What Physiologists Working in Industry Do

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What Physiologists Working in Industry Do

• Liaison with Industry Committee (LWIC)
• American Physiological Society

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Objective
The purpose of this presentation is to 1) inform
you about the responsibilities and types of work
a Physiologist performs as a member of the
pharmaceutical, biotech, or nutritional industry
and 2) describe some of the primary personal
attributes necessary to succeed in this
environment.
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Science and Drug Discovery

• The drug discovery process requires concerted
  efforts of scientists
• across many disciplines (Biochemists,
  Chemists, Molecular Biologists,
• Pharmacologists, Physiologists, Technologists,
  etc) to advance a
• project from initial scientific principles (an
  idea or hypothesis) to a
• clinical candidate, and ultimately a drug to
  treat human disease.
• This extremely challenging undertaking is
  pursued under strict
• guidelines regulated by federal (i.e. FDA,
  USDA) and international
• (EMEA) agencies. Successful drug discovery
  requires critical
• thinking, organizational skills, creativity,
  as well as flexibility and
• resourcefulness.
• In short, success in drug discovery requires
  well-trained, disciplined,
• and rigorous scientists. The process is one
  in which Physiologists
• can assume many critical roles. Do you fit
  these criteria?

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Scope of Scientific Activities of Physiologists
in Drug Discovery

• Activities are listed from first discovery
  principles (hypothesis generation and
• testing) to clinical trials and submission of an
  NDA (New Drug Application)
• Target discovery and validation
• Proof-of-concept studies
• Development of in vitro efficacy models
• Mechanism of compound action
• Development of in vivo models (normal function
  and disease)
• Pharmacokinetic studies
• Pharmacodynamic studies
• Assay development
• Ex vivo functional studies
• Disease efficacy testing
• Development and utilization of biomarkers
• Safety pharmacology
• Interpretation of clinical results
• Exploration of additional indications
• Regulatory submission for product and claim
  approval

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Description of Bench Science Activities of
Physiologists in Industry (Part I)

• Target Discovery and Validation Studies of
  disease mechanisms
• using molecular and genomic approaches
  including genetic
• association studies in humans, knockout and
  transgenic animals,
• engineered tool compounds to identify or
  confirm a biochemical
• target

• Proof-of-Concept Studies Studies are conducted
  to address the
• questions does the enzyme, receptor, channel,
  etc play a role in
• the physiological or disease process? Is the
  target of interest be
• activated/inactivated in this process?

• In Vitro Efficacy Testing Develop and use
  assays to test the
• hypothesis in simple systems such as isolated
  proteins and/or
• cell-based systems. These assays may often
  use high-throughput
• or multiplexed (multiple readouts) platforms.

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Examples of Bench Science Activities of
Physiologists in Industry (Part II)

• Mechanism of Compound Action Studies are
  designed to address
• questions such as does the compound affect
  enzyme, ion channel,
• or receptor activity? Does the compound affect
  a specific signaling
• pathway? Does the compound affect genetic
  regulation (expression)
• of the target?

• Development of Disease Models Studies are
  designed to address
• questions such as does the cell, tissue, or
  animal model resemble
• the human condition? Is the model valid?
  (i.e. does the
• pathophysiology respond to current
  pharmacotherapies?)

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Examples of Bench Science Activities of
Physiologists in Industry (Part III)

• Pharmacokinetic (PK) Studies generally
  considered in terms of what
• the organism does to drug and studies are
  designed to address
• questions such as what is the maximal plasma
  concentration of drug
• after dosing and when does this occur? how
  much drug gets to the
• tissue of interest and how widely is the drug
  distributed in the body?
• how quickly is the drug cleared after dosing?
• Pharmacodynamic (PD) Studies generally
  considered in terms of
• what the compound does to the organism and
  studies are designed
• to address questions such as is the
  biochemical target affected by the
• compound and to what extent? Is the tissue
  of interest affected?

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Examples of Bench Science Activities of
Physiologists in Industry (Part IV)

• Ex vivo functional studies Evaluation of
  integrated tissue or whole
• organ function with ability to carefully
  control dose, duration, and
• exposure to compound (e.g. isolated working
  heart, isolated perfused
• kidney, isolated blood vessel, brain slice,
  etc)

• Disease efficacy testing Acute and/or chronic
  studies are conducted
• to address questions such as does the
  compound modify disease
• progression in vivo (i.e. prevention model)?
  Can the compound
• regress the disease (treatment model)? How
  does the efficacy of
• the compound compare to existing
  pharmacotherapies or potential
• co-therapies?

• Development and utilization of biomarkers
  Studies are conducted to investigate whether
  there a quantifiable blood or urinary biochemical
  marker that predicts severity or progression of
  the disease? Can the marker serve as a surrogate
  for long-term efficacy of the compound?

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Examples of Bench Science Activities of
Physiologists in Industry (pt V)

• Exploration of additional indications Evaluate
  experimental results and literature to determine
  whether additional scientific opportunities exist
  (i.e. does the mechanism of action or signaling
  pathway play a role in other conditions other
  than the primary indication?)

• Interpretation of clinical results mechanistic
  and/or theoretical
• evaluation of unexpected clinical events
  (utilization and identification of
• appropriate biomarkers to track mechanistic
  or pathophysiological
• responses to agent).

• Preclinical safety pharmacology Studies are
  designed to address
• questions such as what is the therapeutic
  index of the compound?
• What is the incidence of adverse events in
  major organ systems (e.g.
• cardiovascular, renal, gastrointestinal,
  respiratory, CNS) at multiples
• (3x, 10x, 30x) of therapeutic plasma
  concentrations of the compound?

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Non-Bench Science Activities of Physiologists in
Industry

• Industry scientists have many
  responsibilities beyond benchwork
• Training and supervision of technical staff
• Generation of novel scientific and technical
  hypotheses
• Rigorous design, analysis, and interpretation of
  experiments
• Presentation of scientific concepts and business
  applications of
• research to various professionals to enable
  business and scientific
• decisions
• Participation in project team and strategic
  planning meetings
• Writing of technical reports and scientific
  manuscripts
• Documentation of all scientific observations and
  submitting patents
• Planning facility development and resource
  (people, space, equipment)
• deployment
• Participation in the preparation and submission
  of documents (IND
• Investigational New Drug NDA New Drug
  Application) to the Food
• Drug Administration (FDA)

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Personal Attributes of Successful Industry
Scientists(Part I)

• To be successful in discovering and developing a
  new drug, you must
• participate in a process that requires concerted
  efforts by many people
• across many departments and disciplines.
  Specific attributes are required
• to succeed in this fast-paced environment
• Critical Thinking Industry scientists identify
  key issues and deliver
• timely scientific responses to discovery
  projects and business
• development opportunities
• Team and Collaborative Behavior Industry
  scientists network with
• internal/external scientists to assure access
  to current and innovative
• technologies and scientific advances.
• Interpersonal Skills The drug discovery and
  development process is a
• huge undertaking, successful industry
  scientists foster a cooperative
• spirit, and work well with other scientific,
  regulatory, clinical, and
• business professionals.

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Personal Attributes of Successful Industry
Scientists (Part II)

• Strong Communication Skills Effective
  communication of ideas
• whether one on one, in small groups, or
  through formal presentations.
• Writing is clear, well-organized and
  logically developed the audience
• is taken into consideration.
• Efficiency The demands on an industry scientist
  are many (various
• experimental models to run and multiple
  compounds to test). Thus,
• industry scientists are constantly challenged
  to implement new processes
• to streamline procedures while maintaining
  rigorous standards.
• Flexibility Effectively initiates change as
  needed and adapts to
• necessary changes in operations or
  strategies also initiates new ways
• of accomplishing work.
• Leadership Industry scientists drive
  operational plans and develop
• and implement tactics to deliver results by
  set timelines. Leads by
• appropriate actions and behaviors inspires
  and guides others to
• achieve corporate and personal goals.

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Physiologists in IndustryTarget Discovery and
Validation
Target discovery studies investigate disease
mechanisms using molecular and genomic approaches
in knockout and transgenic animals.
Physiologists use these approaches to identify or
confirm a role for biochemical targets in organ
and organism function and dysfunction. Below
gene knockout of PKCa improves cardiac
performance following pressure overload (TAC),
while transgenic overexpression of PKCa impairs
cardiac performance.
Overexpression of PKC? (Prkca) in transgenic mice
reduces cardiac ventricular performance
PKC? knockout (Prkca -/-) mice have enhanced
cardiac ventricular performance
Reprinted with permission from Braz et al. Nature
Med 10(3), 2004
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Physiologists in IndustryProof-of Concept
Studies
Proof-of-concept studies address whether a
biochemical target plays a role in a disease
process (i.e. is the target of interest
activated, inhibited or differentially expressed
in disease?) Physiologists use various approaches
to learn whether a biochemical target is involved
in disease. Lower left panel over-expression of
the cardiac enzyme, calcineurin (CN) transgenic
mouse, induces cardiac hypertrophy lower right
panel aortic-banding increases cardiac CN
expression (A) and activity (B), treatment with
CsA, a CN, inhibitor prevents aortic-banding
induced cardiac hypertrophy (C).
C
Reprinted with permission from Molkentin Circ Res
87, 2000
Reprinted with permission from Lim et al.
Circulation 101, 2000
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Physiologists in IndustryIn Vitro Efficacy
Testing
In vitro efficacy studies employ assays utilizing
simple systems (e.g. isolated proteins and/or
cell-based systems). These preparations allow
Physiologists to carefully control experimental
conditions and compound concentrations while
measuring and comparing responses and behaviors
of large numbers of compounds. Below a
classical competition curve utilizes radioligand
binding techniques to evaluate the ability of
compound Y to compete for receptor subtype
binding, in turn generating affinity and potency
data.
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Physiologists in IndustryMechanism(s) of
Compound Action
Enalapril blocks the blood pressure response
to Angiotensin I The mechanism of action is the
antagonism of angiotensin converting enzyme
100
80
60
inhibition of the mean arterial pressure
response to Angiotensin I bolus
40
20
0
-120
-60
0
60
120
180
240
300
360
Time (min)
Angiotensin I
Enalapril
(300 ng/kg, IV)
(10 mg/kg)
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Physiologists in IndustryDevelopment of Disease
Models
Ultimately, drugs developed through the discovery
process must be able to modify disease
progression and outcome. Physiologists develop
models of disease for drug discovery, and must
have an thorough understanding of normal and
pathologic ranges of functional parameters. A
valid disease model must involve many of the
critical biochemical pathways and display many
clinical findings of the human disease state.
Below Surgical instrumentation and induction of
chronic pacing-induced heart failure.
Surgical Instrumentation
Pacing-Induced HF and Recovery

• Cardiac function and coronary flow are measured
  in the conscious state by chronic
  instrumentation.
• Heart failure (elevated end diastolic pressure,
  reduced ejection fraction and cardiac reserve) is
  induced by right ventricular pacing for 3-4
  weeks.
• Recovery from heart failure is allowed by the
  termination of pacing for 5-6 weeks after
  developed heart failure.

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Physiologists in IndustryPharmacokinetic Studies
Pharmacokinetic studies characterize how the body
handles a compound. Physiologists work
alongside Medicinal and Bioanalytical Chemists to
determine if a compound is orally bioavailable
and will achieve adequate plasma and tissue
exposure and duration prior to undertaking an
efficacy or chronic disease modification study.
Below Oral administration of Compound X (10 mpk)
exhibited good fractional bioavailability (F
54) and plasma half-life (t1/2 6 hours).
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Physiologists in IndustryPharmacodynamic Studies
Pharmacodynamic studies characterize the effects
of a compound on the body. Certain enzymes are
activated (e.g. phosphorylated) or modified (e.g.
glycosylated) in disease processes. For example,
to determine if a compound will inhibit an enzyme
of interest, Physiologists determine whether
enzyme phosphorylation and kinase activity are
suitable pharmacodynamic indices for compound
activity. Below intraperitoneal administration
of a physiological stimulus dose-dependently
increased enzyme phosphorylation and kinase
activity, providing a model to assay compound
activity against this enzymes activity.
Western Blot Phosphorylated Enzyme
Immunoprecipitation Kinase Assay
vehicle
3 mpk
10 mpk
p-TXXX
p lt 0.01 vs. vehicle

Total Enzyme


p lt 0.01 vs. vehicle
0.12
0.10

0.08
p-TXXX / Total enzyme
0.06
0.04
0.02
0.00
vehicle
3 mpk
10 mpk
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Physiologists in IndustryEx Vivo Functional
Studies
Ex vivo studies evaluate integrated organs and
organ systems from normal and diseased organisms.
These preparations allow Physiologists to
carefully control experimental conditions and
organ compound exposures while measuring and
comparing functional responses in normal and
diseased organs. Below an isolated working
heart preparation allows careful control of
preload, afterload, heart rate, and compound
exposure.
Cardiac Systolic Performance Endpoints LV
Systolic Pressure mmHg LV End Diastolic
Pressure mmHg Left Atrial Pressure mmHg
Aortic Mean Pressure mmHg Max
/-dP/dt mmHg/sec Peak Pressure mmHg Time
to Peak Press (TPP) msec TPP/PP msec/mmHg Dias
tolic Function Endpoints tau msec 1/2
Relaxation Press (1/2 RP) mmHg 1/2 Relaxation
Time (RT1/2) msec (RT1/2) / (1/2 RP) msec/mmHg
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Physiologists in IndustryDisease Efficacy
Studies
Drugs developed through the discovery process
must show efficacy in modifying disease
progression and outcome. Physiologists develop
models of disease for drug discovery, and are
required to have a thorough understanding of
normal function as well as the pathology of
disease states. Last, models of human diseases
for drug discovery must be amenable to standard
pharmacotherapies. Below Effects of varying
delay (7 day vs. 30 days post-MI) of ACE
inhibitor treatment on a) survival, b) cardiac
hemodynamics, and c) morphology after myocardial
infarction (MI).
b
a
c
untreated
ACEi 30d post-MI
ACEi 7d post-MI
Reprinted with permission from Mulder et al.
Circulation 95, 1997
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Physiologists in IndustryDevelopment and
Utilization of Biomarkers
Blood and/or urinary biochemical markers that are
correlated to disease severity allow tracking of
disease progression and regression following drug
therapy. Physiologists a) develop disease models
that have biomarker profiles similar to those
observed in human disease, b) evaluate biomarker
responses to standard and novel therapeutic
agents, and c) develop assays to quantify
biomarkers. Below Kaplan-Meier survival curve
for mortality and morbidity in human heart
failure patients based on plasma brain
natriuretic peptide (BNP) concentrations. Thus,
plasma BNP is associated with disease severity
and may be used in place of more expensive and
time-consuming assays.
Reprinted with permission from Anand et al.
Circulation 107, 2003
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Physiologists in IndustryPreclinical Safety
Pharmacology

• Studies can be designed to address specific
  questions regarding safety
• of a compound with respect to a) acute plasma
  concentrations of drug
• (does increasing the plasma concentration of a
  drug 10-fold above
• the therapeutic level induce cardiac
  electrophysiological abnormalities?)
• or b) following chronic dosing. For example
• Determine the effects of increasing drug
  concentrations after dosing for
• 7 or 28 days various organ function,
  morphology, and histology
• Determine No Adverse Events Level (NOEL) for
  compound
• Federally required data in 2 species before
  First Time in Human (FIH)
• testing