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TLSC Biotech 101 Noc 2010 (Moore)



"Biotech 101" Course presented as part of the Texas Life Science Conference, November 2010

"Biotech 101" Course presented as part of the Texas Life Science Conference, November 2010



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    TLSC Biotech 101 Noc 2010 (Moore) TLSC Biotech 101 Noc 2010 (Moore) Presentation Transcript

    • Biotech 101 Texas Life Science Conference BioHouston Jason E. Moore, M.S., M.B.A. Vice President PLx Pharma Inc President, Inc. November 12, 2010
    • Course Overview • Overview of the science behind biopharma • Difference between “pharma” and “biotech” pharma biotech • Understanding the “foundational biotechnologies biotechnologies” and bioinformatics • Trends in biotechnology commercialization – what technologies are being advanced g g • Overview of the drug development process and related economics • Houston/Texas Biotech (over lunch)
    • Biotechnology Defined The integration and application of science and engineering to life processes to solve problems or manufacture products • Includes applications in… – Healthcare and Pharmaceuticals – Agricultural production (crops and livestock) – Biodefense – Environmental remediation forensics paternity archaeology remediation, forensics, paternity, – Much more
    • A Little Molecular Biology • Cells are the basic • All cells… building blocks of all – Have same basic design living hi li i things – M d of th same Made f the construction materials • Many different cell types, – Operate using essentially the each of which performs a same processes very specific task – DNA is the genetic material of almost all living things • Despite diversity, many – DNA directs cell construction unifying properties and operation, while proteins • This unity provides the do all the work – All cells speak the same foundation for modern genetic language biotechnology
    • Schematics of Cell and Nucleus
    • Human Chromosomes
    • From Chromosome to DNA Base Pairs • Chromosomes in cells are tightly p g y packed DNA • Various structures are evident as DNA is unwound • The DNA double helix becomes apparent • DNA base pairs carry the information of DNA i f ti f
    • What is the DNA Double Helix?
    • Chromosomes and Genes – Units of Heredity y Gene: a sequence of nucleotides in DNA or RNA that is the functional unit of inheritance controlling 46 chromosomes in expression of traits, by specifying the structure of each human a particular protein or controlling the function of other genetic material (diploid) cell
    • Chromosomes, Genes and Basepairs
    • The “Central Dogma”… Cell Nucleus Chromosome Protein Gene (mRNA), Gene (DNA) single strand Graphics courtesy of the National Human Genome Research Institute
    • Translation and the Genetic Code The particular sequence of codons corresponds to an amino acid, which are what proteins are made of
    • Proteins Do the Work Triose phosphate isomerase • Proteins: (100,000 produced in humans) – Have structural roles – Receptors and transporters – Messengers/signals – Catalyze chemical reactions – Generate force – Regulate genes – The key actors in normal development and disease – MAKE EXCELLENT TARGETS FOR NEW TREATMENTS
    • Summary: Cells, DNA & Proteins • 15-100 trillion cells in the human body • 3.1 billion base pairs in each cell • 2.4 million base pairs in the largest human gene • 20,000-25,000 genes in the human genome • 46 chromosomes in each cell • About 100,000 proteins produced by the human body • Proteins perform many functions are very specific and functions, specific, make excellent targets for new treatments
    • Biotechnology Defined…Again The integration and application of science and engineering to life p g g processes to solve problems or manufacture products
    • Biotechnology Tools and Products • Because biological systems and molecules are extraordinarily specific in their interactions… • Biotechnology’s tools and techniques are also specific • As a result, biotechnology products, are expected to be… be – Very precise – Have greater potential to solve specific problems – Generate gentler or fewer side effect and have fewer unintended consequences • Biotech medicines use the human body’s machinery— y y cells, genes, proteins, enzymes and antibodies—to fight disease.
    • Human Genome Project • Definition: Genome • Completed in 2003, the HGP was a 13- year project to – determine the sequences of the 3 billion base pairs that make up human DNA – identify all the 20 000-25 000 genes in 20,000-25,000 human DNA – store this information in databases – improve tools for data analysis – transfer related technologies to the private sector, and – address the ethical, legal, and social , g , issues that may arise from the project • Though the HGP is finished, analyses of the data will continue for many years
    • Origins and Progression of Disease • Genetic makeup • Diet • Exercise • Pollutants • Virus • Injury • Development • Personality/attitude
    • Baylor’s HGSC • One of 3 large-scale sequencing centers funded by NIH • 78 automated sequencers • 220 staff • 24/7 operation • Sequencing other important genomes – Bovine – Chimpanzee Chi – Drosophila – Honey Bee – Microbial – Mouse – Orangutan – Rat – Rhesus monkey – Sea Urchin
    • How the Human Genome Stacks Up Organism g Genome Size (Bases) Estimated Genes ( ) Human (Homo sapiens) 3 billion 25,000 Laboratory mouse (M. musculus) 2.6 billion 25,000 Mustard weed (A thaliana) (A. 100 million 25,000 25 000 Roundworm (C. elegans) 97 million 19,000 Fruit fly (D. melanogaster) 137 million 13,000 Yeast (S. cerevisiae) 12.1 million 6,000 Bacterium (E. coli) 4.6 million 3,200 Human immunodeficiency virus y 9700 9 (HIV) Source: US Department of Energy Human Genome Project
    • Humans, chimps almost a match August 31, 2005 By Steve Sternberg, USA TODAY "Evolutionary analysis is a handmaiden to Clint the human medicine," says Eric Lander of the chimpanzee, August 31, 2005 Broad Institute of the Massachusetts Institute whose genome Humans and chimpanzees share an almost of Technology and Harvard. sequence identical genetic inheritance, scientists report appears in Thursday in a landmark comparison that they call For example, in a discovery that could offer 'Nature,' helped p an "elegant confirmation" of Charles Darwin's elegant confirmation Darwin s insights into Alzheimer's researchers found Alzheimer s, show there's little theory of evolution. mutations that turn off the human caspase- difference 12 gene, which causes damaged cells to between man and Although scientists have long believed that self-destruct. Those mutations weren't found ape. Yerkes humans and chimps are related, this in chimps, which aren't as susceptible to National Primate comprehensive analysis of their separate genomes Alzheimer's. Knocking out caspase-12 in Research Center, offers the best proof of their shared genetic past. p g p mice makes their brain cells more likely to y AFP/Getty Images The “3 billion 3 billion genetic letters in the two “…The genetic letters intithel two genetic t Th billi tt i th survive with Alzheimer's-like damage. blueprints are blueprints are 96% 40 million with genetic 96% identical with just identical differences, the researchers report in the journal Researchers also identified mutations in Nature. 40 million differences, the researchers just "We can peek into evolution's lab notebook and humans that were important for survival, report in the journal Nature.…” see what went on there," says Francis Collins, including a gene associated with speech and “…The analysis a gene that ramps up response to sugar, an offers clues to the cause of By delving more deeply into those differences, director of the National Human Genome Research researchers h h hope t explain why h to l i h humans are Institute. I tit t diseases such as advantage iin llean ti to why t ti l ti k t Alzheimer's and b t a potential ticket d t times but susceptible to certain diseases; why our to diabetes susceptible to chimps and humans are today. evolutionary paths diverged from ancestral chimps The analysis offers clues to the cause of diseases 6 million years ago; and, on an even more basic such as Alzheimer's and to why chimps diseases..…” these two genomes side by side, different and "Reading level, what makes us human. humans are susceptible to different diseases. it's amazing to see …”
    • 99% of Human Genes Have a Mouse Counterpart p …which makes laboratory mice excellent models of disease and well suited for testing of new medicines.
    • “Small Molecule” vs “Large Molecule” g Drugs”
    • Biological Products are Different
    • • Generally (much) larger • Made in living systems (e.g. yeast or mammalian cells) – More complicated – Elaborate folding – Sugars may be attached (“glycosylation”) – Several forms of the active molecule may be present (Zantac)
    • “Pharma” vs. “Bi t h” “Ph ” “Biotech”
    • “Biotech” and “Pharma” -- Terms of Art • Technical definition – Pharmaceutical: Chemically synthesized, small-molecule drug (b t note t (but, t taxol)l) – Biotech drug: Biologically derived, large molecule drug (but, note synthesized oligonucleotides and polypeptides)
    • “Biotech” and “Pharma” -- Terms of Art • Investor-speak – Pharma (or “Big Pharma”): Any of the larger, revenue-producing companies, th t are well established and h i that ll t bli h d d have marketedk t d products; less risky – Biotech: • Smaller life science companies, less well established, may or may not have marketed products; riskier (can include small medical device companies) • But may include large well established life science companies that large, focus on biological therapeutics (eg, Amgen, Genentech)
    • Core Biotechnologies and Their Use in g Detecting and Treating Human Illness
    • (Very Brief) Introduction to Core Biotechnologies g • Monoclonal • Biosensors antibodies • Nanobiotechnology • Cell culture • Microarrays • Cloning • ‘Omics • Recombinant DNA • Epigenetics • Tissue engineering • Bioinformatics • Protein engineering
    • Spectrum of Biological Therapies • Blood collection and • Vaccines transfusion – Traditional preventative • Protein therapeutics – Therapeutic vaccines – Hormonal therapies • Nucleotides – Monoclonal antibodies – siRNA • Regenerative medicine – Other oligonucleotides and thioaptamers – Tissue grafts/organs • Therapeutic Cloning • N Nanotech th t h therapies i • Autologous tissues • Epigenetics approaches – Cell-based therapies • Gene therapy
    • Monoclonal Antibodies • Immune system cells are used to make proteins Immune-system called antibodies • “Lock and key” relationship Lock key • Incredibly specific population of proteins; used to: – Identify environmental pollutants & biowarfare agents – Detect harmful microorganisms in food – Distinguish cancer cells from normal cells – Diagnose infectious diseases in humans, animals, and plants – Are the basis for a highly specific class of therapeutic compounds
    • “Lock and Key”
    • • FDA approved for the treatment of certain (HER2+) early-stage breast cancers • Herceptin is a monoclonal antibody that interferes with the HER2 receptor • HER proteins regulate cell growth survival growth, survival, adhesion, migration, and differentiation—functions that are amplified or weakened in cancer cells • When it binds to defective HER2 proteins, the HER2 protein no longer causes cells in the breast to reproduce uncontrollably. uncontrollably • This increases the survival of people with cancer
    • Herceptin & HER2 Signaling
    • Targeted Therapies in Cancer
    • Therapeutic Antibodies Have Come of Age! • 18 moAbs approved by FDA to date, including Tanox’s (Genentech’s) Xolair® • ~350 in clinical trials • $10 B in revenues in 2004; $30B market by 2010 • Si moAbs → global revenues > $500M Six Ab l b l • Market expected to grow by 20% per year over next 5 years • Better toxicity profiles/faster approval??
    • Monoclonals Also Used In • Biosensors – Molecular diagnostics • measuring protein and drug levels in serum • typing tissue and blood • identifying infectious agents • identifying clusters of differentiation for the classification and follow- up therapy of leukemias and lymphomas • identifying tumor antigens and auto-antibodies • id tif i th specific cells i identifying the ifi ll involved i th i l d in the immune response • identifying and quantifying hormones – Biowarfare agent detectors – Hazmat sensors – Home pregnancy tests
    • Biosensors • Biology + microelectronics • Detecting devices composed of – Biological component, for example… • cell • enzyme • antibody – Tiny transducer • Rely on great specificity to identify and measure substances at extremely low concentrations
    • Cancer- Cancer-Detecting Nanosensor
    • Cell Culture • Growing cells outside of living organisms (in vitro) • Research tool • Use to create therapeutic products • Pi Primary t types – Mammalian cell culture – Plant cell culture – Insect cell culture
    • Industrial Bioreactors
    • Industrial Bioreactors • Mammalian Cells • Microbial Biopharma • Peptide Synthesis • Fermentation • Adenoviral, AAV and lentiviral vectors • Chemical Synthesis • Replication competent adenovirus • Highly Potent APIs • Plasmid DNA • Cell Therapy • Other viral products
    • Recombinant DNA Technology • Recombinant DNA is made by combining genetic material from different sources – Plant and animal breeding – Molecular recombination
    • Genetic Recombination & Cellular Clones – The Human Insulin Gene
    • Genetic Recombination -- Cohen & Boyer and the Birth of Biotech 1973, 1980 • Invented gene splicing/genetic recombination • Cohen: no commercial value and unpatentable t t bl • Berg: Refusal to patent • Nonexclusively licensed with low fees • Established seminal patents; technology is basis of BT industry • 467 companies licensed; $300 MM in revenues • Among the earliest examples of • Genentech & Boyer technology transfer
    • EPOGEN® • Recombinant erythropoetin alfa • Human erythropoetin transfected into Chinese Hamster ovary cells
    • Cloning • “Clone”: A genetically identical gene, cell, or organism • Allows generation of a population of genetically identical molecules, cells, plants or animals • Types – Molecular or gene cloning Molecular, gene, – Cellular cloning – Plant and animal cloning (aka, reproductive cloning) • Reproductive versus therapeutic cloning • Extremely broad possible applications… applications
    • Fertilization vs. Cloning vs. (somatic cell nuclear transfer)
    • Fertilization vs. Cloning vs. (somatic cell nuclear transfer)
    • Reproductive Cloning of Pets 2004: Genetic Savings & Clone "In FDA's analysis of the available data on delivers Little Nicky, the first animal clones, no differences were commercially- produced pet y p p detected in overall behavior and health of clone, to client from Texas. juvenile and adult animal clones and conventional animals, even at the level of blood chemistry." —FDA press release 10/31/03
    • Regenerative Medicine • Regenerative Medicine: The development and application of innovative medical therapies to fully or partially restore damaged parts of the human organism and to support the regeneration of damaged organs • Tissue engineering: materials science + molecular biology • Natural regenerative proteins • Stem cells • Other cell-based therapies
    • Regeneration in Nature • Outstanding Examples – Planarian – Crayfish • Inverse Relationship – Increase complexity – Decrease regenerative ability
    • Regeneration in Humans High Moderate Low
    • Clinical Needs • Cardiovascular – Myocardial infarction – Stroke • Bone – Non-union fractures Non union – Tumor resections • Nervous – Spinal Cord Injury – Degenerative diseases
    • Stem Cells • Stem cells are… – undifferentiated (unspecialized) cells – with the capacity for unlimited or prolonged self-renewal and – the ability to give rise to differentiated (specialized) cells. • Two types – Adult stem cells – Embryonic stems cells
    • Adult Stem Cells • WHERE are they found? – Found among adult tissue or organs such as the bone marrow, liver, muscle, marrow liver skeletal muscle brain, and skin • Limited developmental p potential; multipotent not ; p totipotent • Better behaved, easier to manage • Lose th i ability t L their bilit to proliferate/differentiate after a time in culture • Less moral ambiguity • Less legal controversy “Stem cells found in adults show surprising versatility, but it’s not yet clear whether they can match the power of cells from embryos. -- G. Vogel, Science 287:1418,2000
    • Hematopoietic Stem Cells ( SCs) (HSCs) Multipotent stem cells that give rise to all the blood cell types…
    • Embryonic Stem Cells • WHERE are they found? – D i d56d Derived 5-6 days afterft fertilization from inner portion of blastocyst (mass of approximately 64 cells ) cells.) • WHAT can they do? – Differentiate into all specialized cells in the body – Totipotent
    • A Little Developmental Biology… gy
    • Stages of Embryogenesis Day 2 2-cell 2 cell embryo Day 3-4 D 34 Day 1 Multi-cell embryo Fertilized egg Day 5-6 Day 11-14 Blastocyst Tissue Differentiation
    • Derivation and Use of Embryonic Stem Cell Lines y Isolate inner cell mass Outer cells (destroys embryo) (forms placenta) Inner cells (forms fetus) Culture cells Day 5-6 Blastocyst “Special sauce” “S i l ” (largely unknown) Liver Li Heart repaired Kidney Heart muscle
    • Diseases Stem Cell Therapy Might Treat g Alzheimer’s Disease Parkinson’s Disease Various Leukemias Hodgkin’s Lymphoma Non-Hodgkin’s Lymphomas Immune Deficiency Disease Liver Failure Heart Disease Diabetes Stroke Multiple Sclerosis Huntington s Huntington’s Disease Osteoarthritis Rheumatoid Arthritis Coeliac Disease Crohn’s Disease Lupus Erythematosus Periodontal Disease Sickle Cell Anaemia Thalassemia Psoriasis Deafness Blindness Osteoporosis Spinal Injuries Burns Blackfan Diamond Anaemia Fanconi Anaemia
    • Stem Cell Company • Geron is developing biopharmaceuticals for the treatment of cancer and chronic degenerative diseases, including spinal cord injury, heart failure and diabetes. • GRNCM1—Cardiomyocytes for Heart Disease • GRNIC1—Islet Clusters for Diabetes • GRNVAC2 Dendritic GRNVAC2—Dendritic Cells for Cellular Vaccines
    • Tissue Engineering • Repair/replace damaged tissues – Enhance natural regeneration Cell Source Embryonic stem cells Adult stem cells Progenitor cells Signals ECM Growth factors Metals Drugs Ceramics Mechanical forces Synthetic polymers Natural polymers
    • Rice Bioengineering • Biomaterials and Drug Delivery • Jennifer West Lab • Biomedical Imaging and – Tissue Engineered Vascular Grafts Diagnostics – NO-Releasing Polymers • Cellular and Biomolecular – Mechanisms of Restenosis Engineering – Medical Applications of Metal • Computational and Th C t ti l d Theoretical ti l Nanoshells N h ll Bioengineering • Supramolecular Biophysics and Bi d Bioengineering i i • AuroLase® Therapy • Systems and Synthetic – Uses "optically tunable" Biology nanoparticles that can convert • Tissue Engineering and light into heat to thermally destroy Biomechanics a solid tumor
    • Other Cell Based Therapeutics • Cell therapy describes the process of introducing new cells into a tissue in order to treat a disease. • There are many other non-stem cell potential forms of cell therapy – The transplantation of mature functional cells that are mature, autologous (from the patient) or allogeneic (from another donor). – The application of modified human cells that are used to produce a needed substance. substance – The xenotransplantation of non-human cells that are used to produce a needed substance. – The transplantation of transdifferentiated cells derived from the patient's own differentiated cells.
    • Cancer Vaccines • Cancer vaccines induce an • PROVENGE is designed to induce immune response against cancer an immune response against cells prostate cancer. • PROVENGE® is the first • Has FDA approval for the autologous cellular treatment of asymptomatic or immunotherapy -- made using minimally symptomatic metastatic cells from a patient's own immune hormone resistant prostate system. system cancer. cancer
    • Opexa Therapeutics • Tovaxin, a personalized T-cell vaccine for the treatment of multiple sclerosis (MS) that is specifically tailored to each patient's disease profile. • Tovaxin is designed to reduce the number of specific g p certain autoreactive T-cells known to attack myelin.
    • Nanotechnology N t h l
    • What is Nanotechnology?
    • Nanotechnology • Nanotechnology: the study, manipulation and manufacture of ultra-small structures and machines made of as f d f few as one molecule l l • Nanometer = 10-9 meter = one-billionth of a meter Most “nano-constructs”
    • Modern Molecular Cell Biology is Nanobiotechnology “Human health has always been determined on the nanometer scale; this is where the structure and properties of the machines l thi i h th t t d ti f th hi of life work in every one of the cells in every living thing. The practical impact of nanoscience on human health will be huge.” --- Richard E. Smalley, 1996 Nobel Laureate
    • • “The strongest fiber that will ever be made.” • “The size and perfection of DNA.” • “Molecular pincushions Molecular pincushions”
    • Rice University – “Birthplace of Nanotechnology”gy • Nobel Laureates – 1996 Prize in Chemistry, “for their discovery of fullerenes” “Many scientists believe the discovery – Dr. Richard Smalley of fullerenes will prove more important than – Dr. Robert Curl that of the – (With Sir Harold Kroto) ( ) semiconductor, atomic fission, or DNA, • Rice because it will impact so many fields.” -- S. – Home to… Ward Casscells, MD • Center for Nanoscale Science and Technology C t f N l S i dT h l • Center for Biological and Environmental Nanotechnology – Small Times ranks Rice • #1 University in US in nanotechnology commercialization • #1 University in US in overall strength of nanotechnology patent portfolio
    • Alliance for NanoHealth • Alliance f NanoHealth is comprised for of eight world-renowned universities and institutions within the Texas Medical Center and the Greater Houston Region • The first multi-disciplinary, multi- institutional collaborative research endeavor aimed solely at using nanotechnology to bridge the gaps between medicine biology materials medicine, biology, science, computer technology and public policy President: • Bridge disciplines to provide new Mauro Ferrari, Ph D Ferrari Ph.D. clinical approaches to saving lives through better diagnosis, treatment, and prevention p
    • Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases • Investigate the causes of human diseases at "Our genes and proteins are the game officials of our lives They lives. the cellular and molecular levels, using DNA already know if you have a cancer and protein technologies in your future. • Current Centers: Or dementia. Or some other devastating disease. g – Cardiovascular Genetic Research We must identify these genes and – Cell Signaling proteins in our bodies and discover – Diabetes and Obesity Research ways in which they might be altered to prevent those diseases from – Hans J Müller Eberhard and Irma Gigli Center for J. Müller-Eberhard occurring in the first place . . . i i th fi t l Immunology and Autoimmune Diseases That research is the role of the IMM" – Human Genetics James T. Willerson, M.D. – Molecular Imaging Founder – Neurodegenerative Diseases IMM – Proteomics and Systems Biology – Stem Cell Research – Senator Lloyd and B A B t S t Ll d d B.A. Bentsen C t f Stroke Center for St k Research
    • “Nanoclinics” Contrast Agent Drug Delivery Indicator Cancer Cell Death Indicator Cancer Cell Targeting Therapeutic
    • DNA as Structure • March 16, 2006 Nature • New method yields DNA nanostructures that are h larger and more complex than previously possible • The method uses a few hundred short DNA strands to 'staple' a very long strand p y g into two-dimensional structures • Can adopt any desired shape, like the 'nanoface' on the cover
    • Microarrays • Research tools • Allows analysis of tens of thousands of samples simultaneously – DNA microarrays – Protein microarrays – S ll Small-molecule l l microarrays – Tissue microarrays – Whole-cell microarrays • These are biosensors
    • The Genomics Hospital • BCM developing PERSONALIZED MEDICINE the “Baylor Chip” – Tests 141 genes on a miniature chip – Tests for 161 important diseases • Eventually will carry out 100,000 to 1 million gene tests • Vision: Test every y patient at the Baylor Clinic – Prevention – Diagnosis 2.5 mm GeneChip® TrueTag ™ 10K Array – Treatment ) (400 chips/wafer format – Follow-up
    • Gene Therapy • Gene therapy: a technique for correcting defective genes responsible for disease development • Researchers use several approaches for correcting faulty genes: – A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene – An abnormal gene could be swapped for a normal gene – The abnormal gene could be repaired through “selective reverse selective mutation,” a process that returns the gene to its normal function – The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered • Use “vectors” – carriers allowing a gene to enter a cell
    • Vector containing intact gene Vector binds with cell surface Some improvement in clinically relevant outcome • Survival • Reduction in pain • Improved immune function Vector enters the cell in a vesicle •… Vector is released from vesicle Cell machinery produces therapeutic protein Vector binds to nucleus, deposits DNA payload inside Cell machinery integrates DNA
    • Biotech's Bright Hope Scientists are newly optimistic that gene therapy will help fight the most serious diseases Gene therapy is making a comeback after a By Linda Marsa, Special to The Times Marsa series of serious setbacks that threatened to permanently derail human tests. In recent August 28, 2006 years, European scientists have cured more than two dozen patients suffering from three TO the shrill whine of a high-speed drill, rare, and in some cases lethal, immune neurosurgeon Dr. Paul Larson makes two nickel- Gene therapy disorders. sized holes in Shirley Cooper's skull. Guided by a y p y involves the computerized MRI map, he plunges a long, thin manipulation of Spurred by this success, plus the needle through one hole and deep into the brain — DNA to replace or development of new techniques aimed at and empties the syringe. repair genes making the therapy safer and more effective, more than 300 gene therapy trials, including A very special payload trickles into her brain: Parkinson's destroys cells in the brain that make the one for Parkinson's at UC San genes that, if all goes well, will help her control the dopamine, and the loss of this key brain transmitter Francisco, are underway in the U.S. and movement of her muscles. t fh l triggers the disease's crippling symptoms: tremors abroad. It is “…Gene therapy is making artist a day in late May and Cooper, 60, an a comebackthe arms, legs and face, stiff or frozen limbs, and in ... whoIn recent years, European UC San lives near Seattle, has come to the scientists have impaired balance and coordination. In the trial The approaches include what people Francisco Medical Center to find some relief from she's involved in — the earliest of clinical tests, traditionally think of as gene therapy: cured more than two dozen patients designed to assess safety — scientists have the Parkinson's disease that is stealing her identity. inserting functional genes to replace single, Without medication, she three rare, andand some cases suffering from has trouble walking in engineered a harmless, stripped-down virus to talking, and can't hold a paint brush. And ” drugs “Gene therapy will evolve intorelatively rare genetic faulty ones to treat a major lethal, immune disorders the lethal can t disorders…” carry a gene that will boost brain dopamine diseases such as muscular dystrophy cystic therapeutic method”… dystrophy, are wearing off — as they eventually do for all through the enzyme it encodes: amino acid fibrosis, sickle cell anemia, beta thalassemia Parkinson's patients. After that, she probably will decarboxylase, or AADC. and hemophilia. But, more and more, gene deteriorate rapidly. therapy is being studied as a treatment for When the virus is injected into her brain, they hope lethal ills that are not inherited in any clear, The experimental treatment Cooper is undergoing the gene will be incorporated into healthy brain simple way — cancer, hepatitis, AIDS, heart is intended to reverse that process. cells and steadily produce the enzyme. yp y disease — and which also plague millions. p g
    • Gene Therapy of X-Linked X- y p y Adrenoleukodystrophy • ALD is always fatal if untreated • Results from a deficiency of an enzyme (“ALD”) which causes y ( ) accumulation of very long chain fatty acids in brain, adrenals, and blood • Causes demyelination, which advances i zones d in • The specific gene that is mutated in X- ALD has been identified (ABCD1 gene) • Combination gene/stem cell therapy genetically corrects the blood stem cells in the patients' own bone marrow • Partially restores enzyme function, stopped disease progression
    • Therapeutic Nucleotides • Nucleotides: Building blocks of DNA, RNA –and related compounds • Consist of… – a heterocyclic base, – a sugar and sugar, – one or more phosphate groups • We can synthesize these and use them as therapies – Oligonucleotides • Antisense therapy A ti th • siRNA • Micro-RNA (miRNA)
    • RNAi, RNAi, siRNAs • RNAi = RNA interference • siRNA = synthetic interfering RNA Sirna Therapeutics is t th f f t f th ff t t i at the forefront of the effort to create t • siRNAs can be used in mammalian cells and leverage RNAi- based therapies for gene the vast potential of this technology to silencing ultimately treat patients. • siRNA works b silencing k sequences on messenger iRNA k by il i key RNA, which acquired by Merck &specific genes by cleaving to Sirna was turns off them ontheInc. in RNA strand Co., is the December of 2006 and Center of Excellence for • Nanosized particlesMerck being research for delivery of Research Laboratories. are RNA technology within siRNA-based drugs • RNAi studies h t di have d demonstrated th clinical potential of t t d the li i l t ti l f siRNAs in dental diseases, eye diseases, cancer, metabolic diseases, neurodegenerative disorders, and g other illnesses
    • miRNAs and Thioaptamers • Discovery-stage company • Thioaptamers are a class of focused on micro-RNA- nucleic acid (DNA or RNA) directed di t d oncology th l therapies i aptamers t • miRNAs are small, non-coding • These short nucleic acid RNA molecules molecules bind to a specific • Misregulation is a frequent target molecule t t l l event in development of some • Binding is often just as specific genetic diseases and strong as with an antibody • miRNA therapies re-introduce • But synthesized chemicals can a synthetic version of a miRNA be easier to produce that is depleted in the diseased • Therapeutic, diagnostic, and tissue. tissue research applications
    • The “Central Dogma”… Cell Nucleus Chromosome Protein Gene (mRNA), Gene (DNA) single strand Graphics courtesy of the National Human Genome Research Institute
    • Epigenetics The t d f i h it d h Th study of inherited changes i phenotype ( in h t (appearance) or gene expression ) i caused by mechanisms other than changes in the underlying DNA sequence -- non-genetic factors cause the organism's genes to behave (or "express themselves ) themselves") differently.
    • Pharmacogenetics & g Pharmacogenomics
    • ‘Omics • The genome and genomics; structural and functional genomics • The proteome and proteomics – Proteome: Constellation of proteins in a biological system (eg, cell, organism) or sample – Proteomics: the qualitative and quantitative comparison of a proteome or proteomes under different conditions to further unravel biological processes • What the structure, functions, and interactions of proteins are in living systems • Including in normal and diseased states, under various physiological conditions, conditions and in all stages of development • Metabolomics: The global analysis of metabolites • Pharmacogenomics: the application of genomic technologies to new drug discovery (vs pharmacogenetics: individual differences ) (vs. differences…) • “’Omics” Requires ‘Systems’ Emphasis – Interactions among elements of complex systems – Requires sophisticated information management q p g
    • Personalized Medicine Personalized Medicine: The effort to match the right drug, with the right patient, at the right time…
    • Interpersonal Variability is the Motive
    • Goals of Personalized Medicine
    • Why Personalized Medicine ? Medicine? INEFFECTIVE “The right drug for the right patient at the right time” The time INEFFECTIVE INEFFECTIVE INEFFECTIVE INEFFECTIVE
    • Imagine the day when you and your doctor sit down to review a copy of y py your own p personal g genome. This vital information about your biology will enable your physician to inform you of your disease susceptibilities, the best ways to keep yourself healthy and how to avoid or lessen the impact of future illness. -- From the X PRIZE for Genomics Web Site
    • Personalized Medicine Made Possible By… y • Converging technologies – Sequencing the human q g genome – Increased understanding the 100,000+ proteins made by the 25,000+ human genes – Identifying biomarkers for all di ll diseases – Nanotechnology • Increasing ability to create new drugs to treat diseases at the molecular/genetic level – “Designer drugs”
    • The “Cheap” Genome • It took 2,000 scientists more than 10 years and $2.7 billion to read the first , y human genome – total of around 3 billion base pairs • Five years ago, the same job took one lab 3 weeks and less than $10,000 • Today, Complete Genomics is doing it for ~$1,700! • Effort ongoing to allow large-scale inexpensive human genome analysis (“$1000 Genome”)
    • The “Cheap” Genome • Within a few years, a standard aspect of your health care could include the decoding of every aspect of your genetic make-up i k • A key facilitator of personalized medicine • Sequence all children – Determine genetic predisposition to acquired diseases – 6,000+ genetic diseases, some treatable – Early diagnosis of genetic diseases • Sequence all adults – Diagnosis of acquired diseases – Early cancer detection – Cancer treatment recommendation
    • Technology Improving Survival
    • Bioinformatics • Context: Massive amounts of complex data; accumulating, organizing, and analyzing data is necessary for the information to be useful • Bioinformatics: The field of science in which biology, computer science, and information technology merge into a single discipline • There are three important sub-disciplines within bioinformatics: sub disciplines – the development of new algorithms and statistics with which to assess relationships among members of large data sets; – the analysis and interpretation of various types of data including nucleotide and amino acid sequences, protein domains, and protein structures; and – the development and implementation of tools that enable efficient p p access and management of different types of information.
    • Bioinformatics (cont) • Makes it possible to… – Compare genomic sequences of various organisms – Identify novel genes and suggest functions – Expedite the identification of genes – Determine genetic variation in the general population – Generate 3 D structures of 3-D gene products – Analyze changes under normal or disease states
    • Computational Modeling and In silico Rational Drug Design g g
    • Protein Engineering • Rational design and modification of proteins – Reliance on computational biology and molecular biology p gy gy – Drug development – Food processing – Industrial manufacturing
    • Life Science Technology Commercialization
    • Some Key Points • Most new technologies arise in academic institutions • Majority of early, discovery funding comes from NIH and other federal agencies – NIH grants more than $31.2 billion annually • Institutions may obtain patents on inventions and inventions, license them to companies “technology transfer” • The real expense of product development and commercialization is paid by companies and their investors
    • New Drug Development Times & Costs
    • New Drug Development 0 2 4 6 8 10 12 14 16 Development Year DISCOVERY PRECLINICAL TESTING PHASE 1 20-30 Healthy Volunteers PHASE 2 100-500 Patient Volunteers PHASE 3 500-10,000 Patient Volunteers FDA REVIEW & APPROVAL PHASE 4
    • Clinical Development and Approval Times 97.7 (8.1 yrs) 90.3 (7.5 yrs) Months Source: DiMasi and Grabowski, Managerial and Dec Econ 2007, in press
    • Clinical and Approval Times Vary Across Therapeutic Classes p 12.1 9.8 8.5 7.6 6.9 7.5 8.0 6.3 For years 2002-04 Source: Tufts CSDD, 2006
    • Selected Product-Development Activities Product- PRECLINICAL CLINICAL • Pharmacology • Protocol design and development – In vitro profiling • Clinical trial management – In vivo animal models – Site & Investigators – Safety pharmacology – Trial monitoring – Combination Pharmacology/Toxicology C bi ti Ph l /T i l – Budget & timeline tracking Studies – Regulatory compliance oversight • PK/ADME – In vitro metabolism • Adverse event reporting & – In vivo pharmacokinetics pharmacovigilance – Tissue distribution/mass b l Ti di t ib ti / balance • Clinical data Cli i l d t management t • Toxicology • Biostatistics – In vitro screening – General Toxicology • Medical Writing – Genetic Toxicology – Reproductive Toxicology REGULATORY CHEMISTRY, MANUFACTURING • Regulatory strategy development & CONTROLS • IND Submission and Amendments • Milestone and ad hoc meetings; other • Formulation development communications i ti • Process development • Compliance • GMP manufacturing • NDA preparation and submission • Analytical methods development • Advisory Committee preparation • Product stability
    • Phase I Goals • Establish Time course of Drug levels in blood (PK), Tolerability and Safety in Healthy Volunteers • Gather evidence that the drug interacts with its molecular target (Proof of Target) – Example: Dosing of statin blocks the enzymatic production of circulating mevalonate (cholesterol precursor) by HMG CoA Reductase • Validate methods that might be used to prove pharmacology in Ph II (surrogate biomarkers of pharmacology and efficacy) • Explore potential issues affecting use in broader populations – Examples: Potential for interactions with other drugs, food effects
    • Phase II Goals • Gather evidence that the drug has the intended pharmacology (Proof of Pharmacology) – Example: Dosing of statin drug in lowers LDL C in patients with high LDL-C cholesterol – Note: Most sponsors are now seeking to establish some aspects of Proof-of-Pharmacology in P1 gy • Explore the pharmacology and safety of the drug in patient populations with different characteristics – Example: Study statins in p p y patients with high cholesterol with and g without previous history of heart disease • Gather more evidence regarding safety • Establish the dose(s) and patients to be used in large P3 pivotal studies
    • Phase III Goals • Establish the safety and efficacy in populations reflecting the population to be treated – Often requires outcome data (eg morbidity and mortality) (eg, – High cost and time consuming (complex) – Develop more complete picture of risk and benefits
    • Overall cost of drug development • “On average, it takes $1.2 billion to develop a single new drug…” • $802 MM also often citeda • These numbers are “capitalized”; include the cost of failures • Total out-of-pocket costs for an individual drug… • $198 million for preclinical period • $361 million for clinical period • These are best thought of as “big pharma” numbers a DiMasi et al., J Health Economics 2003;22(2):151-185)
    • The Cost of Drug Development Continues to Increase Estimate of Average Capitalized Development Cost per NCE, 1976–2001 NCE $900 $802 $800 lions) $700 Nominal Dollars (Mill $600 $500 $500 $400 $359 $300 $231 $200 $125 $100 $54 $0 1976 1986 1987 1990 1997 2001 Sources: R. Hansen, Ph.D., University of Rochester; S.N. Wiggins, Ph.D., Texas A&M University; J.A. DiMasi, Tufts Center for the Study of Drug Development (2002); Office of Technology Assessment (1993)
    • Pre- Pre-Approval Out-of-Pocket Costs per Approved Out-of- New Biopharmaceutical* p * Based on a 30.2% clinical approval success rate ** All R&D costs (basic research and preclinical development) prior to initiation of clinical testing Source: DiMasi and Grabowski Managerial and Dec Econ 2007 in press Grabowski, 2007,
    • Annual Growth Rates for Out-of-Pocket R&D Out-of- Costs Source: DiMasi et al., J Health Economics 2003;22(2):151-185
    • Clinical Development is Expensive Mean Number of Subjects in NDAs for NMEsa • Cost drivers – Total enrollment increasing g – Costs per patient: • Oncology: $35K • Pain/Inflammation: $15K – Costs per investigator – Infrastructure costs Clinical Study “Complexity Index”b – Complexity of protocols is increasing – Competition for patients is great a Sources: Boston Consulting Group, 1993; Peck, Food and Drug Law J, 1997; PAREXEL, 2002 b Source: DataEdge 2002 DataEdge,
    • Drug Development is Risky Market Launch Post-Marketing 15 FDA Review 1 Surveillance Phase III Clinical Trials 2 Pivotal Efficacy & Safety 10 Phase II Clinical Trials 2-5 POC, Dose Response Phase I Clinical Trials 5 – 10 Safety/Tolerance PK Preclinical DMPK, Safety 5 10 - 20 Testing Chemistry Basic Screening 3,000 10,000 3 000 – 10 000 0 Research R h Synthesis S h i Number of Compounds Years Source: PhRMA analysis of Tufts CSDD database y
    • Why Do Drugs Fail? BioCentury, April 12, 2010, PAGE A8 OF 19, “gRED: Small company sensibilities”, by Susan Schaeffer.
    • New Drug Approvals Are Not Keeping Pace with Rising R&D Spending g p g R&D Expenditures New Drug Approvals R&D expenditures are adjusted for inflation Source: Tufts CSDD Approved NCE Database, PhRMA, 2005
    • R&D Costs -- Summary • R&D costs have grown substantially, even in inflation- adjusted terms • The growth rate for discovery and preclinical development costs has decreased substantially • Conversely clinical costs have grown at a much more Conversely, rapid rate • New discovery and development technologies ( g y g (e.g., genomics) may hold the promise of lower costs in the long-run, but likley represent higher costs in the short- run
    • Thank Th k you!! !! Jason E. Moore, M.S., M.B.A. , , jason.moore@plxpharma.com 713-842-1249