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What Physiologists Working in Industry Do Liaison with Industry Committee (LWIC) American Physiological Society Objective

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what physiologists working in industry do

What Physiologists Working in Industry Do

Liaison with Industry Committee (LWIC)

American Physiological Society

objective
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.

science and drug discovery
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?
scope of scientific activities of physiologists in drug discovery
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
description of bench science activities of physiologists in industry part i
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.

examples of bench science activities of physiologists in industry part ii
Examples of Bench Science Activities of Physiologists in Industry (Part II)
  • 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?)

  • 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?

examples of bench science activities of physiologists in industry part iii
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?

examples of bench science activities of physiologists in industry part iv
Examples of Bench Science Activities of Physiologists in Industry (Part IV)
  • 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?

  • 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…)

  • 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?
examples of bench science activities of physiologists in industry pt v
Examples of Bench Science Activities of Physiologists in Industry (pt V)
  • 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).

  • 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?)
  • 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?

non bench science activities of physiologists in industry
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)

personal attributes of successful industry scientists part i
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.

personal attributes of successful industry scientists part ii
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.

physiologists in industry target discovery and validation
Physiologists in Industry:Target 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.

PKC knockout (Prkca -/-) mice have enhanced cardiac ventricular performance

Overexpression of PKC (Prkca) in transgenic mice reduces cardiac ventricular performance

Reprinted with permission from Braz et al. Nature Med 10(3), 2004

physiologists in industry proof of concept studies
Physiologists in Industry:Proof-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

physiologists in industry in vitro efficacy testing
Physiologists in Industry:In 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.

physiologists in industry mechanism s of compound action
Physiologists in Industry:Mechanism(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)

physiologists in industry development of disease models
Physiologists in Industry:Development 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.
physiologists in industry pharmacokinetic studies
Physiologists in Industry:Pharmacokinetic 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).

physiologists in industry pharmacodynamic studies

35000

30000

25000

20000

Counts per Minute

15000

10000

5000

0

Vehicle

3 mpk

10 mpk

Physiologists in Industry:Pharmacodynamic 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, Physiologistsdetermine 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 enzyme’s activity.

Western Blot – Phosphorylated Enzyme

Immunoprecipitation Kinase Assay

vehicle

3 mpk

10 mpk

p-TXXX

* p < 0.01 vs. vehicle

*

Total

Enzyme

*

* p < 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

physiologists in industry ex vivo functional studies
Physiologists in Industry:Ex 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

Diastolic 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

physiologists in industry disease efficacy studies
Physiologists in Industry:Disease 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

physiologists in industry development and utilization of biomarkers
Physiologists in Industry:Development 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

physiologists in industry preclinical safety pharmacology
Physiologists in Industry:Preclinical 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