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>> GOOD MORNING.
I'M MARK, THE DIRECTOR OF THE
NIH OFFICE OF TECHNOLOGY
TRANSFER.
IT'S A PLEASURE TO HAVE YOU ALL
HERE TODAY AND ESPECIALLY IN
HONOR OF PHIL CHEN AND HIS
DISTINGUISHED CONTRIBUTIONS TO
TECH TRANSFER.
PARTICULARLY IN THE EARLY DAYS
AT NIH, AND ESPECIALLY OUR
DISTINGUISHED SPEAKERS, CLIFF
BARRY FROM NIAID AND CAROL NACY
FROM SEQUELA.
JUST TO MAKE A PERSONAL NOTE
BEFORE I JOINED THE OFFICE OF
TECH TRANSFER 12 YEARS AGO, I
WORKED IN THE TECH TRANSFER
OFFICE FOR NIAID.
SO I HAVE FOUND MEMORIES OF
WORKING WITH CLIFF.
AND CAROL ON THEIR COLLABORATION
PROJECTS WHEN CLIFF WAS AT ROCKY
MOUNTAIN AND CAROL IS STARTING
UP LOCALLY.
SO IT'S GREAT TO SEE THEM AND TO
HONOR THEIR WORK.
SO WE LOOK FORWARD TO YOUR
STORY.
BUT I WANT TO INTRODUCE MY
SUPERVISOR AND THE DIRECTOR,
DEPUTY DIRECTOR FOR INTRAMURAL
RESEARCH AMONG HIS MANY DUTIES
IS OVERSEES TECH TRANSFER.
AND THAT'S DR. MICHAEL
GOTTESMAN.
HE'S CELEBRATING HIS 20TH
ANNIVERSARY AS DDIR AND WE THANK
HIM FOR HIS MANY CONTRIBUTIONS
AND ESPECIALLY FOR HIS SUPPORT
TECH TRANSFER.
IT'S A PLEASURE WORKING WITH HIM
AND I THANK HIM FOR ALL THE
SUPPORT.
SO DR. GOTTESMAN.
[APPLAUSE]
>> ONE POINT I WANTED TO
MENTION, IN YOUR BROCHURE,
THERE'S A LIST OF INVENTORS.
SO TO HONOR ALL OF OUR
INVENTORS, WE'VE GIVEN AN
INSTITUTE OF ALL THE INVENTORS
SO WE WANT TO HONOR THEM AS
WELL.
>> THANK YOU, MARK.
THIS IS A WONDERFUL ANNUAL
OCCASION FOR US, A CHANCE TO
RECOGNIZE PHIL CHEN WHO IS, I'LL
TELL YOU IN A FEW MOMENTS, A
VERY IMPORTANT PART OF OUR
INTRAMURAL PROGRAM FOR MANY
YEARS.
AND A CHANCE ALSO TO RECOGNIZE
THE IMPORTANCE THAT TECHNOLOGY
TRANSFER PLAYS IN THE MISSION OF
NIH.
THAT IS TO DO RESEARCH TO
IMPROVE THE PUBLIC HEALTH,
IMPROVE THE PUBLIC HEALTH PART
REQUIRES TECHNOLOGY TRANSFER,
AND IT'S REALLY IMPORTANT THAT
WE HAVE STORIES LIKE THE ONES
YOU'RE GOING TO HEAR TODAY IN
ORDER TO FULFILL OUR MISSION.
SO THIS IS THE 8TH ANNUAL PHILIP
S. CHEN DISTINGUISHED LECTURE ON
INNOVATION AND TECHNOLOGY
TRANSFER.
THIS SERIES I NODE HONORS PHIL
CHEN, A COLLAR, A SCIENCE
ADMINISTRATOR, A TRUSTED ADVISOR
TO MANY DIRECTORS AND DEPUTY
DIRECTORS AND A FRIEND TO MANY
OF US AT NIH, AND MANY OF HIS
FRIENDS I CAN SEE ARE IN THE
AUDIENCE.
PHIL WAS BORN IN MICHIGAN AND
GREW UP IN MASSACHUSETTS.
HE WAS A GRADUATE OF CLARK
UNIVERSITY IN PHYSICS, GOT HIS
PH.D. IN PHARMACOLOGY FROM THE
UNIVERSITY OF ROCHESTER.
AND AT THE TIME WHEN HE WAS A
GRADUATE STUDENT, HE WAS ALSO AN
ATOMIC ENERGY COMMISSION
PREDOCTORAL FELLOW.
AND ACTUALLY SPENT SOME TIME
WITH THE ATOMIC ENERGY PROJECT
OUT IN NEVADA.
ALSO, AS A GRADUATE STUDENT, HE
COAUTHORED A PAPER ENTITLED
MICRO DETERMINATION OF
PHOSPHORUS.
ANY OF YOU IN THE AUDIENCE
VFER MEASURED INORGANIC
PHOSPHORUS HAVE USED THE CHEN
METHOD TO DO THAT.
IT IS ONE OF THE MOST HIGHLY
CITED PAPERS IN THE HISTORY OF
BIOMEDICAL RESEARCH.
CERTAINLY IN THE TOP HUNDRED.
AND THAT'S AN AMAZING
ACHIEVEMENT IN ITS OWN RIGHT.
HE DID A POST DOC IN COPENHAGEN,
DEVELOPED A RELEVANT LOVE FOR
DENMARK AND THINGS DANISH AND
HIS WIFE LISA WHO IS HERE, IS A
REPRESENTATIVE OF THAT.
AND ALSO HERE TODAY ARE MANY OF
HIS CHILDREN AND GRANDCHILDREN
WHO HAVE BEEN FAITHFUL ATTENDEES
TO THIS AND KILEY WHO HAS BEEN
HERE EVERY YEAR.
AND SHE'S GOING DIRECTLY TO HER
POST DOCTORAL FELLOWSHIP NEXT
YEAR.
PHILIP CAME TO NIH IN THE LATE
1950'S WHERE HE WORKED WITH FRED
BARREDDER, THE LEGENDARY
PHYSIOLOGIST ON BINDING OF
CORTISOL TO PLASMA PROTEINS.
WENT BACK TO A FACULTY POSITION
AT ROCHESTER BUT THE SIREN CALL
OF NIH BROUGHT HIM BACK AGAIN
WHERE HE SERVED FOR 30 YEARS
BASICALLY IN THE OFFICE OF THE
DIRECTOR, SERVED EIGHT DIFFERENT
NIH DIRECTORS.
AND MOST OF HIS ACTIVITIES WERE
IN THE OFFICE OF INTRAMURAL
RESEARCH.
AND DURING MY TIME THERE, HE WAS
A TRUSTED SENIOR ADVISOR AND A
WONDERFUL SOURCE OF VERY VALUED
INFORMATION.
PHIL'S SPECIAL INTERESTS INCLUDE
INTERNATIONAL AFFAIRS,
PARTICULARLY ARCTIC RESEARCH.
AND TECHNOLOGY TRANSFER.
HE AS YOU HEARD ESTABLISHED THE
OFFICE OF TECHNOLOGY TRANSFER
AND HE INVENTED OUR MOST BELOVED
DOCUMENT CALLED THE CRADA
COOPERATIVE RESEARCH AND
DEVELOPMENT AGREEMENT.
SO A LOT OF TECHNOLOGY THAT'S
BEEN TRANSFERRED WOULDN'T HAVE
BEEN POSSIBLE WITHOUT PHIL.
AS A SENIOR MEMBER OF THE OFFICE
OF INTRAMURAL RESEARCH, PHIL
OVER THE YEARS BECAME KNOWN AS A
CARING, KNOWLEDGEABLE AND
CREATIVE ADMINISTRATOR.
PEOPLE WOULD COME TO HIM WITH
THE MOST DIFFICULT AND ALMOST
IMPOSSIBLE PROBLEMS AND HE WOULD
FIND SOLUTIONS.
IT'S QUITE AMAZING.
PHIL, WE NEED YOU NOW.
THE SUBJECT OF TODAY'S LECTURES
IS TB.
IT TAKES MORE THAN A VILLAGE TO
RAISE A REMEDY.
WE DON'T HAVE A VILLAGE HERE
ALTHOUGH WE HAVE A NICE
COMMUNITY.
BUT WE DO HAVE TWO WONDERFUL
SPEAKERS.
AS YOU'VE HEARD, DR. CLIFF BARRY
WHO IS CHIEF OF THE TUBERCULOSIS
RESEARCH SECTION IN THE LAB OF
CLINICAL INFECTIOUS DISEASES AT
NIAID.
AND CAROL NACY COFOUNDER AND
CHIEF EXECUTIVE OFFICER AND
CHAIRMAN OF THE BOARD OF
DIRECTORS OF SEQUELA.
WHAT I'M GOING TO DO BECAUSE
THEY'RE GOING TO DO A TAG TEAM.
THEY ARE SO WELL COORDINATED AS
A RESULT OF OUR TECH TRANSFER
PROCESS THAT THEY'RE GOING TO BE
BOUNCING BACK AND FORTH.
SO I'M GOING TO INTRODUCE THEM
BOTH.
DR. BARRY IS AN INTERNATIONALLY
RECOGNIZED RESEARCHER ON TB,
PARTICULARLY IN IDENTIFYING
TARGETS AND DEVELOPING NEW DRUGS
TO TREAT MICRO BACTERIUM
TUBERCULOSIS.
HE HAS A PH.D. IN ORGANIC AND
BIOORGANIC CHEMISTRY FROM
CORNELL.
HE WAS A POST DOC AT HOPKINS.
20 YEARS AGO, HE JOINED THE
ROCKY MOUNTAIN LAB OUT IN
HAMILTON AS YOU HEARD.
AND 15 YEARS AGO WHEN HE WAS TEN
-- TENURED TO NIH HE MOVED
TO TWIN BROOKS NEAR BETHESDA.
HE HAS MANY CONNECTIONS AND
COLLABORATORS WHICH I THINK
YOU'LL HERE ABOUT SOME OF THEM.
THAT HAS HELPED TO MOVE FORWARD
THE DRIVE TO DEVELOP NEW DRUGS
TO TREAT TUBERCULOSIS.
CLIFF, ARE YOU GOING TO START
OUT TODAY?
HE'LL MAKE THE OPENING COMMENTS.
OUR NEXT SPEAKER, OUR OTHER
SPEAKER IS CAROL NACY.
SHE DID HER UNDERGRADUATE DEGREE
IN PH.D. FROM CATHOLIC
UNIVERSITY.
SPENT MOST OF HER SCIENTIFIC
CAREER AT WALTER REED ARMY
INSTITUTE OF RESEARCH WHERE SHE
STUDIED VARIOUS TROPICAL
INFECTIOUS DISEASES.
AND HAS SINCE MOVED TO THE
PRIVATE SECTOR WHERE SHE WAS
CHIEF SCIENTIFIC OFFICER
INITIALLY AT CONTRA MED PART
TIME CHIEF SCIENTIFIC OFFICER AT
ANNERGEN BEFORE SHE FOUND THE
SEQUELA.
SHE'S BEEN RECOGNIZED IN MANY
WAYS FOR BOTH HER SCHOLARLY
WORK, ACADEMIC WORK AND FOR OUR
ENTREPRENEURSHIP.
SHE WAS ELECTED TO THE AMERICAN
ACADEMY OF MICROBIOLOGY AND HE
WAS ELECTED PRESIDENT OF BOTH
THE AMERICAN SOCIETY OF
MICROBIOLOGY AND THE SOCIETY FOR
LEUKOSITE BIOLOGY.
HER BIOTECH HAS BEEN RECOGNIZED
IN MANY WAYS AS WELL INCLUDING
BEING NEED THE TOP 50 INNOVATOR
OF THE U.S. AND TOP ENTREPRENEUR
OF THE YEAR.
SHE WAS AWARD THE HUMANITARIAN
AWARD FOR ALLIANCE AGAINST AIDS
FOR HER WORK TO CREATE NEW DRUGS
FOR TB.
WITHOUT FURTHER ADIEU, I THINK
CLIFF WILL TAKE THE STAGE AND
THEN WE'RE GOING TO HEAR A
WONDERFUL TALK TODAY.
THANK YOU.
[APPLAUSE]
>> IS THIS ON?
YES.
SO I WANT TO START BY SAYING
THANK YOU MICHAEL AND THANKS FOR
THE OPPORTUNITY BECAUSE I DON'T
THINK WE REALLY GET THE
OPPORTUNITY VERY OFTEN TO SAY
THANK YOU TO THE TECH TRANSFER
FOLKS HERE AT NIH.
MARK CAN SAY WITH BEHIND SITE WE
HAVE FOUND MEMORIES OF IT BUT I
DON'T THINK HE REMEMBERS HOW
MUCH WORK IT REALLY WAS.
I THINK I CONTINUE THAT TREND
TODAY TO REALLY OCCUPY A LOT OF
TIME AND ENERGY FROM THE OFFICE
OF TECHNOLOGY DEVELOPMENT
BECAUSE OF THE FIELD THAT I WORK
THIS IS INHERENTLY LINKED TO
INTELLECTUAL PROPERTY AND TO
DEVELOP MANY THINGS.
AND I THINK IT'S GREAT TO HAVE
THE OPPORTUNITY TO SAY THANKS
NOT ONLY TO PHIL BUT THANKS TO
THE ENTIRE TECH TRANSFER
COMMUNITY HERE AT NIH FOR MAKING
THAT POSSIBLE.
AND I THINK TO START OUT, I WANT
TO SORT OF JUST REFRESH YOUR
MEMORY OF WHAT TECH TRANSFER WAS
INTENDED TO DO IN THIS SENSE AND
WHY WE DEVELOPED RELATIONSHIPS
LIKE THIS.
SO THIS IS FROM THE FEDERAL
TECHNOLOGY TRANSFER ACT OF 1986
WHICH WAS AN
WORK THAT FIRST TRIED TO REVERDAITNSTOSI3
RARD OL TUBLS$OF RPROCN
I THINK THE BEST AT THAT WAS AN
EDITORIAL THAT APPEARED IN THE
ECONOMIST IN 2002 THAT'S
CREDITED THAT PIECE OF
LEGISLATION WITH REVERSING
AMERICA'S PRECIPITOUS SLIDE INTO
THE INDUSTRIAL RELEVANCE AND
CALLED FEDERAL AND ACADEMIC
LABS, THE GOLDEN GOOSE OF
INNOVATION THAT TURNS THE U.S.
AROUND COMPETITIVELY.
I THINK THAT'S BEEN GREAT IN
SOME FIELDS AND I THINK WHERE WE
STRUGGLED WITH IT OVER THE YEARS
AND WHAT IS THE STORY THAT
YOU'RE GOING TO HEAR ABOUT TODAY
REALLY SPEAKS TO MORE HOW DO WE
TRANSLATE THAT INTO GLOBAL
HEALTH ISSUES WHERE PERHAPS THE
INCENTIVES AND THE RISKS AND THE
BENEFITS OF THE TECHNOLOGY THAT
YOU'RE TALKING ABOUT AREN'T AS
STRAIGHTFORWARD AS MONETARY
INCENTIVES OR AS BENEFITS TO
U.S. INDUSTRY DIRECTLY.
AND I THINK ONE OF THE THINGS TO
THINK ABOUT WHEN YOU'RE ENTERING
INTO RELATIONSHIPS LIKE THAT IS
YOU REALLY HAVE TO UNDERSTAND
THE RISK AND THE CULTURE IN BOTH
THE PLACE THAT YOU'RE AT THE
GOVERNMENT ACADEMIC LAB AND IN
THE COMPANY SETTING OR THE
PARTNER WITH WHICH YOU'RE
ENTERING THAT.
SO EVERY DIFFERENT KIND OF
ORGANIZATION HAS DIFFERENT
PERSPECTIVES ON WHAT IS RISKY
BEHAVIOR AND WHAT'S RISK, WHAT'S
THE BENEFIT OF TAKING RISK.
WE, GOVERNMENTS AND ACT
DEMONSTRATE YEAH ALL SORT OF
LUMP TOGETHER THINK THAT RISKY
STUFF IS INHERENTLY A GOOD FIND
AND SHOULD BE DOING IT ALL THE
TIME.
IN THE CAVEAT WITH GOVERNMENT
MAYBE YOU TRY TO MINIMIZE THAT
RISK A LITTLE BIT MORE.
BUT IN BIOTECH AND PHARMA WHICH
ARE THE TWO SECTORS I INTERACT
WITH IS MORE DIVERSE THAN ACT
DEMONSTRATE YEAH IS AND PHARMA
IS THE EXTREME CASE THAT NOTHING
ESSENTIAL IS LABORATORY READY
BUT PRODUCTS NOT READY IS REALLY
OF INTEREST TO THEM.
AND I THINK IF YOU DON'T
UNDERSTAND WHO YOU'RE PARTNERING
WITH THROUGH THIS PROCESS THEN
YOU CAN'T TRANSLATE SOMETHING
FROM THE BRAIN TO A PRODUCT IN
THE END.
AND I THINK THAT'S REALLY WHAT
OTT'S AND OTD AND NIAID HAS BEEN
TO REALLY START TO PIECE
TOGETHER THOSE AGREEMENTS AND
PUT TOGETHER PARTNERSHIPS
BETWEEN PROSPECTIVE INDUSTRY
COLLABORATORS THAT CAN TRANSLATE
IDEAS INTO PRODUCTS WITH GROUPS
WITHIN NIH OR GROUPS WITHIN
DIFFERENT INSTITUTES THAT CAN
ACTUALLY COME UP WITH THE IDEAS
THAT ARE THINGS THAT ARE WORTH
TURNING INTO PRODUCTS.
AND I THINK THEY ARE REALLY GOOD
AT FINDING THE RIGHT BALANCE OF
THINGS.
I CAN REMEMBER LONG
CONVERSATIONS WITH MARK ABOUT
THE BEAUTIFUL [INDISCERNIBLE]
NEGOTIATING IT AND TRYING TO
UNDERSTAND WHAT WENT INTO IT AND
ALL OF THE CAVEATS AND THINGS
THAT WE TRIED TO GET RIGHT IN
THIS SO WE COULD TAKE SOMETHING
THAT'S AN IDEA IN THE BRAIN AND
TURN IT INTO SOMETHING THAT IS
LIKE THIS.
THIS IS REALLY THE SUBJECT OF
TODAY'S TALK.
THIS IS A DRUG PACKAGED FOR USE
IN CLINICAL TRIALS THAT ARE
GOING ON NOW IN PHASE THREE.
AND I THINK THAT TRANSLATION
DOESN'T HAPPEN WITHOUT SETTING
THE PARTNERSHIPS UP RIGHT AND I
THINK THE REAL CREDIT TO PHIL
AND TO THE CHECK TRANSFER
COMMUNITY IS THEY'VE LEARNED HOW
TO DO THAT.
THE SUBJECT TODAY IS GOING TO
REVOLVE AROUND GLOBAL HEALTH.
AND GLOBAL HEALTH REALLY IS FROM
A SATELLITE MEETING THAT HAPPENS
LAST WEEK HERE IN WASHINGTON
D.C. REALLY IS THESE DAYS THE
SAME AS AMERICA'S HEALTH.
THERE'S NO WALL YOU CAN ERECT TO
KEEP PEOPLE WITH DRUG RESISTENT
TB OR DRUG RESISTANT ANYTHING
FROM FLYING INTO THE U.S.
IT'S VERY DIFFICULT TO CROSS THE
INTERNATIONAL BORDERS WITH
RESPECT TO INFECTIOUS DISEASES
AND GLOBAL HEALTH ISSUES.
AND I THINK THE MORE WE
RECOGNIZE THAT, THE MORE WE
UNDERSTAND THAT PART OF NIH'S
MIX IS NOT JUST WORRYING ABOUT
HEALTH PROBLEMS THAT ARE
IMMINENT AND CURRENT EPIDEMIC
THAT HAPPEN WITHIN THE U.S. BUT
THING THAT MIGHT EMERGE IN THE
FUTURE OR THINGS THAT WE CAN'T
BLOCK COMING IN THROUGH OUR
BORDERS.
AND OF COURSE, I'M GOING TO LET
CAROL TALK ABOUT INFECTIOUS
DISEASES.
>> IS THIS ALL RIGHT?
SO, INFECTIOUS DISEASES ARE THE
SECOND LEADING CAUSE OF DEATH
WORLDWIDE.
SO TB IS ACTUALLY IN THE TOP 10
LETHAL INFECTIOUS DISEASES AND
IN THIS COUNTRY I CAN'T TELL YOU
I SPEAK WITH VENTURE CAPITAL
FIRMS AND FUNDERS ALL OVER THE
COUNTRY.
THE WORD TUBERCULOSIS HAS NOT
BEEN IN THE LEXICON FOR 50 YEARS
AND THEY DON'T ACTUALLY REALIZE
HOW BIG THE PROBLEM IS OUTSIDE
THE U.S.
BUT INFECTIOUS DISEASES THEY'RE
STARTING TO GET A PICTURE OF
THAT, AND NOW I CAN AT LEAST
TELL THEM THAT 40% OF ALL THE
DEATHS AND THE COUNTRIES WHERE
WE WOULD SELL PRODUCTS IF WE
WERE TO BE A SUCCESSFUL COMPANY
ARE DOING THE TWO INFECTIOUS
DISEASES INTERESTINGLY.
WE'RE NOW SEEING THAT MANY OF
THE AUTOIMMUNE DISEASES HAVE AN
INFECTIOUS ORIGIN.
I THINK THAT'S GOING TO HELP US
ALL IN UNDERSTANDING MORE ABOUT
HOW MICROBES INTERACT WITH OUR
BODIES BOTH IN THE BENEFICIAL
WAY AND IN A DIFFICULT WAY FOR
OUR IMMUNE SYSTEM TO UNDERSTAND.
I THINK MORE THAN ANYTHING
THAT'S SCARING THE PUBLIC HEALTH
COMMUNITY AROUND THE WORLD IS
THE FACT THAT MULTIDRUG
RESISTENT ORGANISMS ARE COMING
TO THE FORE.
AND WE DON'T HAVE ENOUGH
ANTIBIOTICS AND WE'VE REALLY
PAID NO ATTENTION TO ANTIBIOTICS
FOR A NUMBER OF YEARS.
THE CLASSES, THE NEW CLASSES OF
ANTIBIOTICS ARE KNEW AND FAR
BETWEEN, THEY ARE FAIRLY
SPECIFIC FOR WHAT YOU NAME THE
GRAM POSITIVE ORGANISMS THESE
DAYS.
AND WHERE WE'RE ACTUALLY
EXPERIENCING A CRISES BOTH IN
THIS COUNTRY AND IN EUROPE.
AND MULTIDRUG RESISTENT
INFECTIONS AND IN PARTICULAR
MULTIDRUG RESISTANCE IS NOW
CONSIDERED A NATIONAL SECURITY
THREAT BOTH IN THE UNITED STATES
AND IN EUROPE.
SO TB IS A PROBLEM ON EVERY
CONTINENT.
WE'RE NOT WITHOUT OUR TB.
YOU CAN SEE BY THE COLOR OF THE
COUNTRY HOW MANY CASES PER
HUNDRED THOUSAND THAT EXISTS
CLEARLY IN AREAS THAT HAVE THE
DARKEST NUMBER, WE HAVE THE MOST
NUMBER OF TB PATIENTS.
BUT WE HAVE THEM IN THE UNITED
STATES AS WELL.
AND I DON'T KNOW HOW MANY OF YOU
REMEMBER THE SARS EPIDEMIC WHEN
WE WERE COMPLETELY PANICKED
ABOUT SARS.
THIS CAME OUT BASICALLY TALKING
ABOUT SARS IS A PROBLEM YES BUT
THAT'S SARS.
IN TERMS OF NUMBER OF PEOPLE
AFFECTED BY SARS NUMBER OF
PEOPLE WHO DIED OF SARS THERE
WERE AT THAT TIME AROUND 500
PEOPLE WHO DIED OF SARS.
AT THE SAME TIME 2 MILLION
PEOPLE DIED OF TB.
SO THE SCALE OF OUR PANIC OVER
CERTAIN OF THE INFECTIONS ACROSS
OUR BORDERS IS UNFORTUNATE,
LET'S PUT IT THAT WAY.
TUBERCULOSIS WHICH WE HAVE A
WONDERFUL TB ELIMINATION PROGRAM
IN THE UNITED STATES, HAS MOVED
TB DOWN OUT OF OUR LINE OF
SIGHT.
BUT OUTSIDE THE WORLD IT'S
BURGEONING EVERYWHERE.
PART OF THE REASON THAT IT'S SO
SUCCESSFUL IS THAT IT'S AN
AIRBORNE TRANSMITTED DISEASE.
YOU MAY NOT KNOW THIS BUT NO
SPITTING LAWS IN NEW YORK CITY
AREN'T ABOUT THE FACT THAT
SPITTING IS GROSS IT'S ABOUT
TRANSMISSION OF TB.
SO TO BE ABLE TO TRANSMITTED BY
THE AIR EASILY YOU HAVE TO HAVE
A CERTAIN PARTICLE SIZE AND
THAT'S WHERE SARS IS.
AND THAT'S WHERE TB IS.
SO IT IS THE PERFECT SIZE TO BE
PASSED PERSON TO PERSON BY
SITTING NEXT TO ONE WHO IS
INFECTED.
AND IN THE UNITED STATES,
WHETHER WE ARE COMFORTABLE
KNOWING THAT THEY'RE NOT, WE
HAVE DRUG AND MULTIDRUG
RESISTENT TB.
THERE WERE A THOUSAND, OVER A
THOUSAND CASES OF DRUG RESISTENT
TB IN THE U.S. LAST YEAR.
10,000, THAT'S 10%.
AND WE HAD SIX CASES OF
VIRTUALLY UNTREATABLE EXTREMELY
DRUG RESISTENT TB FOR WHICH WE
HAVE NO DRUGS.
AND RIGHT NOW, IN THE WORLD, WE
HAVE POOR DRUGS.
WITH THE DRUGS WE HAVE THERE ARE
EIGHT TO NINE MILLION NEW CASES
OF DRUG SENSITIVE TO TB EVERY
YEAR.
IT TAKES SIX MONTHS OF TREATMENT
WITH FOUR DRUGS, EACH OF WHICH
HAVE THEIR OWN TOXICITIES, SOME
BLINDNESS, SOME LIVER
TOXICITIES, AND THERE'S ABOUT AN
80% TREATING IT GLOBAL.
THERE ARE NOW 500-650,000 CASES
BY THE HEALTH WORLD
ORGANIZATION.
THEY'RE RESISTENT TO THE FIRST
TWO BEST TB DRUGS OUT THERE
[INDISCERNIBLE] YOU THEN HAVE TO
CHOOSE FROM SIX OF THE HOE
RENDOUSLY BAD DRUGS.
ONE IS -- WHICH THE PATIENT
CALLS THAT GIVES THEM A
PSYCHOTIC EPISODE -- YOU HAVE TO
TAKE THESE DRUGS FOR UP TO 24
MONTH IN ORDER TO SECURE THIS
DISEASE.
THERE'S ONLY ABOUT A 48% CURE
RATE.
AN EXTREMELY DRUG RESISTENT TB
WHICH IS NOW HERE IN THE UNITED
STATES AND IS NOW DETECTED IN
EVERY COUNTRY IN THE WORLD.
WE BELIEVE MUCH MORE THAN 24
MONTHS TO TREAT THESE PATIENTS
AND THERE ARE NO DRUGS.
THEY ARE TRYING EVERYTHING IN
THE ARMAMENT TO FIND DRUGS AND
CLIFF IS A LEADER TO FIND DRUGS
THAT WILL RESCUE THESE PEOPLE
FROM CERTAIN DEATH.
HOW TEUFL?
KIND OF ANXIOUS NOW.
THE PROBLEM WE HAVE IN TB IS
THAT THIS IS A PATHOGEN THAT CAN
LIVE INSIDE CELLS AND CAN LIVE
OUTSIDE CELLS.
SO WE HAVE TO HAVE DRUGS THAT
ONLY CAN GET TO THE INTERSTITIAL
FLUIDS IN OUR TISSUES TO KILL
THOSE DRUGS THAT ARE OUTSIDE BUT
WE NEED DRUGS THAT CAN PENETRATE
THE MACROPHAGE WHERE IT LIVES
AND REPLICATES AND KILL THE BUG
THERE.
IT'S PRETTY TRICKY TO GET A DRUG
THAT CAN GO THROUGH A MACROPHAGE
MEMBRANE THAT CAN WADDLE THROUGH
THE MACROPHAGE CYTOPLASM, CAN
GET INTO THE -- WHERE THE TB
ORGANISM IS AND CAN SURVIVE
THERE LONG ENOUGH TO GET INSIDE
THE TB ORGANISM AND THEN TO IT.
SO FINDING THE DRUGS FOR TB IS A
CHALLENGE.
BECAUSE WE HAVE ANOTHER ISSUE
WITH TB, THIS IS CONFOUNDED THE
PROBLEM OF FINDING DRUGS.
AND THAT IS THAT TB USED TO BE
THE NUMBER ONE TUMOR OF U.S.
CITIZENS PRIOR TO 1950.
THOSE OF YOU WHO ARE AS OLD AS I
AM, ALL HAVE A RELATIVE WHO DIED
OF TB.
THIS ORGANISM WAS THE IMPETUS
FOR PHARMACEUTICAL COMPANIES TO
GET INTO THE BUSINESS OF DRUGS,
DISCOVERY AND DEVELOPMENT.
AND ONLY OF THE FIRST DRUGS THAT
CAME OUT WERE SPECIFICALLY
DIRECTED TO TB.
EVERY TIME WE INTRODUCED A DRUG,
WITHIN SIX MONTHS THE ORGANISM
BECAME RESISTENT TO THAT DRUG.
NOW WE KNOW WE HAVE AT LEAST A
MINIMUM OF THREE DRUGS THAT WE
HAVE TO TREAT PEOPLE WITH TO
AVOID RESISTANCE THAT OCCURS, TO
PENETRATE THOSE APPROPRIATE
TISSUES HARBORING THE BACTERIA
AND TO CURE BOTH REPLICATING
BACTERIA.
AND A TRICK THAT MICRO BACTERIA
DOES, IT GOES DORMANT.
LIES THERE UNASSUMINGLY WAITING
FOR A CHANCE TO START
REPLICATING AGAIN AND WE DON'T
EVEN KNOW WHERE IT IS.
SO THE GOALS OF THE TB DRUG
DEVELOPMENT INCLUDE
IDENTIFICATION OF DRUGS WITH
NOVEL MECHANISMS OF ACTION.
WE NEED TO PAIR THREE NOVEL
DRUGS TOGETHER FOR DISTRIBUTION
AND TO KILL BACTERIAL FORMS.
WE NEED TO REDUCE THE REGIMEN
TOXICITY WHICH IS A PROBLEM IN
DRUG SENSITIVE TB BUT WHICH IS A
TERRIFIC PROBLEM IN NDR AND
XDR/TB.
THIS IS NOT A REGULATORY GOAL
BUT IT'S CERTAINLY A PUBLIC
HEALTH COMPLIANCE GOAL.
SO WE'RE GOING TO GO IN, CLIFF
IS GOING TO TAKE OVER HERE BUT I
NEVER ACTUALLY TOLD CLIFF WHY WE
STARTED WORKING TOGETHER.
HE PROBABLY HAS HIS OWN STORY AS
WELL BUT I THOUGHT I WOULD JUST
REVEAL TO YOU WHAT HAPPENED TO
CLIFF AND CAROL TOGETHER 15
YEARS AGO.
SO AT THAT TIME TOM KENT WAS
BOTH A FRIEND AND A COLLEAGUE
AND I HAD A PROBLEM AND HE HAD A
PROBLEM AND WE AGREED TO TRY TO
HELP EACH OTHER.
MY PROBLEM WAS NEARLY TRIVIAL.
MY PROBLEM WAS I STARTED SEQUELA
AND SOMEONE WANTED TO MAKE A
DOCUMENTARY FILM THE SUBJECT OF
WHICH HAS LONG LEFT MY MIND.
AND I NEEDED AN OFFICE THAT LOOK
THE LIKE AN OFFICE.
I WAS RUNNING THE COMPANY OUT OF
MY HOME.
NOT WITH CHILDREN'S BOOKS BUT
WITH MEDICAL TEXTS.
AND HE OFFERED, WE MOVED HIS
BOOKCASE WHICH WAS VERY
BEAUTIFUL AS A BACKGROUND FOR
THAT.
HIS PROBLEM WAS MORE CONCERNING.
HE HAD A VERY VERY BRIGHT YOUNG
SCIENTIST WHO WAS WORKING IN
HAMILTON, MONTANA.
AND WHO HE HAD TO BRING BACK
HERE TO THE NIH CAMPUS.
AND THIS SCIENTIST WAS THE
EXACTLY HAPPY TO BE COMING BACK
HERE.
HE HAD A VERY NICE LIFE IN
HAMILTON, MONTANA.
I DON'T KNOW HOW ONE DOES THAT
BUT NONETHELESS.
[LAUGHTER]
AND SO TOM ASKED IF I WOULD
INTRODUCE MYSELF TO CLIFF AND
SEE IF I COULD GENERATE A
PROJECT WHEN HE GOT HERE THAT
WOULD KEEP HIM INTERESTED
ENOUGH.
HE WAS VERY CONCERNED CLIFF
WOULD GET HERE AND THEN WOULD
LEAVE, LEAVE THE NIH AND HE
THOUGHT THAT THE GOVERNMENT NEED
THE CLIFF.
SO I WENT TO A CONFERENCE ON TB
AND I INTRODUCED MYSELF TO CLIFF
AND WE TALKED AND THIS WHOLE
PROCESS WORKED.
BECAUSE HE'S STILL HERE.
SO ANYWAY, SO THAT'S THE STORY
WHY WE ARE TOGETHER.
NOW I'M GOING TO LET CLIFF TELL
YOU A LITTLE BIT ABOUT HIS LAB.
>> THAT WASN'T IN THE SCRIPT,
CAROL.
>> I KNOW, SORRY.
>> SO WE'RE GOING TO TAKE JUST A
SECOND TO BRIEFLY INTRODUCE EACH
OF OUR RESPECTIVE ORGANIZATIONS
AND WHERE THIS PROJECT FITS AND
THEN WE'RE GOING TO WIND THE
CLOCK BACK 15 YEARS AND
LITERALLY WALK YOU THROUGH THE
PROJECT THAT HAPPENED.
I THINK THERE'S NOBODY IN MY
LABORATORY AND THERE'S A FEW OF
YOU OUT THERE NOW WAS PRESENT IN
THE LABORATORY WHEN THIS BUDGET
STARTED OR EVEN WHEN WE STOPPED
WORKING ON IT FOR A LONG PERIOD
OF TIME.
SO WHAT MY GROUP DOES THESE DAYS
AND WE'VE DONE DIFFERENT
ITERATIONS OF THIS AND HAVE
DIFFERENT EMPHASIS OVER TIME IS
WE TRY TO BUILD A PIPELINE.
THERE'S ALWAYS TALK AT NIH ABOUT
BENCH TO BEDSIDE STUFF.
WELL I'M A CHEMIST SO I DON'T
HAVE BENCHES, I DO HOODS.
WE TALK ABOUT HOODS TO BEDSIDE
STUFF.
WE TRIED TO RECREATE FROM THE
ENTIRE PROCESS OF DOING DRUG
DISCOVERY TO THE POINT THAT WE
CAN DO IT AT NIH WITHIN THE
INTRAMURAL RESEARCH PROGRAM.
SO A LOT OF THE LAB WILL WORK ON
THINGS LIKE THROUGHPUT
SCREENINGS, SYSTEM BIOLOGY,
TRYING TO UNDERSTAND WHAT ARE
VULNERABLE POINTS IN METABOLISM
AND HOW DO WE DEAL WITH THIS
ORGANISM.
THEN WE'LL MOVE IN TO ANIMAL
MODEL STUDIES.
THAT HAPPENS TO BE A VERY CUTE
LITTLE MONKEY THERE SO WE DO
SOME THINGS IN MONKEYS, SOME
THINGS IN MICE.
AND USING TOOLS THAT WE CAN
APPLY IN THE CLINIC LIKE
IMAGINING ANALYSIS.
PET CT SCANS, BIO MARKERS.
YOU TRY TO PILOT INTO CLINICAL
TRIAL DESIGNS.
THEN WE ACTUALLY DO CLINICAL
TRIALS STARTING PRETTY MUCH WITH
PHASE TWO WHERE WE TRY TO TAKE
THOSE THINGS WE LEARN FROM THE
ANIMAL STUDIES AND TRANSLATE
THEM DIRECTLY INTO PEOPLE.
AND I'M NOT GOING TO TALK ABOUT
ANYTHING IN THE LAST TWO PHASES
OF THIS, I JUST WANT TO POINT
OUT THAT WE'RE ENGAGED IN THAT
SORT OF ACTIVITIES THESE DAYS.
BACK IN 1998 OR SO WE REALLY
FOCUSED MUCH MORE ON THE EARLY
PART OF THE PIPELINE BECAUSE WE
DIDN'T HAVE VERY MUCH TO GO WITH
THE PIPE LINE AT THAT POINT.
I WANTED TO SHOW YOU THIS
BECAUSE I THINK IT'S IMPORTANT
FOR TWO REASONS.
ONE, BECAUSE THIS IS MY CURRENT
GROUP.
I LOVE TO MAKE PEOPLE IN THE
GROUP ANGRY BY POINTING THEY ARE
ORDERED BY IMPORTANCE OF
DISCIPLINES, THE SCIENTISTS ARE
IN FRONT AND THE ANIMAL PEOPLE
LANGUISH IN THE BACK.
ALL OF THE CLINICAL WORK WE DO
IS OFFSHORE.
MOSTLY IN SOUTH KOREA AND CHINA.
THIS IS A PART OF MY CLINICAL
TEAM AND OTHER VISITORS.
THAT'S ACTUALLY PUT THESE THINGS
INTO HUMANS AND GET INFORMATION
THAT FEEDS BACK ALL THE WAY BACK
TO THE BEGINNING OF THE PIPELINE
TO DEVELOP BETTER AND BETTER
TOOLS AND BETTER AND BETTER
APPROACHES INTRODUCING NEW
CHEMOTHERAPIES.
I ALSO JUST WANTED TO
ACKNOWLEDGE UP FRONT THE PEOPLE
WHO REALLY DID THIS WORK.
AND THE PRINCIPAL DRIVER OF A
LOT OF THIS PARTICULAR PROJECT
WAS A POST TALK TROUBLE FELLOW
WHO JOINED ME AFTER FINISHING UP
AT OXFORD WHO WAS A VERY
TALENTED CHEMIST AND NOW RUNS
HIS OWN VERY SUCCESSFUL GROUP
THAT STILL WORKS IN TP DRUG
DISCOVERY AT ST. JUDE'S DOWN IN
TENNESSEE.
I'M ABSOLUTELY SURE I LEFT
PEOPLE OFF THIS SLIDE BECAUSE
LITERALLY THIS WAS 15 YEARS AGO
BUT A LOT OF THIS WAS REALLY
STARTING AND PEOPLE WERE JUMPING
IN AND OUT OF IT.
IT ALSO INCLUDED THE PEOPLE IN
TECH TRANSFER THAT MADE
FUNDAMENTAL CONTRIBUTIONS TO
SETTING THIS UP RIGHT AT THE
BEGINNING SO AT THE END WE HAD A
PRODUCT TO SHOW FOR AND WE
DIDN'T GET LOST ALONG THE WAY.
I'M EQUALLY CERTAIN I LEFT
PEOPLE OFF THAT LIST BUT THOSE
ARE THE ONES I CAN REMEMBER THAT
DEALT WITH THE KIND OF
DAY-TO-DAY BASIS IN ESTABLISHING
THIS PROJECT UP FRONT.
>> I WOULD LIKE TO INTRODUCE YOU
TO SEQUELA [INDISCERNIBLE]
STARTED SEQUELA WITH TWO OTHER
FOUNDERS BY THE WAY, IN 1997 AS
A WAY TO FOCUS ENERGY OF A
BIOTECHNOLOGY COMPANY ON A
GLOBAL HEALTH ISSUE WHICH WAS
TUBERCULOSIS.
WE'VE GOTTEN A LOT DIFFERENT IN
THE LAST 15 YEARS FOR A VARIETY
OF DIFFERENT REASONS, AND NOW WE
HAVE ACTUALLY COMPOUNDS THAT
WORK ON ALL OF THESE DIFFERENT
INFECTIONS.
WE DO DRUG DISCOVERY IN HOUSE,
WE PLAYED OFF OF CLIFF, CLIFF
TAUGHT US HOW TO DO CHEMISTRY
AND WE BROUGHT IT IN HOUSE SO
NOW WE HAVE A COMPOUND LIBRARY
OF ABOUT 250,000 MOLECULES ON
VARIOUS DIFFERENT CLASSES.
AND I HAVE TWO FABULOUS RUSSIAN
WOMEN CHEMISTS WHO ARE BEYOND
BELIEF, GOOD AT WHAT THEY DO.
SO WE'RE CURRENTLY FOCUSED
SPECIFICALLY ON THREE
INFECTIONS.
MICRO BACTERIUM TUBERCULOSIS,
ONE THIRD OF THE WORLD INFECTED.
LOTS OF PEOPLE GET IT ANNUALLY.
[INDISCERNIBLE] -- HAVE BETTER
STATISTICS ONE IN TWO, AWESOME
ISN'T THAT IT.
THERE ARE TWO MILLION CASES, TWO
MILLION DEATHS EVERY YEAR AND
THERE'S A LOT OF ANTIBIOTIC
RESISTENT.
I WON'T TALK ABOUT CLOSTRIDIUM
DIFICILE BUT WE DO HAVE A
PROGRAM ON THAT.
WHAT I WILL TALK ABOUT TODAY IS
THE COMPOUND WE ENDED UP WITH
CLIFF AND HE'LL TELL YOU HOW WE
GOT HERE.
THERE'S AN CONSIDERATION THAT'S
CURRENTLY TB.
IT'S NOW IN A RUSSIAN
REGISTRATION TRIAL MULTIDRUG
RESISTENT TB AND THE PHASE TWO
TRIALS ARE DRUG SENSITIVE TB.
IT'S AN AWESOME DRUG.
THIS SHOWS YOU HOW MANY COLONIES
COME OUT OF THE STANDARD OF
CARE.
TB DRUGS AT THE END OF A FOUR
MONTH TREATMENT, AND THIS IS
SQ109.
IT'S A GOOD DRUG.
I ALSO WANTED TO MENTION THAT
IT'S A MULTIFUNCTIONAL DRUG.
IT HAS A VERY LIMITED NUMBER OF
BACTERIA THAT IT CAN WORK ON BUT
IT DOES WORK ON [INDISCERNIBLE]
AND WE'VE DONE ACTUALLY A PHASE
TWO PROOF OF PRINCIPLE TRIAL FOR
VECTORS OF THE STOMACH.
IN FACT WE CAN PULL THE
BIOMARKER ON TO UNDETECTABLE
LEVELS.
WE'RE HAVING OF HAVING ANOTHER
INDICATION AS WELL OF THIS DRUG
BECAUSE IT'S A REALLY GOOD DRUG
AND SO FAR I NOTATE THE ISSUE.
>> SO LET'S WIND BACK THE CLOCK.
SO THE PROJECT STARTED
WITH ETHAMBUTOL -- IT'S IN THAT
REGIMEN SO AT LEAST TWO MILLION
PATIENTS RECEIVE ABOUT 360
MILLION DOSES OF THIS DRUG EVERY
SINGLE YEAR.
AND BECAUSE IT'S THE LEAST
ACTIVE, WE THOUGHT LONG AND HARD
ABOUT WHAT, IF WE COULD IMPROVE
ETHAMBUTOL.
IT CAME FROM A PROGRAM THEN AT
THE LABORATORIES OF AMERICAN --
BEFORE THEY BECAME AMERICAN HOME
PRODUCT, ETCETERA, ETCETERA.
WHEN TB WAS STILL A BIG DEAL IN
THIS COUNTRY IN A PROGRAM IN THE
1950'S, THEY IDENTIFIED IN A
WHOLE CELL SCREEN THIS COMPOUND
[INDISCERNIBLE] AS AN INHIBITOR
OF TUBERCULOSIS DRUG.
THROUGH A VERY LABORIOUS PROCESS
THEY WENT THROUGH AND MADE 2000
ANALOGS WHICH WAS A BIG PROGRAM
AT THE LAB IN THOSE DAYS.
IT WOULD BE A BIG PROGRAM THESE
DAYS IN ANY INDICATION AREA.
WHAT THEY END UP WITH WAS
ETHAMBUTOL.
WHAT THEY KNEW IN 1961 WHEN THEY
DISCLOSED THIS TO THE WORLD,
ETHAMBUTOL WAS REALLY ACTIVE
AGAINST LUNG INFECTIONS IN MICE
WITH HUMAN TB, WITH ORAL
ADMINISTRATION.
AND IT WAS ACTIVE IN VITRO AND
IT LOOKED SAFE AND IT'S REALLY
BLOCKED THE DEVELOPMENT OF
RESISTANCE WHEN YOU DID
CO-THERAPY IN MICE.
AND SO CLINICAL TRIALS BEING
WHAT THEY WERE IN THE 1960'S IN
MID 1961, THEY DISCLOSED THIS BY
THE END OF 1961 IT WAS IN
CLINICAL TRIALS IN HUMANS.
AND SO LESS THAN SIX MONTHS.
DISCOVERY TO ACTUAL FIRST DOSE
IN HUMANS WHICH IS PRETTY
INCREDIBLE AND PRETTY HEART TO
REPLICATE THESE DAYS.
>> IMPOSSIBLE.
>> IMPOSSIBLE.
BUT IT ALSO COMES WITH SOME
RISKS RIGHT AND THIS IS A GOOD
EXAMPLE OF THE RISK BECAUSE IN
THAT FIRST CLINICAL STUDY WHICH
INVOLVED 150, 18 PATIENTS
DEVELOPED AN OCULAR TOXICITY AS
A RESULT OF THAT.
YOU CAN SEE THE EXAMPLE OF THE
TOXICITY AND WE UNDERSTAND THE
MECHANISMS OF THEM BUT IN THOSE
DAYS THEY HAD NEW NO CLUE WHAT
THE MECHANISM WAS.
THIS WAS A DOSE LIMITING
TOXICITY FOR THE DRUG.
SO THE NEXT ROUND OF CLINICAL
TRIALS WE SEQUENTIALLY LOWER AND
LOWER DOSES.
BY THE TIME THEY DROPPED THE
DOSE THE EFFICACY WAS PRETTY
QUESTIONABLE AT THAT POINT WHICH
IS HOW WE ENDED UP WITH THE
WEAKEST DRUG IN THAT FOR-DRUG
REGIMEN.
AND SO IN 1998, CAROL AND I
ASKED THE QUESTION CAN WE DO
BETTER.
PERHAPS IRRATIONALLY EXHILL
RATED BY THE FACT THAT THE LUNAR
PROSPECTS HAD SUCCESSFULLY
CRASHED IN A CRATER ON THE MOON
AND FOUND WATER I THOUGHT WE
COULD MAKE SOMETHING BETTER AN
ETHAMBUTOL.
I WAS REALLY TRYING TO RECREATE
MY FRAME OF MIND BACK IN 1998.
WE, LIKE MUCH OF THE WORLD THAT
DID MEDICINAL CHEMISTRY THOSE
DAYS WERE TOTALLY INFATUATED
WITH COMBINTORIAL CHEMISTRY.
THE ONLY ANALOGY I CAN DRAW TO
THAT I THINK HAS HAD A SIMILAR
IMPACT ON A POPULAR CULTURE WAS
BEANIE BABIES, RIGHT.
EVERYBODY HAD TO HAVE BEANIE
BABIES.
THE MORE YOU HAD THE BETTER AND
IT IS LIKE THIS COMBINTORIAL
CHEMISTRY.
THE MORE COMPOUNDS YOU HAD, THE
BETTER.
SURELY IF WE HAD ENOUGH BEANIE
BABIES THAT DEMAND WOULD GET SO
LARGE WE COULD RETIRE WITH
EVERYTHING WE HAD IN BEANIE
BABIES.
EVERY PHARMACEUTICAL COMPANY IN
THE WORLD WENT DOWN THIS PATH.
TEN YEARS AGO WE STARTED TO BURN
OUT ON THAT AND THESE DAYS
NOBODY BANKS ON THAT.
BUT THAT WAS THE MIND SET AT
THAT TIME WE NEEDED BIGGER AND
BIGGER LIBRARIES.
SO WHAT IS COMBINTORIAL
CHEMISTRY.
IT IS OFTEN CALLED SPLIT AND
POOL CHEMISTRY IT'S THE PROCESS
OF BUILDING THINGS ON A SOLID
SUPPORT.
SUPPOSE I HAD A GREEN MARBLE AND
I TAKE THREE DIFFERENT REACTIONS
WITH GREEN MAR BLEDZ, ONE
REACTED WITH YELLOW ONE RED AND
ONE BLUE.
AT THE END I'VE GOT ONE MOLECULE
WHICH IS GREEN AND RED, GREEN
AND BLUE OR GREEN AND YELLOW.
IF I POOL THOSE ALL TOGETHER, I
HAVE A MIXTURE OF ALL THREE OF
THOSE AND I SPLIT THEM OUT AGAIN
IN THREE DIFFERENT POTS AND WE
HAVE A YELLOW BLUE AND RED
DOUBT.
IN EACH POT I END UP WITH
DISCREET MIXTURES THAT I CAN
PULL BACK TOGETHER AND SPLIT
AGAIN AND ACT WITH ANOTHER ONE.
YOU CAN IN A WAY NOT ONLY MAKE
THESE THINGS COMBINTORIAL BY
SPLIT AND PULL SYNTHESIS BUT YOU
CAN ALSO TRACK THEM.
THERE'S AN INFINITE VARIETY OF
FANCY WAYS OF TRACKING AN
INDIVIDUAL BEAD.
SO IN THIS WAY IT BECOMES
POSSIBLE TO MAKE LIBRARIES OF
MILLIONS OF PERMUTATIONS AND HOW
YOU CODE AND DECODE THEM.
WE DID A VARIETY OF DIFFERENT
ITERATIONS.
SOME USE RADIO FREQUENCY
TRANSMITTERS INSIDE OF AN
INDIVIDUAL BEAD.
SOME USE DNA BAR CODES.
THERE'S AN UNLIMITED NUMBER OF
WAYS OF KEEPING TRACK ON ANY
INDIVIDUAL BEAD BUT I'M NOT
GOING TO TALK ABOUT THAT TODAY.
WHAT I AM GOING TO TALK ABOUT IS
HOW WE REDUCE THAT PRACTICE
TRYING TO LOOK FOR A BETTER
ETHAMBUTOL.
THIS IS THE CHEMISTRY SO THAT
MEANS THERE'S A SOLID INVOLVED.
THIS LITTLE BALL IS THE BEST
REPRESENTATION A CHEMIST CAN
COME UP FOR A PIECE OF PLASTIC.
WE'LL JUST LEAVE IT AS A PIECE
OF PLASTIC AT THIS POINT.
IN THIS CASE THIS IS CALLED A
RINK LINKER THAT JUST LINKS THE
PLASTIC TO WHATEVER YOU'RE GOING
TO PUT SPECIFICALLY ON THE
POSITION OF THE MOLECULE.
THEN YOU CAN ACTIVATE THAT AND
THEN DOWN HERE IS THE ETHAMBUTOL
IN CASE YOU DON'T REMEMBER THE
STRUCTURES IN THE PREVIOUS
SLIDE.
I CAN TAKE HALF OF THIS AND
PATCH IT ON TO THAT LINKER SO IT
LOOKS LIKE THIS.
SO HALF OF THE ETHAMBUTOL.
CAN I TAKE A LINKER AND I'VE
CREATED THIS TWO CARBON UNIT.
I CAN PUT ON THE OTHER HALF SO
NOW THE ENTIRE ETHAMBUTOL
MOLECULE MADE ON A SPECIFIC
BEAD.
I CAN REDUCE THAT AND CLEAVE IT
OFF THE BEAD AND I'VE CREATED
THE MOST EXPENSIVE ETHAMBUTOL.
THAT'S ALL I'VE DONE.
BUT ONE WHERE I CAN CONTROL
WHAT'S IN EACH OF THOSE
POSITIONS BECAUSE I HAVE A SOLID
SUPPORTED SYNTHESIS AND I CAN --
THAT BEAD IS ACTUALLY MADE OF.
IT DOESN'T TAKE A HUGE LEAP OF
IMAGINATION THEN TO ERASE THE AM
BY TALL I PUT IN AND PUT R AS A
GENERIC R AND A GENERIC LINK HE
WERE SUBSTITUTION.
YOU REALIZE YOU CAN CREATE A
LIBRARY OF THINGS.
SO THE STRUCTURES HERE AREN'T
IMPORTANT.
IT JUST LOOKS LIKE A PLATE OF
SPAGHETTI ANYWAYS.
THIS JUST GIVES YOU AN
ILLUSTRATION OF HOW FAST AND
RAPID THIS IS AND HOW QUICKLY
YOU CAN GET TO ASTRONOMICAL
NUMBERS THAT ARE ALMOST
UNCONTROLLABLE.
SO IF I JUST TAKE 58 DIFFERENT R
1'S.
AND MIX THEM UP WITH THEMSELVES
IN THE TWO DIFFERENT POSITIONS.
I'M GOING TO LINK THEM WITH 12
DIFFERENT POSITIONS.
THERE ARE 40,000 UNIQUE
COMBINATIONS.
WE CAN CREATE LOTS AND LOTS OF
THINGS.
WE CAN DO ORDERS OF MAGNITUDE
BETTER THAN LABS DID SURVEYING
WHAT THE CHEMICAL SPACE IS.
WHEN YOU COUPLE NUMBERS LIKE
THAT WITH THE NEED TO DO ASSAYS
OF THE ORGANISM YOU REALIZE IT
BECOMES DIFFICULT TO SCREEN THAT
NUMBER OF COMPOUNDS AGAINST THE
ORGANISM ITSELF.
THIS IS HELD NICELY WITH A
PROJECT HELD ON AT THE LAB AT
THE SAME TIME.
WE'VE LOOKING AT THE
TRANSCRIPTIONAL RESPONSES AND
THIS IS IN THE DARK DAYS OF
MICRO RAYS.
WE WERE DOING SPOTTED ARRAYS.
THE STORY IS THE SAME.
WE DISCOVERED THINGS IN THOSE
DAYS WE JUST HAD AN INCREDIBLE
AMOUNT OF NOISE.
BASICALLY WE TOOK ALL THE KNOWN
INHIBITORS OF TB, WE LOOKED AT
MICRO ARRAY PATTERNS AND MATCHED
GENES THAT WENT UP AND DOWN.
WE LOOKED AT THINGS THAT WERE
COMMON.
WHAT WE COULD TELL THAT WE COULD
LUMP THINGS BASED ON THEIR BIG
IMPACTS ON THE CELL BASED ON
THEIR TRANSCRIPTION.
WITH THE [INDISCERNIBLE] IN
PARTICULAR THERE WAS A UNIQUE
SET OF GENES THAT WAS VERY
SENSITIVE TO INHIBITION OF THAT
PARTICULAR STEP WE COULD THEN
PULL OUT FROM THAT U.S.A. AND
--
FROM THAT ANALYSIS.
WE TOOK THE GENES THAT WAS NO,
SIR SENSITIVE WITH TREATMENT OF
THE ETHAMBUTOL AND TRANSFORM
THAT INTO TB AND NOW WE HAVE A
TRAIN THAT WHEN YOU HIT IT WITH
ETHAMBUTOL PRODUCES LIGHT.
THAT'S THE KIND OF TOOL YOU NEED
TO DO THINGS IN HIGH THROUGHPUT
FORMAT SO YOU CAN SCREEN LOTS
AND LOTS OF COMPOUNDS AGAINST
THAT PARTICULAR KIND OF ORGAN.
THIS JUST SHOWS YOU A DICE
TITRATION WITH DIFFERENT
INHIBITORS AND THEN THE LIGHT
PRODUCTION AND THE LIGHT
PRODUCTION WITH ETHAMBUTOL.
YOU GET A NICE PRODUCTION OF
LIGHT WHEN YOU HIT IT WITH
ETHAMBUTOL.
WE HAVE A NICE ASSAY THAT COULD
BE REDUCED TO PLATES SO WE COULD
SCREEN LOTS AND LOTS OF
COMPOUNDS.
WE HAVE A NICE WAY OF
SYNTHESIZING LOTS AND LOTS OF
COMPOUNDS SO WE DO IT.
THAT'S RICHARD UP IN THE CORNER
WHO WENT AFTER THIS FIRST.
IT'S HARD FOR US TO RECREATE
THESE AND SAY HOW MANY ACTUAL
ANALOGS.
THAT'S WHERE WE ENDED UP
PUBLISHING WHERE WE HAD AN LIT
CUL DATA THAT WAS ACTUALLY
SUPPORTED.
WE MADE A LIBRARY OF THAT AND
DIFFERENT ITERATIONS.
THOSE ARE THE ONES THAT WERE
CHARACTERIZED TO GO INTO IT.
THEN WE SCREAMED THEM USING A
VARIETY OF RELATIVELY AT THAT
TIME SOPHISTICATED ROBOTICS OF
WHICH SEEMED RATHER PRIMITIVE
NOW THAT I LOOK AT THE PICTURES
COMPARED TO WHAT WE DID BUT THAT
WAS THE ROBOTICS OF BEING ABLE
TO DO IT.
AND YOU HAVE A FEW TECHNICIANS
WHO KIND OF LOAD PLATES INTO
THESE AND CONTINUE TO STACK
COMPOUNDS, PARACOMPOUNDS WITH
ORGANIZISMS AND LIGHT
PRODUCTION.
SO AFTER SCREENING 100,000
COMPOUNDS NOW, 50 TIMES THE
NUMBER THAT WAS SCREENED AT THE
LABORATORIES, WHAT WE CAME UP
WITH WAS 65 OF THEM THAT WERE
RELIABLY AS GOOD AS OR BETTER AS
AM BY TALL.
THESE ARE COMPOUNDS WHERE WE
MEASURE THE BEST OF THOSE HAD AN
MIC WITH A NANOMOLAR.
NOW OF COURSE THE BEST ONES
ALWAYS GOT SOME OTHER PROBLEMS,
RIGHT.
SO THIS IS JUST THE FIRST ASSAY
AND WE GO THROUGH A VARIETY OF
DIFFERENT THINGS SELECTED FOR
WHAT THE BEST ONE WAS THAT
APPEARED SAFE AND DIDN'T KILL
ALL OF THESE CELLS AND HAD SOME
PHARMACOLOGY ETCETERA ETCETERA.
I'M NOT REALLY GOING TO TALK
ABOUT THAT IN ANY GREAT AMOUNT
OF DETAIL.
INSTEAD, WHAT I'LL TELL YOU IS
THIS IS WHAT WE ENDED UP WITH
SQ109.
THERE'S MANY PAPERS ABOUT THIS
AT THIS POINT SO I'M NOT GOING
TO GO THROUGH A LOT OF DEPTH IN
THE PHARMACOLOGY.
CAROL WILL GIVE YOU MORE ON WHAT
WE HAD TO DO.
THIS WAS OUR CANDIDATE THAT CAME
OUT OF IT, AND WHAT WE
CONSIDERED TO BE THE MINIMUM
PHARMACOPHORE.
IN THE PROCESS OF GETTING RID OF
THIS -- THAT'S BECAUSE AS I
MENTIONED BEFORE THERE'S A LOT
OF TOXICITY WITH THE PARENT
COMPOUND DUE TO ITS ABILITY TO
FORM A STABLE -- WITH THE
AMINES.
SO WE WANTED TO GET RID OF THAT
AND TRIED TO DESTABILIZE ANY
POTENTIAL METALS TO AVOID THAT
TOXICITY.
WE GOT RID OF THE HYDROXY GROUPS
SO WE DON'T EXPECT TO SEE THE --
THAT WE SAW WITH THE ETHAMBUTOL
IN THE BEGINNING.
SO WE SUCCEEDED RIGHT.
WELL, KIND OF.
THE REASON I SAY KIND OF BECAUSE
WE DID ACTUALLY END UP CREATING
SOMETHING THAT LOOKS LIK
ETHAMBUTOL AND WORKED WITH A
SIMILAR MECHANISM BUT WE SLIPPED
OBVIOUS A LITTLE BIT.
INSTEAD OF HITTING THE TARGET
WITH ETHAMBUTOL IT'S A VERY
COMPLICATED SCHEMATIC ENVELOPE
LOOKS LIKE.
IT'S A VERY COMPLICATED
HETEROPOLYMER THAT CONSISTED OF
THREE DIFFERENT UNITS --
COVALENTLY LINKED.
WITH ETHAMBUTOL WE KNOW BLOCKS
PRODUCTION -- AND WHAT WE FOUND
IN THE END, AND AGAIN THIS IS
ALL PUBLISHED WORK SO I'LL SHOW
YOU JUST A TYPO BIT OF IT THAT'S
MORE CONTEMPORARY IN THE LAB.
WHAT WE FOUND IN THE END IS
ACTUALLY WE PUSHED THE TARGET UP
STREAM A LITTLE BIT AND WE WERE
BLOCKING THIS TRANSPORTER THAT
PUSH THESE ACIDS FROM INSIDE THE
CELL TO OUTSIDE THE CELL WHERE
THEY'RE ATTACHED TO THE CELL
ENVELOPE.
THE EVIDENCE TO THAT IS AGAIN
COMPLICATED I THINK TOO MUCH
DETAIL FOR THIS TOPIC.
I DO WANT TO POINT OUT THAT WE
DISCOVERED THIS, WE SETTLED ON
THE MOLECULE IN ABOUT 2001,
20002 BUT IT WASN'T UNTIL 2012
THAT WE ACTUALLY FIRMLY
ESTABLISHED WHICH DEPTH IN THE
BIO SYNTHESIS WE ARE INHIBITING.
WE DID THAT THROUGH A
COMBINATION OF BOTH BIOCHEMICAL
STUDIES WHERE WE IDENTIFIED
THESE MOLECULES WE WERE
ACCUMULATING WITHIN THE CELL.
AND GENETIC EVIDENCE WHERE WE
RAISE MUTANTS THAT WERE
RESISTENT TO THE DRUG AND WE
RESEQUENCED THEM AND I D THE
TARGETS AND SHOWED THE PROTEIN
WAS ACTUALLY THE TARGET.
AND WE FLIPPED OFF THE
ETHAMBUTOL SLIGHTLY.
IT'S IMPORTANT BECAUSE WHEN YOU
LOOK AT THE IN VITRO DATA FOR
SQ109, CAROL WILL SAY THIS IN A
POSITIVE LIGHT.
FROM MY PUREST ACADEMIC HAT IT'S
ANNOYING BECAUSE WE DIDN'T HIT
THE TARGET I WANTED TO HIT.
FROM THE POSITIVE SPIN ON THIS
IT STILL HAS ACTIVITY AGAINST
THATE AM BY CALL ORGANISM.
WE MOVED THE TARGET PROTEIN BIO
SYNTHETIC.
SO IN VITRO, THIS IS A GOOD
DRUG.
IT HAS AN MIC THAT IS LESS THAN
MICROMOLAR AGAINST MANY
DIFFERENT CLINICAL --
EXTENSIVELY DRUG RESISTENT
DISEASE.
DIFFERENT PHYSICIAN ALWAYS THAT
WERE INTRACELLULAR AND
NON-REPLICATING BUGS AND
INHIBITS GROWTH.
AS LONG AS THE CELL HAS TO BE
MAKING A CELL ENVELOPE IT SEEMS
TO KILL THEM PRETTY EFFECTIVELY.
IN CONTRAST THIS IS INACTIVE
AGAINST A NUMBER OF OTHER CELL
LINES SO IT DOESN'T CARRY --
MICRO BACTERIA OF THE GENUS.
IT'S DIFFICULT FOR THE ORGANISM
TO CARRY RESISTANCE BECAUSE THE
SURFACE WE'RE BLOCKING ACTUALLY
NEEDS A VERY SPECIFIC MUTATION
TO GET RESISTANCE TO IT.
SO IT'S ACTUALLY BETTER IN TERMS
OF RESISTENT FREQUENCIES.
THERE'S SOME IN VITRO EVIDENCE,
THERE'S ENERGY BETWEEN RISKS AND
INH INDICATING THAT THIS MIGHT
REALLY BE SOMETHING THAT COULD
SHORTEN THERAPY IN TB PATIENTS.
IN VIVO, WE KNEW THIS SORT OF
STANDARDIZED WAY COULD PROTECT
MICE FROM TB-INDUCED WEIGHT
LOSS.
THIS IS A HIGH THROUGHPUT
SCREENING WE DO.
WE KNOW IT COULD REDUCE -- THE
ACTIVITY IN VIVO THAT MADE IT
TEN TIMES BETTER THAN ETHAMBUTOL
SO WE ACHIEVED THAT MUCH IN
TERMS OF POTENCY.
WHEN YOU COMBINE IT AND CAROL
JUST SHOWED YOU SOME OF THIS,
I'M GOING TO SHOW YOU THE ACTUAL
NUMBERS FOR IT IN JUST A SECOND
WHEN YOU COMBINE IT IN A FOUR
DRUG STANDARD OF CARE REGIMEN IN
PLACEMENT OF ETHAMBUTOL YOU
CLEAR MICE MUCH QUICKER.
MICE DON'T MEAN ANYTHING WHEN
YOU TALK ABOUT HUMAN DISEASE.
I'LL SHOW A MOUSE DATA WITH A
SHAMED LOOK ON MY FACE BECAUSE I
DON'T REALLY BELIEVE THIS TELLS
YOU ANYTHING ABOUT WHAT WE
SHOULD EXPECT IN PEOPLE.
WE DON'T KNOW WHAT'S GOING TO
HAPPEN IN PEOPLE UNTIL WE DO THE
EXPERIMENTS IN PEOPLE.
IF YOU DO WHAT WE HOPE TO DO IN
PEOPLE YOU TOOK THE ETHAMBUTOL
AND REPLACED IT WITH SQ109.
WHAT THE MICE DO IS CLEAR THE
BACTERIA MUCH MORE QUICKLY.
THIS IS ABOUT THREE MONTHS OF
TREATMENT AND IF THAT TRANSLATED
INTO PEOPLE, THAT WOULD SUGGEST
THAT WE HAD ACHIEVED SOMETHING
THAT WOULD SHORTEN THE DURATION
OF THERAPY AND PEOPLE FROM SIX
MONTHS AS IT IS PRESENTLY DOWN
TO ABOUT FOUR MONTHS.
SO THAT'S WHAT WE KNEW FROM THE
IN VIVO MOUSE STUFF.
FRANKLY SPEAKING IF WE HAD ONLY
BEEN WORKING IN THE INTRAMURAL
PROGRAM THAT'S WHERE WE RUN INTO
THE FIRST HUGE ROAD BLOCK WHICH
IS HOW DO WE GET ENOUGH STUFF TO
BE ABLE TO GO INTO HUMAN TRIALS.
CAROL.
>> YES.
THAT'S WHY IT'S NICE TO HAVE A
COMPANY THAT HAS A CHIEF MEDICAL
OFFICER WHO KNOWS EXACTLY HOW TO
DOAL OF THIS STUFF.
WHAT YOU NEED TO DO IS GET A
DRUG FROM A MOUSE TO A HUMAN.
WHAT I BASICALLY WANT TO TELL
YOU IS THAT WE WOULDN'T HAVE
BEEN ABLE TO DO THIS WITHOUT THE
HELP OF A VARIETY OF INSTITUTES
AT THE NIH.
THIS TRULY WAS AN NIAID
INITIATED PROJECT BUT IT FLOWED
TO OTHER INSTITUTES AT THE NIH
AND OTHER ORGANIZATIONS BOTH
HERE IN THE UNITED STATES AND
ALSO IN EUROPE.
THIS IS A VERY EXPENSIVE
PROCESS.
THE ESTIMATES FOR TAKING THE
DRUG ALL THE WAY THROUGH FROM
BEGINNING TO END IS NOW IS
UPWARD OF $7 BILLION.
IT DOESN'T TAKE THAT MUCH
BECAUSE THEY'RE AMORTIZING
EVERYTHING THAT DOESN'T WORK.
BUT IT DOES TAKE HUNDREDS OF
MILLIONS OF DOLLARS.
AND SO IT'S DIFFICULT TO, IT'S
DIFFICULT TO ACCOMPLISH ALL THE
RESOURCES THAT YOU NEED TO
ACCOMPLISH TO MOVE FROM POINT A
TO POINT B TO POINT C IN A
SYSTEMATIC WAY IN THE CLINIC
BECAUSE THE COST IS SO HIGH.
SO THERE WAS A PROGRAM CALLED
THE INNER INSTITUTE PROGRAM
BETWEEN THE NATIONAL CANCER
INSTITUTE WHICH AT THAT TIME HAD
A NUMBER OF CONTRACTORS THAT
WERE DOING WORK FOR THE CANCER
INSTITUTE ITSELF AND FOR PEOPLE
WHO WERE WORKING WITH THE CANCER
INSTITUTE AND ACADEMIC
INSTITUTIONS.
AND NIAID.
SO IT WAS A JOINT PROGRAM.
AND IT ENABLED NIAID TO SELECT
ONE DRUG THAT THEY WOULD WORK
WITH AT THE CANCER INSTITUTE
WITH THEIR CONTRACTORS TO HELP
MOVE IT IN ORDER AND MOVE ON TO
CONTEST WHEN WE WERE VERY
EXCITED.
SO WE ENDED UP WORKING WITH THE
INNER INSTITUTE PROGRAM AND A
VARIETY OF AWESOME PEOPLE AT THE
NCI ITSELF AND ALSO IN THE
CONTRACTING GROUP.
AND THESE ARE JUST SOME OF THE
STUDIES THAT HAD TO GO ON BEFORE
WE MOVED THIS DRUG INTO FIRST
STUDIES IN HUMANS.
I GUESS THE ONE THAT'S NOT ON
HERE THAT WE DID THAT WAS THE
MOST EXPENSIVE WAS ONE THAT
SEQUELA ACTUALLY DID.
THIS DRUG LIKES TO BE INSIDE OF
CELLS.
IT LIKES TO BE INSIDE OF EXACTLY
THE CELLS WHERE TB HIDES.
AND WHEN IT GETS IN THERE, THE
CELLS WRAP IT UP IN A VESICLE
THAT'S CALLED PHOSPHOLIPIDOSIS.
SO THERE ARE ABOUT 35, 40, 50
COMPOUNDS OUT THERE THAT CAUSE
THE SAME KIND OF THING.
AND FOR A WHILE WE THOUGHT
PHOSPHOLIPIDOSIS WAS A TOXIC
EFFECT.
NOW WE KNOW IT'S A PROTECTIVE
EFFECT AND WHAT IT ACTUALLY DOES
IS IT CAUSES THE DRUG TO GET
INTO CELLS AND THEN TO BE
RELEASED HOW THE INTO THE
CIRCULATION SLOWLY OVER TIME.
SO BUT AT THE TIME THAT WE
SUBMITTED OUR IND, WE HAD 90 DAY
RATS, 90 DAY DOGS -- FROM A BIG
PHARMA COMPANY THAT HAD JUST
GONE THROUGH THE FDA AND THEY
ACTUALLY DEMONSTRATED THAT THERE
IS NO TOXIC EFFECT OF
PHOSPHOLIPIDOSIS [INDISCERNIBLE]
AND IN FAIRNESS TO THE PHARMA
COMPANY, AND THEY DEMONSTRATED
THIS IN MONKEYS.
WE WERE THEN ASKED BECAUSE THEY
DIDN'T WANT TO ASK ONE COMPANY
TO DO THIS AND NOT ASK ANOTHER
TO DO A MONKEY STUDY WHICH ENDED
UP COSTING $3 MILLION AND
DELAYED THE ONSET OF THE HUMAN
CLINICAL TRIALS BY ABOUT A YEAR.
SO WE ALSO FOUND NO TOXIC
EFFECTS OF PHOSPHOLIPIDOSIS.
AND THE PANEL INCLUDING THE --
PEOPLE AND THE FDA DOES NOW,
THEY'RE INTERESTED IN WATCHING
IT BUT THEY'RE NOT REJECTING
DRUGS ON THE BASIS OF
PHOSPHOLIPIDOSIS.
AND WITH THAT $3 MILLION I THINK
HELPS DO THAT.
SO WE DID START SOME STUDIES AND
THE FIRST SET OF STUDIES SEQUELA
DID.
THIS IS IN 19 -- IN 2006.
AND WE WERE COMPLETED THIS STUDY
CLOSE TO THE END OF, MIDDLE OF
2007.
AND AS YOU MAY RECALL IN 2007,
THE ECONOMY COLLAPSED.
AND SO WE TALKED TO THE NIH AND
THEY AGREED THAT WE COULD
CONSERVE OUR MONEY SO WE COULD
STAY ALIVE AS OTHERS AND NIH
ACTUALLY ENDED UP DOING THE REST
OF THE STUDIES.
WE HAD NO TOXICITY IN PATIENTS
UP TO 300 MILLIGRAMS.
IT WAS REALLY LOVELY TO SEE THE
14-DAY STUDIES.
WE THEN WENT ON TO DO A PHASE 2A
STUDY IN TB PATIENT.
THIS IS FUNDED BY THE EUROPEAN
UNION BY A PROGRAM CALLED -- AND
THE AFRICAN SITES WERE CALLED
PANACEAS.
SO WE NOW HAVE MORE PEOPLE
INVOLVED IN DEVELOPMENT OF THIS
DRUG.
THIS IS THE DATA.
THE DATA WOULD TELL YOU THAT ALL
THESE ARE -- BY ITSELF.
THIS IS SQ109 IN THE PRESENCE OF
[INDISCERNIBLE].
SO IN FACT IN THE FIRST 14 DAYS
OF THE PATIENT TREATMENT THERE'S
NOT A LOT OF ACTIVITY OF SQ109
FOR TB BUT WE HAD ALREADY DONE
THE MOUSE STUDIES AND WE ALREADY
KNEW THAT.
SO WE CONSIDER ARE THIS IS A
SAFETY STUDY IN HUMAN PATIENTS.
AND IN FACT, WE DON'T IS A ANY
ACTIVITY OF SQ109 FOR THE FIRST
THREE WEEKS.
THEN WE START SEEING ACTIVITY
AND THEN IT GOES ON FROM THERE.
SO WE ARE NOW, WELL AGAIN, SAFE.
THE ONLY THING IS IT DOESN'T
TASTE VERY GOOD BUT IF YOU FEED
PEOPLE WHILE YOU GIVE THEM THE
DRUG THEY'RE FINE.
AND WE KNOW A LOT ABOUT THE DRUG
NOW IN TB PATIENTS.
SO NOW WE HAVE SOME ONGOING
CLINICAL TRIALS.
THE LICENSED THE RIGHTS TO SELL
THIS DRUG IN RUSSIA AND
AFFILIATED STATES WITH RUSSIA TO
A COMPANY THAT WAS ACTUALLY
CREATED AROUND SQ109 IN RUSSIA.
AND THEY HAD AN ONGOING TRIAL
FOR REGISTRATION OF THIS DRUG
FOR MARKETING AND SALES THERE.
AND IF YOU CAN FUNDED A PHASE 2B
STUDY LOOKING FOR A LONGER
DURATION OF TREATMENT TO DRUG
SENSITIVE TB DONE WITH PANACEA
AND WITH THE [INDISCERNIBLE] GOT
LOTS OF PARTNERS MOSTLY IN
SOUTHERN AFRICA AND IN TANZANIA
DOING THESE STUDIES AND THERE
ARE LOTS TO DO LEFT BEFORE WE
CAN DO A DEFINITIVE TRIAL FOR
REGISTRATION OF THIS DRUG.
WE GOT THEM ALL PLANNED.
WE'RE JUST OUT RAISING MONEY AT
THE MOAFNLT.
THIS IS THE TIME LINE
FOR GETTING THE TIME LINE.
IF YOU HAVE MILLIONS YOU DON'T
KNOW WHAT TO DO WITH SEE ME
AFTER.
BY 2017 WE'RE HOPING THIS DRUG
WILL HAVE GONE THROUGH ITS PACES
AND WILL ACTUALLY BE OUT IN
RUSSIA IN MARKETING AND SALES.
>> I THINK THIS WAS CAROL'S TB
FLARING UP AGAIN.
>> YES, IT IS, DON'T WORRY.
I HAVE A DRUG THAT CAN CURE YOU.
>> ANYBODY LIKE TO TASTE IT SO
SQ109 IT'S A LONG PROCESS.
THIS IS NOT ATYPICAL FOR TB
DRUGS BUT IT TAKES YEARS, IT
TAKES DECADES OFTEN TO COME UP
WITH HOW A PARTICULAR DRUG
REGIMEN.
I THINK THE DRUG'S GOT A LOT OF
GOOD THINGS GOING FOR IT.
IT MIGHT STILL BOMB.
THERE'S NO GUARANTEES IN THIS
GAME.
WE TAKE IT AND TRY TO MAKE THE
BEST GUESSES WE CAN AND MAKE THE
BEST ANIMAL STUDIES WE CAN.
BUT THESE THINGS CAN FAIL FOR
ANY NUMBER OF REASONS.
NONETHELESS WE NEVER WOULD HAVE
GOTTEN TO THE POINT OF HAVING
THE ABILITY TO TEST THIS IN
HUMANS AND PUT THIS IDEA
TOGETHER WITHOUT THE TEAM OF
PEOPLE THAT REALLY GATHERED
AROUND THE INITIAL IDEA AND TO
TRANSLATE THIS INTO A PRODUCT.
ONCE AGAIN I WANT TO TAKE THE
OPPORTUNITY TO THANK THAT WHOLE
TEAM AND TO THANK CAROL AND I
GUESS TOM FOR MAKING THIS
POSSIBLE.
IT'S QUITE GRATIFYING I HAVE TO
SAY.
IT'S MORE OF A BENCH BASIC
SCIENTIST VIBE TO BE ABLE TO PUT
YOUR HAND ON A PILL AND SAY I
MADE THIS.
WE ACTUALLY DID DO THAT AND WE
MADE IT AND CAROL MADE IT
POSSIBLE AND SEQUELA MADE IT
POSSIBLE, AND BEHIND ALL OF
THAT, OTT AND PHIL CHEN MADE
THIS POSSIBLE.
AGAIN, I THINK BOTH I AND CAROL
WANT TO THANK OTT AND PHIL AND
MARK AND THE WHOLE GANG FOR SORT
OF PUTTING THIS TOGETHER RIGHT
FROM THE BEGINNING SO WE GOT THE
CHANCE TO TAKE THIS BIG GAMBLE
AND PUT THIS INTO PEOPLE.
WE HOPE IN THE FUTURE TB
PATIENTS WILL FLEDGE YOU WITH
LETTERS TO THANK YOU FOR THAT
TOO.
>> EXACTLY.
>> I THINK WE'LL END THERE AND
SAY THANKS FOR YOUR ATTENTION
AND THANKS FOR THE HONOR OF
DOING THE PHIL CHEN LECTURES.
[APPLAUSE]
>> I THINK WE COULD HAVE A
COUPLE QUESTIONS.
IT'S A LITTLE LATE BUT LET ME
START.
SO YOU GAVE US SOME INDICATION
THAT THE TARGET WAS NOT THE SAME
AS THE [INDISCERNIBLE] CAN YOU
GIVE US MORE WHAT THE TARGET IS
AND HOW IT IS TOXIC TO TB.
>> SURE.
IT'S JUST LITERALLY TWO STEPS
REMOVED FROM THE TARGET
ETHAMBUTOL.
WE DO THINK IT'S RELATED IN THE
WAY IT WORK BUT THESE MACRO
MOLECULAR COMPLEXES THAT MAKE
THE CELL ENVELOPES SORT OF TALK
TO THE CYTOPLASM.
IT'S AT THE POINT WHERE THE
PRECURSOR IS PULLED IN FROM THE
CYTOPLASM AND INVERTED BEFORE
IT'S ATTACHED TO THE ENVELOPE.
THAT'S WHERE THE DRUG ACTUALLY
BLOCKS THAT EFFLUX.
>> IT'S A CELL WALL, CELL WALL
ACTIVE DRUG.
>> [INDISCERNIBLE].
>> WHILE, YES.
>> RIGHT UP YOUR ALLEY.
>> WHILE CLIFF IS, I JUST WANT
TO ANSWER -- I WANT TO MAKE A
STATEMENT.
WHILE CLIFF WAS DISTURBED WE
STARTED OUT TO MAKE A SECOND
GENERATION OFATE AM BALL AND WE
ENDED UP WITH -- THAT ACTUALLY
CREATED THE OPPORTUNITY FOR A
PATENT.
BECAUSE ETHAMBUTOL WAS ALREADY
PATENTED AND WAS OFF PATENT AND
IT WOULD HAVE BEEN AN OBVIOUS
THING IF WE HAD CREATED A NEW
DRUG.
SO WHILE I AM DELIGHTED THAT WE
HAVE A NEW MECHANISM OF ACTION
AND IT'S GOOD BECAUSE WE CAN NOW
NOT WORRY ABOUT ETHAMBUTOL
RESISTANCE IN MULTIDRUG
RESISTENT TB WHEN WE DO OUR
TREATMENT.
THAT'S ALL.
>> THANK YOU FOR SHARING THIS
WONDERFUL STORY.
I HAVE A QUESTION.
WE'RE SEEING AN EMERGENCE OF A
NEW REQUIREMENT THAT THE
PRECLINICAL WORK WILL HAVE TO BE
AUTHENTICATED BY AN INDEPENDENT
ENTITY BEFORE GOING INTO
PATIENTS.
I WOULD LOVE TO HEAR YOUR
COMMENTS TO YOUR REACTION TO HOW
THAT WOULD IMPACT THE PACE OF
THIS TRANSLATIONAL PROCESS IN
YOUR OPINION.
>> YOU'RE TALKING ABOUT DONE AT
A CLINICAL CENTER OR DONE HERE.
>> IT DOESN'T MATTER WHERE IT'S
DONE.
THERE'S A QUESTION OF THE
VALIDITY OF THE PRECLINICAL
WORK.
PEOPLE HAVE DONE SURVEYS BROADLY
ACROSS PRODUCTS THAT HAVE BEEN
EVALUATED FOR CLINICAL WORK AND
THERE'S BEEN SOME QUESTION OF
THE AUTHENTICITY OF THE PRODUCT
THAT WAS ACTUALLY BROUGHT TO
TRANSLATIONAL, INTO THE
PATIENTS.
AND SO THERE'S DISCUSSION ABOUT
AUTHENTICATING THE PRECLINICAL
PRODUCT TO MAKE SURE ALL THE
WORK IS INDEED WHAT IT'S THOUGHT
TO BE.
>> WELL, BY PRECLINICAL YOU MEAN
NON-CLINICAL BUT THE DISCOVERY
PART OF IT, I CAN UNDERSTAND
THAT COMPLETELY.
ON THE PRECLINICAL SIDE IT'S ALL
DONE GLP AND IT'S ALL CHECKED
AND THE FDA IS VERY RIGOROUS
ABOUT LOOKING AT IT AS WELL.
SO YOU DON'T GET INTO HUMANS
UNLESS --
>> [INDISCERNIBLE]
>> ON THE DISCOVERY SIDE QUITE
HONESTLY IF I HAD ANY ADVICE FOR
UNIVERSITIES I WOULD ASK THEM TO
BEGIN TEACHING PEOPLE HOW TO DO
RESEARCH UNDER GLP LIGHT, GOOD
LABORATORY PRACTICE LIGHT
BECAUSE THAT'S THE BIGGEST
PROBLEM.
IF YOU DON'T HAVE SOMEONE
CHECKING YOUR LAB BOOK, IF YOU
DON'T HAVE VALIDATED ASSAYS.
BY THE TIME IT COMES TO ME, IT
TAKES ME SEVERAL YEARS TO
REENGINEER IT AND TO FIGURE OUT
WHETHER YOU WERE RIGHT OR NOT.
SO IT'S A PROCESS.
THERE IS NOT, I HAVE NEVER SEEN
A TECHNOLOGY COME OUT OF AN
ACADEMIC CENTER-RIGHT INTO A
SMALL COMPANY AND BE READY TO
GO.
THERE'S ALWAYS LOTS OF THINGS WE
HAVE TO DO TO VALIDATE THE
PROCESS.
SO THE MORE YOU CAN USE GOOD
LABORATORY PRACTICE AND IT'S A
PAINFUL THING AND THE MORE YOU
CAN TEACH PEOPLE TO DO THAT, THE
EASIER IT WILL BE TO TRANSLATE
IT BUT THE FASTER WE'LL GET TO
IT.
>> LET ME TAKE A STAB AT THAT.
CAROL HAS A DIFFERENT
PERSPECTIVE.
>> REALLY.
>> THAT'S THE TIME LINE OF
DISCOVERY WHICH WE SHOWED AT THE
BEGINNING.
WE CAN CALL THAT AN INNOVATION
GAP.
THERE ARE NO NEW ANTIBIOTICS
THAT WERE INTRODUCED INTO THE
CLINICAL PRACTICE BETWEEN 1970
AND THE YEAR 2000.
NO NEW CLASS.
WE HAD LOTS OF KNOCK OFFS.
WHAT REALLY CHANGED THE CULTURE
AT FDA.
SOMEONE DISCOVERED STREPTOMYCIN.
WE HAD BECOME SO DRUG REVERSE
[INDISCERNIBLE] AND ALL THE
LOGIC GETTING INTO PHASE ONE
THAT WE KILLED ANTIBIOTICS.
THERE ARE ALMOST NO MAJOR
PROGRAMS CURRENTLY
[INDISCERNIBLE] THE REASON IT'S
TOO HARD.
IT'S TOO HARD TO GET SOMETHING,
IT'S TOO EXPENSIVE TO TAKE THAT
SHOT TO GET INTO HUMANS TO FAIL
AND WE'VE ELECTED ALL THESE
BARRIERS.
SO I TAKE THE OPPOSITE VIEW.
WE SHOULDN'T LEARN HOW TO DO GLP
WE SHOULD LEARN HOW TO
REINHAVEN'T CLINICAL TRIALS SO
WE CAN GET INTO HUMANS FASTER
AND REDUCE THE REGULATION IN THE
CLINICAL TRIAL SO WE CAN GET TO
HUMANS FASTER.
>> I THINK RISK IS THE BIGGEST
ISSUE.
THE FDA GOES BACK AND FORTH.
WE'RE SORT IN THE MIDDLE NOW.
IT'S A LOT EASIER.
OUR DISCUSSIONS WITH THEM,
THEY'RE A LOT MORE OPEN FOR
DISCUSSIONS.
I HAVE NO PROBLEM WITH THE FDA
RIGHT NOW.
IN WHAT THEY'RE ASKING US TO DO.
THERE WAS A POINT AT WHICH THEY
GOT VERY CRANKY ABOUT ANY SAFETY
ISSUES.
WHAT THEY'RE NOW LOOKING AT IS
RISK AND BENEFIT.
AND I THINK THAT'S REALLY
IMPORTANT.
THERE'S NOTHING THAT YOU PUT IN
YOUR MOUTH THAT DOESN'T HAVE
RISK INCLUDING WATER.
BUT WE'VE GOTTEN TO THE POINT IN
OUR COMMUNITIES WHERE WE DON'T,
WE DON'T ALLOW, WE DON'T WANT
RISK.
AND THAT'S WHY THERE ARE PARENTS
ALL OVER THE PLACE NOT
VACCINATING THEIR CHILDREN
BECAUSE ONE OUT OF EVERY 500,000
BABIES HAD THE PROBLEM OF
VACCINATION.
IT'S NO.
THERE IS RISK WITH EVERYTHING
THAT WE DO.
AND I DON'T WANT TO GO BACK TO
FOUR MONTHS BEFORE WE GET TO
HUMANS.
I ALREADY KNOW THAT THAT'S NOT
GOOD.
BUT FROM THE PERSPECTIVE OF
ACTUALLY TAKING THE RISK,
ACTUALLY HAVING THE RISK ONCE
YOU PUT THE PRODUCT OUT THERE.
BUT I DON'T WANT TO HAVE A 15-20
YEAR DEVELOPMENT CYCLE EITHER.
IT HAS TO BE A BALANCE.
>> I WANT TO ASK ABOUT THE
REGULATORY CHALLENGES OF
DEVELOPING A DRUG THAT'S GOING
TO BE USED IN A MULTIDRUG
COMBINATION THERAPY.
SO I NOTICED IN YOUR PHASE ONE
THAT YOU TESTED JUST THE SQ109.
WERE THERE DISCUSSIONS WITH FDA,
DID THEY WANT TO TRY IT IN
COMBINATION WITH THE OTHER DRUGS
THAT YOU MIGHT BE USING IN PHASE
ONE?
AND THEN ALONG WITH THAT, IN
YOUR CLINICAL TRIALS, IT'S, IN
THIS CASE YOU CAN KIND OF SLIP
IT IN FOR EMB BECAUSE IT'S A
SIMILAR KIND OF PATHWAY.
BUT SO HOW DO YOU WORK IT IN
WITH COMBINATION?
DO YOU ADD IT ON OR DO YOU
SUBSTITUTE?
>> SOMETIMES YOU ADD IT ON,
SOMETIMES YOU REPLACE SOMETHING.
IT'S, WHEN YOU, THE FIRST STUDY
YOU HAVE TO DEMONSTRATE THAT
YOUR DRUG IS SAFE THAT IT'S NOT
GOING TO KILL PEOPLE AND IT'S
NOT GOING TO CAUSE AN
IRREPARABLE DAMAGE.
THE PHASE 2A STUDY THAT I THINK
OF AS A TB PATIENT SAFETY STUDY
WE DID AT IT TO IN -- BECAUSE WE
WERE INTERESTED TO SEE WHETHER
IN A SHORT PERIOD OF TIME WE
COULD MAKE IT LOOK BETTER AS IT
DOES IN MICE.
14 DAYS IS TOO SHORT.
AND NOW WE'RE DOING DRUG DRUG
INTERACTION STUDIES IN HEALTHY
HUMANS AND TB PATIENTS BECAUSE
TB PATIENTS ARE SICK.
THEY'RE GOING TO RESPOND
DIFFERENTLY.
SO IT'S A STEP PROCESS AND AT
EACH STEP YOU TRY TO REDUCE THE
RISK FOR THE PEOPLE THAT YOU'RE
USING AS YOUR GUINEA PIGS.
THEY ARE NOT GUINEA PIGS, THEY
ARE HUMAN BEINGS.
AND SO IT'S A PROCESS OF TRYING
TO FIGURE OUT RISK BENEFIT FOR
EACH OF THEM AND MOVING ALONG
CAREFULLY SO THAT YOU ALWAYS
KNOW SAFETY.
THIS IS A PRINCIPAL ISSUE FOR
FDA.
EFFICACY IS IMPORTANT BUT SAFE
AND EFFICACIOUS.
SAFE AND EFFICACIOUS.
>> THAT WAS A GREAT LECTURE
THANK YOU VERY MUCH.
I WANTED TO ASK A QUESTION ABOUT
WHETHER THERE IS ANY ROLE FOR
CONSIDERATION WHEN YOU'RE
DEVELOPING DRUGS FOR -- WIDE
SPREAD IN DEVELOPING COUNTRIES
TAKEN FOR A LONG TIME AND SO
FORTH.
I KNOW CLIFF MENTIONED HE MADE
THE MOST EXPENSIVE
[INDISCERNIBLE] APPROACH BUT FOR
THE FINAL PRODUCT HOW DID THAT
COME OUT?
AND YOU NEED THE DRUG FIRST I
UNDERSTAND BUT IS THAT A
CONSIDERATION AT ALL.
>> OF COURSE.
ANTIBIOTICS ARE NOT BIOLOGICS
AND YOU CAN'T CALL THEM ADD $300
[INDISCERNIBLE] THAT'S A PROGRAM
WE'VE NOW DONE SOLUTION-BASED
CHEMISTRY AND MANUFACTURED ALL
OF OUR BATCHES THAT WE NEED FOR
THE FDA AND THE PRICE WILL GO
DOWN EVEN FURTHER.
IT'S WAY DOWN NOW BUT IT WILL GO
DOWN EVEN FURTHER ONCE WE SCALE
UP FOR COMMERCIAL PRODUCTIONS IF
WE GET TO DO THAT.
AND ANY VENTURE CANT IN HERE?
ARE THERE ANY FUNDERS OF HIGH
NET WORTH INVESTORS HERE?
ALL RIGHT.
SO FROM MY PERSPECTIVE IT
DEPENDS.
THE PRICE OF MY DRUG DEPENDS ON
WHO I'M TALKING TO.
IF I'M RAISING MONEY, I'M GOING
TO TELL THEM THAT THE MARKET IS
X BECAUSE SOMETHING IS SOLD AT
THAT PRICE.
SO IT IS SOLD AT $100 A PILL.
I WILL SAY IT'S A HUNDRED
DOLLARS A PILL.
I KNOW IN MY HEART OF HEARTS WE
PROBABLY WON'T BE SELLING IT FOR
A HUNDRED DOLLARS A PILL BUT I
MIGHT.
THERE IS THAT CHANCE.
FOR FUNDERS THE MARKET
OPPORTUNITY IS BIG MEANS THAT
THEY'LL GIVE ME THE MONEY TO GET
IT TO THE POINT WHERE I'LL KNOW
WHAT THE PRICE WILL BE.
SO THANK YOU FOR NOT HAVING ANY
VENTURE CAPITALISTS AND DON'T
PUBLICIZE THIS TO ANY VENTURE
CAPITAL PEOPLE.
>> YOU'RE BEING TELEVISED.
>> I KNOW.
>> LET'S TAKE ONE FINAL QUESTION
AND THEN WE'LL HAVE A REZIPPION
IN THE BACK, YOU CAN MEET WITH
PHIL.
>> PHIL TALK VERY MUCH FOR THE
LECTURE.
MY QUESTION HAS TO DO WITH THE
SLIDE BEFORE THIS SHOWING THAT
THE TECHNOLOGY TRANSFER IN DRUG
DEVELOPMENT IS CONCERNED YOU
NEED LOTS OF PARTNERSHIPS AND I
NOTICE YOU WORKED IN TANZANIA --
BRINGING ALL THESE DIFFERENT
PEOPLE TOGETHER.
WHAT WOULD YOU RECOMMEND OR
SUGGEST IS THE MOST IMPORTANT
THING TO CONSIDER WHEN YOU'RE
TRYING TO DO SOMETHING LIKE THIS
IN A PLACE LIKE TANZANIA.
>> I THINK THE MOST IMPORTANT
PLACE FOR ANY RELATIONSHIP IS TO
UNDERSTAND THE ROLE EACH GROUP
PLAYS AND TO HAVE RESPECT FOR
THE WORK THEY DO.
INCLUDING THE PATIENTS BY THE
WAY.
IT'S OPEN AND TRANSPARENT AND
YOU TALK ABOUT IT I THE THINGS I
NEED TO DO IS DIFFERENT FROM THE
PEOPLE IN TANS KNEE YEAH WANTS
TO DO FOR A PATIENT.
WE HAVE TO TALK, COMMUNICATE, WE
HAVE T
O
U
N
DERSTAND THE AGENDAS FOR
EVERYBODY.
WE HAD GREAT SUCCESS WITH THE
PANACEA GROUP AND THE
INVESTIGATOR FOR OUR PARTICULAR
STUDY IS MICHAEL WHO HAD A SITE
IN TANZANIA.
>> ALL RIGHT.
SO FIRST OF ALL LET ME THANK THE
SPEAKERS FOR A WONDERFUL
COORDINATED PRESENTATION.
[APPLAUSE]
AND THANK PHIL AND OTT FOR
MAKING THIS ALL POSSIBLE.
AND THERE IS A RECEPTION IN THE
REAR.
YOU CAN TALK TO THE SPEAKERS.
AND SHARE THOUGHTS ABOUT DRUG DEVELOPMENT