1. For Bite of Science (October 9, 2012)
Dr. Robert Kernstock
For Bite of Science (October 9, 2012)

2. You May Be Wondering Why I Am Here?...
Why Science?
How Did I Get Here?
What is Astellas?
My Job Now?
How are Drugs made?
Open up presentation by:
Stating your name, where you work
Take a step back – Introduce how you became inspired by science – Think Specific!
Give an example of a teacher who “wowed” you; an experiment that opened your eyes, etc
Follow with an brief overview of how you got to where you are:
How did you pick your career pathway? What types of classes did you pursue and enjoy the most, and why? Any eye-opening internships?
Remember that you want to inspire the pursuit of science careers – how can you demonstrate science as a “cool”, cutting-edge field?
Include examples of some of the challenges that you’ve faced; was school/college tough for you? Have you encountered any frustrations working in a lab setting? What’s it like to see compounds fail? etc
End with how you got to Astellas and what you do now. Students respond well when given an overview of what a typical day or week is like for you.
Always describe your job tasks in easy to understand language (e.g. In the development process, I help ensure the quality of a drug and that it meets its specifications and that it is fit for its intended use vs. I am responsible for Quality Assurance...)

3. Why science, and ‘how did I get here’?

4. Pharma: From ‘Bad Rap’ to Sought After Field
“Old-School” Thought
Current Thinking
Current thought
Academic Science
Nobel Aspirations
Pharmaceutical Science
Money-Generating
Working Together!
Applied Science
Using Each Other’s Strengths
Sharing the Real Rewards
Improving Quality of Life
Use this slide to talk through:
How perceptions of the pharmaceutical & biotechnology industries have changed over the years

5. So Who is Astellas?
At Astellas, our mission is to identify safe and effective medicines for people all over the world
Cardiovascular
Suggested Talking Points:
Astellas is a global research and development-driven pharmaceutical company. In the U.S., Astellas is focused on five key therapeutic areas and two new, emerging areas so we can develop a very deep understanding of the disease, our customers and patient needs.
Our mission is simple: we want to improve the health of people all over the world by identifying safe and effective therapies for our patients. As scientists at Astellas, we work hard everyday to help improve people’s lives.
Infectious Disease
Dermatology
Urology
Immunology
Oncology
Central Nervous System

6. U.S. Therapeutic Franchises
Immunology
Dermatology
Cardiovascular
Infectious Disease
Our efforts in the U.S. currently address unmet medical needs in some key areas of focus.
Astellas is a leader in transplantation and the area that remains a priority for our company. Prograf® is a unique product first introduced in 1994 and protects against organ rejection. The key ingredient in Prograf, tacrolimus, was discovered in the soil at the foot of Mount Tsukuba. Our Astellas researchers utilized cutting edge processing technology to turn this unique substance into an effective medicine which now serves as the cornerstone of therapy around the world to protect against organ rejection in liver, kidney and heart transplant patients.
With expanded R&D capabilities in cardiovascular, Astellas is positioned to make a difference in this area. Our products include Adenoscan, Adenocard and Vaprisol, and we are committed to advancing treatment in this area. Adenoscan, in-licensed from Gilead, is a pharmacologic stress agent that produces consistent, reliable maximal vasodilation of coronary arteries, making it useful for diagnostic evaluation and risk stratification in coronary artery disease. Vaprisol is used for the management of euvolemic and hypervolemic hyponatremia in hospitalized patients. And, Adenocard, an adenosine injection, is the drug recommended by the AHA to treat paroxysmal supraventricular tachycardia (PSVT) or a rapid heart rate. Finally, Lexiscan which is designed for rapid delivery and to selectively stimulate the A2A-adenosine receptor.
In infectious disease, Astellas has improved the results of treatment through antifungals such as AmBisome, an agent consisting of a liposomal preparation of amphotericin B that is administered by I.V. injection and used to treat serious fungal infections throughout the body, and Mycamine, an antifungal agent consisting of micafungin sodium also administered by I.V. injection.
In Urology, Astellas has researched the human genitourinary system and various disease processes. Astellas findings in benign prostate hyperplasia and urinary muscle instability has led to the introduction of products including VESIcare and Flomax. Flomax has been licensed to Boehringer Ingelheim for marketing since the U.S. launch in 1997 and Astellas began co-promoting the product in the U.S. in October VESIcare was a discovery of Astellas’ and was launched in June In the U.S., we co-promote VESIcare with GlaxoSmithKline.
Urology
Oncology

7. Our Lab Stuff Flow Cytometry Genotyping Ligand Binding Fluorescence
Cycles

8. BioPharma: It’s Real World Science!
Biology
Pharmacodynamics
Physical Science
Product Development
Histology
Anatomy
Industry
Genetic Engineering
Physics
Academic
Drug Discovery
Astronomy
Use this slide to segue into what types of disciplines and job positions contribute to developing new medicines that improve patient’s lives:
Suggested talking points:
How subjects you learn in middle/high school translate into specialties/job fields down the line
Introduce how your favorite subjects help to lead you to the field you currently work in
Medical Science Liaison
Chemistry
Clinical Trial Research

9. Science Career Opportunities in Pharma
Degree
Regulatory
& QA
R&D
Gov’t Affairs
Science Liaison
Business Dev’t
Sales & Marketing
PK Modeling
Pharmaco-vigilance

10. So How Do Drugs Work?
Cells in our bodies carry out molecular reactions to perform every function, for example:
Digesting your lunch
Moving your finger
Transmitting thoughts in your brain
One molecule interacts with another, which interacts with another, and so on.
These cascades are called chemical pathways
A mistake in one of the steps in a pathway can lead to disease.
Drug molecules interact with a molecule in the pathway, changing their activity.
Slide self-explanatory

11. How Do We Fulfill this Mission?
Drug Discovery then Development
Example
Discovered
The environment is extremely important to scientists, as it provides us with a wealth of possibilities for discovering new medicines. In fact, Prograf® is a unique product that was first introduced in 1994 and protects against organ rejection. The key ingredient in Prograf, tacrolimus, was discovered in the soil at the foot of Mount Tsukuba. Our Astellas researchers utilized cutting edge processing technology to turn this unique substance into an effective medicine which now serves as the cornerstone of therapy around the world to protect against organ rejection in liver, kidney and heart transplant patients. Astellas is a leader in transplantation and this is an area that remains a priority for our company.

12. The Discovery Process 3 – 6 YEARS Discovery Preclinical Pre-Discovery:
Goal: Understand the disease and choose a target molecule.
How: Scientists in pharmaceutical research companies, government, academics and for-profit research institutions contribute to basic research.
Discovery
Goal: Find a drug candidate.
How: Create a new molecule or select an existing molecule as the starting point. Perform tests on that molecule and then optimize it (change its structure) to make it work better.
Preclinical
Goal: Test extensively to determine if the drug is safe enough for human testing.
How: Researchers test the safety and effectiveness in the lab and in animal models.
3 – 6 YEARS
Discovery
Scientists' knowledge of disease is growing rapidly and today we are tackling diseases more complex than ever before. Armed with some understanding of how the disease works, the first step in making a new medicine is to identify a specific target that is a promising focal point for a medicine - for example, a molecule that plays a crucial role in a particular disease.
Teams of chemists, pharmacologists and biologists then screen thousands of compounds - or chemically or genetically engineer new ones - to generate "lead compounds." These molecules have some desirable properties, but researchers usually must modify them to increase activity or minimize side effects - a process called "lead optimization." Out of this process come hundreds of potential drugs.
In choosing compounds for further testing researchers must weigh basic concerns: Is it likely to be more effective than current therapies? Will it be possible to manufacture? Does it have a reasonable dose range and delivery system (e.g., oral, inhaled)? To find the right molecule scientists must have plenty of ingenuity and diligence, but a little serendipity can help, too.
Even after a medicine is discovered teams of engineers, biologists, chemists and physicists must spend long hours figuring out how to mass produce the results achieved by an individual scientist at his or her lab bench. Often promising experiments are not replicable on a large scale -the reaction may give off extreme heat, or cause an explosion, or release a toxic gas. The research may fail because it is not possible to manufacture the drug safely or to the proper specifications.
Preclinical Testing
Once a drug candidate has been identified in the laboratory, it begins years of testing. It starts with lab and animal studies to evaluate its safety and demonstrate that it has biological activity against the disease target.
Key preclinical tests include pharmacokinetics, the study of how drugs move through living organisms. Scientists examine four key processes - absorption, distribution, metabolism and excretion - to ensure that the medicine reaches its intended target and passes through the body properly.
In addition to biological tests, researchers conduct a number of other preclinical studies. Chemistry tests establish the compound's purity, stability and shelf life. Manufacturing tests determine what will be involved in producing the medicine on a large scale. And pharmaceutical development studies explore dosing, packaging and formulation (e.g., pill, inhaler, injection).
The main goal of preclinical studies is to rigorously assess safety before human tests begin and this can take anywhere from 3-6 years. Some preclinical safety tests continue even after the start of clinical trials in people to determine if there are any long-term adverse effects researchers should look for.

13. The Development Process
Drug Discovery then Development
NUMBER OF SUBJECTS
Clinical Trials
In clinical trials teams of physicians carry out studies designed to determine if the drug is safe in people and an effective treatment for the disease in question. Of the 250 compounds that enter preclinical testing, only five will make it this far.
There are three phases of clinical trials:
Phase I: The medicine is tested in a small group (20-100) of healthy volunteers - often in a hospital setting - to determine its safety profile, including the safe dose range. Pharmacokinetic studies examine how a drug is absorbed, distributed, metabolized and excreted, as well as the duration of its action. Phase I studies can take from six months to one year to complete.
Phase II: Placebo-controlled trials involving approximately 100 to 500 volunteer patients who have the disease being studied. The goal of this phase is to establish the "proof of concept" - i.e., the medicine effectively treats the disease. Researchers continue to evaluate the drug's safety and look for side effects, and determine optimal dose strength and schedule (e.g., once or twice daily). Phase II studies can take from six months from one year to complete.
Phase III: The medicine is tested in large, randomized, placebo-controlled trials with much larger numbers of patient volunteers - from 1,000 to 5,000, in hospitals, clinics and/or physician offices - to generate statistically significant data. Researchers closely monitor patients at regular intervals to confirm that the drug is effective and identify side effects (also called adverse events). Phase III studies can take from one to four years to complete, depending on the disease, length of the study, and the number of volunteers.
While Phase I-III studies are taking place, researchers are also conducting a number of crucial parallel studies: toxicity tests and other long-term safety evaluations; dosage forms; plans for full-scale production; package design; and preparation of the complex application required for FDA approval.
Ongoing Studies
Even after approval, the studies and observation continue. A much bigger group of patients may begin to use a medicine upon approval compared with the thousands of patients in clinical trials and in this larger scale rare side effects may occur, so companies must continue to monitor the drug carefully. The FDA requires them to continue to submit periodic reports, including any cases of adverse events (side effects or complications).
Sometimes, the FDA requires a company to conduct additional studies. Known as Phase IV or "post-marketing" studies, they evaluate long-term safety or generate more data about how the medicine affects a particular group of patients (e.g., children or the elderly).
Phase IV studies can continue for years; one study can cost between $20-30 million. Depending on the findings, a company can use the studies to submit a Supplemental NDA, seeking additional indications for the medicine.
(3-6 years)
(1 year)
(2 years)
(4 years)
Preclinical
Phase I
Phase II
Phase III
Phase IV
Number of Subjects
NDA
(2 yrs)

14. Personalized Medicine
“The Dream”
Plug and play medicine based on individual’s gene signature
We are all unique and a ‘conglomerate’ of our biological relatives

15. Personalized Medicine EML4-ALK fusions in Lung Cancer
Tyr Kinase 1
1620 TM
981
Basic WD
EML4
1059
496
ALK
（Anaplastic Lymphoma Kinase）
（Echinoderm microtubule-associated protein like protein 4）
A fused gene EML4 is connected to ALK (in DNA)
ALK fusions exist in 5% of lung cancer. A simple PCR test to detect fusion.
Over 70% of ALK fusion + cancers are cured!

16. Question & Answer
Special thanks to Astellas and Center of Excellence in Education
(SCI: Science Career Investigation)

17. Mission of a Pharmaceutical Research Company
Take the path from understanding a disease to bringing a safe and effective new therapy to patients.
Select a molecule in a pathway => target
Validate the target
Discover the right molecule to interact with the target
Test the compound in the lab for efficacy and safety
Test the compound in the clinic for efficacy and safety
Gain approval to get the drug to doctors and patients
Suggested Talking Points:
Reiterate mission: Our mission at Astellas is a simple one - to contribute towards improving the health of people around the world through leadership, innovation and growth. At all levels throughout the company our people are committed to the opportunity to positively affect and improve patient lives while remaining socially responsible to our community and those we work and partner with.
As a research-based company, we work to identify and validate new targets, test the selected compounds in both a laboratory and clinical setting and submit our findings for approval by the U.S. Food and Drug and Administration, a government agency.
On the following slides, I will go into more detail about these processes.

18. What Sets Astellas Apart
Our Values
At Astellas we are committed to providing patients, customers, community and employees with a bright future by changing tomorrow.
Our Approach
Astellas is different, not only because of what we do but because of how we do it.
Our commitment to providing our patients, customers, the community and our employees with a brighter future is possible because we are different. This is apparent not only in what we do, but because of how we do it.
In the U.S., Astellas is focused on five key therapeutic areas, so we can develop a very deep understanding of the disease, our customers and patient needs.
Our Focus
In the U.S., we are intensely focused on five key therapeutic areas so we can develop a deep understanding of the disease, our customers and patient needs. 18

19. A Commitment to Changing Tomorrow
Our efforts align with our strong scientific orientation and a focus on the community we work and live in
COMMUNITY
Encourage employee involvement and volunteerism
SCIENCE AND EDUCATION
Building a strong foundation in science to ignite passion and interest in science among today’s youth
SUSTAINABILITY
Helping to improve the environment through internal and external practices
Astellas’ commitment to changing tomorrow aligns with our strong scientific orientation and our focus on the community we work and live in.
In the U.S., we provide opportunities for our employees to participate in community activities including volunteering as well as opportunities to provide contributions via charitable donations and gifts. We partner with organizations such as iBIO Institute and the National Science Teachers Association to support science education by helping science teachers ignite passion and interest in science among today’s youth that will extend to a strong foundation for the future.
Additionally, we are committed to helping improve the environment through internal and external practices.

20. State-of-the-Art R&D Facilities
Astellas Research Institute of America (ARIA)
Based in Illinois, ARIA is committed to strengthening research in transplantation through:
Drug targeting research
Clinical biomarker translation research
Absorption, Distribution, Metabolism and Excretion (ADME) prediction research 
Collaborations with delegate researchers (KOLs)
The Astellas lab in Skokie, Illinois has been another center of progress for the company. This lab was originally established in Northwestern University Research Park in August For over a decade, the lab focused on Pharmacokinetics research of our immunosuppressant Prograf as well as Molecular Biology/Pharmacology research for the elucidation mechanism of immunology and related diseases.
In April 2005, we changed the facility name to Astellas Research Institute of America or ARIA. And in May 2007, the lab was relocated to the Illinois Science Technology Park.

21. Phase 1 - Pharmacokinetics
Establish Dose and Frequency

22. The Approval Process
Investigational New Drug (IND):
Goal: Obtain FDA approval to test the drug in humans.
How: FDA reviews all preclinical testing and plans for clinical testing to determine if the drug is safe enough to move to human trials.
Clinical Trials:
Goal: Test in human to determine if the drug is safe and effective.
How: Candidate drug is tested in clinical setting in three phases of trials, beginning with tests in a small group of healthy volunteers and moving into larger groups of patients.
5 – 7 YEARS
Review:
Goal: FDA reviews results of all testing to determine if the drug can be approved for patients to use.
How: The FDA reviews hundreds of thousands of pages of information, including all clinical and preclinical findings, proposed labeling and manufacturing plans. They may solicit the opinion of an independent advisory committee.
Investigational New Drug (IND) Application
After preclinical testing is completed, a company files an IND with the U.S. Food and Drug Administration (FDA) prior to beginning any human testing.
The application must show results of preclinical experiments; the chemical structure of the compound; how it is thought to work in the body; any side effects found in animal studies; and how the compound is manufactured.
The IND must also include a detailed clinical trial plan, including how, where and by whom the studies will be conducted. All clinical trials must be reviewed and approved by the Institutional Review Board (IRB) where the trials will be conducted. Progress reports on clinical trials must be submitted at least annually to FDA and the IRB.
[The IND becomes effective, and clinical trials can proceed, if the FDA does not disapprove it within 30 days.]
New Drug Application (NDA)
Then. once all three phases of the clinical trials are complete, a company analyzes all of the data. If the findings demonstrate that the experimental medicine is both safe and effective, the company files an NDA with the U.S. Food and Drug Administration (FDA).
NDAs typically run 100,000 pages or longer, just one illustration of the extensive testing a medicine must go through in order to gain FDA approval. They contain all of the information about all of the studies - including preclinical testing, all clinical trials, dosing information, manufacturing details and proposed labeling for the new medicine.
FDA Review/Approval
In this final stage, the FDA scientists review all the results from all the studies carried out over the years and determine if they show that the medicine is safe and effective enough to be approved.
Depending on the medicine or disease in question, the FDA sometimes convenes an Advisory Committee meeting. These independent panels of experts, appointed by the FDA, consider data presented by company representatives and FDA reviewers. Committees then vote on whether the FDA should approve an application, and under what conditions. The FDA is not required to follow the recommendations of the advisory committees, but they often do.
If the medicine is approved, or "cleared for marketing," it becomes available for physicians and patients.
It took an average of 16.9 months for the FDA to review each medicine it approved in The proportion of rejected applications has remained constant over the years at about 10% to 15%.
0.5 – 2 YRS