challenges for the future….drug from transgenic animal • 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

  25. DRUG DISCOVERY

  26. Drug Discovery Respiratory Cancer Diseases -defects in cellular communication & control Osteoporosis Diabetes Viral infections Neurological Mediated by post-translational modification e.g.phosphorylation, acetylation Cardiovascular Amplification &expansion - cascades of phosphorylation events: signal transduction pathways. Obesity Aberrations linked to disease Idea for targets Drug Discovery Process

  27. Company-financed R&D by Product Class, Estimated 2000 (US only)

  28. Drug Targets

  29. Target universe –post genomics Human genome 22,300 genes Disease modifying ~ 4,500 genes Addressable by protein therapeutics ~10,000 genes Additional targets for antisense and siRNA therapies ~2,100 genes Additional targets for protein therapeutics ~1,800 genes Target for small molecular drugs ~10,000 genes Druggable ~3,000 genes 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)

  30. 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)

  31. The phases of discovery & development of a new drug Identify disease area Target Selection Lead Optimization Clinical Trials Market Assay Development Hit Identification Profiling Screens ADME-TOX Target Validation 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

  32. Process flow of discovery of new compound from nature Microbial culture collection Plant extracts Bioassay screening for bioactive compound Characterization and structure elucidation of active compound Potential lead compound Clinical trial to drug

  33. List of companies involved in natural compound libraries

  34. 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.

  35. 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:

  36. Human Genome contains many variations or polymorphisms No two human genomes are identical

  37. 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.

  38. Applications of the SNP Analysis • Disease gene hunting • Prognostics / diagnostics of genetic risks • Pharmacogenomics and drug discovery • Personalized medicine

  39. SNP & Disease Gene ID % Normal Population % % Patient Population GENE X GENE Y

  40. SNP and Drug Response Evaluation PopulationA Population B Most likely Drug acts ontherapy Most likely Drug has no efficacy Drug treatment Choose other drug

  41. Genetic Variation 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% Polymorphisms vary across populations

  42. SNP and Drug Development Chemical Proteomics Target ID Drug screen Natural Genomics Combinatorial SNP applications > 7 years High throughput screen Lead compound Clinical trial SNP applications 2-4 years Diagnosis/ Therapy

  43. Personalized medicine 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).

  44. 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).

  45. Challenges to 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).

  46. 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)

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