>> WELCOME, EVERYBODY.
TO TODAY'S SEMINAR.
PRIVILEGED TO HAVE MARK DENNISON
WORLD'S LEADER IN CORONAVIRUS
VIROLOGY AND IMMUNOLOGY.
MARK IS NOW THE
DIRECTOR OF THE
DIVISION OF PEDIATRIC INFECTIOUS
DISEASES AT VANDERBILT
UNIVERSITY.
HE WAS AN UNDERGRADUATE FIRST AT
THE UNIVERSITY OF KANSAS AND
KANSAS IS CLEARLY DOING
SOMETHING RIGHT.
THEY'VE MADE HUGE CONTRIBUTIONS
TO THE CORONAVIRUS.
MARK HAD THE GOOD FORTUNE OF
WORKING WITH STAN PERLMAN.
ONE OF THE HEROES OF THE COVID
EPIDEMIC.
ONE OF THE FEW VIE LOCAL JUST
WHO UNDERSTOOD THE IMPORTANCE OF
IT EARLY ON.
AND I'M SURE MARK DID VERY
WELL BY TRAINING WITH HIM.
I LOOKED UP SOME OF YOUR EARLY
PAPERS AND I SAW THIS REMARKABLE
PAPER, THE PROTOTYPE CORONAVIRUS
THAT MOST OF THE FIELD WORKED ON
AS A PROTOTYPE AND MARK WAS PUN
U ONE OF THE FIRST PEOPLE -- HE
WAS THE FIRST ONE TO SHOW THE
POLLY PROTEIN CLEAVAGE.
SO THAT WAS A LANDMARK THAT GOT
MARK'S CAREER GOING.
HE MOVED ON TO AN ASSISTANT
PROFESSOR SHIP AT THOMAS
JEFFERSON UNIVERSITY WHERE HE
STARTED A FRUITFUL COLLABORATION
WITH SUSAN WISE AND RALPH BARAK
WAS IN YOUR LAB.
>> NO.
BUT WE'LL TALK ABOUT THAT LATER
>> THEY PUBLISHED SOME OF THE
MOST IMPORTANT EARLY PAPERS ON
MOLECULAR VIROLOGY OF
CORONAVIRUS.
MANY OF THE ORIGINAL STUDIES --
DESCRIBING THE BASIC MOLECULAR
VIROLOGY.
HE MOVED ON TO VANDERBILT WHERE
HE HAS HAD A FANTASTIC CAREER.
ONE OF THE PIONEERS IN
CORONAVIRUS.
SOME NOTABLE FINDINGS 2004 HE
ESTABLISHED THE EXPRESSION AND
CHARACTERISTICS OF MANY OF THE
SARS-CoV-SARS-CoV-2.
2014 A BEAUTIFUL PAPER WITH CELL
BIOLOGY SHOWING HOW IT'S
EXPLORED TO GENERATE AND
REPLICATE.
2018 ANOTHER PRACTICAL
DISCOVERY.
DISCOVERED THAT THE REMDESIVIR
ACTIVITY BETWEEN THE CORONAVIRUS
-- SO MARK HAS HAD A REMARKABLE
CAREER.
HIGHLY PRODUCTIVE.
A SUPERSTAR FOR THE LAST FEW
YEARS AND MARK YOU MUST BE
GIVING A SEMINAR A WEEK NOW.
MAYBE HIS MOST UNIQUE CLAIM TO
FAME, $1 MILLION FROM DOLLY
PARTON.
THAT MIGHT HAVE BEEN QUITE A
THRILL.
I'M SURE YOU DIDN'T GET THE
WHOLE MILL BUT A GOOD CHUNK OF
IT.
THANK YOU FOR AGREEING TO
PARTICIPATE AND WE'RE LOOKING
FORWARD TO YOUR SEMINAR.
>> JONATHAN, THAT IS ONE OF THE
NICEST INTRODUCTIONS I'VE HAD.
I'LL TRY TO LIVE UP TO THE
IMAGE.
IT'S AN HONOR TO BE INVITED.
I THOUGHT ABOUT WHERE TO GO WITH
THIS AND I TITLED IT ANTIVIRALS
FOR CORONAVIRUS: MECHANISMS,
RESISTANCE AND REGULATION.
AND I HAVE SEVERAL GOALS.
I WANT TO DESCRIBE SOME EXCITING
WORK THAT WE'VE DONE WHICH GOES
DEEP INTO THINKING AND HOW WE
APPROACH IT.
AND I ALSO WANT TO MAKE THIS --
AN RCR.
HOW WE THINK ABOUT THE
EXPERIMENTS AND THE TYPES OF
EXPERIMENTS THAT WE CAN PERFORM
WITH PANDEMIC VIRUSES.
AND EXPECTATIONS AND
REQUIREMENTS.
FOR MOVING THINGS FORWARD IN
DRUG DEVELOPMENT FOR HUMAN USE
BUT ALSO FOR REGULATION OF
BIOSAFETY AND BIOSECURITY.
SO I HOPE THIS WILL BE
INFORMATIVE AND USEFUL AND I'M
HAPPY TO TAKE QUESTIONS.
BECAUSE I'VE BEEN SPENDING A LOT
OF TIME THINKING ABOUT THESE
ISSUES.
I WANT TO ACKNOWLEDGE THE
SUPPORT AND POTENTIAL OR
INTERACTIONS THAT I HAVE.
FIRST THE SUPPORT OF -- AM I
GETTING AN ECHO?
SO, I WANT TO THANK THE FOLKS
FROM MY LAB OF COURSE.
AND THE LONG TIME INTERES -- TIME
INTERACTIONS.
AND THEN EMORY UNIVERSITY.
AND THEN COLLABORATIONS AND
CONSULTATIONS THAT I MAY HAVE
ENGAGED IN.
I ALSO WANT TO MENTION BECAUSE
SOME OF MY OF COMES I'LL MAKE --
I'M A MEMBER OF NSABB.
SO THE NEED FOR ANTIVIRALS I
WISH WE DIDN'T OF COURSE.
WHY DO WE NEED THEM?
-- NOW WITH NEW CASES THIS VIRUS
IS NOT DONE WITH US YET.
IT DECIDES TO MUTATE TO A NEW
CHESS BOARD.
AND SO WE OF COURSE HAVE A LOT
THAT WE NEED TO DEAL WITH.
CONTINUED QUESTION EMERGENCE OF
VARIANTS THAT CAN RENDER MONEY
COLONIAL VACCINES THAT ARE
INEFFICIENTIVE.
AND BECAUSE EVERYBODY IS
PREDICTING THIS VIRUS IS GOING
TO BASKETBALL -- BECOME THE NEXT
SEASONAL FLU BUT I HAVE
SKEPTICISM ABOUT IT.
THESE ALSO CONSIDERED SOMETHING
-- PER USE.
TARGETING MULTIPLE CONSERVATIVE
FUNCTIONS AND ANYONE WHO HAS
WORKED ON HIV AND INFLUENZA
CERTAINLY RECOGNIZES -- THAT WE
SHOULD TARGET MULTIPLE FUNCTIONS
AND WORKING WITH COMBINATIONS
FROM THE BEGINNING.
THE RESISTANCE TESTING SHOULD BE
INTEGRATED IN THE INITIAL
DEVELOPMENT.
THIS SHOULD BE IN INVITRO AND
ENVY VOTE.
ANTICIPATION.
TO DEFINE PATHWAYS THAT VIRUSES
CAN USE TO ESCAPE FROM
ANTIVIRALS AND THEN EDUCATION
FOR USE AND HOW THEY WORK DURING
THE INFECTION.
MAYBE HALF OF THE CONVERSATIONS
I HAD HAVE BEEN ABOUT TRYING TO
GET PEOPLE TO UNDERSTAND TO USE
SOMETHING EARLY AND EFFECTIVELY
AND HOW ANTI VIRAL SHOULD WORK
AND WHEN IT SHOULD BE USED.
SO WHY SHOULD WE DETERMINE THE
GENETICS AND MECHANISM?
MONO THERAPY WILL FAIL.
THERE IS NO QUESTION THAT WE CAN
MAKE COMMENTS -- DIFFICULT TO
ACQUIRE RESISTANCE BUT I'M NOT
AS PATIENT AS THE VIRUS IS AND
THE EMPHASIS -- CONTINUES IN THE
UNVACCINATED POPULATIONS AND IN
THAT SELECTION IT MAY BE RAPID.
THERE MAY BE 100 TIMES LESS
MUTATIONS BUT THAT STILL MEANS
THEY HAVE A MILLION TIMES MORE
MUTATIONS THAN HUMAN DNA.
SLOW MUTATION IS A RELATIVE
TERM.
THE RAPID COMPARED TO --
ORGANISMS THEY MAY BE SLOW ERAS
THEIR BASELINE IN TERMS -- BUT
THEY CAN RAPIDLY ADAPT.
SO PREDICTIONS OF RESISTANCE FOR
SURVEILLANCE FROM NATURALLY
OCCURRING MUTATIONS AND FROM
TREATED PATIENTS.
TO DEFINING NEW ANTIVIRAL
TARGETS.
WE'VE BEEN -- AMAZED -- AT THE
FLEXIBILITY OF THE BIOLOGY THAT
YOU CAN SEE ADAPTED MUTATIONS
OCCURRING IN LOCATIONS THAT
SHOULD MAKE NO SENSE IN TERMS OF
A PROTEIN FUNCTION.
IT MEANS WE DON'T HAVE A CLUE --
AND THEN I THINK THAT WE NEED TO
BE MOVING TO A TERM ANTIVIRAL
STEWARDSHIP.
WE DON'T NEED TO WAIT UNTIL WE
SEE MASSIVE RESISTANCE.
WE NEED TO THINK ABOUT HOW WE
MANAGE THESE COMPOUNDS BOTH FOR
THEIR USE AND THE ADHERENCE OF
INDIVIDUALS WHO GET THEM AND FOR
HOW WE THINK SMART ABOUT
DEVELOPMENT SO THAT WE DON'T GET
IN A POSITION WHERE WE USE THE
DRUGS ONE AT A TIME AND NONE OF
THEM WORKING.
I WANT TO SPEND A FEW MINUTES ON
REPLICATION.
I HAVE A LOT OF THINGS, WE'RE
WORKING ON A NEW -- THE
REPLICATION STRATEGY -- I WANT
TO SAY OF COURSE EVERYBODY KNOWS
IS A STRANGE STATEMENT FOR ME
EVEN NOW.
BUT THE CONCEPT OF THE VIRAL
ENTRY AND WHERE IT'S TARGETING
-- FOLLOWED BY THE TRANSLATION
OF THE LARGE UP TO 30KB SINGLE
STRAND RNA GENOME.
IT'S TRANSLATED INTO TWO
OVERLAPPING POLLY PROTEINS.
THOSE ARE THEN PROCESSED IN THE
CASE OF SARS-CoV-2.
AND IN THE CASE OF SOME OF THE
VIRUSES THEY HAVE THREE.
PROCESS THESE 1 -- 16 PROTEINS.
AND ALSO HAVE OTHER STEPS IN RNA
MODIFICATION.
THAT CAN LEAD TO THE FORMATION
OF THE REPLICATION FACTORIES IN
THE CELL.
AND I COULD SPEND THE ENTIRE
TIME TALKING ABOUT THE BEAUTIFUL
COMPLEX DETAILS OF RNA VIRUS
REPLICATION.
ONE, THIS IS THE STAGE WHERE YOU
COPY THE GENOME RNA.
AND ALSO THE GENOMIC RNAs FOR
SCENT PROTEINS THAT ARE USED FOR
VIRUS REPLICATION.
AND ALSO ENGAGE IN RELY
COMBINATION OF LIFESTYLE.
THEY ARE SURPRISINGLY ROBUST.
NOW THE MAIN POINT, -- IS THAT
LOOKING AT A NEW INHIBITOR AND
THAT IS SUPPORTED THROUGH -- R19
AS WELL.
ONE THING THAT I GO BACK TO IS
BACK IN THE DAY IN 1995 WE
PERFORMED EXPERIMENTS
DEMONSTRATING THAT THE INHIBITOR
ABORTED AT ANY STAGE.
IT STOPPED NO MATTER.
SO THIS INDICATED THAT YOU WERE
NOT JUST BLOCKING THE PROTEIN
PROCESSING BUT THAT THE
PROCESSING OF THE PROTEINS FOR
REPLICATION WAS ACQUIRED
THROUGHOUT THE ENTIRE
REPLICATION CYCLE.
SO THE INHIBITOR CAN BE
PROFOUNDLY ACCURATE.
I'M GOING TO SPEND MORE TIME
TALKING ABOUT THE SYNTHESIS.
AND WHERE WE ARE WITH REMDESIVIR
AND RESISTANCE.
CORONAVIRUSES TAKE MONEY OF
THEIR NONSTRUCTURED PROTEINS TO
FORM A MULTI-PROTEIN REPLICATE
-- AND THEY ARE MEDIATED ON
THESE LITTLE BLOG WALLS HERE
THAT ARE WELL DESCRIBED.
RICK SNYDER AND OTHERS TO FORM
THESE -- THAT CAN BE MEMBRANE
MODIFICATIONS.
I AM GOING TO MOVE ON TO THAT
DISCUSSION.
SO ON THE UPPER LEFT IT'S SHOWN
THE TWO REGIONS OF THE POLLY
PROTEIN.
ONE POLLY PROTEIN.
THE TRANSLATION OCCURS AT THIS
OF ENTIRE DOMAIN.
THE WORK THAT I DID WAS SHOWING
THAT IF YOU TRY TO INVITRO
TRANSLATE THAT THE FIRST STARTED
ALMOST IMMEDIATELY.
IT TRANSLATES A STRING OF PEARLS
AND THOSE INCLUDE IMPORTANT
DOMAINS LINE THE RNA DEPENDENT
-- AND CAPPING ENZYMES.
AND THEN OTHER CO-FACTORS WHICH
DON'T SEEM OVEN VIMMATIC
FUNCTION.
-- IT'S A SYMBOL AND LOOKS LIKE
A DNA MULTI-PROTEIN ENZYME --
CO-FACTORS -- TYPE OF
ACTIVITIES.
STIMULATING FACTORS SUCH AS --
10 AND THEN OTHER ONES THAT MAY
BE IMPORTANT FOR STABILIZING AND
PROCESSING THE RNA STRAND
THROUGH IT.
SO CORONAVIRUS IS BIGGER AND
BADDER IN MANY WAYS AND ARGUED
FOR MANY YEARS THAT THIS COMPLEX
-- WHAT I'M GOING TO TALK ABOUT
NOW I'M GOING TO MOVE ON TO
TALKING ABOUT WHERE WE'VE GONE
WITH RESISTANCE AND I'M GOING TO
SUMMARIZE BRIEFLY WITH WHAT IS
HAPPENING WITH REMDESIVIR.
WHAT WE'RE TARGETING IS WITH THE
PROCESS OF RNA SYNTHESIS.
WHAT THEY FUNCTION AT THE LEVEL
OF -- IS THE RNA SIN THUS.
AND I'M GOING TO BE -- THIS IS
ALSO NOW MATURED.
THIS SCHEMATIC -- YOU CAN SEE
IT'S LACKING TREMENDOUS NUMBER
OF -- BUT IT'S ALWAYS WORTHWHILE
TO DESCRIBE WHEN PEOPLE TALK
ABOUT THE CORONAVIRUS THEY STILL
REPRESENT THE MORE CLOSELY
RELATED THAN THOSE OF THE ALPHA
OR THE GAMMA OR DELTA OF
CORONAVIRUS.
THAT THERE IS A TREMENDOUS
CONTRIBUTION OF BAT CORONAVIRUS
IN OTHER ANIMAL SPECIES.
I WANT TO BRING IT UP FOR A
COUPLE OF REASONS.
STILL AFTER 38 YEARS IT IS STILL
A ROBUST AND POWERFUL MODEL AND
MAYBE EVEN BECOMING MORE
IMPORTANT AGAIN FOR REASONS THAT
I'LL DESCRIBE.
AND SO TO SUMMARIZE REMDESIVIR
WHAT IT DOES ON THE LEFT IS --
SHOWING YOUR FIRST DOLLAR BILL
IN THE RESTAURANT.
THIS IS ONE OF THE FIRST FIGURES
-- THAT A GRADUATE STUDENT IN MY
LAB DESCRIBED AND SHOWED.
THE TREMENDOUS AN VITRO
ACTIVITY.
AND THAT IS IF YOU LOOK AT THE
CHANGE IN VIRUS CONCENTRATIONS
-- YOU'RE GETTING REALLY SIX
LOGS OF VIRUS INHIBITION OVER
TIME.
FULL LOG REDUCTION IN VIRUS
REPLICATION AND WHEN WE LOOKED
AT -- I WAS NOT A DRUG
DEVELOPMENT PERSON.
BUT WHEN WE STARTED AND I
STARTED REALIZING -- THE
EFFECTIVE CONCENTRATION.
WHICH IS CALCULATED FROM 10
POINT EXPERIMENTS FOR MORE WHICH
ALLOWS YOU TO LOOK FROM 0-100%.
SO WE'RE LOOKING AT SIX LOG
SCALE.
HERE WE'RE LOOKING AT 100
PERCENTAGE.
THIS IS THE CURVE.
THIS DRUG WAS COOL IN BOTH.
SO WHAT IS REMDESIVIR?
IT'S CALLED A MONO --
PHOSPHORAMIDATE.
IT FUNCTIONS AS A DELAYED OR
NONOBLIGATE -- FOGGING INITIAL
-- IT FUNCTIONS BY INCORPORATING
AND BECAUSE OF WHAT THE FACTORS
ARE WITHIN IT CAUSES A
TERMINATION OF THE -- ONE TO
THREE NUCLEOTIDES.
IT CAN GET INCORPORATED.
AND IT BYPASSES THE PROOFREADING
FUNCTION.
THIS IS WHAT PROFOUNDLY IMPACTED
US THAT THIS DRUG COULD DO THIS.
BECAUSE MOST TEST EDUCATED A
FLAT LINE WHERE THEY HAD NO
IMPACT.
IT FUNSE FUNS -- FUNCTIONS --
--
[ INDISCERNIBLE ]
AND NOT REALLY 100% CLEAR WHY
IT'S ABLE TO ESCAPE THIS.
SO OF COURSE IN THE INITIAL
STUDY -- IT SHOWED SHORTENED
HOSPITALIZATION EVEN IN SEVERELY
ILL PATIENTS.
IT STILL SHOWED A REDUCED
HOSPITALIZATION WHICH SHOCKED ME
THAT IT WAS ABLE TO BE EFFECTIVE
THAT LATE.
BUT A MORE RECENT STUDY WHICH
GETS TO AN IMPORTANT POINT IS AN
87% DECREASE IN HOSPITALIZATION
AND DEATH.
BUT AT A HIGH RISK PATIENT THAT
BENEFIT IS SIGNIFICANT.
AND SO IN ORAL FORMS OF
REMDESIVIR HAVE BEEN DEVELOPED
BY MULTIPLE AND STUDIED BY
MULTIPLE GROUPS AND A RECENT
STUDY LOOKED AT ITS EFFICACY --
SHOWING IT TO BE -- EFFICACIOUS.
BECAUSE OF A LOT OF BIOLOGY OF
HOW THAT WORKS.
AS PART OF THOSE INITIAL STUDIES
AND ALSO PUBLISHED -- IN 2018 WE
DID DEVELOPMENT TESTING OF
RESISTANCES.
WE DISCOVERED THAT IT WAS VERY
DIFFICULT TO GET.
IT TOOK 23 PASSAGES.
THIS IS OLD DATA AND WHAT WE
FOUND IS THAT AFTER PASSAGE WE
COULD SEE A SUM DIFFERENCE IN
RESISTANCE IN LOG ORDER
RESISTANCE.
WHEN WE SEQUENCED THE PASSAGE
POPULATION AT THE TIME WE WERE
NOT DOING MULTIPLE LINEAGES.
WE JUST DID ONE.
WE IDENTIFIED TWO MUTATIONS.
THERE ARE ONLY SIX IN THE WHOLE
GENOME.
SO IT WAS EASY TO DISCRIMINATE.
WHAT WE SHOWED IS THERE ARE TWO
MUTATIONS THAT OCCUR UP HERE AND
HERE.
AND THAT SIT IN REASONABLE
PROXIMITY.
AND THAT WHEN WE LOOK ON THE
RIGHT PANEL THAT THIS IS WILD
TYPE INHIBITIONS.
STILL SOME SENSITIVITY TO HIGHER
CONCENTRATIONS BUT DEFINITELY A
DISTINCTION OF ABOUT TWO LOGS
DIFFERENT.
WHEN WE LOOKED AT THE INDIVIDUAL
VIRAL MUTANTS -- WE SAW THAT
THEY BOTH HAD A LITTLE
INTERMEDIATE PHENOTYPE BUT WHEN
WE PUT THEM TOGETHER WE SAW WHAT
ALMOST LIKED LIKE PASSAGE 23.
THIS TO ME IS AN UNCOMFORTABLE
ZONE AND I WANT TO SEE IF THERE
ARE ADDITIONAL MUTATIONS THAT
CAN HAVE AFFECTS THAT ARE NOT IN
THE -- AS MENTIONED BEFORE.
THIS WAS THE MOST PROVOCATIVE.
WE CAN FIND IT BUT IT'S
ASSOCIATED WITH THE MUTATIONS
AND IT CAUSES A LOSS OF FITNESS
IN VITRO AND ATTENUATION IN
VIVO.
WE SAW A LOSS OF THE MUTANT
VIRUS AND AN INCREASE IN THE
WILD TYPE VIRUS.
WHEN THEY WERE INTRODUCED INTO
THE SARS-CoV -- THEY SAW THAT
IT HAD THE SAME RESISTANCE
PHENOTYPE.
AND WHEN THEY PUT IT IN ANIMALS
THEY SAW EVIDENCE THAT SUGGESTED
ATTENUATION -- THAT IS A
SIGNIFICANT CONCENTRATION.
BUT THEY RECOVERED MORE RAPIDLY
AND DID NOT GET AS SICK.
AND HAD LESS VIRAL SHED.
ONE OF THE IMPORTANT THINGS FOR
US -- ONE OF THE POINTS -- ALSO
WAS THE FACT THAT WE SAW WHEN WE
WERE INTERESTED IN THIS TISSUE
ACROSS RESISTANCE OR SENSITIVITY
THIS WAS THE SLIDE I JUST
SHOWED.
WHAT WE SAW IS BASICALLY
DECREASED SENSITIVITY WITH THE
DRUG WITH THE MUTATIONS.
IF WE TOOK THE SAME VIRUSES AND
TESTED THEM WE SAW INCREASE.
AND SO INTERESTINGLY THE
INDIVIDUAL MUTATIONS CAUSE AN
INTERMEDIATE LOSS OR INCREASED
SENSITIVE AND COMBINED THEY HAD
INCREASED SENSITIVITY.
SO OF COURSE THIS IS THE KIND OF
THING THAT ENCOURAGESES US.
SO IF I WERE THERE AND I COULD
SEE ALL OF YOU I WOULD PAUSE AND
ASK IF YOU HAVE ANY QUESTIONS.
I WANT TO DESCRIBE RECENT
RESULTS.
AND TAKE A CHANCE TO GO THROUGH
THE COMPLICATED STORY THAT HAS
TWO COMPONENTS.
THE ISSUE OF SCIENCE AND
DISCOVERY AND THE OTHER IS HOW
WE GET THERE AND WHAT THIS MEANS
WHEN WE THINK ABOUT RESISTANCE
TESTING FOR SARS-CoV-2 AND
OTHER PANDEMIC VIRUSES.
AND THESE ARE THE TEAMS THAT
PERFORMED THIS.
VANDERBILT, BIOCHEMICAL STUDIES
IN ALBERTA.
ANIMAL STUDIES THAT ARE MOVING
FORWARD WITH NOW IN DIRECTION OF
THE GRANTS WITH UNC AND THEN
GILLEAD.
THE STRATEGY OF RESEARCH BASED
ON THIS WE KNEW THAT THIS TOOK
TIME AND WE WANTED TO GET
STARTED IMMEDIATELY SO AS SOON
AS THE VIRUS WAS AVAILABLE TO US
WE WERE ONE OF THE FIRST PEOPLE
TO GET FROM IT THE CDC.
WE OBTAINED THE VIRUS AND WE DID
THE ACTIVITY STUDIES AND THEY
WERE DONE HERE IN VITRO AND ENVY
VOTE AT UNC TO LOOK AT THE
ACTIVITY OF REMDESIVIR AGAINST
SARS-CoV-2.
AT THE SAME TIME AS SOON AS WE
IDENTIFIED WE WANTED TO BEGIN
THE STUDIES.
WITH IT REQUIRING MULTIPLE
PASSAGES WE WANTED TO DO THAT
IMMEDIATELY.
TO DO EXACTLY WHAT WE DID WITH
MHV.
AND THEN LOOK AT THOSE AND
IMMEDIATELY TAKE THOSE AND
INTRODUCE THEM BACK INTO CLONES
OF SARS-CoV-2.
LIFE IN A PANDEMIC IS
COMPLICATED.
AND AS WE WERE PREPARING THIS
AND DOING THIS WE WERE
APPROACHING OCTOBER OF 2020 AND
LOW AND BEHOLD REMDESIVIR
RECEIVED EUA AND -- THE
CONVERSATION THAT I HAD -- WE
MAY HAVE SOME CHALLENGES.
SO THE FDA APPROVAL REQUIRED
DATA ON RESISTANCE AND AT THE
SAME TIME NOW BECAUSE THIS IS AN
APPROVED DRUG AND BECAUSE THIS
IS A PANDEMIC VIRUS AND BECAUSE
WE ARE DOING BOTH FORWARD
GENETICS AND REVERSE GENETICS
SUDDENLY WE HAVE ISSUES RELATED
TO PC30.
AND THE POTENTIAL FOR WHAT IS
CALLED A MAJOR ACTION WHICH
REQUIRES NIH APPROVAL WITH
SARS-CoV-2 THAT MIGHT
INTRODUCTION RESISTANCE.
LET ME SUMMARIZE THE INTERESTING
DILEMMA THAT WE FACED AT THIS
TIME.
YOU CAN CLAIM THIS IF YOU'RE A
GRAD STUDENT.
THIS IS FROM THE FDA -- NDA.
THEREFORE BASED ON APPROPRIATE
SCIENTIFIC DATA FDA HAS
DETERMINED THAT YOU ARE REQUIRED
TO CONDUCT THE FOLLOWING
STUDIES:
THAT IS EXACTLY WHAT WE WERE
DOING.
AT THE SAME TIME WE WERE MADE
AWARE THAT THE NIH GUIDELINES
INVOLVING MOLECULES -- HAVE A
SECTION THAT -- EXPERIMENTS THAT
REQUIRE APPROVAL.
AND I WON'T GO THROUGH THE WHOLE
THING BUT SOMETHING THAT
DESCRIBED AS A MAJOR ACTION THAT
CANNOT BE INITIATED WITHOUT --
THESE WERE THE THINGS -- IN LATE
OCTOBER THAT WE PAUSED OUR WORK
AND WE LOOKED AT THIS AND IT
SAYS SUBMIT RELEVANT
INFORMATION.
THE PUBLICATION -- THE
INFORMATION -- TO DO THE
EXPERIMENTS IN THE FEDERAL
REGISTER FOR 15 DAYS OF COMMENT
AND SPECIFIC APPROVAL BY THE NIH
-- SO ALTHOUGH THIS IS NOT THE
ONLY LANGUAGE -- THIS IS SOME OF
THE LANGUAGE.
SO THIS IS WHERE WE WERE AT THE
TIME.
SO WHAT DID WE DO?
WELL WE THOUGHT ABOUT THIS A LOT
AND WE DETERMINED THAT WE NEEDED
TO KEEP MOVING FORWARD WHILE WE
TRY TO CONSIDER THIS IN THE
CONTEXT OF A GREAT COMPLEXITIES
OF THE PANDEMIC WHICH CONTINUE.
SO HOW DID WE PURSUE OUR WORK?
WE WENT AHEAD AND DID ANALYSIS.
WE COMPLETED ANALYSIS AND
COMPLETED PASSAGE VIRUSES.
WE COMPLETED ALL OF OUR
SEQUENCING AND HAD OBTAINED OUR
PHENOTYPIC -- -- AND WE CHOSE TO
MOVE TO REVERSE GENETICS.
AND WE CAN DISCUSS ABOUT WHETHER
THAT IS AN APPROPRIATE WAY TO
LOOK AT THIS OR NOT.
BUT THAT IS WHAT WE DID AND THEN
BIOCHEMISTRY IN COLLABORATION
AND STRUCTURAL MODELING.
IT HAS HAD GOOD OUTCOMES BUT IT
LED TO WHAT WOULD BE A TWO OR
THREE MONTH PROCESS INTO A YEAR
-- EXTRA TIME THAT WAS REQUIRED
TO COMPLETE THIS WORK.
HOW DID WE APPROACH THIS?
BACK TO THE SCIENCE.
THE PASSAGE OF SARS-CoV-2 --
THIS IS THE RDV ACTIVE
METABOLITE.
WITH OUR MODEL WE CHOSE TO DO
THREE LINEAGES.
AND THE DRUG CONCENTRATION
THAT'S WERE APPLIED.
SO PLAYING ALONG WITH THE VIRUS
TRYING TO GET THE DRUG HIGH
ENOUGH TRYING NOT TO KILL IT
COMPLETELY.
AND SO YOU KEEP APPLYING DRUG
AND YOU KEEP CODDLING IT ALONG.
AND THAT IS WHAT WE DID.
SO WE WERE ABLE TO SELECT
RESISTANCE AND THEN AND
DEMONSTRATED -- BY POTENCY AND
EFFICACY.
THE THREE ON THE BOTTOM ARE --
THREE PARALLEL PASSAGES IN DMSO
WHICH IS THE CARRIER.
THIS SHOWS SIGNIFICANT
INHIBITION.
ALL THREE OF THEM CLOSELY
PARALLEL LINES.
ALL THREE LINEAGES SHOW
SIGNIFICANT LINK TO RESISTANCE.
ONE OF THEM SHOWING SIGNIFICANT
REDUCTION.
SO WHEN WE USED THESE POINT TO
CALCULATE ON THE RIGHT AND SHOWN
IN THE SHADED BLUE YOU CAN SEE
WHAT WE SAW WAS THAT ALL OF THE
PASSAGES HAD SIMILAR CURVES AND
VERY LITTLE CHANGE.
THERE WAS NO CHANGE IN THE
CONCENTRATION.
SO THEN WE WANTED TO KNOW WHAT
IS GOING ON IN THESE LINEAGES?
AND WHAT WE SAW WAS SOMETHING
THAT WAS VERY DIFFERENT.
DIFFERENT PATTERNS AND THERE
WERE THREE DIFFERENCES IN THREE
LINEAGES.
BY THE TIME WE PASSAGE THESE --
THIS IS PASSAGE 13 WE IDENTIFIED
THAT THERE WERE MUTATIONS OCCUR
OCCURRING -- AND RANGING FROM
38% TO GREATER THAN 99%.
FREQUENCY IN THE POPULATION.
AND PARTICULARLY YOU CAN SEE --
I WON'T DESCRIBE WHAT THEY ARE
NOW BECAUSE I'M GOING TO GO
THROUGH THEM IN MORE DETAIL.
BUT WE WANTED TO -- SAY WHAT WAS
THE EVOLUTION OF THESE MUTATIONS
AND HOW DID THEY OCCUR?
WE DID THIS IN PART BECAUSE WE
WERE FORCED TO DO THE MORE
DETAILED ANALYSIS OF FORWARD
GENETIC STUDIES, THE LIMITATIONS
THAT WERE PLACED ON US AT THE
TIME WITH THE EUA AND THE
APPROVAL OF THE DRUG BUT IT LED
TO SOME REAL INTERESTING
UNDERSTANDING AND OBSERVATIONS.
AND I WANT TO GO THROUGH A
COUPLE OF THESE.
LINEAGE 1 -- THEREOF WAS ONE
LINEAGE 1 THERE WAS ONE
SUBSTITUTION AND THAT STAYED AND
THEN YOU SAW THE GRADUAL
INCREASE IN THE OTHER MUTATIONS.
AND THIS OTHER MUTATION WHICH
WAS NOT PRESENT AT ALL CAME UP
LATE.
WHICH IS INTERESTING.
LINEAGE 2 WAS -- ONLY A SINGLE
MUTATION THAT CAME UP AND IT
CAME TO DOMINANCE AT 799 BUT THE
ONE THAT WAS THE MOST
INTERESTING WAS THIS ONE.
WE'RE FOLLOWING A MUTATION THAT
BYPASS AGE 13 WAS AT 100%.
759 AND 792.
AND THAT THESE MUTATIONS AROSE
AND CAME TO DOMINATE THE
POPULATION AND THIS HAD A
PATTERN WHICH SUGGESTED THAT YOU
HAD ONE THAT AROSE FIRST
FOLLOWED BY ANOTHER ONE THAT
AROSE LATER.
WE DID DIRECT RNA SEEK WITH
NANOPORE SEQUENCING.
WE CHOSE TO LOOK AT LINEAGES 1
AND 3.
IT HAD BETTER RESISTANCE
PHENOTYPE AND THEY GAVE US
EVOLUTIONARY PATTERNS.
SO THIS IS JUST SHOWING IF YOU
LOOK AT LINEAGE 1 IT'S EASY TO
SHOW IT THIS WAY.
FROM PASSAGE 6 TO PASSAGE 13.
AND WHAT WE SAW WAS THIS ONE
THAT CAME UP AT HIGH
CONCENTRATION AND IN COMBINATION
WE WERE ABLE TO TRACK.
IF YOU LOOK AT THOSE THAT OH
OCCURRED IN GENOMES YOU SEE THE
TRACKING FOLLOWED BY ULTIMATELY
THE STABILITY OF IT WITH THIS
S759 MUTATION.
IN LINEAGE 3 WE WENT FROM THIS
DOWN TO A DOMINANT COMBINES OF
THE TWO THAT WERE CO-OCCURRING.
WE CHOSE TO STUDY THIS IN MORE
DETAIL BECAUSE IT GAVE US A
CLEAN GENOTYPE.
WE WENT BACK AND LOOKED AT -- SO
WE SAW THESE IN THE POPULATION.
SINCE WE'RE DOING FORWARD
GENETICS CAN WE ISOLATE VIRUSES
AND LOOK AT THEM.
AND WE HAD MULTIPLE ONES THAT WE
DID.
BUT THE PATTERNS WE SAW WERE
EITHER THE 792 BY ITSELF OR THE
COMBINES OF THE TWO SO THIS WAS
THE REMAINDER OF THE WORK THAT
WE DID.
JASON PERRY AT GILEAD HAD DID
SOME NICE MODELING FOR US.
AND THEN LOOKING AT THE LOCATION
OF THESE PARTICULAR MUTATIONS
AND THIS IS SHOWING ALL OF THEM.
I WANT TO MAKE A COUPLE OF
IMPORTANT POINTS AND THAT IS THE
LOCATION OF THE S759 AND THE
792.
THIS IS SHOWN IN THE -- OVER
HERE.
THIS IS THE CATALYTIC CLEFT OF
THE POLYEERASE AND THEN THE
COVID MOLECULE -- THIS IS
SHOWING THE LOCATION OF 759.
THIS IS UNIQUE AND VERY EXCITING
IS BECAUSE IT OCCURS -- IN THE
CATALYTIC TRIAL.
IT WAS SURPRISING AND REALLY
GAVE US FOCUS.
IT DID NOT PREDICT ANY REAL
INTERACTIONS ASSOCIATED.
WHEN JASON WENT ON TO LOOK AT
THE PREDICTIONS OF HOW THESE
MIGHT INTERACT WITH REMDESIVIR
IT DID SUGGEST OR PREDICT THAT
S759 IN THE ACTIVE CORE MIGHT
HAVE A DIFFERENT INTERACTION
THAT MIGHT BE LOST.
SO THIS WAS A REDUCTION BUT IT
NEVERTHELESS GAVE US THE
ENTHUSIASM.
SO WHAT DID WE DO?
WE TOOK THE LINEAGES AND THE --
PLAQUE ISOLATES.
THESE WERE IN THE BACKGROUND OF
POPULATION VIRUSES.
SO WE HAD TO COMPARE THOSE.
WHAT WE SAW WAS -- IF WE LOOKED
AT THE DSMO -- WHEN WE TOOK THE
792 ALONE WE SAW AN INTERMEDIATE
PHENOTYPE.
WHEN WE LOOKED AT EITHER THE
COMBINES OF 759 PLUS 792 WE
CAPITULATES THE LINEAGE.
SO COULD NOT PROVE IT BECAUSE WE
DID NOT ISOLATE IT.
AND WHEN WE TOOK THAT SAME DATA
AND CONVERTED IT -- -- WE SAW
SIGNIFICANT DIFFERENCES
ASSOCIATED WITH THOSE ISOLATED
VIRUSES WITH A SHIFT OF 2.6X
INCREASE COMPARED TO WILD TYPE
UP TO 8X.
WITH THE LINEAGE AND THE SIMILAR
ALMOST IDENTICAL CURVES BUT THE
VALUE IS ALMOST IDENTICAL WITH
THE TWO MUTATIONS.
SO AGAIN REMEMBER WE FELT WE
WERE NOT IN A POSITION TO DO
REVERSE GENETICS WITH
SARS-CoV-2 BASED ON THE DATA
THAT I PRESENTED AT THE TIME SO
WE MOVED TO DO THIS IN ANOTHER
BETA CORONAVIRUS -- AND MOUSE
HEPATITIS VIRUS.
IT'S ABOUT 75% 85%.
POLYMER AS.
WHAT WE SAW WAS A SIGNIFICANT
CONS FIR MAKINGS.
-- CONFIRMATION.
*.
WHAT WE SAW WAS ICE GENETIC WILD
TYPE -- WITH SIGNIFICANT
INHIBITION.
-- AND INTERMEDIARY PHENOTYPE
WITH THE ACTIVE RESIDUE AND THEN
ALMOST COMPLETE RESISTANCE
PHENOTYPE.
SO THIS TO US PROVIDED
SIGNIFICANT CONFIRMATION.
ONE, THAT THE MUTATIONS COULD
REMEDIATE RESISTANCE BY
THEMSELVES AND TWO, THIS IS
TRANSFERABLE BROADLY ACROSS
DIFFERENT -- GROUPS OF
CORONAVIRUSs.
SO THIS WAS AN IMPORTANT
OBSERVATION FOR US.
AND WHEN WE LOOKED AT THAT THAT
ALSO WA -- RECAPITULATES.
SO THE DATA WE HAD SEEN IN TERMS
OF THE CO-EVOLUTION AND THE
SEPARATE ADDITION OF THE 7th
MUTATION -- THIS REALLY SUPPORTS
HOW THAT EVOLUTION AND WHY THAT
EVOLUTION MIGHT HAVE OCCURRED.
SO NEXT QUESTION WAS ABOUT WHAT
WAS THE IMPACT ON VIRUS
REPLICATION AND FITNESS OF THE
VIRUS.
WE DEFINE IT AS COMPETITIVELY
BUT WE WERE NOT YET IN THE
POSITION OF DOING COMPETITIVE
EXPERIMENT.
-- COMPARING REGULAR REPLICATION
REPLICATION.
THOSE MAY BE REAL AND WE'LL KNOW
THAT BY DOING COMPUTATION.
BUT REMEMBER THESE WERE ALL FROM
GROWTH ADAPTATION.
SO THERE IS A LOT OF GROWTH
ADAPTATION THAT MAY GO ON TO
CHANGE THAT BUT WHEN WE ISOLATED
IT AND LOOKED AT THEM WE SAW A
DIFFERENT STORY.
WILD TYPE -- THESE HAD AN
IMMEDIATE DEFECT WITH
SIGNIFICANT DELAY.
WHEREAS IN THE DOUBLE MUTANT HAD
A SIGNIFICANT ALTERATIONS AND
DELAY IN ITS REPLICATION
SUGGESTING A FITNESS COST THAT
WAS ASSOCIATED WITH THE
INDEPENDENT MUTATIONS WHICH WAS
ENCOURAGING.
SO NEXT WE WANTED TO LOOK AT THE
BIOCHEMISTRY AND THIS WAS A
BEAUTIFUL WORK DONE IN THE LAB.
I WANT TO SUMMARIZE.
THIS IS IMPORTANT AND IT IS
AVAILABLE TO THOSE WHO WANT TO
REVIEW IT.
LOOKING AT S759A AND 792A IN THE
COMPLEX.
WILD TYPE VIRUS FAVORED
INCORPORATION OF REMDESIVIR.
YOU SUE TH ---IN CONTRACT YOU SAW THE
SIGNIFICANT SHIFT TO THE OTHER
SIDE WHERE NOW ATP IS FAVORED
OVER REMDESIVIR.
AND S792A HAD NO DIFFERENCE.
THIS WAS EXCITING TO SEE.
IT WAS VERY ENCOURAGING AND
SUPPORTING OF THE RESULTS THAT
WE HAD SEEN THAT WE WERE SEEING
THE SIGNIFICANT DIFFERENCE WITH
759 ALONE AND THEN WITH THE
COMBINES.
-- COMBINATION.
WHEN WE LOOKED -- THE BASIC
THING IS THAT WHEN YOU LOOKED AT
WILD TYPE THIS IS SHOWING THE
SAME DATA IS THAT THIS IS ATP
INCORPORATION VERSUS REMDESIVIR
INCORPORATION SO THE EFFICIENCY
WAS SIGNIFICANTLY HIGHER.
TWO AND A HALF FOLD HIGHER.
IN THE SETTINGS OF THE 759
MUTATION IT HAD SIGNIFICANT
DECREASE -- BUT THE DIFFERENTIAL
DIFFERENCE THE DELTA DELTA WAS
THAT IT FAVORED ATP OVER
REMDESIVIR.
AND 792 HAD NO CHANGE.
SURPRISINGLY IT INCREASED ATP
INCORPORATION BUT IT DID NOT
ALTER REMDESIVIR IN CORPORATION.
SO IT WAS A WASH IN THAT REGARD.
SO THIS RESULTED IN NUMBERS AND
-- MANY OF YOU MAY UNDERSTAND
THESE BETTER THAN I DO.
BUT THE ISSUE OF SELECTIVITY
WHICH REPRESENTS THE V MAX OVER
KM DIFFERENCE BETWEEN ATP AND
REMDESIVIR AND IT WAS LIKE FOUR
FOLD INCREASE FOR ATP OR
DECREASE FOR REMDESIVIR AND
DISCRIMINATION IS LOOKING AT
THIS NUMBER COMPARED TO THAT OF
WILD TYPE.
COMPARING THAT WITH WILD TYPE
AND THAT WAS ABOUT 10 TIMES MORE
AND THESE NUMBER WERE ALL
CONSISTENT AND BEAUTIFULLY
RESOLVED.
SUGGESTING THIS REAL SHIFT IN
HOW THIS DRUG WORKS.
SO SINCE 792 DIDN'T DO THIS THE
QUESTION WAS WHAT DID IT DO?
AND THE GROUP HAD SOME IDEA FROM
OTHER WORK THAT THERE MAY BE
OTHER MECHANISMS AND ONE WAS HOW
MUCH ATP DOES IT TAKE.
THAT MEANS IS WE NEED TWO
DIFFERENT TEMPLATES.
ONE THAT BASICALLY HAD -- IN THE
RUN OF TEMPLATE THAT WOULD
NORMALLY INCORPORATED --
REMDESIVIR AND THAT THIS WOULD
REPRESENT A PLACE WHERE YOU
WOULD HAVE POTENTIAL
INCORPORATION AND YOU CAN SEE
HOW THAT WORKS.
IN CONTRAST TO REMDESIVIR IT
INCORPORATED INTO THE STRAND SO
WITH WILD TYPE VIRUS IT DOES
JUST FINE ACROSS THE TEMPLATE A.
WITH UTP AS IT IS SUPPOSED TO
INCORPORATING HERE BUT WITH
TEMPLATE R INCORPORATED IT TAKES
HIGH CONCENTRATIONS TO GET UP TO
-- A HIGHER CONCENTRATION TO
OVERCOME THE INHIBITION.
SO WHEN THEY LOOKED AT THAT WITH
THE 792 MUTANT THEY SAW WITH
WILD TYPE THIS IS ESSENTIALLY
REPRESENTS THE CURVE SEEP OVER
HERE IN READ.
IT DIDN'T -- WAS NOT ABLE TO USE
UTP TO OVERCOME.
IN CONTRAST THE 792 MUTATION WAS
MUCH MORE PROFOUNDLY AT VERY LOW
CONCENTRATIONS OF UTP TO
OVERCOME.
SO THESE TWO THINGS TOGETHER
SUGGESTED THAT THERE ARE TWO
MECHANISMS.
ONE BUT IS FAVORING ATP OVER
REMDESIVIR AND THE OTHER IS
FAVORING LOW CONCENTRATIONS OF
ATP TO OVERCOME -- -- ALREADY IN
THE TEMPLATE.
THEN NEXT I WANT TO FINISH UP --
LOOKED AT THIS OF COURSE.
WHAT IS HAPPENING IN THE
POPULATION?
AT THE TIME WHICH WAS ABOUT A
MONTH AGO -- WE HAD LOOKED AT
ABOUT 7 MILLION GENOMES IN THE
DATABASE AND YOU CAN SEE THE
MUTATIONS THAT WE'VE IDENTIFIED
AND SELECTED AND THERE ARE
PROFOUNDLY LOW CONCENTRATIONS.
759A WAS SEEN IN ONE.
SEQUENCE OUT OF 6 OR 7 MILLION.
AND THERE WERE MANY 759
SUBSTITUTIONS -- OF ALL OF THESE
RESIDUES AND THE MOST FREQUENT
WAS IN 189S.
REALLY NATURALLY OCCURRING ONES
ARE VERY FEW.
WHICH IS ENCOURAGINGS ALSO.
BUT IT ALSO SUGGEST THAT WE NEED
TO UNDERSTAND THIS BECAUSE THIS
IS NATIVE SUBSTITUTIONS.
THIS IS A REPLICATED PROTEIN.
HIGH LEVEL OF SELECTION WITH A
HIGHLY EFFECTIVE DRUG LEADS TO
HIGH GENETIC BOTTLENECK THERE --
THAT ARE THERE.
759 WAS PRESENT IN THE VIRUS
STOCK THAT WE HAD WHICH WAS A P3
STOCK.
.046%.
SO WAS THAT A PASSAGE ADAPTATION
FROM THEM OR SOMETHING THAT
ACTUALLY DID COME FROM THE
ORIGINAL STRAIN?
SO IT WAS PRESENT.
AND IT DID POTENTIALLY HAVE THAT
ADVANTAGE.
WE DID NOT SELECT IT OR FURTHER
PASSAGE THE VIRUS TO GET THAT.
SO I DON'T KNOW WHAT THIS MEANS
BUT WE HAVE A LOT TO LOOK AT.
TO SUMMARIZE -- PASSAGE OF
SARS-CoV-2 IS IN MULTIPLE
POTENTIAL GENETIC PATHWAYS TO
RDV RESISTANCE WITH HIGH GENETIC
BARRIER.
MUTATIONS AT 759 -- --
THIS WAS BOTH INTERESTING AND
NOT SURPRISINGS BUT THE CURRENT
VIRUSES CAN DO THIS.
SO I THINK THIS IS THE SORT OF
BROAD VIEW WE WANT TO HAVE OF
THIS KIND OF RESISTANCE STUFF.
THE QUESTION IS WHAT TO WE DO
NOW?
WHAT IS OUR IDEAL TO-DO LIST?
TO DO DIRECT CO-IN FIBS
COMPETITION FITNESS AND.
AND OF COURSE SO THEN TESTING
CROSS RESISTANCE --
HOW DO WE GO ABOUT THAT AND
WHERE DO WE GO FROM HERE?
EUA AND NDA, WE'RE AT THE
BARRIER AND SO WHERE DO WE GO?
SO I HAVE BEEN THINKING ABOUT
THIS A LOT.
AND I THINK THAT THIS IS
SOMETHING THAT WHEN I -- MENTION
THIS WE HAVE WHAT APPEAR TO BE
DIFFERENTIAL REQUIREMENTS AND
ARE VALID PUBLIC HEALTH NEEDS
WITH PUBLIC HEALTH CONCERNS CAN
WE DO GENETIC STUDIES.
IF IT HASN'T BEEN PROVEN TO BE A
RESISTANCE WE CANNOT TEST IT.
BECAUSE IT IS NOT PROVEN.
IF IT'S PROVEN -- BUT WE CANNOT
PROVE IT UNLESS IT'S BEEN TESTED
SO, THAT IS THE QUESTION.
OR DO WE WAIT UNTIL THEY EMERGE.
SO WITH THAT WITH THOSE TWO
DIFFERENT ASPECTS I'LL STOP.
I WANT TO THANK AGAIN ALL OF THE
PEOPLE THAT DID ALL OF THIS WORK
OVER THE LAST COUPLE OF YEARS.
I'M GRATEFUL TO BE PART OF THE
TEAM.
I CAN LEAVE MY SLIDES UP OR STOP
THEM AND HAPPY TO TAKE
QUESTIONS.
>> THANK YOU, MARK.
THIS WAS A WONDERFUL TALK.
VERY THOUGHT PROVOKING AND WE
HAVE A LOT OF QUESTIONS.
SO I'M GOING TO -- GROUP THEM.
>> I CAN END MY SHARING.
>> OKAY.
SO GIVEN WHAT YOU'VE SHOWN TODAY
-- AND THE LEVEL OF INFECTIOUS
AROUND THE GLOBE DO YOU FEEL
THAT GIVING ONE DRUG REMDESIVIR
IS STILL -- OR SHOULD PHYSICIANS
GO WITH GIVING A GROUP OF DRUGS
SO THAT TO MINIMIZE THE
POTENTIAL FORGETTING RESISTANCE.
>> THANK YOU FOR THAT QUESTION.
AS A PHYSICIAN AND A INFECTIOUS
DISEASE PERSON -- I THINK I SAID
IT LAST YEAR AT THE NIH
ANTIVIRAL -- WE SHOULD BE
DEVELOPING COMBINATIONS.
THERE ARE SO MANY THINGS I'M NOT
AN EXPERT IN SO I'M WITH PEOPLE
WITH THE FDA AND OTHERS I'M
GOING TO TREAD ON THIN ICE.
AN EUA DOES NOT ALLOW YOU TO GO
OFF LABEL.
SHOULD TRIALS BE DONE AND I
BELIEVE THEY SHOULD.
WHEN WE LOOK AT THE EUAs --
THERE ARE CONSTRAINING IN MANY
WAYS AND MANY QUESTIONS ARISE.
HOW CAN WE USE THESE
INDIVIDUALLY AND HOW CAN WE FIND
THEM INDIVIDUALLY AND USE THEM.
BUT THE ANSWER IS I BELIEVE ONE
OF THE THINGS THAT HASN'T COME
UP IS THAT WE SHOULD ONLY BE
LOOKING AT COMBINATIONS.
ABSOLUTELY FOR PREVENTION.
CAN PEOPLE JUST GO AND DO THAT?
NO.
THERE WOULD NEED TO BE AN
ENCOURAGEMENT -- TO WORK ACROSS
COMPANIES TO TEST THESE THINGS
TOGETHER BECAUSE I THINK -- ONE
PLUS ONE EQUALS 4.
ONE ALONE IS GOING TO EQUAL ZERO
IF YOU'RE NOT CAREFUL
>> THERE WAS A QUESTION
REGARDING LIFE-THERE IS ANY DATA
ON THE EFFECTIVENESS OF
REMDESIVIR IN VAXED VERSUS
UNHAVE BEENED INDIVIDUALS?
>> I ALWAYS RETREAT BACK TO THE
LAB.
WHEN THIS HAPPENS.
THE DRUG IS GOING TO WORK
AGAINST ANY VIRUS AND EARLY ON
IT'S GOING TO -- VIRUS
REPLICATION.
WHAT WE DON'T KNOW IF YOU'RE
ONLY REPLICATED 10 TO THE 5th
INSTEAD OF 10 TO THE 8th DOES
IT MATTER.
IF YOUR DURING RACE I -- DURATION
IS SHORTER.
THEY NEED TO BE USED EARLY.
AND THE LIMITATIONS ON TESTING
AND DIAGNOSTICS AND DOCTORS
SAYING YOU'RE NOT SO BAD.
LET'S SEE HOW DO YOU.
SO I THINK TO GET THESE IN AN
ORGANIZED WAY IS GOING TO BE ONE
OF THE CHALLENGES.
ALSO IF THEY ARE USED PARTIALLY.
YOU HAVE LOTS OF PEOPLE AROUND
THEM.
THE PEOPLE THAT ARE AT RISK ARE
THOSE THAT ARE NOT VACCINATED
AND THEN THEY START TAKING THE
DRUG AND START FEELING BETTER
AND THEN STOP TAKING THE DRUG.
>> TRACK WHERE THE DRUGS ARE
GOING AND HOW MANY PEOPLE ARE
USING IT AND HOW LONG?
>> I'M NOT PRIVY TO THAT BUT IF
YOU READ THE NDA AND THE
EXPECTATIONS FROM THE FDA TO
PROVIDE A LOT OF DATA ON
INFORMATION.
I THINK THAT IS ALL DATA THAT --
THEY ARE ASKED OR ENCOURAGED TO
PROVIDE.
THAT IS PART OF THE EUAs IS TO
LOOK FOR RESISTANCE ISSUES.
>> ONE QUESTION IS MIGHT THERE
BE AN INDEPENDENT REVIEW PROCESS
THAT CAN SPEED THIS APPROVAL
PROCESS?
>> I SUPPOSE.
I'VE SEEN INCENTIVES THAT APPEAR
TO GO -- I'LL COMMENT THAT
RECENTLY A THING CAME OUT --
WITHOUT A PUBLIC COMMENT.
THIS IS SO IMPORTANT THAT WE'RE
NOT DOING PUBLIC COMMENT.
ANY INTRODUCTION OF A -- ACID --
FROM SARS-CoV IS NOW SELECT
AGENT.
SO WHAT CONSTITUTES A VIRULENCE
DETERMINANT?
WOULD A SINGLE MUTATION FROM
SARS CORKS V2 DO THAT?
THAT WOULD BE INTERESTING.
I WOULD LIKE TO SO THIS
RECONCILED OR PUT IN A WAY THAT
DOESN'T REQUIRE ME TO GO IN THE
FEDERAL REGISTER FOR 15 DAYS
EVERY TIME I WANT TO INTRODUCE A
MUTATION INTO SARS-CoV-2.
THERE ARE STRATEGIES TORAH
ALLOWING SURVEILLANCE -- * THERE
NEEDS TO BE SOME MECHANISM FOR
BEING ABLE TO ALLOW WORK LIKE
THIS TO GO FORWARD WITHOUT THE
DATA.
THE DAY THAT YOU'VE GOT THE DATA
THE DAY THAT THE DRUG IS
APPROVED NOW YOU CAN -- NOW YOU
HAVE TO PAUSE AT LEAST ANY
FORWARD OR REVERSE GENETIC
STUDIES WITH RESISTANCE.
IT SURPRISES A LOT OF PEOPLE
WHEN I BRING IT UP SO I THINK
THERE SHOULD BE SOME REVIEW
PROCESS THAT POTENTIALLY
RECOGNIZES THE IMPORTANCE OF
THIS PROCESS.
>> ONE QUESTION ASKED -- I
MENTIONED YOU ARE SKEPTICAL OF
COVID BECOMING A NEW SEASONAL
VIRUS LIKE FLU?
>> IT'S GOING TO GO WHERE IT
GOES A. REMEMBER FOR ALL OF THE
YEARS I'VE BEEN DOING SELECTION
IN THE LAB BECAUSE OF COURSE --
IT'S WHAT I DO.
I ALWAYS FIND OUT WHAT MY
SELECTION PROCESS WAS ONCE I SEE
THE VIRUS.
I THINK I KNOW WHAT IT WAS AND
THEN THE VIRUS DEMONSTRATES --
-- AND SO I THINK WE DON'T KNOW.
PEOPLE WOULD LIKE TO EXPECT THAT
IT WILL BE LESS AND LESS
VIRULENT.
THAT WILL HAPPEN AND ONE OF THE
REASONS IS IF THAT VIRUS HAS
INCREASED FITNESS FOR MANY OTHER
REASONS.
INCREASED TRANSMISSIBILITY.
CAPACITY -- THE ONLY THICK THAT
MATTERS -- THE VIRUS THAT IS
HERE TOMORROW IS THE ONE THAT IS
SUCCESSFUL TODAY AND WE DON'T
HAVE ENOUGH NATURAL HISTORY
EXPERIMENTS.
IT'S LIKE PREDICTING THE STOCK
MARKETS.
YESTERDAY'S RETURNS ARE NO
INDICATION OF FUTURE NEEDS.
>> THANK YOU.
THANK YOU SO MUCH.
I HAVE A FEW OTHER QUESTIONS BUT
I'M GOING TO E-MAIL THEM TO YOU.
>> I'M FINE WITH EITHER WAY.
>> AND SOME ARE VERY TECHNICAL
DETAILED.
>> I WOULD BE HAPPY FOR YOU TO
PUT ME IN TOUCH WITH ANYONE.
>> THANK YOU SO MUCH
AND THIS ENDS TODAY'S COVID-19
SEMINAR INTEREST GROUP
SESSION.