What Physiologists Working in Industry Do

Physiologists in Industry Committee (PIC)

American Physiological Society

Objective

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

Science and Drug Discovery

• The drug discovery process requires concerted efforts of The drug discovery process requires concerted efforts of scientists scientists across many disciplines (Biochemists, Chemists, Molecular across many disciplines (Biochemists, Chemists, Molecular Biologists, Biologists, Pharmacologists, Pharmacologists, PhysiologistsPhysiologists, Technologists, etc…) to , Technologists, etc…) to advance a advance a project from initial scientific principles (an idea or hypothesis) project from initial scientific principles (an idea or hypothesis) to a to a clinical candidate, and ultimately a drug to treat human clinical candidate, and ultimately a drug to treat human disease.disease.

• This extremely challenging undertaking is pursued under This extremely challenging undertaking is pursued under strict strict guidelines regulated by federal (i.e. FDA, USDA) and guidelines regulated by federal (i.e. FDA, USDA) and international international (EMEA) agencies. Successful drug discovery requires critical (EMEA) agencies. Successful drug discovery requires critical thinking, organizational skills, creativity, as well as flexibility thinking, organizational skills, creativity, as well as flexibility and and resourcefulness.resourcefulness.

• In short, success in drug discovery requires well-trained, In short, success in drug discovery requires well-trained, disciplined, disciplined, and rigorous scientists. The process is one in which and rigorous scientists. The process is one in which PhysiologistsPhysiologists can assume many critical roles. Do you fit these criteria?can assume many critical roles. Do you fit these criteria?

Scope of Scientific Activities of Physiologists in Drug Discovery

Activities are listed from first discovery principles (hypothesis Activities are listed from first discovery principles (hypothesis generation and generation and

testing) to clinical trials and submission of an NDA (New Drug testing) to clinical trials and submission of an NDA (New Drug Application)Application)

Target discovery and validationTarget discovery and validation Proof-of-concept studiesProof-of-concept studies Development of Development of in vitroin vitro efficacy models efficacy models Mechanism of compound actionMechanism of compound action Development of Development of in vivoin vivo models (normal function and disease) models (normal function and disease) Pharmacokinetic studies Pharmacokinetic studies Pharmacodynamic studiesPharmacodynamic studies Assay developmentAssay development Ex vivoEx vivo functional studies functional studies Disease efficacy testingDisease efficacy testing Development and utilization of biomarkersDevelopment and utilization of biomarkers Safety pharmacologySafety pharmacology Interpretation of clinical resultsInterpretation of clinical results Exploration of additional indicationsExploration of additional indications Regulatory submission for product and claim approvalRegulatory submission for product and claim approval

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

Target Discovery and Validation: Studies of disease mechanismsStudies of disease mechanisms using molecular and genomic approaches including geneticusing molecular and genomic approaches including genetic association studies in humans, knockout and transgenic association studies in humans, knockout and transgenic

animals, animals, engineered tool compounds to identify or confirm a biochemical engineered tool compounds to identify or confirm a biochemical targettarget

Proof-of-Concept Studies: Studies are conducted to Studies are conducted to address the address the questions: does the enzyme, receptor, channel, etc… play questions: does the enzyme, receptor, channel, etc… play a role in a role in the physiological or disease process? Is the target of the physiological or disease process? Is the target of interest be interest be activated/inactivated in this process?activated/inactivated in this process? In Vitro Efficacy Testing: Develop and use assays to test Develop and use assays to test the the hypothesis in simple systems such as isolated proteins hypothesis in simple systems such as isolated proteins and/or and/or cell-based systems. These assays may often use high-cell-based systems. These assays may often use high-throughput throughput or multiplexed (multiple readouts) platforms.or multiplexed (multiple readouts) platforms.

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

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

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

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

Pharmacokinetic (PK) Studies:Pharmacokinetic (PK) Studies: generally considered in terms generally considered in terms of “what of “what the organism does to drug” and studies are designed to the organism does to drug” and studies are designed to address address questions such as: what is the maximal plasma concentration questions such as: what is the maximal plasma concentration of drug of drug after dosing and when does this occur? how much drug gets after dosing and when does this occur? how much drug gets to the to the tissue of interest and how widely is the drug distributed in the tissue of interest and how widely is the drug distributed in the body? body? how quickly is the drug cleared after dosing?how quickly is the drug cleared after dosing?

Pharmacodynamic (PD) Studies:Pharmacodynamic (PD) Studies: generally considered in terms generally considered in terms of of “ “what the compound does to the organism” and studies are what the compound does to the organism” and studies are designed designed to address questions such as: is the biochemical target to address questions such as: is the biochemical target affected by the affected by the compound and to what extent? Is the tissue of interest compound and to what extent? Is the tissue of interest affected?affected?

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

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

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

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

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

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

Preclinical safety pharmacology: Preclinical safety pharmacology: Studies are designed to Studies are designed to address address

questions such as: what is the therapeutic index of the questions such as: what is the therapeutic index of the compound? compound?

What is the incidence of adverse events in major organ What is the incidence of adverse events in major organ systems (e.g. systems (e.g.

cardiovascular, renal, gastrointestinal, respiratory, CNS) at cardiovascular, renal, gastrointestinal, respiratory, CNS) at multiples multiples

(3x, 10x, 30x) of therapeutic plasma concentrations of the (3x, 10x, 30x) of therapeutic plasma concentrations of the compound?compound?

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

Non-Bench Science Activities of Physiologists in Industry

Industry scientists have many responsibilities beyond benchwork…Industry scientists have many responsibilities beyond benchwork…

Training and supervision of technical staffTraining and supervision of technical staff Generation of novel scientific and technical hypothesesGeneration of novel scientific and technical hypotheses Rigorous design, analysis, and interpretation of experimentsRigorous design, analysis, and interpretation of experiments Presentation of scientific concepts and business applications of Presentation of scientific concepts and business applications of research to various professionals to enable business and scientific research to various professionals to enable business and scientific decisionsdecisions Participation in project team and strategic planning meetingsParticipation in project team and strategic planning meetings Writing of technical reports and scientific manuscriptsWriting of technical reports and scientific manuscripts Documentation of all scientific observations and submitting patentsDocumentation of all scientific observations and submitting patents Planning facility development and resource (people, space, Planning facility development and resource (people, space,

equipment) equipment) deploymentdeployment Participation in the preparation and submission of documents (IND: Participation in the preparation and submission of documents (IND: Investigational New Drug; NDA: New Drug Application) to the Food & Investigational New Drug; NDA: New Drug Application) to the Food & Drug Administration (FDA)Drug Administration (FDA)

Personal Attributes of Successful Industry Scientists

(Part I)To be successful in discovering and developing a new drug, you must To be successful in discovering and developing a new drug, you must participate in a process that requires concerted efforts by many people participate in a process that requires concerted efforts by many people across many departments and disciplines. Specific attributes are required across many departments and disciplines. Specific attributes are required to succeed in this fast-paced environment…to succeed in this fast-paced environment…

Critical Thinking:Critical Thinking: Industry scientists identify key issues and deliver Industry scientists identify key issues and deliver timely scientific responses to discovery projects and business timely scientific responses to discovery projects and business development opportunities development opportunities

Team and Collaborative Behavior:Team and Collaborative Behavior: Industry scientists network Industry scientists network with with internal/external scientists to assure access to current and innovative internal/external scientists to assure access to current and innovative technologies and scientific advances. technologies and scientific advances.

Interpersonal Skills:Interpersonal Skills: The drug discovery and development process is a The drug discovery and development process is a huge undertaking, successful industry scientists foster a cooperative huge undertaking, successful industry scientists foster a cooperative spirit, and work well with other scientific, regulatory, clinical, and spirit, and work well with other scientific, regulatory, clinical, and business professionals.business professionals.

Strong Communication Skills:Strong Communication Skills: Effective communication of ideas Effective communication of ideas whether one on one, in small groups, or through formal presentations. whether one on one, in small groups, or through formal presentations.

Writing is clear, well-organized and logically developed; the audience Writing is clear, well-organized and logically developed; the audience is taken into consideration.is taken into consideration.

Efficiency:Efficiency: The demands on an industry scientist are many (various The demands on an industry scientist are many (various experimental models to run and multiple compounds to test). Thus, experimental models to run and multiple compounds to test). Thus, industry scientists are constantly challenged to implement new industry scientists are constantly challenged to implement new

processes processes to streamline procedures while maintaining rigorous standards.to streamline procedures while maintaining rigorous standards.

Flexibility:Flexibility: Effectively initiates change as needed and adapts to Effectively initiates change as needed and adapts to necessary changes in operations or strategies; also initiates new ways necessary changes in operations or strategies; also initiates new ways of accomplishing work.of accomplishing work.

Leadership:Leadership: Industry scientists drive operational plans and develop Industry scientists drive operational plans and develop and implement tactics to deliver results by set timelines. Land implement tactics to deliver results by set timelines. Leads by eads by appropriate actions and behaviors; inspires and guides others to appropriate actions and behaviors; inspires and guides others to achieve corporate and personal goals.achieve corporate and personal goals.

Personal Attributes of Successful Industry Scientists (Part II)

Physiologists in Industry:Target Discovery and Validation

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

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

performance

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 PKC improves cardiac performance following pressure overload (TAC), while transgenic overexpression of PKC impairs cardiac performance.

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

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).

Reprinted with permission from Molkentin Circ Res 87, 2000 Reprinted with permission from Lim et al. Circulation 101, 2000

C

Physiologists in Industry:In Vitro Efficacy Testing

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In vitroIn vitro efficacy studies employ assays utilizing simple systems (e.g. isolated efficacy studies employ assays utilizing simple systems (e.g. isolated proteins and/or cell-based systems). These preparations allow proteins and/or cell-based systems). These preparations allow PhysiologistsPhysiologists to to carefully control experimental conditions and compound concentrations while carefully control experimental conditions and compound concentrations while measuring and comparing responses and behaviors of large numbers of measuring and comparing responses and behaviors of large numbers of compounds.compounds. Below: a classical competition curve utilizes radioligand binding Below: a classical competition curve utilizes radioligand binding techniques to evaluate the ability of compound Y to compete for receptor subtype techniques to evaluate the ability of compound Y to compete for receptor subtype binding, in turn generating affinity and potency data. binding, in turn generating affinity and potency data.

Physiologists in Industry:Mechanism(s) of Compound Action

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Physiologists in Industry:Development of Disease Models

Ultimately, drugs developed through the discovery process must be able to Ultimately, drugs developed through the discovery process must be able to modify disease progression and outcome. modify disease progression and outcome. PhysiologistsPhysiologists develop models of develop models of disease for drug discovery, and must have an thorough understanding of disease for drug discovery, and must have an thorough understanding of normal and pathologic ranges of functional parameters. A valid disease normal and pathologic ranges of functional parameters. A valid disease model must involve many of the critical biochemical pathways and display model must involve many of the critical biochemical pathways and display many clinical findings of the human disease state. many clinical findings of the human disease state. Below: Surgical Below: Surgical instrumentation and induction of chronic pacing-induced heart failure.instrumentation and induction of chronic pacing-induced heart failure.

Surgical Instrumentation

1. Cardiac function and coronary flow are

measured in the conscious state by chronic

instrumentation.

2. Heart failure (elevated end diastolic

pressure, reduced ejection fraction and

cardiac reserve) is induced by right

ventricular pacing for 3-4 weeks.

3. Recovery from heart failure is allowed by

the termination of pacing for 5-6 weeks after

developed heart failure.

Pacing-Induced HF and Recovery

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).

Pharmacokinetic Characterization ofCompound X

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oral dose Cmax = 535 pg/ml; Tmax = 3 hrs, F = 53%

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i.v. dose Cmax = 1004 pg/ml

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Physiologists in Industry:Pharmacodynamic Studies

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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 enzyme’s activity.

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Physiologists in Industry:Ex Vivo Functional Studies

Cardiac Systolic Performance EndpointsCardiac Systolic Performance Endpoints LV Systolic PressureLV Systolic PressuremmHgmmHg LV End Diastolic PressureLV End Diastolic Pressure mmHgmmHg Left AtrialLeft Atrial PressurePressuremmHgmmHg Aortic Mean PressureAortic Mean PressuremmHgmmHg Max +/-dP/dtMax +/-dP/dt mmHg/secmmHg/sec Peak PressurePeak Pressure mmHgmmHg Time to Peak Press (TPP)Time to Peak Press (TPP) msecmsec TPP/PPTPP/PPmsec/mmHgmsec/mmHgDiastolic Function EndpointsDiastolic Function Endpoints tautau msecmsec 1/2 Relaxation Press (1/2 RP)1/2 Relaxation Press (1/2 RP) mmHgmmHg 1/2 Relaxation Time (RT1/2)1/2 Relaxation Time (RT1/2) msecmsec (RT1/2) / (1/2 RP)(RT1/2) / (1/2 RP)msec/mmHgmsec/mmHg

Ex vivoEx vivo studies evaluate integrated organs and organ systems from normal and studies evaluate integrated organs and organ systems from normal and diseased organisms. These preparations allow diseased organisms. These preparations allow PhysiologistsPhysiologists to carefully control to carefully control experimental conditions and organ compound exposures while measuring and experimental conditions and organ compound exposures while measuring and comparing functional responses in normal and diseased organs.comparing functional responses in normal and diseased organs. Below: an Below: an isolated working heart preparation allows careful control of preload, afterload, isolated working heart preparation allows careful control of preload, afterload, heart rate, and compound exposure.heart rate, and compound exposure.

Physiologists in Industry:Disease Efficacy Studies

Drugs developed through the discovery process must show efficacy in modifying Drugs developed through the discovery process must show efficacy in modifying disease progression and outcome. disease progression and outcome. PhysiologistsPhysiologists develop models of disease for drug develop models of disease for drug discovery, and are required to have a thorough understanding of normal function 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 as well as the pathology of disease states. Last, models of human diseases for drug discovery must be amenable to standard pharmacotherapies. drug discovery must be amenable to standard pharmacotherapies. Below: Effects Below: Effects of varying delay (7 day vs. 30 days post-MI) of ACE inhibitor treatment on a) 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 survival, b) cardiac hemodynamics, and c) morphology after myocardial infarction (MI).(MI).

a b

cuntreated

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

Blood and/or urinary biochemical markers that are correlated to disease severity Blood and/or urinary biochemical markers that are correlated to disease severity allow tracking of disease progression and regression following drug therapy. allow tracking of disease progression and regression following drug therapy. PhysiologistsPhysiologists a) develop disease models that have biomarker profiles similar to those a) develop disease models that have biomarker profiles similar to those observed in human disease, b) evaluate biomarker responses to standard and novel observed in human disease, b) evaluate biomarker responses to standard and novel therapeutic agents, and c) develop assays to quantify biomarkers. therapeutic agents, and c) develop assays to quantify biomarkers. Below: Kaplan-Below: Kaplan-Meier survival curve for mortality and morbidity in human heart failure patients based Meier survival curve for mortality and morbidity in human heart failure patients based on plasma brain natriuretic peptide (BNP) concentrations. Thus, plasma BNP is 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 associated with disease severity and may be used in place of more expensive and time-consuming assays.time-consuming assays.

Reprinted with permission from Anand et al. Circulation 107, 2003

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