Biotech 101Biotech 101Biotech 101Biotech 101

Texas Life Science ConferenceBioHouston

Jason E. Moore, M.S., M.B.A.Vice President PLx Pharma IncVice President, PLx Pharma Inc.

November 12, 2010

Course OverviewCourse Overview

• Overview of the science behind biopharma• Difference between “pharma” and “biotech”Difference between pharma and biotech• Understanding the “foundational

biotechnologies” and bioinformaticsbiotechnologies and bioinformatics• Trends in biotechnology commercialization –

what technologies are being advancedg g• Overview of the drug development process and

related economics• Houston/Texas Biotech (over lunch)

Biotechnology DefinedBiotechnology Defined

The integration and application of science and engineering to life processes to solve

problems or manufacture products

• Includes applications in…– Healthcare and PharmaceuticalsHealthcare and Pharmaceuticals– Agricultural production (crops and livestock)– Biodefense

Environmental remediation forensics paternity archaeology– Environmental remediation, forensics, paternity, archaeology – Much more

A Little Molecular BiologyA Little Molecular Biology

• Cells are the basic building blocks of all li i hi

• All cells…– Have same basic design

M d f thliving things• Many different cell types,

each of which performs a

– Made of the same construction materials

– Operate using essentially the same processeseach of which performs a

very specific task• Despite diversity, many

same processes– DNA is the genetic material of

almost all living things– DNA directs cell construction

unifying properties • This unity provides the

foundation for modern

DNA directs cell construction and operation, while proteins do all the work

– All cells speak the same foundation for modern biotechnology

genetic language

Schematics of Cell and NucleusSchematics of Cell and Nucleus

Human ChromosomesHuman Chromosomes

From Chromosome to DNA Base PairsFrom Chromosome to DNA Base Pairs

• Chromosomes in cells are tightly packed DNAg y p

• Various structures are evident as DNA is unwoundas DNA is unwound

• The DNA double helix becomes apparentbecomes apparent

• DNA base pairs carry the i f ti f DNAinformation of DNA

What is the DNA Double Helix? What is the DNA Double Helix?

Chromosomes and Chromosomes and Genes Genes –– Units of HeredityUnits of Heredityyy

Gene: a sequence of nucleotides in DNA or RNA that is the functional unit of inheritance controlling

46 chromosomes in each human (diploid) cell

that is the functional unit of inheritance controlling expression of traits, by specifying the structure of a particular protein or controlling the function of other genetic material

Chromosomes, Genes and Chromosomes, Genes and BasepairsBasepairs

The “Central Dogma”…The “Central Dogma”…

Cell Nucleus

Chromosome

ProteinGraphics courtesy of the National Human Genome Research Institute

Gene (DNA)Gene (mRNA), single strand

Translation and the Genetic CodeTranslation and the Genetic Code

The particular sequence of codons corresponds to an amino acid, which are

what proteins are made of

Proteins Do the WorkProteins Do the Work Triose phosphateisomerase

• 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– The key actors in normal development and disease

– MAKE EXCELLENT TARGETS FOR NEW TREATMENTSNEW TREATMENTS

Summary: Cells, DNA & ProteinsSummary: 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• Proteins perform many functions, are very specific, and make excellent targets for new treatments

Biotechnology Defined…AgainBiotechnology Defined…Again

The integration and application of science and engineering to life processes to solve g g p

problems or manufacture products

Biotechnology Tools and Biotechnology Tools and ProductsProducts

• 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

bebe…– 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 ycells, genes, proteins, enzymes and antibodies—to fight disease.

Human Genome ProjectHuman Genome Project• Definition: Genome• Completed in 2003, the HGP was a 13-

year project toyear 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– identify all the 20,000-25,000 genes in

human DNA– store this information in databases– improve tools for data analysisimprove 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 DiseaseOrigins and Progression of Disease

• Genetic makeup• Diet• Exercise• Pollutants• Virus• Injury• Development• Development• Personality/attitude

Baylor’s HGSCBaylor’s HGSC

• One of 3 large-scale sequencing centers funded by NIHfunded by NIH

• 78 automated sequencers• 220 staff• 24/7 operation24/7 operation• Sequencing other

important genomes– Bovine

Chi– Chimpanzee– Drosophila– Honey Bee– Microbial

Mouse– Mouse– Orangutan– Rat– Rhesus monkey

Sea Urchin– Sea Urchin

How the Human Genome Stacks UpHow the Human Genome Stacks Up

Organism Genome Size (Bases) Estimated Genesg ( )Human (Homo sapiens) 3 billion 25,000

Laboratory mouse (M. musculus) 2.6 billion 25,000

Mustard weed (A thaliana) 100 million 25 000Mustard weed (A. thaliana) 100 million 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 3,200Human immunodeficiency virus 9700 9y(HIV) 9700 9

Source: US Department of Energy Human Genome Project

Humans, chimps almost a matchAugust 31, 2005

By Steve Sternberg, USA TODAY

August 31, 2005Humans and chimpanzees share an almostidentical genetic inheritance, scientists reportThursday in a landmark comparison that they callan "elegant confirmation" of Charles Darwin's

"Evolutionary analysis is a handmaiden tohuman medicine," says Eric Lander of theBroad Institute of the Massachusetts Instituteof Technology and Harvard.

For example, in a discovery that could offerinsights into Alzheimer's researchers found

Clint the chimpanzee, whose genome sequence appears in 'Nature,' helped an elegant confirmation of Charles Darwin s

theory of evolution.

Although scientists have long believed thathumans and chimps are related, thiscomprehensive analysis of their separate genomesoffers the best proof of their shared genetic past.

insights into Alzheimer s, researchers foundmutations that turn off the human caspase-12 gene, which causes damaged cells toself-destruct. Those mutations weren't foundin chimps, which aren't as susceptible toAlzheimer's. Knocking out caspase-12 inmice makes their brain cells more likely to

pshow there's little difference between man and ape. Yerkes National Primate Research Center, AFP/Getty Images“ Th 3 billi ti l tt i th t

p g pThe 3 billion genetic letters in the two geneticblueprints are 96% identical with just 40 milliondifferences, the researchers report in the journalNature.

By delving more deeply into those differences,h h t l i h h

"We can peek into evolution's lab notebook andsee what went on there," says Francis Collins,director of the National Human Genome ResearchI tit t

ysurvive with Alzheimer's-like damage.

Researchers also identified mutations inhumans that were important for survival,including a gene associated with speech anda gene that ramps up response to sugar, and t i l ti b t t ti l ti k t

AFP/Getty Images

“…The analysis offers clues to the cause of diseases such as Alzheimer's and to why

“…The 3 billion genetic letters in the two genetic blueprints are 96% identical with just 40 million differences, the researchers report in the journal Nature.…”

researchers hope to explain why humans aresusceptible to certain diseases; why ourevolutionary paths diverged from ancestral chimps6 million years ago; and, on an even more basiclevel, what makes us human.

Institute.

The analysis offers clues to the cause of diseasessuch as Alzheimer's and to why chimps andhumans are susceptible to different diseases.

advantage in lean times but a potential ticketto diabetes today.

"Reading these two genomes side by side,it's amazing to see …”

diseases such as Alzheimer's and to why chimps and humans are susceptible to different diseases..…”

99% of Human Genes 99% of Human Genes Have a Mouse CounterpartHave a Mouse Counterpartpp

…which makes laboratory mice excellent models ofdisease and well suited for testing of new medicines.

“Small Molecule” vs “Large Molecule” “Small Molecule” vs “Large Molecule” ggDrugs”Drugs”

Biological Products are Biological Products are DifferentDifferent

• Generally (much) largerGenerally (much) larger

• Made in living systems (e.g. yeast or mammalian cells)

– More complicated– Elaborate folding– Sugars may be attached

(“glycosylation”)– Several forms of theSeveral forms of the

active molecule may be present

(Zantac)

“Ph ” “Bi t h”“Ph ” “Bi t h”“Pharma” vs. “Biotech”“Pharma” vs. “Biotech”

“Biotech” and “Pharma” “Biotech” and “Pharma” ---- Terms of ArtTerms of Art

• Technical definition– Pharmaceutical: Chemically synthesized, small-molecule drug

(b t t t l)(but, note taxol)– Biotech drug: Biologically derived, large molecule drug (but, note

synthesized oligonucleotides and polypeptides)

“Biotech” and “Pharma” “Biotech” and “Pharma” ---- Terms of ArtTerms of Art

• Investor-speak– Pharma (or “Big Pharma”): Any of the larger, revenue-producing

i th t ll t bli h d d h k t dcompanies, that are well established and have marketed 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• But may include large, well established life science companies that focus on biological therapeutics (eg, Amgen, Genentech)

Core Biotechnologies and Their Use in Core Biotechnologies and Their Use in ggDetecting and Treating Human IllnessDetecting and Treating Human Illness

(Very Brief) Introduction to Core (Very Brief) Introduction to Core BiotechnologiesBiotechnologiesgg

• Monoclonal • Biosensors• Monoclonal antibodies

• Cell culture

• Biosensors• Nanobiotechnology• MicroarraysCell culture

• Cloning• Recombinant DNA

• Microarrays• ‘Omics

Epigenetics• Recombinant DNA• Tissue engineering• Protein engineering

• Epigenetics• Bioinformatics

• Protein engineering

Spectrum of Biological TherapiesSpectrum of Biological Therapies

• Blood collection and transfusion

• Vaccines– Traditional preventative

• Protein therapeutics– Hormonal therapies– Monoclonal antibodies

– Therapeutic vaccines

• Nucleotides– siRNAMonoclonal antibodies

• Regenerative medicine– Tissue grafts/organs

siRNA– Other oligonucleotides and

thioaptamers

N t h th i• Therapeutic Cloning• Autologous tissues

– Cell-based therapies

• Nanotech therapies• Epigenetics approaches• Gene therapyGene therapy

Monoclonal AntibodiesMonoclonal AntibodiesImmune system cells are used to make proteins• Immune-system cells are used to make proteins called antibodies

• “Lock and key” relationship• Lock and key relationship• Incredibly specific population of proteins; used to:

– Identify environmental pollutants & biowarfare agents– Detect harmful microorganisms in foodDetect 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”“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• HER proteins regulate cell 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 uncontrollablyuncontrollably.

• This increases the survival of people with cancer

HerceptinHerceptin & HER2 Signaling& HER2 Signaling

Targeted Therapies in Targeted Therapies in CancerCancer

Therapeutic Antibodies Have Therapeutic Antibodies Have Come of Age!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 Ab l b l $500M• Six moAbs → global revenues > $500M• Market expected to grow by 20% per year over next 5

yearsyears• Better toxicity profiles/faster approval??

Monoclonals Also Used In 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 ifi ll i l d i th i• identifying the specific cells involved in the immune response • identifying and quantifying hormones

– Biowarfare agent detectors– Hazmat sensors– Home pregnancy tests

BiosensorsBiosensors

• Biology + microelectronics• Detecting devices composed of

– Biological component, for example… • cell• enzymeenzyme• antibody

– Tiny transducer

• Rely on great specificity to identify and measure substances at extremely low concentrations

CancerCancer--Detecting Detecting NanosensorNanosensor

Cell CultureCell Culture

• Growing cells outside of living organisms (in vitro)• Research tool• Use to create therapeutic

productsP i t• Primary types– Mammalian cell culture– Plant cell culture– Insect cell culture

Industrial BioreactorsIndustrial Bioreactors

Industrial BioreactorsIndustrial Bioreactors

• Mammalian Cells• Microbial Biopharma• Peptide Synthesis• Fermentation• Chemical Synthesis• Adenoviral, AAV and lentiviral vectors Chemical Synthesis• Highly Potent APIs• Cell Therapy

Adenoviral, AAV and lentiviral vectors• Replication competent adenovirus• Plasmid DNA• Other viral products

Recombinant DNA TechnologyRecombinant DNA Technology

• Recombinant DNA is made by combining genetic material from different sources– Plant and animal breeding– Molecular recombination

Genetic Recombination & Cellular Genetic Recombination & Cellular Clones Clones –– The Human Insulin GeneThe Human Insulin Gene

Genetic Recombination Genetic Recombination ---- Cohen & Cohen & Boyer and the Birth of BiotechBoyer and the Birth of BiotechBoyer and the Birth of BiotechBoyer and the Birth of Biotech

1973, 1980

• Invented gene splicing/genetic recombination

• Cohen: no commercial value and t t bl

• Nonexclusively licensed with low fees

• 467 companies licensed; $300

unpatentable

• Berg: Refusal to patent

• Established seminal patents; technology • 467 companies licensed; $300

MM in revenues• Genentech & Boyer

is basis of BT industry

• Among the earliest examples of technology transfer

EPOGEN®EPOGEN®

• Recombinant erythropoetin alfa

• Human erythropoetin transfected into Chinese Hamster ovary cellsHamster ovary cells

CloningCloning

• “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, or gene, cloning– Cellular cloning– Plant and animal cloning (aka, reproductive cloning)

• Reproductive versus therapeutic cloning• Extremely broad possible

applicationsapplications…

Fertilization Fertilization vsvs. Cloning . Cloning (somatic cell nuclear transfer)(somatic cell nuclear transfer)

Fertilization Fertilization vsvs. Cloning . Cloning (somatic cell nuclear transfer)(somatic cell nuclear transfer)

Reproductive Cloning of PetsReproductive Cloning of Pets

2004: Genetic Savings & Clone delivers Little Nicky, the first commercially- produced pet

"In FDA's analysis of the available data on animal clones, no differences were detected in overall behavior and health ofy p p

clone, to client from Texas. detected in overall behavior and health of juvenile and adult animal clones and conventional animals, even at the level of blood chemistry."—FDA press release 10/31/03—FDA press release 10/31/03

Regenerative MedicineRegenerative 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 ofto support the regeneration of damaged organs

• Tissue engineering: materials science + molecular biologyscience + molecular biology

• Natural regenerative proteins

• Stem cells

• Other cell-based therapies

Regeneration in NatureRegeneration in Nature

• Outstanding Examples– Planarian– Crayfish

• Inverse Relationship– Increase complexityIncrease complexity– Decrease regenerative

ability

Regeneration in HumansRegeneration in Humans

High Moderate Low

Clinical NeedsClinical Needs

• Cardiovascular– Myocardial infarction– Stroke

• Bone– Non-union fracturesNon union fractures– Tumor resections

• Nervous– Spinal Cord Injury– Degenerative diseases

Stem CellsStem 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 typesTwo types– Adult stem cells– Embryonic stems cells

Adult Stem CellsAdult Stem Cells• WHERE are they found?

– Found among adult tissue or organs such as the bone marrow liver skeletal musclemarrow, liver, skeletal muscle, brain, and skin

• Limited developmental potential; multipotent not p ; ptotipotent

• Better behaved, easier to manageL th i bilit t• Lose their ability to proliferate/differentiate after a time in culture

• Less moral ambiguityLess 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 Hematopoietic Stem Cells (HSCs)(HSCs)( SCs)( SCs)

Multipotent stem cells that give rise to all the blood cell types…

Embryonic Stem CellsEmbryonic Stem Cells

• WHERE are they found?D i d 5 6 d ft– Derived 5-6 days after fertilization from inner portion of blastocyst (mass of approximately 64 cells )of approximately 64 cells.)

• WHAT can they do?– Differentiate into all

specialized cells in the bodyspecialized cells in the body– Totipotent

A Little Developmental A Little Developmental Biology…Biology…gygy

Stages of EmbryogenesisStages of Embryogenesis

Day 22 cell embryoDay 22 cell embryo D 3 4D 3 4Day 1

Fertilized eggDay 1Fertilized egg

2-cell embryo2-cell embryo Day 3-4Multi-cell embryoDay 3-4Multi-cell embryo

Day 5-6BlastocystDay 5-6BlastocystDay 11-14

Tissue DifferentiationDay 11-14Tissue DifferentiationTissue DifferentiationTissue Differentiation

Derivation and Use of Derivation and Use of Embryonic Stem Cell LinesEmbryonic Stem Cell Linesyy

Isolate inner cell mass(destroys embryo)Isolate inner cell mass(destroys embryo)Outer cells

(forms placenta)Outer cells(forms placenta)

Inner cells(forms fetus)Inner cells(forms fetus) Culture cellsCulture cells

“S i l ”Day 5-6BlastocystDay 5-6Blastocyst

Li

“Special sauce”(largely unknown)

BlastocystBlastocyst

Heart muscleKidney

LiverHeartrepaired

Heart muscleKidney

Diseases Stem Cell Therapy Diseases Stem Cell Therapy Might TreatMight Treatgg

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 DiseaseStroke Multiple Sclerosis 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 CompanyStem Cell Company

• Geron is developing biopharmaceuticals for the treatment of cancer and chronictreatment 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 CellsGRNVAC2 Dendritic Cells for Cellular Vaccines

Tissue EngineeringTissue Engineering

• Repair/replace damaged tissues– Enhance natural regeneration

Cell SourceEmbryonic stem cells

Adult stem cellsProgenitor cellsProgenitor cells

SignalsGrowth factors

ECMMetalsGrowth factors

DrugsMechanical forces

MetalsCeramics

Synthetic polymersNatural polymers

Rice BioengineeringRice Bioengineering

• Biomaterials and Drug Delivery• Biomedical Imaging and

Diagnostics

• Jennifer West Lab– Tissue Engineered Vascular

Grafts Diagnostics • Cellular and Biomolecular

EngineeringC t ti l d Th ti l

– NO-Releasing Polymers– Mechanisms of Restenosis– Medical Applications of Metal

N h ll• Computational and Theoretical Bioengineering

• Supramolecular Biophysics d Bi i i

Nanoshells

and Bioengineering• Systems and Synthetic

Biology

• AuroLase® Therapy – Uses "optically tunable"

nanoparticles that can convert • Tissue Engineering and

Biomechanicslight into heat to thermally destroy a solid tumor

Other Cell Based TherapeuticsOther 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 areThe transplantation of mature, functional cells that are

autologous (from the patient) or allogeneic (from another donor).– The application of modified human cells that are used to produce

a needed substancea needed substance.– The xenotransplantation of non-human cells that are used to

produce a needed substance. The transplantation of transdifferentiated cells derived from the– The transplantation of transdifferentiated cells derived from the patient's own differentiated cells.

Cancer VaccinesCancer Vaccines• Cancer vaccines induce an • PROVENGE is designed to induceCancer vaccines induce an

immune response against cancer cells

• PROVENGE® is the first

PROVENGE is designed to induce an immune response against prostate cancer.

• Has FDA approval for the autologous cellular immunotherapy -- made using cells from a patient's own immune system

treatment of asymptomatic or minimally symptomatic metastatic hormone resistant prostate cancersystem. cancer.

OpexaOpexa TherapeuticsTherapeutics

• Tovaxin, a personalized T-cell vaccine for the treatment of multiple sclerosis (MS) that is specificallytreatment of multiple sclerosis (MS) that is specifically tailored to each patient's disease profile.

• Tovaxin is designed to reduce the number of specific g pcertain autoreactive T-cells known to attack myelin.

N t h lN t h lNanotechnologyNanotechnology

What is Nanotechnology?What is Nanotechnology?

NanotechnologyNanotechnology

• Nanotechnology: the study, manipulation and manufacture of ultra-small structures and machines

d f f l lmade of as few as one molecule• Nanometer = 10-9 meter = one-billionth of a meter

Most “nano-constructs”

Modern Molecular Cell Biology Modern Molecular Cell Biology isis NanobiotechnologyNanobiotechnologyis is NanobiotechnologyNanobiotechnology

“Human health has always been determined on the nanometer l thi i h th t t d ti f th hiscale; this is where the structure and properties of the machines

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 Rice University –– “Birthplace of “Birthplace of Nanotechnology”Nanotechnology”gygy

• Nobel Laureates – 1996 Prize in Chemistry, “for their discovery of fullerenes” “Many scientists

believe the discovery– Dr. Richard Smalley– Dr. Robert Curl– (With Sir Harold Kroto)

believe the discovery of fullerenes will prove more important than that of the semiconductor, atomic ( )

• Rice– Home to…

C t f N l S i d T h l

fission, or DNA, because it will impact so many fields.” -- S. Ward Casscells, MD

• Center for Nanoscale Science and Technology • 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 Alliance for NanoHealthNanoHealthf• Alliance for NanoHealth is comprised

of eight world-renowned universities and institutions within the Texas Medical Center and the GreaterMedical Center and the Greater Houston Region

• The first multi-disciplinary, multi-institutional collaborative researchinstitutional collaborative research endeavor aimed solely at using nanotechnology to bridge the gaps between medicine biology materialsbetween medicine, biology, materials science, computer technology and public policy

• Bridge disciplines to provide newPresident: Mauro Ferrari Ph DBridge disciplines to provide new

clinical approaches to saving lives through better diagnosis, treatment, and prevention

Mauro Ferrari, Ph.D.

p

Brown Foundation Institute of Molecular Brown Foundation Institute of Molecular Medicine for the Prevention of Human Medicine for the Prevention of Human

DiseasesDiseases• Investigate the causes of human diseases at "Our genes and proteins are the

game officials of our lives Theythe cellular and molecular levels, using DNA and protein technologies

• Current Centers:

game officials of our lives. They already know if you have a cancer

in your future.

Or dementia. Or some other devastating disease.

– Cardiovascular Genetic Research – Cell Signaling – Diabetes and Obesity Research

Hans J Müller Eberhard and Irma Gigli Center for

g

We must identify these genes and proteins in our bodies and discover ways in which they might be altered

to prevent those diseases from i i th fi t l– Hans J. Müller-Eberhard and Irma Gigli Center for

Immunology and Autoimmune Diseases– Human Genetics– Molecular Imaging

occurring in the first place . . .

That research is the role of the IMM"

James T. Willerson, M.D.Founder

– Neurodegenerative Diseases – Proteomics and Systems Biology – Stem Cell Research

S t Ll d d B A B t C t f St k

FounderIMM

– Senator Lloyd and B.A. Bentsen Center for Stroke Research

Contrast

“Nanoclinics”“Nanoclinics”

Drug Delivery

Contrast Agent

Indicator

Cancer Cell Death Indicator

Cancer CellCancer Cell Targeting Therapeutic

DNA as StructureDNA as Structure

• March 16, 2006 Nature• New method yields DNA

hnanostructures that are larger and more complex than previously possible

• The method uses a few hundred short DNA strands to 'staple' a very long strand p y ginto two-dimensional structures

• Can adopt any desired• Can adopt any desired shape, like the 'nanoface' on the cover

MicroarraysMicroarrays

• Research tools• Allows analysis of tens

of thousands of samples simultaneouslysimultaneously– DNA microarrays– Protein microarrays

S ll l l– Small-moleculemicroarrays

– Tissue microarrays– Whole-cell microarrays

• These are biosensors

The Genomics HospitalThe Genomics Hospital

• BCM developing the “Baylor Chip” – Tests 141 genes on a

PERSONALIZEDMEDICINE

Tests 141 genes on a miniature chip

– Tests for 161 important diseases

Eventually will carry out• Eventually will carry out 100,000 to 1 million gene tests

• Vision: Test every

2.5 mm

ypatient at the Baylor Clinic– Prevention– Diagnosis

GeneChip® TrueTag ™ 10K Array(400 chips/wafer format)

Diagnosis– Treatment– Follow-up

Gene TherapyGene 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 withinA 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– The abnormal gene could be repaired through selective reverse 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 altereda 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

Vector enters the cell in a vesicle

• Survival• Reduction in pain• Improved immune function• …

Vector is released from vesicle

Cell machinery producesCell machinery producestherapeutic protein

Vector binds to nucleus, depositsDNA payload inside

Cell machinery integrates DNA

Biotech's Bright HopeScientists are newly optimistic that gene therapy willScientists are newly optimistic that gene therapy will help fight the most serious diseases

By Linda Marsa Special to The TimesGene therapy is making a comeback after a

By Linda Marsa, Special to The Times

August 28, 2006

TO the shrill whine of a high-speed drill, neurosurgeon Dr. Paul Larson makes two nickel-sized holes in Shirley Cooper's skull. Guided by a

series of serious setbacks that threatened to permanently derail human tests. In recent years, European scientists have cured more than two dozen patients suffering from three rare, and in some cases lethal, immune disorders.Gene therapy

involves the y p ycomputerized MRI map, he plunges a long, thin needle through one hole and deep into the brain —and empties the syringe.

A very special payload trickles into her brain: genes that, if all goes well, will help her control the

t f h l

Parkinson's destroys cells in the brain that make dopamine, and the loss of this key brain transmitter

Spurred by this success, plus the development of new techniques aimed at making the therapy safer and more effective, more than 300 gene therapy trials, including the one for Parkinson's at UC San Francisco, are underway in the U.S. and

manipulation of DNA to replace or repair genes

movement of her muscles.It is a day in late May and Cooper, 60, an artist who lives near Seattle, has come to the UC San Francisco Medical Center to find some relief from the Parkinson's disease that is stealing her identity. Without medication, she has trouble walking and talking, and can't hold a paint brush. And the drugs

triggers the disease's crippling symptoms: tremors in the arms, legs and face, stiff or frozen limbs, and impaired balance and coordination. In the trial she's involved in — the earliest of clinical tests, designed to assess safety — scientists have engineered a harmless, stripped-down virus to carry a gene that will boost brain dopamine

abroad.

The approaches include what people traditionally think of as gene therapy: inserting functional genes to replace single, faulty ones to treat relatively rare genetic diseases such as muscular dystrophy cystic

“Gene therapy will evolve into a major

“…Gene therapy is making a comeback ... In recent years, European scientists have cured more than two dozen patients suffering from three rare, and in some cases lethal immune disorders ”talking, and can t hold a paint brush. And the drugs

are wearing off — as they eventually do for all Parkinson's patients. After that, she probably will deteriorate rapidly.

The experimental treatment Cooper is undergoing is intended to reverse that process.

carry a gene that will boost brain dopamine through the enzyme it encodes: amino acid decarboxylase, or AADC.

When the virus is injected into her brain, they hope the gene will be incorporated into healthy brain cells and steadily produce the enzyme.

diseases such as muscular dystrophy, cystic fibrosis, sickle cell anemia, beta thalassemia and hemophilia. But, more and more, gene therapy is being studied as a treatment for lethal ills that are not inherited in any clear, simple way — cancer, hepatitis, AIDS, heart disease — and which also plague millions.

therapeutic method”…lethal, immune disorders…”

y p y p g

Gene Therapy of XGene Therapy of X--Linked Linked AdrenoleukodystrophyAdrenoleukodystrophyy p yy p y

• 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 d iadvances in zones

• The specific gene that is mutated in X-ALD has been identified (ABCD1 gene)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 NucleotidesTherapeutic Nucleotides

• Nucleotides: Building blocks of DNA, RNA –and related compoundscompounds

• Consist of…– a heterocyclic base,

a sugar and– a sugar, and – one or more phosphate

groups

• We can synthesize these• We can synthesize these and use them as therapies– Oligonucleotides

A ti th• Antisense therapy• siRNA• Micro-RNA (miRNA)

RNAiRNAi, , siRNAssiRNAs

• RNAi = RNA interference• siRNA = synthetic interfering RNASirna Therapeutics

i t th f f t f th ff t t tSirna Therapeutics i t th f f t f th ff t t tSirna Therapeutics i t th f f t f th ff t t t

• siRNAs can be used in mammalian cells for gene silencingiRNA k b il i k

is at the forefront of the effort to create RNAi- based therapies and leverage the vast potential of this technology to ultimately treat patients.

is at the forefront of the effort to create RNAi- based therapies and leverage the vast potential of this technology to ultimately treat patients.

is at the forefront of the effort to create RNAi- based therapies and leverage the vast potential of this technology to ultimately treat patients.

• siRNA works by silencing key sequences on messenger RNA, which turns off specific genes by cleaving to them on the RNA strand

Sirna was acquired by Merck & Co., Inc. in December of 2006 and is the Center of Excellence for

• Nanosized particles are being research for delivery of siRNA-based drugsRNAi t di h d t t d th li i l t ti l f

is the Center of Excellence for RNA technology within Merck Research Laboratories.

• RNAi studies have demonstrated the clinical potential of siRNAs in dental diseases, eye diseases, cancer, metabolic diseases, neurodegenerative disorders, and gother illnesses

miRNAsmiRNAs andand ThioaptamersThioaptamersmiRNAsmiRNAs and and ThioaptamersThioaptamers

• Discovery-stage company focused on micro-RNA-di t d l th i

• Thioaptamers are a class of nucleic acid (DNA or RNA)

tdirected oncology therapies• miRNAs are small, non-coding

RNA molecules

aptamers• These short nucleic acid

molecules bind to a specific t t l l• Misregulation is a frequent

event in development of some genetic diseases

target molecule• Binding is often just as specific

and strong as with an antibody• miRNA therapies re-introduce

a synthetic version of a miRNA that is depleted in the diseased tissue

• But synthesized chemicals can be easier to produce

• Therapeutic, diagnostic, and tissue. research applications

The “Central Dogma”…The “Central Dogma”…

Cell Nucleus

Chromosome

ProteinGraphics courtesy of the National Human Genome Research Institute

Gene (DNA)Gene (mRNA), single strand

EpigeneticsEpigeneticsTh t d f i h it d h i h t ( ) iThe study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence --non-genetic factors cause the organism's genes to behave (or "express themselves") differently.themselves ) differently.

Pharmacogenetics & Pharmacogenetics & ggPharmacogenomicsPharmacogenomics

‘‘OmicsOmics• The genome and genomics; structural and functional genomics• The proteome and proteomics

– Proteome: Constellation of proteins in a biological system (eg, cell,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 processesbiological processes

• What the structure, functions, and interactions of proteins are in living systems

• Including in normal and diseased states, under various physiological conditions and in all stages of developmentconditions, 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 )drug discovery (vs. pharmacogenetics: individual differences…) • “’Omics” Requires ‘Systems’ Emphasis

– Interactions among elements of complex systems– Requires sophisticated information managementq p g

Personalized MedicinePersonalized Medicine

Personalized Medicine: The effort to match the right drug, with the right patient, at thethe right drug, with the right patient, at the right time…

Interpersonal Variability is the MotiveInterpersonal Variability is the Motive

Goals of Personalized MedicineGoals of Personalized Medicine

Personalized MedicinePersonalized Medicine??WhyWhy

“The right drug for the right patient at the right time”INEFFECTIVE

The right drug for the right patient at the right time

INEFFECTIVE

INEFFECTIVE

INEFFECTIVE

INEFFECTIVE

Imagine the day when you and your doctor sit down to review a copy of your own personal genome. This vital py y p ginformation 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 Personalized Medicine Made Possible By…Possible By…yy

• Converging technologies– Sequencing the human q g

genome– Increased understanding

the 100,000+ proteins made by the 25,000+ human genes

– Identifying biomarkers for ll diall diseases

– Nanotechnology• Increasing ability to create

new drugs to treat diseases at the molecular/genetic level– “Designer drugs”

The “Cheap” GenomeThe “Cheap” Genome

• It took 2,000 scientists more than 10 years and $2.7 billion to read the first , yhuman 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” GenomeThe “Cheap” Genome

• Within a few years, a standard aspect of your health care could include the decoding of every aspect of your

i kgenetic make-up• A key facilitator of personalized medicine• Sequence all children• 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– Diagnosis of acquired diseases– Early cancer detection– Cancer treatment recommendation

Technology Improving SurvivalTechnology Improving Survival

BioinformaticsBioinformatics

• Context: Massive amounts of complex data; accumulating, organizing, and analyzing data is necessary for the information to be usefuluseful

• 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:• There are three important sub-disciplines within bioinformatics: – 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– 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 paccess and management of different types of information.

Bioinformatics (cont)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 populationGenerate 3 D structures of– Generate 3-D structures of gene products

– Analyze changes under normal or disease statesnormal or disease states

Computational Modeling and Computational Modeling and Rational Drug DesignRational Drug Design In silicog gg g

Protein EngineeringProtein Engineering

• Rational design and modification of proteins– Reliance on computational biology and molecular biologyp gy gy– Drug development– Food processing

Industrial manufacturing– Industrial manufacturing

Life Science TechnologyLife Science Technology Commercialization

Some Key PointsSome 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• Institutions may obtain patents on inventions, and 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 DevelopmentNew Drug Development2 4 6 8 10 12 14 160

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 TimesClinical Development and Approval Times

97.7 (8.1 yrs)

90.3 (7.5 yrs)

Source: DiMasi and Grabowski, Managerial and Dec Econ 2007, in press

Months

Clinical and Approval Times Vary Across Clinical and Approval Times Vary Across Therapeutic ClassesTherapeutic Classespp

12.1

8.5

9.8

7.6

7.5

6.9

8.0

6.3

For years 2002-04Source: Tufts CSDD, 2006Source: Tufts CSDD, 2006

Selected ProductSelected Product--Development ActivitiesDevelopment ActivitiesPRECLINICAL CLINICAL• Pharmacology

– In vitro profiling– In vivo animal models– Safety pharmacology

C bi ti Ph l /T i l

• Protocol design and development• Clinical trial management

– Site & Investigators– Trial monitoring

PRECLINICAL CLINICAL

– Combination Pharmacology/Toxicology Studies

• PK/ADME– In vitro metabolism– In vivo pharmacokinetics

Ti di t ib ti / b l

– Budget & timeline tracking– Regulatory compliance oversight

• Adverse event reporting & pharmacovigilanceCli i l d t t– Tissue distribution/mass balance

• Toxicology– In vitro screening– General Toxicology– Genetic Toxicology

• Clinical data management• Biostatistics• Medical Writing

REGULATORY– Reproductive Toxicology

CHEMISTRY, MANUFACTURING & CONTROLS• Formulation development

REGULATORY • Regulatory strategy development• IND Submission and Amendments• Milestone and ad hoc meetings; other

i tiFormulation development• Process development• GMP manufacturing• Analytical methods development• Product stability

communications• Compliance• NDA preparation and submission• Advisory Committee preparation

• Product stability

Phase I GoalsPhase 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• 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 Reductasemevalonate (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• Explore potential issues affecting use in broader populations

– Examples: Potential for interactions with other drugs, food effects

Phase II GoalsPhase 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– Example: Dosing of statin drug in lowers LDL-C in patients with high cholesterol

– Note: Most sponsors are now seeking to establish some aspects of Proof-of-Pharmacology in P1gy

• Explore the pharmacology and safety of the drug in patient populations with different characteristics– Example: Study statins in patients with high cholesterol with and p y p g

without previous history of heart disease• Gather more evidence regarding safety• Establish the dose(s) and patients to be used in large P3 pivotalEstablish the dose(s) and patients to be used in large P3 pivotal

studies

Phase III GoalsPhase III Goals

• Establish the safety and efficacy in populations reflecting the population to be treated

Often requires outcome data (eg morbidity and mortality)– Often requires outcome data (eg, morbidity and mortality)– High cost and time consuming (complex)– Develop more complete picture of risk and benefits

Overall cost of drug developmentOverall 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” numbersa DiMasi et al., J Health Economics 2003;22(2):151-185)

The Cost of Drug Development The Cost of Drug Development Continues to IncreaseContinues to Increase

Estimate of Average Capitalized Development Cost per NCE 1976–2001

lions

)lio

ns)

Development Cost per NCE, 1976–2001

$700$700

$900$900

$800$800$802$802

Dol

lars

(Mill

Dol

lars

(Mill

$400$400

$500$500

$600$600

$359$359

$500$500

Nom

inal

N

omin

al

$54$54

$200$200

$300$300

$100$100$125$125

$231$231

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)

$0$019761976 19861986 19871987 19901990 19971997 20012001

PrePre--Approval OutApproval Out--ofof--Pocket Costs per Approved Pocket Costs per Approved New Biopharmaceutical*New Biopharmaceutical*pp

** All R&D costs (basic research and preclinical development) prior to initiation of clinical testing

* Based on a 30.2% clinical approval success rate

Source: DiMasi and Grabowski Managerial and Dec Econ 2007 in pressSource: DiMasi and Grabowski, Managerial and Dec Econ 2007, in press

Annual Growth Rates for OutAnnual Growth Rates for Out--ofof--Pocket R&D Pocket R&D CostsCosts

Source: DiMasi et al., J Health Economics 2003;22(2):151-185

Clinical Development is ExpensiveClinical Development is ExpensiveMean Number of Subjects in NDAs for NMEsa

• Cost drivers– Total enrollment increasing

Mean Number of Subjects in NDAs for NMEs

g– Costs per patient:

• Oncology: $35K• Pain/Inflammation: $15KPain/Inflammation: $15K

– Costs per investigator– Infrastructure costs

Complexity of protocols is Clinical Study “Complexity Index”b

– Complexity of protocols is increasing

– Competition for patients is greatgreat

a Sources: Boston Consulting Group, 1993; Peck, Food and Drug Law J, 1997; PAREXEL, 2002b Source: DataEdge 2002Source: DataEdge, 2002

Drug Development is RiskyDrug Development is Risky

Market Launch FDA Review

Post-Marketing Surveillance115

Phase III Clinical Trials Pivotal Efficacy & Safety

Phase II Clinical Trials POC, Dose Response

2

2 - 510

Preclinical DMPK, Safety

Phase I Clinical Trials Safety/Tolerance PK5 – 10

10 20Preclinical Testing

Basic R h

Screening S h i

DMPK, Safety Chemistry10 - 20

3 000 – 10 000

5

Research Synthesis3,000 10,000

Number of CompoundsSource: PhRMA analysis of Tufts CSDD database

0

Yearsy

Why Do Drugs Fail?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 New Drug Approvals Are Not Keeping Pace with Rising R&D SpendingPace with Rising R&D Spendingg p gg p g

R&D Expenditures

New Drug Approvals

R&D expenditures are adjusted for inflationSource: Tufts CSDD Approved NCE Database, PhRMA, 2005

R&D Costs R&D Costs ---- SummarySummary

• 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, clinical costs have grown at a much more rapid rate

• New discovery and development technologies (e.g., y g ( ggenomics) may hold the promise of lower costs in the long-run, but likley represent higher costs in the short-runrun

Th k !!Thank you!!

Jason E. Moore, M.S., M.B.A.Jason E. Moore, M.S., M.B.A., ,, ,jason.moore@plxpharma.com713-842-1249