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Biotech & Pharma The Science, The Jobs, & Skills for Success
Biotech & Pharma The Science, The Jobs, & Skills for Success
Overview
Overview
My Experience
My Experience
Science at a Company
Science at a Company
Differences Between Academia & Industry
Differences Between Academia & Industry
Some Myths of Industry
Some Myths of Industry
Attributes for Success at a Company
Attributes for Success at a Company
Biotech vs Big Pharma
Biotech vs Big Pharma
Biotech : Innovation & Risk
Biotech : Innovation & Risk
The Promise of the Human Genome Sequence
The Promise of the Human Genome Sequence
Target Validation : Velocigene Allows Rapid Creation of Mutant Mice,
Target Validation : Velocigene Allows Rapid Creation of Mutant Mice,
Huge Opportunities in Protein-Based Therapeutics
Huge Opportunities in Protein-Based Therapeutics
Protein Therapeutics - Examples
Protein Therapeutics - Examples
Protein Therapeutics Strengths & Weaknesses
Protein Therapeutics Strengths & Weaknesses
Regeneron Technology: Heteromeric Soluble Receptors Form Tight-Binding
Regeneron Technology: Heteromeric Soluble Receptors Form Tight-Binding
In-Line Heteromeric Traps
In-Line Heteromeric Traps
Making a Proof of Concept into a Drug
Making a Proof of Concept into a Drug
PreClinical Development Checklist
PreClinical Development Checklist
BioMolecular Engineering
BioMolecular Engineering
Something Old, Something New Ways to Isolate Over-Expressing Cell
Something Old, Something New Ways to Isolate Over-Expressing Cell
FASTR Cell Line Selection
FASTR Cell Line Selection
Process Development
Process Development
Formulation
Formulation
Assay Development/Pharmacokinetics
Assay Development/Pharmacokinetics
Pharmacology: Murine Model of Collagen-Induced Arthritis
Pharmacology: Murine Model of Collagen-Induced Arthritis
Toxicology
Toxicology
Regulatory
Regulatory
Clinical Trial Overview
Clinical Trial Overview
Entry Level Positions in Biotech
Entry Level Positions in Biotech
Career Opportunities Outside of Research
Career Opportunities Outside of Research
Getting Hired
Getting Hired
Application & Hiring Process
Application & Hiring Process
CV & Cover Letter Essentials
CV & Cover Letter Essentials
CV
CV
Summary & Technical Skills
Summary & Technical Skills
Cover Letter
Cover Letter
Current Trends
Current Trends
Personalized Medicine
Personalized Medicine
Markers of IL-1 Driven Disease
Markers of IL-1 Driven Disease
CIAS1 Gene Encodes Cryopyrin (NALP-3) central to regulation of
CIAS1 Gene Encodes Cryopyrin (NALP-3) central to regulation of
IL1 Driven Genetic AutoInflammatory Syndromes
IL1 Driven Genetic AutoInflammatory Syndromes

: ppt. : Neil Stahl. : ppt.ppt. zip-: 2506 .

ppt

ppt.ppt
1 Biotech & Pharma The Science, The Jobs, & Skills for Success

Biotech & Pharma The Science, The Jobs, & Skills for Success

Neil Stahl Ph.D. Regeneron Pharmaceuticals

2 Overview

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

3 My Experience

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 activate cytoplasmic signaling pathways Figured out a way to make tight binding cytokine blockers based on the mechanism of cytokine activation, using multiple cytokine receptor components 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 Clinical Development, present to investors, analysts, potential partners

4 Science at a Company

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 can accomplish more than any individual scientist Discoveries can be translated into therapeutic opportunities with the potential to create new drugs and technologies Understand molecular and cellular pathways defining a particular 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

5 Differences Between Academia & Industry

Differences Between Academia & Industry

You will have access to far more resources, equipment, core facilities, and collaborative colleagues to advance your project You will be required to work on projects of the companys choosing You may be asked to switch to (or add on) new projects Although you will report to one person, you will interact with many Scientists instead of a single PI Participate and present in cross-functional meetings where data is vetted and the future directions of a project are established by discussion and consensus More heads are better than 1! You are likely to publish and attend scientific conferences

6 Some Myths of Industry

Some Myths of Industry

You have failed if you dont pursue an academic position Thats what some told me, but there are many, many incredibly competent 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 compensated similarly to Assistant Professors, but much better than post-docs, and there are stock options! However, opportunity for advancement is more frequent and more rapid 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 and perspective, making a reverse move more likely

7 Attributes for Success at a Company

Attributes for Success at a Company

Team player who can collaborate effectively with others Ability to become interested in a wide variety of different scientific 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 your particular talent and expertise toward the common goal Success means that your project grows so that hundreds of people work on it!

8 Biotech vs Big Pharma

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-making process

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

9 Biotech : Innovation & Risk

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 achieve new 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 realistic business plan of how to create an income-generating product before their ability to raise money runs out You need to assess whether the companys scientific and business plan makes sense, their history and future potential of raising capital, partnering deals they have closed, and how soon they will generate revenue

10 The Promise of the Human Genome Sequence

The Promise of the Human Genome Sequence

The Hype: Drug Development will be revolutionized following the identification of novel genes in druggable classes The Fact: Identifying novel genes is the first baby step. Understanding their biology and creating therapeutics against them is the difficult step that, in many instances, can take decades Accelerating these steps is the key to creating novel therapeutic opportunities

11 Target Validation : Velocigene Allows Rapid Creation of Mutant Mice,

Target Validation : Velocigene Allows Rapid Creation of Mutant Mice,

and Detailed Visualization of Expression

1 Nature Biotechnology paper described 10% of KOs ever made!

12 Huge Opportunities in Protein-Based Therapeutics

Huge Opportunities in Protein-Based Therapeutics

Good Drug Targets are hard to come by Many companies make Me Too drugs against targets for which drugs already exist Many Interesting Targets are large proteins (eg Cytokines and Growth Factors) that drive broad biological responses These pathways cause disease if inappropriately stimulated These targets are usually not amenable to small molecule approaches Current successful approaches include monoclonal antibodies that block cytokine action, and receptor - Fc fusion proteins As we learn more about Biology, we will uncover an ever growing number of Targets that will require protein-based interventional approaches

13 Protein Therapeutics - Examples

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

14 Protein Therapeutics Strengths & Weaknesses

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 break tolerance More difficult to evaluate toxicology injectable

15 Regeneron Technology: Heteromeric Soluble Receptors Form Tight-Binding

Regeneron Technology: Heteromeric Soluble Receptors Form Tight-Binding

Traps

Ra

Rb

Fc

Cytokine

Kd = 5 nM

Kd = 10 pM

Rb

Ra

Antibody Structure

Heavy Chain

Light Chain

Fc (Drives Dimerization)

16 In-Line Heteromeric Traps

In-Line Heteromeric Traps

Must Overexpress 2 cDNAs Must Purify Heterodimer away from Homodimers Waste Cells Production Capacity with Unwanted Homodimers In-Line fusion of 2 receptors without intervening linkers creates simple homodimer with very high affinity

17 Making a Proof of Concept into a Drug

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

18 PreClinical Development Checklist

PreClinical Development Checklist

BioMolecular Engineering Cell line Development - FASTR Process Development Formulation Assay Development Pharmacology Pharmacokinetics Toxicology Regulatory - IND = Investigational New Drug Application

19 BioMolecular Engineering

BioMolecular Engineering

Create Trap candidates with different receptor order (eg: ???-Fc, ???-Fc, ?-Fc-?, ?-Fc-?), different fusion position in receptor sequence + linkers to increase flexibility Evaluate for bioactivity, high expression level from CHO cells, clean folding ???-Fc with no extraneous linkers

20 Something Old, Something New Ways to Isolate Over-Expressing Cell

Something Old, Something New Ways to Isolate Over-Expressing Cell

Lines

How to isolate clones after transfection:

21 FASTR Cell Line Selection

FASTR Cell Line Selection

Flow cytometry-based Autologous Secretion Trap CHO Parental cell with doxycyline-inducible expression of FcR Binds Trap internally and displays on cell surface Whole population of transfected cells can be sorted by FACS with fluorescent anti-Fc Allows selection of highest expresser from amongst millions of transfected cells Turn off expression of FcR after selection to allow unhindered secretion for manufacturing

22 Process Development

Process Development

Goal is to have protein secreted from CHO (Chinese Hamster Ovary cells) which have low viral burden and make human carbohydrate structures Batch-Fed Bioreactor Process - yield is 1-3 g/L after 10-12 days of culture Start at 2L scale, eventually to 10,000 L, which yields 10 kg at expression of 1 g/L 3 step purification process (Protein A, ion exchange, hydrophobic interaction chromatography) with up to 70% yield

23 Formulation

Formulation

Desire high concentration with adequate stability to give > 2 year shelf-life Add GRAS (Generally Regarded as Safe) excipients to stabilize protein from aggregation, deamidation, oxidation, fragmentation Polysorbate, sucrose, amino acids, PEG IV formulations generally <10 mg/ml Subcutaneous (SC) - 25-100 mg/ml IL1 Trap: liquid at 50 mg/ml or lyophilized at 80 mg/ml

24 Assay Development/Pharmacokinetics

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

IV & SC pharmacokinetics in Monkeys

25 Pharmacology: Murine Model of Collagen-Induced Arthritis

Pharmacology: Murine Model of Collagen-Induced Arthritis

Arthritis Severity Index

CIA model in dba-1 mice is the most widely accepted model of rheumatoid arthritis Injection of bovine collagen II induces immune response that results in progressive autoimmune joint destruction Injection of zymosan IP at day 30 gives more robust and synchronous arthritis response Arthritis severity index grades inflammation, swelling, and deformity IL1 Trap blocks cartilage erosion, as well as joint swelling and deformity

Vehicle

Trap 10 mg/kg

Trap 31 mg/kg

Vehicle

Trap

26 Toxicology

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 tested in primates, but often KO data in animals is predictive of safety issues IL1RI KO shows no adverse phenotype except increased susceptibility to some types 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 an antibody response was observed after a few weeks that resulted in clearance of Trap from circulation No MTD observed, adequate safety to proceed to clinical trials!

27 Regulatory

Regulatory

FDA regulates testing of experimental drugs in people Must submit IND - Investigational New Drug Application Usually takes us ~1 year to complete, and may involve ~100 people Describes everything you know about the manufacturing and structure, PK, pharmacology, formulation, stability, toxicology, proposed clinical plan for Phase I trials FDA gets 30 days to respond, allowing you to go forward, or request more information, or to tweak your clinical trial design

28 Clinical Trial Overview

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 overall safety and look for less frequent adverse events (AEs) As few as 4 clinical studies (each one a single experiment) could suffice to get a drug approved for use in humans!!

29 Entry Level Positions in Biotech

Entry Level Positions in Biotech

Research Post-Doctoral Scientist Analogous to Academia, except more resources and mentoring available As in academic post-doc, a good publication record should allow return to Assistant Professor route Pharmaceutical Post-Doctoral Scientist Contribute to Clinical Development Projects or Core Technologies in ways that may not result in high profile publications Would lead to a career in Biotech/Pharma Scientist 2-5 years post-doctoral experience Staff Scientist 3 years experience following Post-Doc

30 Career Opportunities Outside of Research

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

31 Getting Hired

Getting Hired

32 Application & Hiring Process

Application & Hiring Process

Typically, job descriptions are posted, applications solicited 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

33 CV & Cover Letter Essentials

CV & Cover Letter Essentials

Must communicate to multiple audiences Scientists - trying to figure out if you have the raw materials that they can mold into a productive scientist and useful contributor Human Resources - non-scientists checking for a match between your 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 of the open questions in your field Skill set - techniques that you really know as well as those for which you may have a passing knowledge and vocabulary Enthusiasm!

34 CV

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 mean you 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

35 Summary & Technical Skills

Summary & Technical Skills

36 Cover Letter

Cover Letter

Ideally should be customized for each application Should connect your skill set and experience to the job you are applying for so that its easy for HR to understand and pass on to hiring scientist Should describe your project and findings in the broad context of your field - often the best way to convey to the Hiring Scientist that you were not just a skilled set of hands directed by your PI Rarely is an applicant perfect for the job - often we look for someone that appears to be smart, communicates well, and can grow into a job Therefore, its usually a stretch to say that you can make Regeneron a success More reasonable to emphasize your flexibility and ability to learn quickly

37 Current Trends

Current Trends

Protein Therapeutics Large number in clinical trials Currently constitute a large percentage of approved Drugs Big Pharma licensing protein therapeutic candidates from biotech Example: Aventis committed ~$800 Million for 50% share of Regenerons VEGF Trap, which was largest deal ever for Phase I drug Biomarkers Accelerate clinical trial process May provide earlier evidence of biological activity than clinical readouts Also potential to predict responders in a complex disease state Personalized Medicine predicting who will respond best to each drug

38 Personalized Medicine

Personalized Medicine

Many drugs work in some individuals but not others with the same disease Unresponsive patients get the risk of side-effects without the benefit of efficacy What if responsive patients could be identified based on their genetic makeup or a simple blood test for a protein or mRNA fingerprint Second best, what if responders could be identified after a single dose of a drug based on a surrogate marker that was a reliable predictor of eventual clinical response

39 Markers of IL-1 Driven Disease

Markers of IL-1 Driven Disease

Discover an IL-1 gene expression fingerprint in patients with genetically driven IL-1 disease Microarray analysis of patients during flare and in remission while on drug vs. normal volunteers Examine more diverse disease population (eg rheumatoid arthritis) for patients that display the IL-1 fingerprint, and evaluate whether they are more responsive to the IL-1 Trap

40 CIAS1 Gene Encodes Cryopyrin (NALP-3) central to regulation of

CIAS1 Gene Encodes Cryopyrin (NALP-3) central to regulation of

Inflammatory processes

(Dinarello, 2004)

Mutant NALP-3 activates Caspase-1 -------- Overproduction of IL-1

41 IL1 Driven Genetic AutoInflammatory Syndromes

IL1 Driven Genetic AutoInflammatory Syndromes

Autoinflammatory Syndromes -FCAS, MW, NOMID Genetic Diseases with mutations in cryopyrin (NALP3) resulting in upregulation of IL1 Symptoms range from daily fevers & rash, uveitis, arthralgia, deafness, neurological syndromes

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