Biotech and Pharma

7/31/2019 Biotech and Pharma

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Biotech & Pharma

The Science,The Jobs, & Skills for Success

Neil Stahl Ph.D.

Regeneron Pharmaceuticals


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Overview

Science at a Company vs. Academia Attributes for Success at a Company

Biotech vs. Big Pharma

Biotech : Innovation and Risk

Drug Development 101

Job Opportunities Outside of Research

Getting Hired


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My Experience

BS Zoology Duke 1978

Duke Marine Lab 1977, 78, 79 brought me to Science

PhD Biochemistry Brandeis 1979-1985

Quantitative fundamentals of equilibria, kinetics,& how to make a conclusion

Post-Doc at UCSF with Stan Prusiner - Scrapie Prions

Learned many fields ranging from protein chemistry, cell biology,transgenics, human genetics

Regeneron Discovery, 1991 (65 employees)

Explored mechanisms of how cytokine receptors are activated and activatecytoplasmic signaling pathways

Figured out a way to make tight binding cytokine blockers based on themechanism of cytokine activation, using multiple cytokine receptorcomponents in a recombinant fusion protein = Cytokine Trap

Regeneron Drug Development (1999-2005; now 565 employees)

Established preclinical development group - put 3 Traps into clinical trials

Joined Senior Management - reorganized program management, clinical

project teams, jointly manage all aspects of Research and ClinicalDevelopment, present to investors, analysts, potential partners


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Science at a Company

Scientific endeavor on a project can be carried out at a scale

that is very rare in a University setting

Teams of competent people aligned toward a common goal canaccomplish more than any individual scientist

Discoveries can be translated into therapeutic opportunities withthe potential to create new drugs and technologies

Understand molecular and cellular pathways defining aparticular biology and how it goes wrong in disease

Create a drug to impact those pathways

Explore how that drug works in animals and humans

Design Clinical Program to prove that the drug is safe &effective

Register the drug with the FDA and Rest of World


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Differences Between Academia & Industry

You will have access to far more resources, equipment, corefacilities, and collaborative colleagues to advance your project

You will be required to work on projects of the companyschoosing

You may be asked to switch to (or add on) new projects

Although you will report to one person, you will interact withmany Scientists instead of a single PI

Participate and present in cross-functional meetings where datais vetted and the future directions of a project are established bydiscussion and consensus

More heads are better than 1!

You are likely to publish and attend scientific conferences


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Some Myths of Industry

You have failed if you dont pursue an academic position

Thats what some told me, but there are many, many incrediblycompetent people doing Science & Drug Discovery in Industry

The working day is 9-5

Hard, effective work is expected and rewarded!

Compensation is dramatically better than academia

Entry level scientist positions (3-5 year postdoc) are compensatedsimilarly to Assistant Professors, but much better than post-docs,and there are stock options!

However, opportunity for advancement is more frequent and morerapid than Academia

You never get to publish

I published more rapidly at Regeneron than anywhere else! Also,compensation is based on contributions beyond publishing

You cant move from Industry to Academia

More and more, Universities value Industry experience andperspective, making a reverse move more likely


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Attributes for Success at a Company

Team player who can collaborate effectively with others

Ability to become interested in a wide variety of differentscientific areas - learning is a continuous Life-long experience!

Superb analytical, communication, and presentation skills

All of us have particular skills that make us good Scientists,although my exact skill set may not be the same as yours

Contribute yourparticular talent and expertise toward thecommon goal

Success means that yourproject grows so that hundreds ofpeople work on it!


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Biotech vs Big Pharma

Often more innovative, high-risk scientific

approaches

Typically more traditional small molecule

Drug Discovery, unless partnered with

Biotech

More informal working environment, with a

were all in this together spirit.

A do what it takes to get the job done

attitude that may provide more variety

More likely to participate in decision-makingprocess

Typically more hierarchical

Employees can become pigeon-holed in a

particular function.

Larger organizations usually have more

rules!

Much larger experience base

More resources than Academia, but often

partners with Pharma for expensive late

stage clinical programs

Can bring huge resources to bear on a

project, although there is always internal

competition for resources

Can be acquired, have layoffs, or slowly go

out of business

Can be acquired, or have periodic layoffs

More opportunities for advancement than

Academia or Pharma if company grows

Stock options can provide financial windfall

if company successful

Base compensation often higher than

Biotech, but usually doesnt have as large a

stock option upside

Promotion may occur more slowly


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Biotech : Innovation & Risk

Biotech companies have traditionally been founded to exploit cutting edge ideas

and technology. Examples include: Using our own cytokines, growth factors, and enzymes as drugs

Engineering human fusion proteins, combining functionalities to achievenew properties

Creating Humanized and Human Monoclonals as drugs

Transcriptional control

siRNA

Ribozymes

Aptamers

Gene Therapy

Many Biotech ventures are unsuccessful, often because there is not a realisticbusiness plan of how to create an income-generating product before their abilityto raise money runs out

You need to assess whether the companys scientific and business plan makessense, their history and future potential of raising capital, partnering deals theyhave closed, and how soon they will generate revenue


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The Promise of the Human Genome Sequence

The Hype:

Drug Development will be revolutionized following theidentification of novel genes in druggable classes

The Fact:

Identifying novel genes is the first baby step.

Understanding their biology and creating therapeuticsagainst them is the difficult step that, in many instances, cantake decades

Accelerating these steps is the key to creating noveltherapeutic opportunities


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Target Validation : Velocigene Allows Rapid Creation of MutantMice, and Detailed Visualization of Expression

1 Nature Biotechnology paper described10% of KOs ever made!


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Huge Opportunities in Protein-Based Therapeutics

Good Drug Targets are hard to come by

Many companies make Me Too drugs against targets forwhich drugs already exist

Many Interesting Targets are large proteins (eg Cytokines andGrowth Factors) that drive broad biological responses

These pathways cause disease if inappropriately stimulated

These targets are usually not amenable to small moleculeapproaches

Current successful approaches include monoclonal

antibodies that block cytokine action, and receptor - Fcfusion proteins

As we learn more about Biology, we will uncover an evergrowing number of Targets that will require protein-basedinterventional approaches


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Protein Therapeutics - Examples

Success Stories

Insulin - First administered to humans in 1922

Interferons

Erythropoietin - 1989

Growth Hormone

Enbrel - a receptor-Fc fusion protein

Antibodies - eg Herceptin, Rituxan, Remicade, Humira,Avastin

Less Successful Stories

Mouse immunoglobulins - antigenicity Thrombopoietin (Tpo)- efficacy, immunogenicity

Lenercept - Receptor-Fc fusion - immunogenicity

Leptin - misunderstood mechanism - efficacy

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Protein Therapeutics Strengths & Weaknesses

Strengths

high specificity compared to small molecules

Little off-target toxicity - less likely to fail in early trials

Block Targets not amenable to small molecules - eg growth factors &receptors

Weaknesses

More difficult to manufacture

Potential immunogenicity even from fully human proteins

Low abundance proteins that dont circulate

Protein variants (aggregates, oxidation, deamidation) that breaktolerance

More difficult to evaluate toxicology

injectable


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Regeneron Technology: Heteromeric SolubleReceptors Form Tight-Binding Traps

Ra Rb

CytokineKd = 5 nM Kd = 10 pM

RbRa

Fc

Light

Chain

Heavy

Chain

Fc

(Drives

Dimerization)

Antibody Structure


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In-Line Heteromeric Traps

Ra RbRa Ra Rb Rb

Must Overexpress 2 cDNAs

Must Purify Heterodimer away fromHomodimers

Waste Cells Production Capacity with Unwanted

Homodimers

In-Line fusion of 2 receptors without interveninglinkers creates simple homodimer with very highaffinity


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Making a Proof of Concept into a Drug

Make T-shirts Do Preclinical Work

File Investigational New

Drug Application with FDA

Clinical Trials File Biologics License

Application


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PreClinical Development Checklist

BioMolecular Engineering

Cell line Development - FASTR

Process Development

Formulation

Assay Development

Pharmacology

Pharmacokinetics

Toxicology

Regulatory - IND = Investigational New Drug Application


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BioMolecular Engineering

Create Trap candidates with differentreceptor order (eg: ab-Fc, ba-Fc,

a-Fc-b, b-Fc-a), different fusion

position in receptor sequence +

linkers to increase flexibility

Evaluate for bioactivity, highexpression level from CHO cells,

clean folding

a-Fc with no extraneous linkers

IL1R-AcP

IL1R Type 1

hIgG Fc

s ss s

CH2

CH3

IL1 Single Chain Trap

ExtracellularDomains

S thi Old S thi N


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Something Old, Something NewWays to Isolate Over-Expressing Cell Lines

How to isolate clones after transfection:

FACSGOIELISA

FASTR: Isolation based on expression / characteristic of secreted protein

DilutioncloneELISA

Pickclones

GOIELISA

Traditional: Random isolation of clones


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FASTR Cell Line Selection

Flow cytometry-based Autologous

Secretion Trap

CHO Parental cell with doxycyline-inducible expression of FcR

Binds Trap internally and displayson cell surface

Whole population of transfectedcells can be sorted by FACS withfluorescent anti-Fc

Allows selection of highestexpresser from amongst millions oftransfected cells

Turn off expression of FcR afterselection to allow unhinderedsecretion for manufacturing

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Process Development

Goal is to have protein secreted

from CHO (Chinese Hamster Ovarycells) which have low viral burdenand make human carbohydratestructures

Batch-Fed Bioreactor Process -yield is 1-3 g/L after 10-12 days ofculture

Start at 2L scale, eventually to10,000 L, which yields 10 kg atexpression of 1 g/L

3 step purification process (Protein

A, ion exchange, hydrophobicinteraction chromatography) with upto 70% yield


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Formulation

Desire high concentration with adequate stability to give > 2 year shelf-

life

Add GRAS (Generally Regarded as Safe) excipients to stabilize proteinfrom aggregation, deamidation, oxidation, fragmentation

Polysorbate, sucrose, amino acids, PEG

IV formulations generally


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Assay Development/Pharmacokinetics

Immunoassays to measure

Trap and their complexes

with target cytokines in

plasma

Assays to detect formation of

antibodies against the Trap Use to measure PK - how

the blood levels change over

time, which often guides

dosing frequency and active

dose levels

0

1

10

100

1000

10000

100000

0 50 100 150 200 250

Time (hr

Group 4: 3 mg/kg IV

Group 5: 3 mg/kg SC

IV & SC pharmacokinetics in Monkeys


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Pharmacology: Murine Model ofCollagen-Induced Arthritis

CIA model in dba-1 mice is the

most widely accepted model ofrheumatoid arthritis

Injection of bovine collagen II

induces immune response that

results in progressive

autoimmune joint destruction

Injection of zymosan IP at day30 gives more robust and

synchronous arthritis response

Arthritis severity index grades

inflammation, swelling, and

deformity

IL1 Trap blocks cartilage

erosion, as well as joint swellingand deformity

26 30 34 38 42 46 500

1

2

3

4

Day

Trap 10 mg/kg

Trap 31 mg/kg

Vehicle

ArthritisSeverityIndex

Trap

Vehic

le


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Toxicology

Usually, new drugs are tested at high doses in 2 animal species to identify

NOAEL (No Adverse Event Level) and MTD (Maximum Tolerated Dose)

Test drugs at >10x higher doses than expected human dose

Many protein therapeutics have strict species specificity, and can only be testedin primates, but often KO data in animals is predictive of safety issues

IL1RI KO shows no adverse phenotype except increased susceptibility to sometypes of bacterial infections

Moreover, human proteins are often immunogenic in animals

Immunogenicity in animals not predictive of Ab response in humans

IL1 Trap only binds primate IL1

6 week toxicology study in monkeys showed no evidence of toxicity, but anantibody response was observed after a few weeks that resulted in clearance ofTrap from circulation

No MTD observed, adequate safety to proceed to clinical trials!


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Regulatory

FDA regulates testing of

experimental drugs in people

Must submit IND - InvestigationalNew Drug Application

Usually takes us ~1 year tocomplete, and may involve ~100

people Describes everything you know

about the manufacturing andstructure, PK, pharmacology,formulation, stability, toxicology,proposed clinical plan for Phase I

trials FDA gets 30 days to respond,

allowing you to go forward, orrequest more information, or totweak your clinical trial design


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Clinical Trial Overview

Phase I

Safety Dose Escalation in Volunteers or Patients

Phase II

Dose Ranging Efficacy Studies to decide on dose and interval

Phase III

Proof of Efficacy

Treat larger number and broader range of patients to evaluate overallsafety and look for less frequent adverse events (AEs)

As few as 4 clinical studies (each one a single experiment) couldsuffice to get a drug approved for use in humans!!


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Entry Level Positions in Biotech

Research Post-Doctoral Scientist

Analogous to Academia, except more resources and mentoringavailable

As in academic post-doc, a good publication record should allowreturn to Assistant Professor route

Pharmaceutical Post-Doctoral Scientist

Contribute to Clinical Development Projects or CoreTechnologies in ways that may not result in high profilepublications

Would lead to a career in Biotech/Pharma

Scientist

2-5 years post-doctoral experience

Staff Scientist

3 years experience following Post-Doc


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Career Opportunities Outside of Research

Preclinical Development

Immunoassays & Sample Analysis from Human Clinical Trials

Formulation Development

Pharmacology - Assessing Drugs in Animal Models

Protein Sciences

Cell line generation to overexpress recombinant proteins

Protein characterization

New technology and assay development

Protein Manufacturing Process Development

Program Coordination & Management

Core Facilities

Methodology Oriented (DNA, in situ, FACS, Mass Spec, Biacore)

Clinical

Regulatory - understand FDA Guidance, liason for company to FDA, EU

Scientific Writing

Quality Control

Business Development


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Getting Hired


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Application & Hiring Process

Typically, job descriptions are posted, applicationssolicited

Human Resource personnel (non-scientists) review

applications, winnowing down to those that match job

description, and pass on to Hiring Scientists Unsolicited applications to HR and Hiring Scientists

can sometimes hit paydirt and find an opening before

its even listed


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CV & Cover Letter Essentials

Must communicate to multiple audiences

Scientists- trying to figure out if you have the raw materials thatthey can mold into a productive scientist and useful contributor

Human Resources- non-scientists checking for a match betweenyour CV and a job description

Usually your First & Only Chance to make a positive impression

Should convey your

Intelligence & ability to communicate (Clear Writing = Clear Mind!)

Perspective of your field beyond your own project

Accomplishments - aimed at a non-expert and placed in context ofthe open questions in your field

Skill set - techniques that you reallyknow as well as those for whichyou may have a passing knowledge and vocabulary

Enthusiasm!


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CV

Same CV can be used for all applications

Need not be 1 page - can be 3-4 or longer

Research summary

explain in 1 paragraph your projects and conclusions

aimed at someone who is not in your field

Can also briefly describe rotation & graduate research Clearly identify core skill sets

Dont exaggerate -youll get busted

just because you have seen a mass spectrometer doesnt meanyou should list it as a core competency!!!

Presentations

Awards/Grants

Initiatives that youve undertaken outside your core requirements

Publications - including submitted / in preparation

Supervisory & Collaborative experiences


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Summary & Technical Skills


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Cover Letter

Ideally should be customized for each application

Should connect your skill set and experience to the job you areapplying for so that its easy for HR to understand and pass onto hiring scientist

Should describe your project and findings in the broad context of

your field - often the best way to convey to the Hiring Scientistthat you were not just a skilled set of hands directed by your PI

Rarely is an applicant perfect for the job - often we look forsomeone that appears to be smart, communicates well, and cangrow into a job

Therefore, its usually a stretch to say that you can makeRegeneron a success

More reasonable to emphasize your flexibility and ability to learnquickly

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