Vasilios Papademetriou, MD, DSc, FACC, FACP, FAHAProfessor of Medicine (Cardiology)Georgetown UniversityWashington DC

Options for Medical Students to Follow: The Biomedical Industries Pathway

› I am a cardiologist-Interventional› Professor of Medicine ( Cardiology)› Director of Cardiovascular Research for > 25 years› Have done basic research ( early on)- NIH, VA Medical

Center› Lately Clinical Trials ( Mostly)

– Collaborated with the industry– Part of several NIH , VA sponsored trials

› For the last 5 years I served as a member of the Cardio renal Panel of the FDA ( Approval of new drugs)– Rivaroxaban– Droxidopa etc

A few things about myself

› Develop New Drugs

› Develop New Devices – Diagnostic– Interventional– Sensors– Imaging

Aim of the Industry

New DrugsDiscovery and Development

Test many compounds Mechanism of action Rout of administration etc

Preclinical Research In vitro and in vivo Dosing and toxicity in animal models

Clinical Research FDA ReviewFDA Post-Marketing Safety

Monitoring

Clinical ResearchPhase 1

Dosage & safety 20 to 100 healthy volunteers

Phase 2 Efficacy & side effects Several 100s of people

Phase 3 Efficacy and adverse events 300 to 3,000 people

Phase 4 Safety and efficacy Several 1000s of people

RESEARCH & DEVELOPMENT

Only 1:10 new drugs makes it to the FDA and cost can be up to one BILLION $

New DevicesDevice discovery and conceptPreclinical research-PrototypePathway to approvalFDA ReviewFDA Post_ Marketing

Monitoring

Pathway to approvalFDA established risk-based

classification system Class I Class II Class III

Safety and Efficacy Proof of concept/First in man study Controlled trials

Placebo or sham control studies Outcome data

DEVICE DEVELOPMENT PROCESS

Foreign Medical Graduates:Options in Biomedical

Industries

Work for the Industry

Maximize your potentialOptimize chances for success

Collaborate with the industry

Graduates of the EUC

› As a Physician working in private practice or Academia– Clinical Research ( Phase I,II,III or IV studies)– Investigator initiated projects – sponsored by the industry– Basic research of interest to the industry

› Serve on advisor boards– Help the industry understand clinical implications of their studies– Design the right kind of research– Interpret the results of clinical trials

› Steering committees– Direct and supervise clinical studies– Analyze results– Publish research papers

Collaborate with the industry(Part time job)

› Physicians of DCRI– Robert Calif

› Brigham and Women's Research Center– Mark Pfeffer

› Contributed to the development of many of the drugs we use today:– ACE inhibitors– Beta blockers– Statins– Diabetes drugs

Collaborating with the industry

• Pre clinical testing• Toxicity studies

Drug Development

• First in human study• Proof of efficacy and safety

Proof of concept

• Pivotal study• Phase I, II, III and IV studies

Clinical Development Program

› Research & Development– Invent and test new

therapies– Design and Direct

Clinical Trials› Direct Marketing

– Education– Promotion

Working for the Industry as a Physician

Afferent and Efferent Renal fibers Can affect blood pressure control

Afferent fibers originate from the kidney and transfer signals to the brain

After processing can affect the function of the heart, the blood vessels and the kidney

Efferent fibers transfer signals from the brain to the kidney and can affect Na and fluid absorption, plasma renin activity and aldosterone production

SYMPATHETIC RENAL DENERVATION CONCEPT

Papademetriou et al. Circulation 2014;129:1440-51

FIRST IN MAN STUDY: SYMPLICITY HTN-1

1 month(n=41)

3 months(n=39)

6 months(n=26)

9 months(n=20)

12 months(n=9)

-30

-20

-10

0

10

-14 -21 -22 -24 -27-10 -10 -11 -11 -17

SystolicDiastolic

MeanChange in

Blood Pres-sure

(mmHg)Presented

with 95% Con-fidence Inter-

vals

Lancet 2009

RENAL DENERVATION SYSTEMS WITH CE MARK APPROVAL IN EUROPE

ST JUDE MEDICAL RENAL DENERVATION SYSTEM

STAGES OF RENAL DENERVATION

Papademetriou, Tsioufis, Doumas…… Circulation 2014;129:1440-51

LESION PATTERNS USING THE ENLIGHTEN SYSTEM

NOREPINEPHRINE REDUCTION

16

R e n a l n e r v e a b l a t i o n u s i n g t h e E n l i g H T N a b l a t i o n s y s t e m s h o w s s i g n i f i c a n t r e d u c t i o n i n k i d n e y N E a t t h e 3 0 a n d 9 0 d a y t i m e p o i n t s v s . S h a m P TA B a l l o o n ( N = 3 0 k i d n e y s )

65% reduction

Average sys to l ic b lood pr essur edur ing contr o l (CON) and for 8 weeks a f ter rena l

denerva t ionCorre la t ion between SBP and mean

and renal t issue norepinephrine (NE) levels

CATHETER-BASED RADIOREFREQUENCY RENAL DENERVATION LOWERS BLOOD PRESSURE

IN OBESE HYPERTENSIVE DOGS

Each bar represents the average of 7 days of blood pressuremeasurements, 18 hours a day

NEPI change: -42%

ENLIGHTN I: 12 MONTH DATA

Papademetriou V, Tsioufis C,,,,,,,,Hypertension 2014Worthley S, Tsioufis C……Papademetriou V; EHJ 2013

Almost two decades ago the 4S first showed that simvastatin effectively improve survival in patients with cardiovascular disease (CVD), and initiated a revolution in the treatment of atherosclerotic heart disease

Results with other statins confirmed and enhanced these resultsOther newer and/or novel compounds were abandoned either because of

lack of efficacy or unacceptable side effectsRecently ezetimibe-in the IMPROVE-IT study- showed further

improvement of outcomes when added to a statin.Yet the incremental reduction of LDL-C was modest and

additional benefits small, but the study confirmed the impression that “ Lower is better”

That’s where PCSK9 come into play

MANAGEMENT OF DYSLIPIDEMIAS AND PCSK9 INHIBITORS

“Are considered a breakthrough in the management of dyslipidemias because”Are safe andVery-very effective

WHY ARE PSCK9 INHIBITORS IMPORTANT?

SAFE BECAUSE ARE HUMANIZED MONOCLONAL ANTIBODIES

HOW LDL PARTICLES ARE CLEARED

PSCK9 TAGS LDL-R FOR DESTRUCTION

EVOLOCUMAB BINDS TO PCSK9PREVENTING IT FROM BINDING THE LDL RECEPTORS

CARRIER WITH THE INDUSTRY

Graduated from the School of Pharmacy

Graduated from Medical school Specialized in Internal

Medicine Practiced for 10 years Finally Joined Astra Zeneca as

a Scientist-Medical Leeson Works in that position ever

since Lives a comfortable-fulfilling

Interesting lifeMedical Leeson specialist with Astra Zeneca

BRIGHT EXAMPLES Aris Baras MD

Graduated from London high School Duke college Duke Medical Worked on his MD/MBA dual degree at

Duke University. As an undergraduate at Duke, he studied biology and economics. Aris has been fascinated with pursuing biomedical discoveries and the development of life-saving therapies since he was in high school. One of Aris’ mentors has been Dr. Roy Vagelos, former CEO and chairman of Merck. Aris lives in Durham, North Carolina with his wife, Lia, and their son, Parker.School

Joined Regeneron 2years ago, his already a multimillioneur

Through my association with Dr. Roy Vagelos, I started working with the translational medicine team at Regeneron. One of the group’s functions is to thoroughly vet drug candidates before embarking on risky and expensive investments in clinical development programs

LEADING WITHIN THE INDUSTRY Graduated Medical School in Athens

Greece Scholarship at the NIH. Worked and

discovered the gene for Parkinson’s disease

Recruited by Novartis and worked as a researcher for a few years on Gene targeted therapies

Recruited to start his own biotech company

Formed VANDA pharm Developed and sold first drug for

$570 million

Vanda Pharmaceuticals Reports Preliminary Fourth Quarter and Full Year 2015 Results and 2016 Financial Guidance- Fourth quarter 2015 HETLIOZ® net product sales are expected to be approximately $15.1 million

- 2015 Total revenues are expected to be approximately $109.9 million

- 2016 Total revenues are expected to be between $143 and $153 million

REACHING THE TOP George Yancopoulos, MD, PhD of Greek origin, Founding scientist, President and CEO of Regeneron. Graduated from Columbia Un and

Joined Regeneron in 1989 11th most highly cited scientists in the

word in the 1990s He was the PI and got approval of 4

drugs ( aflibercept, ziv-aflibercept,rilonacept and alirocumab)

He is now the highest paid Chief executive

His Company is worth more than $48 billion

The quality of Regeneron science has been recognized in the academic scientific community as well as through a very tangible metric: our four FDA-approved products, as well as every one of our clinical candidates, were discovered and validated in Regeneron's labs. Regeneron Genetics Center ,Target Discovery , Drug Candidate Platforms, Protein Production -