TLSC Biotech 101 Noc 2010 (Moore)

Biotech 101Biotech 101Biotech 101Biotech 101
Texas Life Science Conference
BioHouston
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 andChromosomes and
GenesGenes –– 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 andChromosomes, Genes and BasepairsBasepairs

The “Central Dogma”…The “Central Dogma”…
Cell Nucleus
Chromosome
Protein
Graphics 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 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– 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 solveg g p
problems or manufacture products

Biotechnology Tools andBiotechnology 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 y
cells, 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 3,200
Human immunodeficiency virus
9700 9
y
(HIV)
9700 9
Source: US Department of Energy Human Genome Project

Humans, chimps almost a match
August 31, 2005
By Steve Sternberg, USA TODAY
August 31, 2005
Humans and chimpanzees share an almost
identical genetic inheritance, scientists report
Thursday in a landmark comparison that they call
an "elegant confirmation" of Charles Darwin's
"Evolutionary analysis is a handmaiden to
human medicine," says Eric Lander of the
Broad Institute of the Massachusetts Institute
of Technology and Harvard.
For example, in a discovery that could offer
insights 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 that
humans and chimps are related, this
comprehensive analysis of their separate genomes
offers the best proof of their shared genetic past.
insights into Alzheimer s, researchers found
mutations that turn off the human caspase-
12 gene, which causes damaged cells to
self-destruct. Those mutations weren't found
in chimps, which aren't as susceptible to
Alzheimer's. Knocking out caspase-12 in
mice makes their brain cells more likely to
p
show 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 p
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.
By delving more deeply into those differences,
h h t l i h h
"We can peek into evolution's lab notebook and
see what went on there," says Francis Collins,
director of the National Human Genome Research
I tit t
y
survive with Alzheimer's-like damage.
Researchers also identified mutations in
humans that were important for survival,
including a gene associated with speech and
a gene that ramps up response to sugar, an
d 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 are
susceptible to certain diseases; why our
evolutionary paths diverged from ancestral chimps
6 million years ago; and, on an even more basic
level, what makes us human.
Institute.
The analysis offers clues to the cause of diseases
such as Alzheimer's and to why chimps and
humans are susceptible to different diseases.
advantage in lean times but a potential ticket
to 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 Genes99% of Human Genes
Have a Mouse CounterpartHave a Mouse Counterpartpp
…which makes laboratory mice excellent models of
disease and well suited for testing of new medicines.

“Small Molecule” vs “Large Molecule”“Small Molecule” vs “Large Molecule”gg
Drugs”Drugs”

Biological Products areBiological 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 inCore Biotechnologies and Their Use ingg
Detecting 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 Antibodies
Immune 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 inTargeted Therapies in
CancerCancer

Therapeutic Antibodies HaveTherapeutic 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 InMonoclonals 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--DetectingDetecting NanosensorNanosensor

Cell CultureCell Culture
• Growing cells outside of living organisms (in vitro)
• Research tool
• Use to create therapeutic
products
P 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 & CellularGenetic Recombination & Cellular
ClonesClones –– The Human Insulin GeneThe Human Insulin Gene

Genetic RecombinationGenetic 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…

FertilizationFertilization 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 notp ; p
totipotent
• Better behaved, easier to
manage
L 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 CellsHematopoietic 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 DevelopmentalA Little Developmental
Biology…Biology…gygy

Stages of EmbryogenesisStages of Embryogenesis
Day 2
2 cell embryo
Day 2
2 cell embryo D 3 4D 3 4
Day 1
Fertilized egg
Day 1
Fertilized egg
2-cell embryo2-cell embryo Day 3-4
Multi-cell embryo
Day 3-4
Multi-cell embryo
Day 5-6
Blastocyst
Day 5-6
BlastocystDay 11-14
Tissue Differentiation
Day 11-14
Tissue DifferentiationTissue DifferentiationTissue Differentiation

Derivation and Use ofDerivation 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 5-6
Blastocyst
Day 5-6
Blastocyst
Li
“Special sauce”
(largely unknown)
BlastocystBlastocyst
Heart muscleKidney
Liver
Heart
repaired
Heart muscleKidney

Diseases Stem Cell TherapyDiseases 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 Source
Embryonic stem cells
Adult stem cells
Progenitor cellsProgenitor cells
Signals
Growth factors
ECM
MetalsGrowth factors
Drugs
Mechanical forces
Metals
Ceramics
Synthetic polymers
Natural polymers

Rice BioengineeringRice Bioengineering
• Biomaterials and Drug Delivery
• Biomedical Imaging and
Diagnostics
• Jennifer West Lab
– Tissue Engineered Vascular
Grafts
Diagnostics
• Cellular and Biomolecular
Engineering
C 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
Biomechanics
light 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 specificg p
certain 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 BiologyModern Molecular Cell Biology
isis NanobiotechnologyNanobiotechnologyisis 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 UniversityRice 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 forAlliance for NanoHealthNanoHealth
f• 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 new
President:
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 MolecularBrown Foundation Institute of Molecular
Medicine for the Prevention of HumanMedicine for the Prevention of Human
DiseasesDiseases
• Investigate the causes of human diseases at "Our genes and proteins are the
game officials of our lives They
the 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
Founder
IMM
– 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 strandp y g
into 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-molecule
microarrays
– Tissue microarrays
– Whole-cell microarrays
• These are biosensors

The Genomics HospitalThe Genomics Hospital
• BCM developing
the “Baylor Chip”
– Tests 141 genes on a
PERSONALIZED
MEDICINE
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
y
patient 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 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 willScientists are newly optimistic that gene therapy will
help fight the most serious diseases
By Linda Marsa Special to The Times
Gene 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 they p y
computerized 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--LinkedLinked
AdrenoleukodystrophyAdrenoleukodystrophyy p yy p y
• ALD is always fatal if untreated
• Results from a deficiency of an
enzyme (“ALD”) which causesy ( )
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 t
Sirna Therapeutics
Sirna Therapeutics
• siRNAs can be used in mammalian cells for gene
silencing
iRNA 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.
• 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 drugs
RNAi 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, andg
other illnesses

miRNAsmiRNAs andand ThioaptamersThioaptamersmiRNAsmiRNAs andand 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

EpigeneticsEpigenetics
Th 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 &gg
PharmacogenomicsPharmacogenomics

‘‘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 vitalpy y p g
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 MadePersonalized Medicine Made
Possible By…Possible By…yy
• Converging technologies
– Sequencing the humanq 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, 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” 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 efficientp p
access 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 population
Generate 3 D structures of– Generate 3-D structures of
gene products
– Analyze changes under
normal or disease statesnormal or disease states

Computational Modeling andComputational Modeling and
Rational Drug DesignRational Drug Design In silico
g 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 Development
2 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 AcrossClinical 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 2002-04
Source: Tufts CSDD, 2006Source: Tufts CSDD, 2006

Selected ProductSelected Product--Development ActivitiesDevelopment Activities
PRECLINICAL 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 &
pharmacovigilance
Cli 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 ti
Formulation 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 andp 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” numbers
a DiMasi et al., J Health Economics 2003;22(2):151-185)

The Cost of Drug DevelopmentThe Cost of Drug Development
Continues to IncreaseContinues to Increase
Estimate of Average Capitalized
Development Cost per NCE 1976–2001
lions)lions)
Development Cost per NCE, 1976–2001
$700$700
$900$900
$800$800
$802$802
Dollars(MillDollars(Mill
$400$400
$500$500
$600$600
$359$359
$500$500
NominalNominal
$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$0
19761976 19861986 19871987 19901990 19971997 20012001

PrePre--Approval OutApproval Out--ofof--Pocket Costs per ApprovedPocket 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&DPocket R&D
CostsCosts
Source: DiMasi et al., J Health Economics 2003;22(2):151-185

Clinical Development is ExpensiveClinical Development is Expensive
Mean 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, 2002
b 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 20
Preclinical
Testing
Basic
R h
Screening
S h i
DMPK, Safety
Chemistry
10 - 20
3 000 – 10 000
5
Research Synthesis
3,000 10,000
Number of Compounds
Source: PhRMA analysis of Tufts CSDD database
0
Years
y

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 KeepingNew 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 inflation
Source: Tufts CSDD Approved NCE Database, PhRMA, 2005

R&D CostsR&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 ( g
genomics) 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.com
713-842-1249

TLSC Biotech 101 Noc 2010 (Moore)

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