>>WELCOME TO
DAY TWO OF OUR VIRTUAL WORKSHOP.
CURRENT AND FUTURE NEEDS IN THE
ERA OF HIGHLY EFFECTIVE
MODULATOR THERAPIES FOR CYSTIC
FIBROSIS AND I'M AT NHLBI AND
OVERSEE THE PORTFOLIO IN CYSTIC
FIBROSIS AND OTHER DISORDERS AND
GENE THERAPY TECHNOLOGIES.
IT IS ALSO MY PLEASURE TO
WELCOME TO YOU DAY TWO AND
PROVIDE YOU WITH SOME OF OUR
MEETING LOGISTICS AS WELL AS THE
CHARGE FOR THE WORKSHOP AND
RECAP OF YESTERDAY'S MEETING.
SO YESTERDAY MORNING OUR
DIVISION DIRECTOR DR. JIM KILEY
SHARED THE CONCEPT CAME OUT OF A
TRANS-NIH WORKING GROUP WITH
REPRESENTATIVES FROM NIDDK AND
THE CYSTIC FIBROSIS FOUNDATION
TOGETHER WITH INPUT FROM THE
RESEARCH COMMUNITY WE REALIZED
THERE WAS A CHANGE AFTER THE
APPROVAL OF TRI KAPTA AND BRING
EXPERTS IN THE FIELD TO ADDRESS
CRITICAL QUESTIONS AND INFORM
FUTURE RESEARCH NEEDS IN THE ERA
OF HIGHLY EFFECTIVE MODULATED
THERAPIES FOR THE TREATMENT.
TO ORGANIZE THE WORKSHOP WE
BROUGHT TOGETHER A PANEL OF
EXPERTS ON THE PLANNING
COMMITTEE WITH A BREADTH OF
EXPERTS FROM CLINICAL BACKGROUND
TO BEGIN TO ADDRESS THESE
QUESTIONS.
THE GOAL OF THE WORKSHOP IS TO
HIGHLIGHT THE CHALLENGES AND
OPPORTUNITIES FOR RESEARCH IN
THE CONTEXT OF TREATMENT OPTIONS
FOR ALL PEOPLE WITH CF INCLUDING
THOSE NOT ELIGIBLE FOR CURRENT
MODULATED THERAPIES.
YESTERDAY AND TODAY WE ALSO HAVE
A CHANCE TO HEAR PERSPECTIVES
FROM INDIVIDUALS WITH CF AND
THEIR CAREGIVERS.
IT'S CLEAR FROM THE SHEER NUMBER
OF REGISTRANTS THERE'S A HIGH
PRIORITY FOR THIS AREA FOR THE
FIELD.
WE'RE LOOKING TO HEAR FROM ALL
OF YOU ABOUT YOUR EXPERIENCES,
INSIGHTS AND KNOWLEDGE TO HELP
MOVE THE FIELD FORWARD IN THE
NEXT 5 TO 10 YEARS.
I HOPE THIS GROUP WILL ALSO FORM
NEW COLLABORATIONS AND BE BOLD
AND INNOVATIVE WITH THE IDEAS
YOU SHARE.
I'D LIKE TO BRIEFLY REMIND THE
GROUP OF MEETING LOGISTICS.
THIS MEETING IS BEING RECORDED.
SOME SPEAKERS MAY SHARE
PRELIMINARY TODAY WE ASK YOU
KEEP CONFIDENTIALITY AND WE'LL
HAVE THE CHAT FUNCTION FOR
QUESTIONS YOU WANT ADDRESSED BY
THE SPEAKERS AND A DEDICATED Q&A
AT THE END OF EACH SESSION AND
YOU CAN ALSO USE THIS IF YOU
NEED ANY TECHNICAL ASSISTANCE.
FINALLY, AS WE HAVE A LOT OF
REGISTRANTS AS YOU ENTER THE
WORKSHOP YOU ARE MUTED AND OFF
CAMERA.
WE ASK YOU STAY THIS WAY TO SAVE
BAND WIDTH.
YOU'RE WELCOME TO SPEAK AND USE
YOUR CAMERA FREELY IN THE
AFTERNOON AT THE INSTRUCTION OF
YOUR MODERATORS TO HELP
FACILITATE OPEN DISCUSSION AND
COLLABORATION.
WE ALSO HAVE A PROGRAM BOOKLET
WITH BIOS AND MEETING MATERIALS.
TO STAY ON TIME WE ASK YOU USE
THIS AS A RESOURCE AS THE
MODERATORS WILL NOT BE READING
FULL BIOS.
FOR EACH SESSION WE'LL HAVE
15-MINUTE PRESENTATIONS BACK TO
BACK AND THEN WE'LL HAVE A
DEDICATED Q&A SESSION FOR EACH
PANEL.
AGAIN, PLEASE USE THE CHAT TOOL
FOR YOUR QUESTIONS THAT YOU WANT
DIRECTED FOR THAT SESSION.
THREE BREAKOUT SESSIONS WILL
OCCUR TOWARDS THE END OF THE DAY
AND WILL OCCUR SIMULTANEOUSLY.
THEY'LL BE MODERATED BY A PANEL
AND DESIGNED TO BE WORKING
BREAKOUT SESSIONS WHERE WE DO
WELCOME YOUR PARTICIPATION AND
DISCUSSION.
YOU CAN USE YOUR COLLABORATIVE
TOOLS SUCH AS CHAT, HAND RAISING
AND CAMERA DURING THE SESSIONS
AND HOPE YOU'LL BE FULLY ENGAGED
IN THE WORKING GROUP.
YOU'LL BE INSTRUCTED TO ENTER
THE BREAKOUT SESSIONS FROM THE
MAIN ZOOM ROOM.
IF YOU'RE WATCHING FROM THE NIH
LIVE CAST AND WISH TO JOIN YOU
MUST ENTER THROUGH THE ZOOM LINK
IF YOU WANT REPLACEMENT YOU CAN
COME BACK TO THE MAIN MEETING
AND ASK FOR ASSISTANCE.
AS I MENTIONED, WE'LL FREQUENTLY
POST THE AGENDA AND PROGRAM BOOK
IN THE CHAT AS A RESOURCE FOR
WORKSHOP PARTICIPANTS.
OUR STRUCTURE FOR TODAY IS
SIMILAR AS TO YESTERDAY AND WE
WILL HAVE THREE ADDITIONAL
SCIENTIFIC SESSIONS.
SESSION 3 WILL ADDRESS EARLY
LUNG DISEASE IN CYSTIC FIBROSIS
HOW WE CAN MONITOR DISEASE
PROGRESSION AND IMPORTANT
QUESTIONS REGARDING INITIATING
OR STOPPING THERAPIES.
SESSION 4 WILL CONSIDER THE USE
OF HIGHLY EFFECTIVE MODULATED
THERAPIES IN SPECIAL POPULATIONS
INCLUDING DURING PREGNANCY,
POST-TRANSPLANT AND ALSO DISCUSS
THE RISK FOR AGE-RELATED
COMORBIDITIES IN CYSTIC
FIBROSIS.
WE'LL ALSO DISCUSS WAYS TO
BRIDGE THE GAP FOR THOSE
CURRENTLY NOT ELIGIBLE FOR
MODULATED THERAPIES.
AND SESSION 5 WILL DISCUSS
CLINICAL CARE THROUGH NEW TOOLS
AND TECHNOLOGIES AND WE'LL
CONCLUDE THE SESSION WITH
ANOTHER COMMUNITY MEMBER
PERSPECTIVE.
AS WE DID YESTERDAY, WE'LL HAVE
THREE CONCURRENT BREAKOUT
SESSIONS WITH A GROUP REPORT OUT
AS WELL AS A DISCUSSION OF THE
MAJOR THEMES FROM BOTH DAYS.
SO AS A SAID SEVERAL TIMES, WE
WOULD LIKE TO HEAR YOU FROM.
WE HAVE THE BREAKOUT SESSIONS
DESIGNED FOR YOUR PARTICIPATION.
YOU CAN ALSO SEND YOUR THOUGHTS
VIA LIVE TWEETS USING THE
MEETING HASH TAG OR E-MAIL US
DIRECTLY TO SEND YOUR COMMENTS,
IDEAS OR FEEDBACK.
WE'LL ALSO POST THIS CONTACT
INFORMATION IN THE CHAT
THROUGHOUT THE WORKSHOP.
I WANT TO TAKE THIS OPPORTUNITY
TO SAY A HUGE THANKS TO THE
WORKSHOP PLANNING TEAM AND
CO-CHAIRS AND ALL OF OUR
SPEAKERS AND BREAKOUT
MODERATORS.
THEY'VE PUT A LOT OF TIME AND
EFFORT IN PLANNING THE EVENT AND
THANK YOU ALL FOR PARTICIPATING
AND REGISTERING FOR THE WORKSHOP
AND THIS WOULD NOT BE POSSIBLE
WITHOUT OUR SUPPORT MEMBERS
WORKING BEHIND THE SCENES TO
MAKE THIS A FANTASTIC EVENT.
BEFORE WE BEGIN OUR FIRST
SESSION, I WANTED TO RECAP A FEW
OF THE THEMES FROM YESTERDAY AS
A PRIMER FOR MOVING INTO OUR
FINAL DAY OF THE MEETING.
SO ONE OF THE TOPICS THAT WAS
DISCUSSED IS WHEN WE'RE THINKING
ABOUT IN VITRO MODELS THERE WAS
A DISCUSSION ON THE NEED TO
DEVELOP MORE COMPLEX AND MIXED
CELLULAR MODELS THAT BETTER
REFLECT THE IN VIVO SITUATION
AND REMINDED WE NEEDED TO BE
AWARE OF SENESCENCE AND
EPIGENETIC PATTERNS IN THE
SYSTEMS.
AN OPPORTUNITY WAS IDENTIFIED TO
FIND BETTER WAYS TO LEVERAGE THE
MODELS FOR PRE-CLINICAL AND
CLINICAL APPLICATAPPLICATIONS.
THERE WERE WAYS TO USE ANIMAL
MODELS FOR THE HUMAN CONDITION
AND HOW TO BE USED FOR DISEASE
PHENOTYPES AND BIOMARKERS.
A GAP WAS IDENTIFIED HERE AS A
POTENTIAL BARRIER TO ACCESS SOME
OF THESE MODELS IS THE HIGH
LEVEL OF TRAINING NEEDED TO
BRING THEM INTO NEW LABS AND
ALSO FOR THE COST OF MAINTAINING
RESEARCH COLONIES.
FINALLY, THERE WAS A LOT OF
DISCUSSION ABOUT LATE-STAGE LUNG
DISEASE AND HOW TO MONITOR
INDIVIDUALS WITH CYSTIC FIBROSIS
AND MUCH OF THE DISCUSSION WAS
AROUND WHAT ARE THE BEST
CLINICAL END POINTS.
AS DISCUSSED, FEB1 IS NOT THAT
SENSITIVE.
SHOULD WE LOOK AT OTHER
TECHNOLOGIES OR OMICS-BASED
BIOMARKERS?
THERE WAS A DISCUSSION AROUND
THE CHANGES IN NUTRITION AND
PANCREATIC FUNCTION IN THE ERA
OF MODULATED THERAPIES OR
KNOWLEDGE GAPS WERE IDENTIFIED
AND SHARED INTEREST IN THIS AREA
COULD MEAN A NEED FOR RESEARCH
STIMULATION.
AND OPPORTUNITIES TO CONTINUE
DEVELOPING BETTER MODULATORS OR
NEW DRUGS OR ADVANCING GENE
THERAPY TECHNOLOGIES WAS
DISCUSSED AS A WAY TO ADDRESS
NEEDS FOR THOSE WITH CF NOT
CURRENTLY ELIGIBLE OR CANNOT
TAKE CURRENT MODULATED
THERAPIES.
AS WE MOVE INTO TODAY'S
SESSIONS, I'M SURE WE WILL HEAR
ADDITIONAL AREAS THAT NEED
CRITICAL ATTENTION AND I LOOK
FORWARD TO ALL OF YOUR
CONTRIBUTIONS.
AT THIS TIME I'LL TURN OUR
MEETING OVER TO MODERATORS.
I'M JENNIFER BOMBERGER AND
DR. LAGUNA.
WE'LL BE TALKING ABOUT THE
CLINICAL CHALLENGES FOR THOSE ON
MODULATOR WHO HAVE NOT YET
DEVELOPED CHRONIC LUNG DISEASE.
OUR SPEAKERS ARE DR. LAGUNA AND
MYSELF, DR. CHRISTOPHER FORTNER
AND DR. CUTTING.
IN THE INTEREST OF TIME WE'LL
START THE TALK WITH DR. TERI
LAGUNA FROM NORTHWESTERN INVEST.
I'M GOING TO TALK TO YOU GUYS
ABOUT HIGHLY EFFECTIVE
MODULATORS IN EARLY LUNG
DISEASE.
THE MAGIC 8 BALL.
FIRST, DISCLOSURES I RECEIVE
GRANT FROM THE NIH AND CFF AND
REVIEW GRANTS AND I'M A PU
PULMONOLO
PULMONOLOGIST.
THREE OBJECTIVES TO RUN THROUGH.
THE FIRST IS TO GET THINKING BY
REVIEWING PATIENT CASES
INVOLVING HIGHLY EFFECTIVE
MODULATORY USE AND TALK ABOUT
THE CLINICAL CARE OF CHILDREN
WITH CF ON HIGHLY EFFECTIVE
MODULATORS OR WAITING FOR ONE
AND I'LL END BY IDENTIFYING THE
GAPS IN KNOWLEDGE I FEEL SHOULD
BE ADDRESSED.
LET'S START BY REVIEWING SOME
CASES WITH CLINICAL DILEMMAS.
SO BEFORE I JUMP TO THE CASES, I
WANT TO HAVE A FOUNDATION THAT
WE'RE STARTING FROM IN REGARDS
TO MODULATOR THERAPIES.
SO JUST TO REMIND YOU, SO
IVACAFTOR IS FDA APPROVED FOR
CHILDREN GREATER THAN 4 MONTHS
OF AGE AND ORKAMBI IS APPROVED
FOR KIDS GREATER THAN YEARS WITH
TWO COPIES OF DELTA A508 AND THE
LAST ONE IS APPROVED FOR
CHILDREN GREATER THAN 6 YEARS OF
AGE WITH TWO COPIES OF F508DEL
AND TRIKAFTA IS CONSIDERED A
MODULATOR AND APPROVED FOR KIDS
GREATER THAN 6 YEARS OF AGE WITH
AT LEAST ONE COPY WHENEVER WE
USE THE TERM HIGHLY EFFECTIVE
MODULATORS WE'RE REFERRING TO
THESE.
BASED ON THE LIST THERE'S
CURRENTLY SOME GAPS YOU CAN SEE.
AND THERE'S NO MODULATOR
APPROVED FOR CHILDREN LESS THAN
6.
THERE'S MUTATION GAPS.
SO PEOPLE OFTEN DON'T QUALIFY
FOR A MODULATED THERAPY.
THERE'S TOLERABILITY GAP.
SOME PEOPLE WITH CF AREN'T ABLE
TO TOLERATE THE MODULATOR GIVEN
DRUG INTERACTIONS, ETCETERA.
AND THEN THERE ARE STUDY DESIGN
GAPS.
THIS IS SOMETHING TO KEEP IN
MIND.
ALL MODULATOR STUDIES WERE DONE
IN THE SETTING OF STANDARD OF
CARE, BASELINE MEDICATIONS AN
AIRWAY CLEARANCE REGIMENTS.
I'LL START WITH SOME CASES.
SOME ARE A MIX OF REAL AND
FICTION.
I HAVE PERMISSION FROM ALL THE
PATIENTS TO USE THEIR PHOTOS.
GRACIE IS A 6-YEAR-OLD GIRL WITH
PANCREATIC INSUFFICIENT CF AND
ON ORKAMBI AND SHE HAS ENZYMES
AND VITAMINS AND AIRWAY
CLEARANCE AND NEBULIZED
ALBUTEROL AND HER F EV1 IS
PREDICTED AND HAS NEVER BEEN
HOSPITALIZED.
QUESTIONS TO THINK ABOUT, WOULD
YOU SWITCH HER CF MODULATOR FROM
ORKAMBI TO TRIKAFTA AND HAS DONE
WELL WITH AN FEV OVER 100% WOULD
YOU DECREASE HER VEST, WHY OR
WHY NOT?
AND FINALLY WITH THE DECISION TO
SWITCH TO TRIKAFTA DECREASE HER
BURDEN OF CARE WITH MEDS AND
THERAPIES?
WHY OR WHY NOT?
MADDIE IS A 2-YEAR-OLD INFANT
CASE 2, THIS IS HER GENOTYPE.
SHE WILL NOT QUALIFY FOR A CF
MODULATOR UNTIL ONE IS DEVELOPED
FOR HER MUTATION.
QUESTION TO CONSIDER.
HOW WOULD YOU APPROACH CLINICAL
CARE KNOWING ONE WILL QUALIFY
ONCE APPROVED FOR HER AGE AND
ONE MAY NOT FOR MANY YEARS.
WOULD YOU BE MORE AGGRESSIVE
WITH NUTRITION AND/OR MORE
VIGILANT ABOUT THE APPROACH TO
LUNG DISEASE AND WHAT WOULD IT
LOOK LIKE AND WOULD IT BE
DIFFERENT IN CASE 1 VERSUS CASE
2 AND WHAT WOULD THE
CONVERSATION OF INFANTS SOUND
LIKE?
CASE 3, AUSTIN IS A 12-YEAR-OLD
BOY WITH PANCREATIC INSUFFICIENT
CF.
HE WAS SWITCHED TO TRIKAFTA AND
GETS ENZYMES AND VITAMINS AND
VEST TWIS A DAY WITH ALBUTEROL
AND CHRONICALLY GROWS TOBI
CYCLES AND HE HASN'T BEEN
HOSPITALIZED SINCE AGE 4.
AGAIN, QUESTION TO CONSIDER.
GIVEN HOW WELL HE'S DOING NOW
WOULD YOU MAKE CHANGES TO HIS
AIRWAY CLEARANCE REGIMENT,
REMOVE THESE AND WHAT WOULD GET
TO YOU STOP HIS VEST AND WHAT
WOULD THAT LOOK LIKE.
AND A HYPOTHETICAL CASE.
EMMA IS A 6-MONTH-OLD GIRL WITH
FORMERLY PANCRECATTIC
INSUFFICIENT CF AND HER FECAL
ELASTASE IS NORMAL.
HER THROAT SWABS HAVE BEEN
NEGATIVE FOR BACTERIA AND HER
GROWTH IS NORMAL.
WOULD YOU HAD START HER ON
PANCREATIC ENZYMES, VITAMINS AND
SALTS?
WHY OR WHY NOT AND WOULD YOU
START HER ON PULMOZYME.
WOULD YOU FOLLOW CARE FOR
INFANTS?
WHY OR WHY NOT?
THESE ARE PATIENT WE TAKE CARE
OF OR THINK ABOUT IN THE ERA OF
HIGHLY EFFECTIVE MODULATORS.
I'LL REVIEW WHAT CURRENT
LITERATURE EXIST THE CLINICAL
CARE OF KIDS WITH CF ON HIGHLY
EFFECTIVE MODULATOR OR WAITING
FOR A MODULATOR.
SO A FEW FACTS IN GAPS.
FACT, MOST INFANTS AND YOUNGER
CHILDREN WITH CF ARE NOT
CANDIDATES FOR HIGHLY EFFECTIVE
MODULATORS.
WHEN I SAY YOUNGER CHILDREN I'M
TALKING LESS THAN 6 RIGHT NOW.
A RIGOROUS APPROACH IS WARRANTED
AND THOSE ON CF ON A HIGHLY
EFFECTIVE MODULATOR HAVE
IMPROVED GROWTH AND QUALITY OF
LIFE.
WE KNOW THAT FROM THE ORIGINAL
STUDIES DONE.
PATIENTS, FAMILIES AND PROVIDERS
ARE ASKING IF AND WHEN THE LARGE
BURDEN OF DAILY CARE CAN BE
DECREASED.
HOWEVER, HOW-TO GUIDELINE
DOESN'T YET EXIST.
AND RARE CF MUTATIONS ARE
CONCENTRATED IN BLACK AND BROWN
CHILDREN WITH CF RESULTING IN A
SIGNIFICANT DISPARITY IN CARE.
THE GAP HERE IS IDENTIFYING AND
CHARACTERIZING RARE MUTATIONS
AND FOCUSSING RESEARCH ON
SUPPORTING THESE COMMUNITIES
SHOULD BE PRIORITIZED.
SO THE WAY IT FEELS NOW AS A
PEDIATRIC LUNG DOCTOR TAKING
CARE OF THESE KIDS ON MODULATORS
AND DOING WELL OR DON'T QUALIFY,
IT FEELS LIKE A MAGIC 8 BALL.
I THINK DATING MYSELF IN TERMS
OF WHAT THIS IS.
BUT IT'S A BALL YOU USED TO
SHAKE AND ASK A QUESTION AND
TURN IT OVER AND AN ANSWER WOULD
TURN UP AN IT DOESN'T SIT WELL
WITH THOSE OF US IN THE
SCIENTIFIC COMMUNITY.
WHAT ABOUT THE KIDS WAITING FOR
A MODULATOR.
WE KNOW THE ACHIEVEMENTS OF
NUTRITION THROUGH METRICS
STUDIED AND PUBLISHED IS THE KEY
TO HIGHER LUNG FUNCTION LATER IN
LIFE AND PREVENTING THE ONSET OF
PROGRESSION OF CF LUNG DISEASE
SHOULD BE PRIORITIZED.
KIDS WAITING FOR A MODULATOR AND
KEEPING THEM HEALTHY IS A
STANDARD OF CARE FOR KIDS
GREATER THAN OR EQUAL TO 6 BUT
THIS IS HARD FOR KIDS TO PERFORM
WHEN YOUNGER THAN 6.
CHEST CT AND MRI ARE NOT
ROUTINELY PERFORMED AND SWABZ --
SWABS ARE DONE AND THIS IS WHAT
WE DO NOW BUT IS THAT AGGRESSIVE
AND GOOD ENOUGH.
QUESTIONS TO CONSIDER.
IS THERE A ROLE FOR A MORE
AGGRESSIVE NUTRITIONAL
MANAGEMENT APPROACH.
SO EARLIER GT PLACEMENT AND
FEEDS IN PATIENTS WAIT BEING FOR
A CF MODULATOR?
SHOULD WE BE PUSHING FOR MORE
WIDESPREAD IMPLEMENTATION OF
THINGS LIKE A LUNG CLEARANCE
INDEX AND MORE ROUTINE IMAGEING
STUDIES LIKE CHEST CT OR MRI AND
MY COLLEAGUE WILL TALK ABOUT
THIS AND SHOULD WE CONSIDER
SURVEILLANCE BRONCHOSCOPY TO
MITIGATE THE PROGRESSION OF LUNG
DISEASE?
WE KNOW IT'S BEEN STUDIED IN THE
PAST PRIOR TO HIGHLY EFFECTIVE
MODULATOR THERAPY BUT I THINK
THE QUESTION IS NOW IF WE'RE
LOOKING FOR PATHOGENS WE CAN
TREAT WHILE WAITING FOR A
MODULATOR.
WHAT DO WE KNOW ABOUT DECREASING
THE BURDEN OF CARE IN THE
MODULATOR ERA?
AND WHAT ABOUT ADULTS STARTED ON
A HIGHLY EFFECTIVE MODULATOR.
WE DON'T KNOW MUCH YET.
I WANT TO DRAW YOUR ATTENTION TO
A STUDY MENTIONED YESTERDAY.
THIS IS A STUDY TO EVALUATE THE
IMPACT OF STOPPING CHRONIC
THERAPIES AFTER A HIGHLY
EFFECTIVE MODULATOR WAS STARTED
AND I'LL DRAW YOUR ATTENTION TO
A SIMILAR STUDY CALLED CF STORM
OCCURRING IN THE U.K.
SO BRIEFLY, THE TRIAL STUDY
DESIGN WAS TO TEST WHETHER OR
NOT IT IS SAFE TO STOP TAKING
INHALED HYPERTONIC SALINE IN
PEOPLE WITH CF TAKING HIGHLY
EFFECTIVE MODULATOR IN THIS CASE
DEF
THERE ARE THREE ARMS.
PEOPLE WHO CAME IN ON HYPER
TONIC SALINE AND PEOPLE WHO CAME
IN ON BOTH HYPER TONIC SALINE
AND PULMOZYME.
THE KIDS WOULD STAY ON
MEDICATIONS TWO WEEKS AND
RANDOMIZED TO EITHER STOP IT OR
CONTINUE IT.
ALL WHILE CONTINUING TO TAKE
THEIR TRIKAPTA.
THIS WENT FOR SIX WEEKS AND HAD
THE OPTION TO SWITCH TO THE
OTHER ARM IF THEY WANTED.
WHAT ARE WE GOING LEARN FROM THE
STUDY?
THE GOAL OF THIS AGAIN IS TO
REDUCE THE TREATMENT BURDEN.
WE'RE HOPING TO DO WITHOUT
SACRIFICING THE INCREMENTAL
HEALTH GAINS ACHIEVED THROUGH
THE ACCUMULATIVE CONDITIONS AND
MOST ARE ON MULTIPLE THERAPIES
WE DON'T KNOW WHAT WILL HAPPEN
IF WE START TO REMOVE THEM ONE
AT A TIME.
THAT'S THE GOAL TO TEST THAT AND
SEE HOW THINGS GO.
IT'S IMPORTANT TO HAVE BUY-IN
FROM THE COMMUNITY TO COMPLETE A
STUDY LIKE THIS.
YESTERDAY THERE WERE COMMENTS
HOW PATIENTS HAVE JUST STOPPED
DOING THEIR THERAPIES.
SOME HAVE STAYED HEALTHY AND
SOME HAVE NOT SO HEALTHY.
THE IMPORTANCE OF PARTNERING
WITH A COMMUNITY AND ENCOURAGING
THEM TO HAVE PATIENCE AS WE
STUDY THIS TO MAKE SURE THE
DECISIONS THEY MAKE ARE GOING TO
KEEP THEM HEALTHY.
THE FOCUS HERE WAS ON TWO
MEDICATIONS ONLY AND ON THE
SHORT TERM IMPACT.
SIX WEEKS WAS WHAT WAS GOING TO
BE STUDIED AND SIMPLIFIED.
AGAIN, THE STUDY POPULATION IS
GREATER AND EQUAL TO 12.
THEY'RE NOT INFANTS OR YOUNG
KIDS.
WE SHOULD HAVE MORE INFORMATION
COMING HOPEFULLY BY THE END OF
THE SUMMER.
SO WHAT ARE THE REMAINING GAPS?
I'M GOING TO CLOSE BY TALKING
ABOUT A FEW GAPS WE SHOULD BE
THINKING ABOUT AS A COMMUNITY
THAT WE SHOULD START TO ADDRESS.
SO ONE OF THE THINGS IS WHAT
CLINICAL PROTOCOL SHOULD WE
FOLLOW TO BRIDGE THE GAP SO
HIGHLY EFFECTIVE MODULATOR
APPROVAL OR AVAILABILITY FOR AN
INFANT WITH CF?
I DRAW YOUR ATTENTION TO TWO
GUIDELINES WE CURRENTLY HAVE FOR
THE CARE OF INFANTS AND PRE
SCHOOLERS WITH CF AS WELL AS A
RECENT ARTICLE TALKING ABOUT
THIS VERY CLINICAL SCENARIO.
THE WHOLE CONCEPT SHOULD BE MORE
AGGRESSIVE AND LOU TO MONITOR
NUTRITION AND LUNG DISEASE
KNOWING WE MAY NOT BE ABLE TO
REVERSE BRONCHIEPSIS SO WHAT IS
THE OPPORTUNITY TO TAKE CARE OF
THE INFANTS AND KIDS TO KEEP
THEM AS HEALTHY AS POSSIBLE?
IN SOME SCENARIOS THIS MAY BE
YEARS IF YOU HAVE A RARE
MUTATION BEFORE A MODULATOR OR
THERAPY IS AVAILABLE FOR YOUR
CF.
SO IF HIGHLY EFFECTIVE
MODULATORS CAN BE STARTED AT
BIRTH OR IF THEY'RE STARTED IN
UTERO WILL INFANTS STILL NEED
THE CLINICAL STANDARD OF CARE
FOR CF?
AGAIN, I DRAW YOUR ATTENTION TO
THE TWO GUIDELINES WE HAVE FOR
THE CARE OF INFANTS AND
PRESCHOOLERS.
DOES THIS CHANGE NOW THAT WE
KNOW OUR KID HAS A NORMAL SWEAT
TEST AND FECAL ELASTASE AND THE
CF AIRWAY AND LUNG DISEASE IN
KIDS IS WEEK AND THAT NEEDS TO
BE STUDIED.
THE EFFECTIVE MODULATORS IN THE
MICROBIOME OVER TIME AND CHRONIC
OR ACUTE INFECTION AND
INFLAMMATION IN THE PRESENCE OF
MODULATORS AND THE REMOVAL OF
AIRWAY CLEARANCE AND FINALLY WE
NEED CONTINUED WORK ON THOSE
WITH CF WHO DO NOT QUALIFY FOR A
MODULATOR.
WE HEARD SOME PATIENTS AND
FAMILY TESTIMONIALS WHAT THAT'S
LIKE TO FEEL LIKE YOU'RE LEFT
BEHIND AND THERE ARE SUBSTANTIAL
NUMBER OF PEOPLE WHO EITHER
DON'T QUALIFY OR DON'T TOLERATE
A MODULATOR.
THAT'S AN IMPORTANT GROUP OF
PEOPLE WE HAVE TO CONTINUE
WORKING FOR UNTIL THEY HAVE A
THERAPY FOR THEMSELVES AS WELL.
WITH THAT I'D LIKE TO THANK YOU
FOR YOUR ATTENTION.
I LOOK FORWARD TO QUESTIONS IN
THE QUESTION AND ANSWER SESSION
AND NOW I'D LIKE TO HAND IT OFF.
>> THANK YOU, TERI AND I'D LIKE
TO THANK THE ORGANIZERS.
IT'S BEEN HIGH QUALITY ALREADY
AND I'M LOOKING FORWARD TO THE
ONGOING DISCUSSIONS TODAY.
IT'S ALSO VERY NICE THAT
PREVIOUS TALKS HAVE SET THE
SCENE FOR WHAT I'M GOING TO TALK
ABOUT EARLY DISEASE MONITORING
IN THE ERA OF MODULATED THERAPY.
I CAN'T TOUCH UPON ALL THE AREAS
BECAUSE IT'S A RELATIVELY BROAD
AREA TO COVER AND FOCUS ON LUNG
DISEASE AND FUNCTIONAL MEASURES
AND TOUCH A LITTLE BIT ABOUT
MONITORING OF OTHER AREAS.
SO WHAT ARE THE CHALLENGES IN
EARLY DISEASE THERE'S SOME NOT
CONSIDERED IN THE AGE GROUP WE
USUALLY THINK ABOUT WHICH IS
YOUNGER PEDIATRIC PATIENTS.
WHAT WE SEE IN THESE PATIENTS IS
SYMPTOMS ARE LIMITED OR ABSENT
AND LUNG FUNCTION BASED ON
TRADITIONAL MEASURES SPIROMETRY
ARE MOSTLY NORMAL AND IN THIS
SCENARIO WE HAVE PROGRESSION OF
DISEASE.
WE CAN'T SAY THEY HAVE NO
SYMPTOMS WE DON'T HAVE TO BE
AGGRESSIVE IN TERMS OF TREATMENT
AND IN TERMS OF INTERVENTIONS.
AS JP HAS POINTED OUT NICELY IN
THE TALK YESTERDAY, THIS GROUP
OF PATIENTS IN THIS CATEGORY
WILL CONTINUE TO GROW AND
CERTAINLY MORE GROW WITH THE
INTRODUCTION AND BROADER
INTRODUCTION OF HIGHLY EFFECTIVE
MODULATORS.
WE SEE THIS IN ASSESSMENT AND
WITH SPIROMETRY WE HAVE THIS
THIS MEASURED.
IF WE LOOK AT INDIVIDUAL DISEASE
PROGRESSION WHICH IS WHAT WE TRY
TO AVOID, THAT HAS BEEN RATHER
DIFFICULT TO PREDICT IN
INDIVIDUAL PATIENT EVEN BEFORE
HIGHLY EFFECTIVE MODULATED
THERAPY AND THERE'S HOW MUCH
DISEASE MODIFYING POTENTIAL HAS
WITH EXPECT TO SEE IT AT A LOWER
RATE BUT IS THAT THE CASE FOR
THOSE WITH LIMITED OR NO LUNG
DAMAGE?
AND WE NEED AND LOOKING AT
THERAPIES.
TO HIGHLIGHT THE ISSUE WITH
SPIROMETRY IF WE USE IT IT'S THE
SWEET SPOT OF MODERATE DISEASE
WHERE THIS HAS BEEN HELPFUL AND
USEFUL.
THAT'S USUALLY WHERE WE
RECOMMEND THIS TO BE USED IN
CLINICAL TRIALS AND MOST PIVOTAL
CLINICAL TRIALS HAVE BEEN USED
IN THIS GROUP OF PATIENTS WHO
HAVE AN FE1 BETWEEN 30% AND 90%.
THOSE WITH NORMAL FE 1 IS
INCREASING AND YOU'LL SEE
LIMITED RESPONSE AND THE TWO
TECHNOLOGIES THAT SEEM TO BE
PROMISING IS THE INDEX LCI AND
MRI.
FOCUS ON THAT.
I'LL NOT FOCUS ON THE SEVERE
DISEASE SPECTRUM.
IN THE GREENISH AREAS YOU SEE
PATIENTS WITH A NORMAL FE1 AND
THAT'S THE CASE FOR THE MAJORITY
OF PATIENTS THAT HAVE BEEN
STUDIED IN THIS SETTING.
IF WE LOOK BEFORE HIGHLY
EFFECTIVE MODULATED THERAPY FOR
SCHOOL AGE CHILDREN THAT WAS THE
CASE FOR 70% OF THE PATIENTS IN
PRESCHOOLERS IT'S HALF THE
PATIENTS.
THIS SLIDE SHOWS THE TECHNOLOGY
AND HOW YOU MEASURE IT AND
THERE'S DIFFERENT TRACES YOU CAN
USE AND A WON'T GO IN THE
DETAILS OF THE CONS FOR BOTH AND
THE WASH OUT IS BEING USED WHERE
YOU SWITCH A PATIENT FROM ROOM
AIR TO IF YOU GO TO THE NEXT
SLIDE AND USE 100% OXYGEN TO
WASH OUT THE NITROGEN OF THE
LUNG AND LCI IS THE TURN OVERS
AND WE SAY 1/40 CONCENTRATION
AND IN THIS OBSERVATIONAL STUY
WITH DID A NUMBER OF YEARS AGO
FUNDED BY NHLBI WE LOOK AT CF
PATIENTS AND HOW TO CONTROL
SYMPTOMS OF THE EVOLUTION OVER A
ONE YEAR TIME PERIOD.
WHAT WE SAW STUDY UNLESS THIS
REMAINS RELATIVELY STABLE WE SEE
A WORSENING IN LCI OVER THE
ONE-YEAR PERIOD IN PRESCHOOL
CHILDREN.
THIS WAS NOT PICKED UP ON THE
RIGHT-HAND SIDE.
WHAT ABOUT THE PATIENTS BECOMING
ASYMPTOMATIC AND I WON'T SHOW
THE DATA THE PRESCHOOL STUDY
BECAUSE WE HAVE RECENTLY DONE
THIS IN ANOTHER COHORT IN THE CF
FUNDED STUDY AT TWO CENTERS IN
INDIANAPOLIS AND TORONTO.
WE LOOKED AT PATIENTS WHEN THEY
WERE SYMPTOMATIC AND HOW THE
LUNG INDEX CHANGES AND HOW
SYMPTOM S DID NOT SHOW CHANGE
AND THE PREVIOUS DATA SHOWED 50%
OF THE EVENTS ARE NOT ASSOCIATED
WITH REDUCTION IN FE 1.
HOWEVER YOU SEE AN INCREASE AND
INDICATES IT MAY BE MORE
SENSITIVE IN PICKING UP ACUTE
WORSENING IN THIS SCENARIO WHERE
PATIENTS ARE HERE AND WHICH
COULD BE HELPFUL FOR THE
CLINICAL SETTING IN DECIDING
WHEN TO TREAT AND NOT TREAT.
YOU MAY ARGUE I MAY NOT BE
RELEVANT IN THE LONGER TERM
OUTCOME AND PATIENTS COME BACK
TO THEIR NORMAL BASELINE.
YOU CAN SEE AT THE LOWER PART OF
THE SLIDE THAT'S NOT THE CASE.
IF WE LOOK AT 90% OF BASELINE
RECOVERED AND THIS IS NOT
NECESSARY THE BEST AIM WE HAVE
BECAUSE IDEALLY WE WANT TO
RECOVER 100% OF PREVIOUS LUNG
FUNCTION.
YOU CAN SEE FOR BOTH FE 1 AND
THE INDEX AT THE NEXT VISIT
THAT'S ONLY THE CASE FOR A
PROPORTION OF THE PATIENT AND
THAT IS LOWER FOR THE INDEX.
IF YOU RELY ON IT ALONE IT MAY
BE FAULTY THE PATIENT HAS
RECOVERED.
WHAT YOU SEE ALSO IS AS A
MEASURE OF LCI SEEMS TO BE MORE
VARIABLE AND WE ASK ASK THAT
DRIVEN BY THE FACT OF WHAT WE
SEE IN STABLE PATIENTS IS
EVIDENCE OF WORSENING OF
DISEASE.
WHEN WE LOOKED AT THE DATA IT
WAS SIMILAR IN HEALTH AND
DISEASE WHAT WE SAW IN AND THE
MAJORITY OF WHAT WE SAW WAS A
SIGNAL OF CLINICAL WORSENING
PICKED UP.
AS A TEST IT'S NOT NECESSARILY
MORE VARIABLE IT'S YOU PICK UP
MORE SIGNALS.
I WON'T GO IN THE STUDY BUT I'LL
USE THIS SLIDE AS AN EXAMPLE OF
WHAT WE MIGHT SEE IN THE FUTURE
FOR PATIENTS IF WE LOOK AT
INTERVENT
INTERVENTIONS THAT MAY NOT BE AS
EFFECTIVE AS HIGHLY EFFECTIVE
MODULATORS AND THESE ARE
PATIENTS THAT WERE INTRODUCED TO
T
TRIKACTA.
THERE WENT A SIGNIFICANT CHANGE
IN THE LUNG CLEARANCE INDEX AND
THE MAJOR THEME I WANTED TO
POINT OUT IS THE EFFECT SIZE FOR
LCI WAS THREE TIMES OF THAT FOR
FE1.
THIS IS IMPORTANT IF WE THINK OF
PATIENTS HAVING OVERALL BETTER
LUNG FUNCTION AND MAY NOT BE AS
EFFECTIVE AS HIGHLY EFFECTIVE
MODULATOR.
SHOULD WE MOVE LCI TO THE
CLINIC?
THE PRO IS THE NEED IS THERE AND
THE POPULATION OF F EV1 IS
GROWING.
IT'S ALSO NOT A SIMPLE TEST.
IT'S TIME CONSUMING AND NOT
REIMBURSED IN THE UNITED STATES.
WE NEED TO FIND THE RIGHT
BALANCE AND EVIDENCE TO MAKE
SURE THIS HAS DATA AND IS
IMPORTANT TO ENSURE THE BENEFIT
OUTWEIGHS THE BURDEN.
WE ARE CURRENTLY EXPLORING THAT
IN A PLANNING STUDY SUPPORTED BY
CFF TO SEE HOW CAN WE DO THIS
BEST IN THE COMMUNITY AND LOOK
AT FAMILIES AND PATIENTS AND
CENTERS AND SEE WHAT IS FEASIBLE
IN TERMS OF MOVING THIS FORWARD.
THIS IS A PANEL AND THIS IS MORE
EFFECTIVE IN FEV1.
HOW CAN WE POTENTIALLY USE THIS
IN THE FUTURE?
AND ON THE NEXT SLIDE IS THE SET
UP FOR THAT WHICH IS QUITE
COMPLICATED.
YOU NEED AN MRI MEASURE AND
POLARIZER AND CURRENTLY NOT
SOMETHING THAT CAN BE UTILIZED
ACROSS MANY CENTERS IN NORTH
AMERICA.
ACCESS TO THE EQUIPMENT CHANGES
OVER TIME AND OTHER MRI DO NOT
REQUIRE HYPERPOLARIZED GASES AND
MAY BE EASIER TO USE IN A
BROADER COMMUNITY.
THIS IS A LONGITUDINAL STUDY IN
THE U.K. AND LOOKED AT DISEASE
PROGRESSION IN PATIENTS WHO HAD
RELATIVELY MILD LUNG DISEASE TO
BEGIN WITH FOR TWO YEARS.
THEY DID NOT FIND A CHANGE IN
FEV1 OVER THE TIME PERIOD.
THE SIGNAL THAT WAS THE
STRONGEST WAS THE VENTILATION
EFFECT PERCENTAGE WAS ONE OF THE
OUTCOME MEASURES OF MRI THAT WAS
SEEN ON HYPERPOLARIZED GAS MRI.
THIS MAY POTENTIALLY BE THE MOST
SENSITIVE TECHNIQUE AND STILL
HAVE TO LEARN THIS TO FOLLOW
PATIENTS OVER TIME AND THIS WILL
BECOME IMPORTANT AS WE THINK OF
HOW MUCH DISEASE PROGRESSION WE
HAVE IN THE ERA OF HIGHLY
EFFECTIVE MODULATORS.
TO GIVE YOU A BIT OF A TEASER IN
TERMS HOW THIS COULD BE USED IN
AN INTERVENTIONAL STUDY IS A
HIGH POINT STUDY WHICH IS A
STUDY TO LOOK AT HOW THE IMAGING
CHANGES IN PATIENTS INTRODUCED
TO HIGHLY EFFECTIVE THERAPY.
THEY'RE NOT COMPLETELY ABSENT WE
HAVE TO LOOK INTO THIS MORE AND
UNDERSTANDING THE LONG-TERM
EFFECTS OF THESE MODULATORS ON
VENTILATION.
I TALKED ABOUT THE DISEASE AND
AS DISCUSSED YESTERDAY
INFORMATION WILL LIKELY CONTINUE
TO BE A PROBLEM FOR PATIENTS
WITH THE DISEASE.
AND PATIENTS IN THE PEDIATRIC
POPULATION I DON'T THINK
SURVEILLANCE BRONCOSCOPIES WILL
BE WIDELY USED IT HASN'T SHOWN
TO BE HIGHLY EFFECTIVE
I SUMMARIZED THE FOCUS ASPECTS
OF MY TALK HERE.
EARLY LUNG DISEASE IS NOT
ADEQUATELY CAPTURED WITH ROUTINE
MONITORING TOOLS AND CLINICAL
MONITORING IS CHALLENGING AS
SYMPTOMS ARE LATER RATHER THAN
EARLY INDICATORS AND WE NEED
TOOLS TO FIND THE RIGHT BALANCE
OF EARLY INTERVENTION AND
TREATMENT AND MRI MAY HAVE
DEFINED DISEASE PROGRESSION AND
THE LACK THEREOF WHICH IS AS
IMPORTANT IN THE ERA OF HIGHLY
EFFECTIVE MODULATOR AND COULD
FACILITATE CLINICAL DECISION
MAKING AND THE LATER I FEEL
STILL NEEDS TO BE PROVEN.
WE ALSO NEED TO DEFINE HOW
FREQUENT MONITORING IS FOR A
CURE, ROUTINELY OR ONLY AT TIMES
OF SYMPTOMS?
THESE ARE IMPORTANT QUESTIONS.
AND ONE MENTION OF PANCREATIC
AND LIVER DISEASE ONE EFFECTIVE
WITH HIGHLY EFFECTIVE MODULATOR.
THE KNOWLEDGE IS STILL LACKING
WHETHER THIS IS THE CASE FOR ALL
CFTR MUTATIONS.
AND LOWER NUMBER OF PATIENTS
HAVING INEFFICIENT AND WE'LL SEE
WHETHER THIS IS ALSO ASSOCIATED
WITH OTHER COMPLICATIONS SUCH AS
PANCREATITIS AND TRACKING LIVER
DISEASE HAS BEEN A CHALLENGE.
ON ONE HAND IT COULD BE
EFFICAC
EFFICACIOUS.
ON THE OTHER HAND IT CAN MAKE IT
MORE DIFFICULT.
HERE'S RESEARCH OPPORTUNITIES.
I ALLUDED TO SOME ALREADY.
WE NEED ALTERNATIVE MEASURES TO
SPUTUM AND FOR THE OTHER ASPECTS
OF PANCREATIC DISEASE AS WELL AS
LIVER DISEASE THERE'S LOTS OF
GAPS AND I'M NOTE REALLY THE
EXPERT IN THIS FIELD BUT I CAN
SAY IT'S BEEN QUITE CHALLENGING
IN TERMS OF MONITORING LIVER
DISEASE EVEN BEFORE WE HAVE THE
ISSUE OF HIGHLY EFFECTIVE
MODULATORS.
SO WITH THAT TO MY FINAL SLIDE.
AND THE MEASURES CAN HELP
IDENTIFY SUBGROUPS OF PATIENT TO
PREDICT IN THE FUTURE TO SAY
SOME MAY NOT NEED MORE INTENSE
THERAPIES OR OTHERS AND WITH
THAT I THANK YOU FOR YOUR
ATTENTION AND HAPPY TO TAKE
QUESTIONS LATER ON BUT BEFORE WE
DO QUESTIONS, I HAND IT OVER TO
JIM.
>> I'VE USED GRANTS BY THE NIH
AND WE'LL START TALK ABOUT ACUTE
RESPIRATORY VIRAL INFECTIONS IN
CYSTIC FIBROSIS.
THESE ARE ASSOCIATED WITH HALF.
MOST COMMONLY ASSOCIATED WITH CF
ARE RHINO VIRUS AND INFLUENZA A
VIRUS.
CYSTIC FIBROSIS WILL EXPERIENCE
ONE TO TWO RESPIRATORY
COMPLICATIONS PER YEAR BUT THE
SYMPTOMS ARE OFTEN MORE SEVERE
INCLUDING INCREASES IN
HOSPITALIZATION, INCREASED
RESPIRATORY SYMPTOMS, INCREASED
USE OF ANTIBIOTICS AND
REDUCTIONS IN PULMONARY
FUNCTION.
THESE VIRUS DETECTED BY OUR
CELLS THROUGH PATTERN
RECOGNITION RECEPTORS THAT THEN
INDUCE INFLAMMATORY RESPONSES AS
WELL AS INITIATING INTERFERON
SIGNALING
THE CYTOKINES SIGNAL THROUGH THE
RECEPTOR AND TURN ON A SUITE OF
GENES THAT INITIATE THE
ANTIVIRAL PROGRAM TO CARRY OUT
THE DEFENSE AGAINST VIRUS.
WHAT WE KNOW IN CYSTIC FIBROSIS
THERE'S REDUCED INTERFERON
SECRETION DURING VIRAL
INFECTIONS AND THERE'S AN
ALTERATION OF INITIATION OF THE
PROGRAM AND DIFFERENTIAL SUITE
OF GENES ACTIVATED DURING CF
LEADING TO POOR CONTROL OF VIRAL
INFECTION.
THE GAPS MOVING FORWARD WITH
MODULATORS IF MODULATORS IMPROVE
THE ANTIVIRAL IMMUNITY DURING
THESE EXACERBATIONS WITH PEOPLE
WITH CF AND DO MODULATORS REDUCE
EXACERBATIONS AND REDUCE
SEVERITY AND HOSPITALIZATIONS OF
THE EVENTS?
THINKING OF VIRAL AND BACTERIAL
INTERACTIONS.
WHAT WE KNOW IS VIRAL INFECTION
ASSOCIATED WITH INCREASES IN
ANTIBODIES AND CYSTIC FIBROSIS
PATIENTS.
INCREASED PSEUDOMONIS INFECTIONS
AND IF CHANGE HAPPENING DURING
EXACERBATIONS.
IT'S BEEN A MAJOR FOCUS.
WE STARTED BY USING A MODEL
SYSTEM AND THEY'RE HARD TO CLEAR
BY THE IMMUNE SYSTEM AND WE
THINK ASSOCIATED WITH THE
DEVELOPMENT OF CHRONIC
INFECTIONS IN CF.
WE USE A MODEL SYSTEM WHERE WE
GROW HUMAN CELLS AND SIMILAR TO
WHAT WE SEE IN VIVO.
IF WE GIVE A PRECEDING VIRAL
INFECTION AND HOW IT MIGHT
IMPACT BIO GENESIS WE SEE THIS
AS A TOP-DOWN VIEW AND SEE GREEN
CLUSTERS OF BACTERIA AND
AGGREGATES FORMING IN OUR MODEL
SYSTEM.
IF WE GIVE A PRECEDING VIRAL
INFECTION WE SEE A DRAMATIC
ENHANCEMENT IN THE FORMATION,
INCREASES IN THE GREEN CLUSTERS
OF BACTERIA.
AND IT CREATES OTHER PATHOGENS.
AND WHAT HAS BEEN CHARACTERIZED
IS THAT THERE ARE INEFFECTIVE
ANTIMICROBIAL RESPONSES IN
CYSTIC FIBROSIS.
OUR GROUP HAS PUBLISHED
DYSREGULATION IN NUTRITIONAL
IMMUNITY ALLOWING IRON THAT'S A
NUTRIENT FORCE TO CREATE
BACTERIAL GROWTH AND THERE'S
METABOLIC CHANGES IN THE
RESPIRATORY EPITHELIAL DURING
VIRUS INFECTION THAT CAN SERVE
AS A SOURCE OF HE METABOLITES
THAT CAN EFFECT PSEUDOMONAS
MODULATORS.
IT'S NOT CLEAR WHICH WILL END UP
BEING CYSTIC FIBROSIS SPECIFIC.
IN OUR WORK WE SEE THE
MAGNITUDES OF THE DYSFUNCTIONS
IN NUTRITIONAL IMMUNITY OF
METABOLISM ARE MORE MAGNIFIED
AND THINK IT WILL BE IMPORTANT
TO THINK ABOUT ADJUNCTIVE
THERAPIES THAT TARGET THE
DISRESOLUTION LIKE NUTRITIONAL
IMMUNITY AND METABOLISM AS MAYBE
SECONDARY THERAPIES IN ADDITION
TO MODULATED THERAPY.
THE STUDIES HAVE BEEN DONE
PRIMARILY HOW THEY IMPACT ONE
MICROBE OR BACTERIA.
WE KNOW IN CYSTIC FIBROSIS
INFECTIONS IN THE RESPIRATORY
TRACT ARE POLY MICROBIAL.
MY GROUP IS INTERESTED IN TRYING
TO UNDERSTAND HOW VIRAL
INFECTIONS SHAPE THE ENTIRE
COMMUNITY IN THE RESPIRATORY
TRACT AND ARE INTERESTED IN
COLLABORATION WITH STELLA LEE AN
OTOLARYNGOLOGIST AND NOW MOVED
TO BRIGHAM AND HAVE LOOKED AT
HOW VIRAL INFECTIONS IMPACT
MICROBIAL COMMUNITIES IN THE
UPPER AND LOWER RESPIRATORY
TRACT.
PART OF THE INTEREST IS THE
GROWING AC ACCEPTANCE IN OUR
FIELD THE UPPER RESPIRATORY
TRACT MAY SERVE AS A RESERVOIR
FOR LOWER RESPIRATORY TRACT
INFECTIONS MOVING FORWARD.
WE'VE BECOME INTERESTED IN HOW
VIRUSES MAY CHANGE THE
COMMUNITIES IN BOTH COMPARTMENTS
AND HOW VIRUSES MAY CHANGE
COMMUNICATION BETWEEN THESE TWO
COMPARTMENTS IN A STUDY I'M
GOING EXPLAIN.
THE WORK HAS BEEN DONE BY TWO
POST-DOCTORAL FELLOWS IN MY LAP
AS WELL AS A TEAM AT THE
UNIVERSITY OF PITTSBURGH.
WE WE STUDIED A GROUP AND THEY
HAD SINUS AND SPUTUM SAMPLES TO
GET SINUS AND SPUTUM SAMPLES AND
HAVE SWABS FOR MICROBIOME AND
COLLECT SINUS WASHES AND SPUTUM
TO ANALYZE CYTOKINES UNDERSTAND
WHAT IT'S GOING ON DURING THESE
PERIODS OF SURVEILLANCE AND
CAPTURE THE PSEUDOMONAS
POPULATION TO LOOK AT THE
PSEUDOMONAS POPULATION AND HOW
THE POPULATIONS OF PSEUDO MOW --
PSEUDOMONAS SAMPLING AND DO WE
SEE CHANGES IN MICROBIAL
COMMUNITIES AT THE PSEUDOMONAS
POPULATION LEVEL AND DID A
MODULATOR STUDY BECAUSE TRIKAFTA
WAS ROLLED OUT AND LOOKED AT IT
BEFORE AND AFTER THE INITIATION
OF MODULATORS IN OUR PATIENT
POPULATION.
SO WHEN WE LOOK FIRST AT
RESPIRATORY VIRAL DISTRIBUTION.
WE SEE INFECTION DETECTED MORE
FREQUENTLY IN THE UPPER
RESPIRATORY TRACT AND THE
DIVERSITY IS MORE DIVERSE IN THE
UPPER RESPIRATORY TRACT.
WE CAN LOOK AT 16S SEQUENCING.
ONE PATIENT'S LONGITUDINAL
SERIES IS GOING FROM LEFT TO
RIGHT.
SINUS SAMPLES ARE IN THE TOP
PANEL AND BOTTOM PANEL ARE
SPUTUM SAMPLES.
I'M SHOWING THE RELATIVE
ABUNDANCE OF THE BACTERIAL
COMMUNITY MEMBERS AND THE DOTS
ARE ASSESSMENTS OF VIRAL
INFECTION STATUS WITH COLORED
DOTS WHEN WE SEE A VIRUS
INFECTION.
FIRST YOU MIGHT NOTICE IN SOME
VISITS WE SEE SINUS VIRAL
INFECTIONS.
AND IN SOME CASES WE SEE
DRAMATIC CHANGES IN THE
MICROBIAL COMMUNITIES WITH THE
VIRAL INFECTIONS BUT IN OTHER
CASES MORE SUBTLE CHANGES IN THE
MICROBAL COMMUNITIES AND IT WILL
BE IMPORTANT STUDYING THE
LONGITUDINAL STUDIES AND
UNDERSTANDING HOW VIRUSES MAY BE
IMPACTING MICROBIAL COMMUNITY
CHANGES.
HERE'S ENTIRE PATIENT COHORT WE
HAVE 39 PATIENTS WE'VE NOW
FOLLOWED.
WE HAVE PAIRED SAMPLES FOR THE
MAJORITY OF THE PATIENTS AND THE
MAJORITY OF THEIR VISITS.
WE HAVE A NUMBER OF THE FILLED
IN CIRCLES IN RED DOTS IS
SHOWING VIRAL INFECTIONS
DETECTED AND THE PEACH BLOCKS
ARE WHEN PATIENTS WERE ENROLLED
IN TRIKAFTA.
USING THIS COHORT WE'LL BE ABLE
TO ASK WHEN MODULATORS WERE
ROLLED OUT DO WE SEE CHANGES IN
THE FREQUENT OF RESPIRATORY
VIRAL INFECTION.
I WANT TO CAUTION INTERPRETATION
OF THE DATA IN THE CURRENT
COHORT AS MANY FOLKS HAVE
ALREADY SAID THE ROLL OUT
CORRESPONDED BIG THE PANDEMIC
AND SOCIAL DISTANCING AND
MASKING.
IT'S GOING TO BE HARD FOR US TO
PULL APART THE CONTRIBUTIONS OF
THE PANDEMIC AND MODULATORS.
WE MAY NEED TO STUDY THESE GOING
FORWARD BUT WE CAN ASK QUESTION
ARE IMPORTANT AND WE DON'T KNOW
ALL THE ANSWERS BUT DO VIRAL
INFECTIONS SHAPE MICROBIAL
COMMUNITIES AND DO MODULATORS
IMPACT THAT DIVERSITY AND DO WE
SEE SHIFTS WITH ACUTE
RESPIRATORY VIRAL INFECTION AND
DO MODULATORS IMPACT THAT.
NOW IF WE FOCUS IN ON
PSEUDOMONAS FORMS AND WE WERE
INTERESTED IN UNDERSTANDING THE
COMMUNICATION OF THE MICROBIAL
COMMUNITIES PARTICULARLY THE
PSEUDOMONAS ARE THERE SHARED
STRAINS BETWEEN THE COMMUNITIES.
IF WE LOOK AT THE POPULATION OF
PSEUDOMONAS WE SEE THAT THE
POPULATIONS OF PSEUDOMONAS IF WE
ORIENT THEM WITH THE THREE CLADS
AND THE ONE PATIENT I'M SHOWING
IN THIS PARTICULAR FIGURE ALL
CLUSTER TOGETHER SUGGESTING THIS
IS A CLONAL LINEAGE OF
PSEUDOMONAS DETECTED IN THE
PATIENT AND BOTH IN THE UPPER
AND LOWER RESPIRATORY TRACT
SHOWING SIMILAR STRAINS.
IF WE THEN ASK QUESTIONS ABOUT
ARE THESE STRAINS MOVING BETWEEN
THE UPPER AND LOWER RESPIRATORY
TRACT BRUISE WE HAVE PSEUDOMONAS
POPULATIONS WE CAN LOOK AT
VARIANTS THAT TRACT TOGETHER
THAT SHOW UP IN ONE COMPARTMENT
AND MOVE TO BOTH COMPARTMENTS.
WE SEE HERE WITH ONE LINEAGE OR
ONE CLUSTER OF VARIANTS THAT
SHOWS UP FIRST IN SIGN --
SINUSES THIS IS KNOWN IN THE
LITERATURE OF THE SINUS SEARCH
AS A RESERVOIR FOR LOWER
RESPIRATORY TRACT INFECTIONS AND
WE SEE IN THE PATIENT POPULATION
IF WE LOOK WE SEE A CLUSTER OF
VARIANTS THAT SHOW UP FIRST IF
THE SPUTUM AND SHOW LATER DATES
IN THE TRAJECTORY OF PATIENT
SAMPLES IN THE UPPER RESPIRATORY
TRACT AND PERSIST OVER TIME.
AND IT'S INTERESTING TO TRACT
OVER TIME AND WE CAN ASK IF
THEY'RE TRACTING TOGETHER AND
CAN LOOK AT ALLELE FREQUENCY.
THIS IS SHOWING IN THE ALLELE
FREQUENCY GRAFT SHOWING THE
VARIANTS.
YOU CAN SEE THE ALLELE FREQUENCY
INCREASES AND THE LINES TRAVEL
TOGETHER SUGGESTING ONE SUB
LINEAR PSEUDOMONAS AND
INTERESTINGLY IF WE ASK AND IT
CORRELATES WITH THE RESPIRATORY
INFECTION SUGGESTING MUCOSAL
CHANGES THAT ALLOW THE NEW
VARIANT TO BE ACQUIRED.
THAT VARIANT THEN IS DETECTED AT
LATER TIME POINTS IN THE SINUS.
THESE RISE TO HIGH FREQUENCY TO
OBSERVE IN THE POPULATION BEFORE
THEN BEING REPLACED BY OTHER
PSEUDOMONAS LINEAGES.
WE'RE EXCITED TO USE THE DATA
AND MUTATIONS TO SUGGEST WHAT
THE SELECTIVE PRESSURES ARE IN
THE DIFFERENT MUCOSAL SITES AND
HOW VIRUSES MAY BE CHANGING THE
SELECTIVE PRESSURES BY CHANGES
IN THE VARIANTS THAT APPEAR AND
HOW THE MODULATORS MAY ALSO
CHANGE THAT.
INITIALLY THERE'S REDUCTIONS IN
BACTERIAL BURDEN.
WE'D LIKE TO KNOW IN GAPS ARE
THE SAME STRAINS OF PSEUDOMONAS
PERSISTING OR IS THIS SELECTING
FOR NEW DOMINANT STRAINS.
ARE VIRUS INFECTIONS IMPACTING
THE MOVEMENT BETWEEN THE
COMPARTMENTS AND REDUCTIONS OF
BACTERIAL BURDEN BEING
MAINTAINED WITH MODULATORS.
I WANT TO STOP BY SAYING WE
THINK IT'S IMPORTANT TO CONTINUE
DOING THE DEEP STUDIES IN
PATIENTS TO UNDERSTAND MICROBIAL
COMMUNITY MOVEMENTS AND SUGGEST
NEW THERAPEUTIC TARGETS AS WE
THINK OF BACTERIAL INTERACTIONS
IN THE RESPIRATORY TRACT.
WE NEED TO IMPROVE OUR
UNDERSTANDING OF HOW THEY CHANGE
MICROBIAL COMMUNITYIES AND WE
NEED TO STUDY THE INTERACTIONS
IN THE NEW SETTING.
WE ALSO KNOW IN THIS SETTING OF
REDUCED SPUTUM AVAILABILITY WE
MAY NEED TO RELY ON SURVEILLANCE
OF OTHER SITES BECAUSE WE HAVE
PAIRED COLLECTIONS WE MAY BE
ABLE TO ANSWER IF THE
RESPIRATORY TRACT IS A NEW
SURVEILLANCE SITE AND ADVOCATE
FOR THE CONTINUED COMMITMENT TO
TRACKING MICRO -- MICROBIAL
INTERVENTIONS.
I'D LIKE TO THANK MY LAB MEMBERS
THAT HELPED DO THE WORK.
>> THANK YOU TO THE ORGANIZERS
FOR INVITE MEG TO SHARE.
-- INVITING ME TO SHARE.
I'M SHARE FACTS IN THE WAY OF
REPORTS.
I'M A CLINICIAN NOT A LAB
RESEARCHER SO NONE OF THESE ARE
EXPERIMENTS JUST OBSERVATIONS
MADE FOR PATIENTS WITH MODULATOR
EXPOSURE IN UTERO.
WE WILL TALK WITH THE
POSSIBILITIES THEY SUGGEST AND
MAKE INFERENCES AND GIVE
OPINIONS AND THEN TALK ABOUT
QUESTIONS FOR THE FUTURE.
AT LEAST FIVE INFANTS HAVE BEEN
BORN AFTER MOTHERS TOOK THIS
MODULATOR AND ALL BUT ONE HAD
NORMAL IRTs SO NOT DETECT
NEWBORN SCREENING AND ALL AT
SOME POINT HAD NORMAL FECAL E
ELASTASE AFTER BIRTH AND I'LL
START WITH THE FIRST ONE THAT IS
FROM OUR CENTER.
THE TRADITIONAL NEWBORN
SCREENING FOR IFRT DID NOT
DETECT ANY PROBLEMS.
IF WE HADN'T REQUEST THE
GENETICS TO BE RUN WE WOULDN'T
HAVE KNOWN SHE HAD CF.
AND IF YOU LOOK AT HER GROWTH
CURVE AND THINK AS A
PEDIATRICIAN WOULD ANYONE HAVE
SENT THIS CHILD FOR EVALUATION?
NO.
THIS CHILD'S THRIVING.
AND ALONG THE BOTTOM FOR THE
CASE REPORTS YOU CAN SEE I HAVE
DIFFERENT LEVELS OF MODULATOR
EXPOSURE.
IN UTERO WE LEAVE THE EXPOSURE
TO MODULATORS IS SIMILAR TO
THERAPEUTIC LEVELS IN MATERNAL
SERUM.
THERE'S EVIDENCE THAT THE
INGREDIENTS IN TRIKAPTA GO INTO
THE BREAST MILK BUT A LOWER
LEVEL THAN IS FOUND IN THE
SERUM.
MY PATIENT BREAST FED AND MOM
REMAINED ON TRIKAFTA FOR HER OWN
HEALTH WELL SHE REMAINS BUT WAS
ABLE TO BREAST FIELD AND THE
CHILD WEANED AT ABOUT 10 MONTHS
OLD AND MOM HAD A SUPPLY TO
STRETCH TO 12 MONTHS OLD BUT
SINCE THAT POINT SHE'S BEEN OFF
CF MODULATORS BECAUSE THERE'S NO
FDA APPROVED MODULATORS FOR THE
PATIENTS BELOW AGE 2.
WE'VE HAD NO LOOK GETTING HER
PRESCRIBED MODULATOR OFF LABEL
FOR HER AGE.
HER SWEAT CHLORIDE WAS
INTERESTING.
IT REMAINS CONSISTENT WITH CF
ABOVE 60 NANO MOLS PER LATER AND
IT WAS OVER 100.
I'VE BEEN MONITORING HER FECAL
ELASTASE.
I CAN'T SPOT A TREND IN HERE.
I WAS CONCERNED AROUND 6 MONTHS
WHERE IT SEEMED TO DROP TOWARDS
THE INEFFICIENCY RANGE AND
POPPED BACK UP.
SHE REMAINS CONSISTENT AND HAS
NOT AND I GAVE HER A WEEK'S
WORTH WHEN SHE WAS FIRST BORN
BEFORE WE GOT THE ELASTASE
LEVELS BACK BASED ON HER TWO
MUTATIONS.
AROUND 10 MONTHS OLD I STARTED
CHECKING SERUM LIPASE AND IT'S
BEYOND THE LOWER LIMITS THAN
NORMAL BECAUSE THEY DON'T HAVE A
WORKING EXOCRINE PANCREAS AND
THERE'S EVIDENCE OF PANCREATIC
CELLULAR LEAKAGE OR INJURY GOING
ON WHENEVER WE'VE CHECKED.
I DON'T KNOW IF THIS IS A TREND
EITHER WITH THE LIMITED NUMBER
OF DATA POINTS BUT WE'LL
CONTINUE TO MONITOR THAT JUST
MOST AS OFTEN AS WE CHECK THE
STOOL BECAUSE IT'S A PROCEDURE
TO DRAW BLOOD FROM AN INFANT.
CASE 2 ILLUSTRATED PART OF THIS
CASE HE WAS UNABLE TO BREAST
FEED AND MOMENT'S SUPPLY NEVER
CAME IN BUT THE CHILD WAS
THRIVING WITH WEIGHTS GREATER
THAN THE 50th PERCENTILE
INITIALLY AND BETWEEN 6 AND 8
WEEKS OLD HE STARTED DEVELOPING
SIGNIFICANT SYMPTOMS OF
MALABSORPTION AND HE EVEN WAS
FOUND TO BE PANCREATIC
INSUFFICIENT.
HE HAD TO START ON PANCREATIC
ENZYME REPLACEMENT THERAPY.
SIMILAR TO WHAT WAS REPORTED IN
THE ANIMAL MODELS LIKE THE
FERRET AT THE SAME TIME HE HAD
THE PANCREATIC INFLAMMATION AND
CASE 3 IS THE YOUNGEST.
HE'S CARED FOR AT OUR CENTER AND
HIS FACETS ARE HE ONLY HAS ONE
F508 MUTATION AND THE OTHER IS A
CLASS 1 MUTATION.
BUT LIKE THE OTHERS THOUGH HE
WASN'T ABLE TO BREAST FEED HE'S
BEEN THRIVING AND BASED ON
PATIENT'S 2s EXPERIENCE I'VE
BEEN CHECKING HIS FECAL ELASTASE
MORE FREQUENTLY AND MOM AND DAD
DROP IT OFF TO A LAP CLOSER TO
THEIR HOME EVERY WEEK BECAUSE IF
HE'S STARTING TO HAVE PANCREATIC
PROBLEMS I DON'T WANT TO MISS
THEM OR PROGRESS TO POOR WEIGHT
GAIN OR ANYTHING.
ALL THE KIDS HAVE BEEN EVALUATED
FOR MODULATOR AND MOST HAD LIVER
FUNCTION AND WHEN A PEDIATRIC
OPHTHALMOLOGIST MONITORED THEM
AND IT WILL BE YEARS BEFORE WE
KNOW IF THERE'S A FUNCTIONAL
INSTRUCTION BUT THE MERE
PRESENCE OF A VAS DEFERENCE WITH
A BOY WITH CF IS REMARKABLE IN
ITSELF.
AGAIN, HE'S BEEN THRIVING.
THEY'VE ALL BEEN WELL ABOVE THE
NORMAL RANGE.
HIS SWEAT CHLORIDE IS NOT AT THE
LEVEL YOU'D EXPECT FOR SOMEBODY
WITH THE TWO MUTATION.
I'D EXPECT A VALUE GREATER THAN
THIS AND WE DO PLAN TO REPEAT A
SWEAT WHEN HE'S A LITTLE OLDER.
CASE 4 WAS PUBLISHED WE A TEAM
AT SOUTH CAROLINA.
THE MOM IS A CARRIER AND THE
FAMILY KNOWS DAD'S A CARRIER AND
HAVE A FAMILY WITH CF AND
FAMILIAR WITH THE MANIFESTATIONS
OF THE DISEASE.
WHAT HAPPENED IN THIS CASE WAS
THE PREGNANCY SEEMED TO BE GOING
WELL AND THEN THERE WERE
FINDINGS ON ULTRASOUND THAT
SUGGESTED MECONIUM ILLIUS.
THEY WORKED WITH THE CARE TEAMS
AND BUT THEY STARTED TO START
MORNING LATE-- MODULATORS AND T
WAS NO CHANGE MECONIUM ILEUS AND
SLOWED NO FURTHER SIGNS.
THE BABY WAS BORN A COUPLE DAYS
LATER AND WHEN SHE WAS BORN
THERE WAS NO EVIDENCE OF
MECONIUM ILEUS AND HER FECAL
ELASTASE WAS LOW BUT IN WANTING
TO CONTINUE THE BENEFITS OF
MODULATORS THROUGH THE BREAST
MILK MOM CONTINUED TO TAKE
MODULATOR THERAPY AND BREAST
FEED AND WITH THAT THE FECAL
ELASTASE CLIMBED IN THE NORMAL
RANGE AND THE CHILD CONTINUED TO
THRIVE BUT AT ABOUT FOUR MONTHS
OLD MOM HAD TO DO SAFETY
MONITORING LABS FOR HERSELF ON
THE TRIKAFTA AND HER OWN HEPATIC
LEVELS AST AND ALT WERE THREE
TIMES NORMAL SO HAD TO STOP THE
THERAPY.
THOUGH SHE CONTINUED BREAST
FEEDING AT THIS POINT THE CHILD
WAS NOT GETTING ANY MODULATOR
THROUGH THE BREAST MILK ANY
LONGER AND WAS DEVELOPING
MALABSORPTION AND ABDOMINAL
ISSUES AND CRAMPING AND THE
PARENTS BEING FAMILIAR WITH CF
DIDN'T WANT TO SEE THEIR CHILD
GO THROUGH THIS WITHDRAWAL
PROFESSION AND BECAUSE THEY HAD
MODULATOR IN THE HOUSE SINCE MOM
WASN'T USING HERS ANYMORE THEY
CRUSHED IT UP AND GAVE A TINY
DOSE KIND OF IN CONSULTATION
WITH EXPERTS AROUND THE COUNTRY
AND THEY STARTED VERY LOW WITH
2% OF THE ADULT DOSING AND THAT
LED TO AN IMPROVEMENT IN
SYMPTOMS AND ALSO AN IMPROVEMENT
IN FECAL ELASTASE AND EVERYTHING
WAS GOING WELL AND PUSHED IT 3%
OF THE ADULT DOSE AND SAW
FURTHER IMPROVEMENT IN THE FECAL
ELASTASE.
AND STARTED OFF LABEL.
AND BY THE TIME SHE TURNS 2 SHE
WOULD BE A CANDIDATE WITH THE
MEDICATION.
THEY MADE AN ESTIMATE ON WHAT
HER DOSE WOULD BE AND CONSISTENT
WITH THE DOSING IN THE TRIAL
THEY'VE DONE IN UNDER FOR
PATIENTS AGES 1-2.
THIS MAY BENEFIT FROM EARLY
MODULATORS AND THOSE WITH
RESPONSE MUTATIONS YOU WILL THE
CASES SUGGESTED THE DEVELOPING
PANCREAS BENEFITS FROM MODULATOR
EXPOSURE.
I THINK CASES 2 AND 4 SHOW RISKS
TO THE PANCREAS IS MODULATOR
THERAPY IS WITHDRAWN AND THE
FERRET MODEL SUGGESTS IT'S TRUE.
I DON'T KNOW IF IT WILL REQUIRE
THE FULL DOSE TO HELP THE
PANCREAS.
THAT'S BECAUSE IT DOESN'T TAKE
MUCH CFTR FUNCTION TO BE
PANCREATIC SUFFICIENT.
AND YOU NEED A LEVEL OF RESERVE
TO GET INFLAMED BUT WHAT'S
HAPPENING WITH THESE KIDS IS
THEY'VE GOT THE WORKING PANCREAS
TO BEGIN WITH BUT THEIR
MUTATIONS ARE SUCH THEY'LL HAVE
LOW CFTR FUNCTION.
FROM THE BEGINNING THEY'RE AT
RISK FOR PANCREATITIS AS IT
WORSENS WITHOUT THE BENEFIT OF
MODULATOR THERAPY.
I THINK CASE 4 AT LEAST ANSWERS
THE QUESTION OF COULD IT BE
OFFERED TO MOTHERS CARRYING A
FETUS BUT THAT'S A DISCUSSION OF
SHOULD AND A LARGER DISCUSSION.
AND COULD IT BENEFIT FROM LOWER
DOSES OR IVACAFTOR HAS BEEN ABLE
TO BE STARTED YOUNG.
I'D LIKE TO LEARN ABOUT THE CELL
LINES.
THE DOSE RESPONSE CURVES HAVE
BEEN GENERATED IN EPITHELIAL OR
INTESTINAL CULTURES BUT WOULD
LOVE TO SEE SOME IN PANCREATIC
CELL LINES AND WE NEED TO KNOW
WHAT THE RISKS ARE OF MODULATOR
WITHDRAWAL AND HOW TO TREAT
INFANTS.
I'LL TURN IT OVER TO DR. CUTTING
FROM JOHNS HOPKINS.
>> WE HAD A BLUE JOURNAL PAPER
AND MANY HAVE BEEN INSTRUMENTAL
IN PREPARING THE SLIDES I'M
GOING TO SHOW YOU.
DISCLOSURES I HAVE A RELATIVE
THAT WORKS AT THE COMPANY I'LL
TALK ABOUT.
AND CLINICAL TRIALS REPORT
SHORT-TERM EFFECTS AND WE'RE
TALKING ABOUT WEEKS.
THESE ARE OBVIOUSLY PROFOUND
CHANGES IN SWEAT CHLORIDE WITH A
TRIPLE COMBINATION OVER 24 WEEKS
AND SAME WITH LUNG FUNCTION
IMPRESSIVE CHANGES.
AND HOW MUCH DO THEY TRANSLATE
TO LONG-TERM IMPROVEMENTS ARE
THERE OTHER COMPARISONS.
AND IN ACUTE INCREASE IN THE
LEVEL OF CFTR FUNCTION AND HOW
MUCH COMPARES TO A LIFE TIME OF
FUNCTION.
HIGH CFTR FUNCTION FROM
CONCEPTION.
DEVELOPMENT ISSUE ADDRESSED AND
SO FORTH.
I CAN POSE A QUESTION TO YOU.
AN THERE'S SOME FEATURES THEY
MANIFEST BUT THEY DON'T DEVELOP
LIFE TIME LUNG DISEASE.
IF YOU ACHIEVE 50% FUNCTION THAT
MATCHED?
IF YOU FALL SHORT OF THAT AND
HAVE LESSER RECOVERY OF FUNCTION
WHAT HAPPENS?
SO MOVING TO THE NEXT SLIDE, ANY
CONTEXT AND WE JUST SAW CONTEXT
AND SHOWING A GROWTH CURVE.
I'M GOING SHOW A GROWTH CURVE
FIRST.
HERE'S THE CHART AGAINST YEARS.
THERE'S CLEARLY A BIG
DIFFERENCE.
WHAT'S IT MEAN?
IF YOU PUT IT ON A GROWTH CURVE
YOU CAN NOW SEE WHAT HAPPENED.
IT GIVES CONTEXT AND LIFE TIME
CONTEXT BECAUSE NOW SHE'S
REACHED 50th PERCENTILE AND WHAT
THE EXPECTATION WOULD BE AND
THAT THERAPY WENT WELL AND
LIKELY SHE'LL CONTINUE ON THE 50
PERCENTILE.
AND WE'LL LOOK AT LUNG FUNCTION
AND RELATED DISEASE AND WE
STARTED WITH A COUPLE ELEMENTS
AND LOOKING AT MORE AND USE THE
DATA FROM THE CFTR PROJECT WITH
THOUSANDS OF INDIVIDUALS TO
STUDY.
AND WE NEED TO ESTABLISH THE
RELATIONSHIP BETWEEN CFTR AND
THE DIFFERENT TRAITS AND BY CFTR
FUNCTION I'LL DERIVE THAT BASED
ON THE CELL-BASED STUDIES AND
WE'RE LOOKING AT CHLORIDE AND
THERE'S OTHER PROPERTIES WE ARE
NOT ASSAYING AND IF YOU THINK OF
CHLORIDE TRANSPORT AND LOOK AT
THE STUDIES DONE YOU CAN
ESTIMATE WHAT THE CFTR FUNCTION
COULD BE AND WE DID IT FOR 226
GENOTYPES AND WE USED AN
ADDITIVE MODEL AND TAKE THE
FUNCTION OF THE VARIANT 1 AND
ADD IT TO VARIANT 2.
YOU PLOT IT OUT AND THE 226
GENOTYPES.
THERE'S A LOT OF DOTS ON THE
PAGE BUT THIS IS REAL DATA FROM
PATIENTS AND INDIVIDUALS WITH CF
AND SO YOU'LL HAVE EXPECTATIONS
WITH THIS OF DISTRIBUTION BUT
YOU CAN DRAW A ROBUST
STATISTICALLY RELEVANT BEST FIT
LINE AND THIS IS A NON-LINEAR
RELATIONSHIP BETWEEN SWEAT
CHLORIDE AND CFTR FUNCTION.
LUNG FUNCTION HAS THE SAME
ATTRIBUTES AND FITS A NON-LINEAR
RELATIONSHIP AND CAN IT BE
REPRESENTED IN A DIFFERENT WAY?
SO HERE IS NOW PUTTING ON A PLOT
AND YOU CAN LOOK AT THAT CFTR
FUNCTION INVERTED AGAINST THE
SWEAT CHLORIDE AND CAN YOU SEE
THE DATA NOW SCATTERS IN A WAY
TO LOOK AT THE PERCENTILE.
AND THAT'S WHAT THE MEANS IF YOU
TAKE SOME OF THE GENOTYPE S LIKE
THE F508 HOMO ZYGOTE AND SEE IT
DROP ALONG THE LINE.
YOU CAN DRAW THE LINE AND USE
THIS NOW TO PLOT OUT CLINICAL
RESULT DATA AGAINST IT.
AND ONE ISSUE IS THAT THIS END
OF THE SPECTRUM ONCE YOU GET
BEYOND 50% FUNCTION, WE DON'T
HAVE A LOT OF INFORMATION
BECAUSE MOST OF OUR DATA IS
DERIVED FROM CF PATIENTS AND
CFTR AND AS PUBLISHED IN THE
JOURNAL OF CYSTIC FIBROSIS AN
ELEGANT RE-ANALYSIS AT 100% WILD
TYPE YOU EXPECT IT TO BE BELOW
40.
AND IT FITS THE LUNG FUNCTION
AND THERE'S THE CURVE AND AT
100% FUNCTION YOU'RE START TO
REACH THE MEAN.
WHAT HAPPENS?
IF YOU START PLOTTING CLINICAL
TRIAL DATA THIS IS WHAT IS
PUBLISHED.
YOU SEE IT PLOT OUT IN THE OPEN
SYMBOLS AND THE SWEAT CHLORIDE
AND POST-TRIAL VALUES AND THEY
FOLLOW THIS NATURAL HISTORY
PLOT.
SO 65% IN FUNCTION AND A
DECREASE IN 58 NORMAL FOR AN
AVERAGE FOR THAT GROUP AND FITS
NICELY.
WHAT HAPPENS WITH LUNG FUNCTION?
THERE'S A DECREASE IN FUNCTION
BUT ONLY A 9% INCREASE IN FEV1.
ARE WE FALLING SHORT FOR SOME
REASON AND WHY?
PERHAPS WE ARE IF YOU COULD PLOT
MORE DATA OUT MAYBE WE CAN SEE
WHY WE'RE FALLING SHORT MAYBE
SOMETHING ELSE IS IMPORTANT TO
CONSIDER IN THE PLOT.
MAYBE THERE'S AN IRREVERSIBLE
COMPONENT WE CAN'T RECOVER.
LOOKS LIKE PERHAPS WE MIGHT HAVE
FALLEN SHORT BUT LOOKING AT MORE
DATA WE CAN CONSIDER THIS AND
THAT'S WHAT WE'VE DONE.
WE HAVE DATA PLOTTED OUT USING
MORE RECENT INFORMATION FROM
FIVE TRIALS WITH THE SWEAT
CHLORIDE SLOPE IS BETTER THAN WE
WOULD HAVE PREDICTED AND WE
CHANGED THE ASSUMPTIONS OF THE
FUNCTION IN THE CELL LINE BASED
SYMPTOMS AND EITHER WAY WE HAVE
QUITE A SUBSTANTIAL RESPONSE IN
THESE TRIALS AND NEXT ALSO SHOWS
A VERY NICE RESPONSE IN LUNG
FUNCTION BUT MATCHES WHAT WE
EXPECT FROM HISTORICAL DATA AND
GOOD INFORMATION SWEAT CHLORIDE
AT LEAST ASSOCIATES WITH A
CHANGE IN LUNG FUNCTION AND YOU
CAN DO THIS FOR ANY AGE IF THEY
HAVE A CHANGE OF SWEAT CHLORIDE
YOU CAN EXPECT A CHANGE IN LUNG
FUNCTION.
AND IVACAFTOR AND TESS -- TE
TEZACAFTOR.
WE HAVE F508 AND PROFOUND
CHANGES IN THOSE WITH ONE OR TWO
VARIANTS.
SHORT TERM RESULTS AFTER 29 DAYS
SHOWING HERE AND SOME LONGER
TERM DATA HAS NOW BEEN PUBLISHED
ARE PROMISING.
WHAT'S GOING ON LONG TERM?
THIS IS THE PLOT.
THE 508s ARE PLOTTED OUT AGAINST
THE EXPECTATION AND CHANGE IN
SWEAT CHLORIDE AND INDEED THEY
MATCH UP FOR THE SIX TRIALS.
AND LUNG FUNCTION FALLS SHORT.
WE KNOW DATA FALLS SHORT AND
THIS IS RETROSPECTIVE ANALYSIS
AND BELIEVE THE PLOTS COULD BE
USED FOR DESIGN PROSPECTIVE
STUDIES BUT FROM WHAT WE HAVE IN
HAND RIGHT NOW IT SEEMS THERE'S
A BIT OF A GAP FROM OUR
EXPECTATION MAY BE.
PROVEN LUNG FUNCTION ONCE YOU
PUSH CFTR FUNCTION TO 100% WILD
TYPE.
WHAT ABOUT SINGLE MUTATIONS?
WE HAVE 508 MUTATION AND SWEAT
CHLORIDE RESULTS LOOK PRETTY
GOOD.
THEY'RE RESPONDING VERY NICELY.
LUNG FUNCTION AGAIN IS NOT QUITE
ACHIEVING WHAT WE THINK IT
SHOULD HAVE.
AGAIN, THIS IS POPULATION DATA.
IT'S DIFFICULT TO THEN TRANSLATE
COMPLETELY TO AN INDIVIDUAL BUT
IT'S DIFFICULT TO DO.
THERE ARE SOME WAYS WE THINK YOU
CAN CONSIDER THEM.
THIS IS A PLOT THAT WE'VE
PRODUCED FOR THE BLUE JOURNAL
PAPER CITATION IS THERE.
WE ARE REVISITING IT NOW TO REDO
THIS BASED AND THE FACT WE NOW
HAVE 122,000 INDIVIDUALS IN
RECRUITMENT OF CFTR AND
PREDICTED A DIFFERENT AGE RANGES
AND DIFFERENT PREDICTED LEVELS
RANGE FROM LESS THAN 2% UP TO
25% TO 50% FUNCTION.
EACH BOX IS STARTING OUT
APPROXIMATELY 100% FEV1 IN
INDIVIDUALS BASICALLY CHILDREN
AND WE'RE SEEING HOW THEY
PROGRESS OVER TIME.
IF YOU HAVE AN INDIVIDUAL OVER
40 YEARS OF AGE AND ACUTELY
RAISE THEIR FUNCTION FROM 2% UP
TO 10% OR 15%, WHAT MIGHT YOU
EXPECT?
YOU MIGHT EXPECT FROM THIS PLOT
TO GET ABOUT A 15% TO 20%
IMPROVEMENT IN FEV1.
IF WE COMPLETELY REVERSE THE
DISEASE IN THAT INDIVIDUAL.
WHAT REALLY IS IMPORTANT THOUGH
IS THIS.
IF YOU HAVE 25% TO 50% CFTR
FUNCTION YOU CAN MAINTAIN 100
FEV1 LIFE TIME.
YOU HAVE TARGETS THAT WILL NEED
TO BE HIGHER.
PROBABLY 20% AND PROBABLY NEED
TO TARGET 50%.
AND THIS DATA PROVIDES EVIDENCE
THAT THAT IS THE CASE.
CAN IT BE USED TO PREDICT
OUTCOMES?
I THINK SO.
IF YOU SEE THEM MATCH HISTORICAL
EXPECTATIONS THAT'S PRETTY GOOD
EVIDENCE LIKELY YOU'LL HAVE
CHANGES IN LUNG FUNCTION THAT
ARE GOING TO AT LEAST IMPROVE.
IT'S NOT A 1:1 CORRELATION BUT
THERE'S A QUANTITATIVE
CORRELATION BUT PREDICTIVE OF
LUNG FUNCTION.
CAN THE DIFFERENCE IN PREDICTED
IN IMPROVEMENT OF DISEASE
SUGGEST IT COULD BE BUT KEEP IN
MIND WE'RE ONLY LOOKING AT THE
CHLORIDE FUNCTION OF CFTR.
NOT LOOKING AT REGULATION OF
EMAP.
IT'S POSSIBLE THOSE OTHER
FUNCTIONS WHEN ASSAYED FILL THAT
GAP AND CAN WE USE THE
PREDICTIONS THERE'S BEEN PUBLS
ON THIS AND I SHOWED WAYS TO
START THINKING ABOUT IT IN THIS
MANNER.
THANKS VERY MUCH FOR YOUR
ATTENTION.
APPRECIATE IT.
I'VE ENJOYED THE CONFERENCE.
>>ALL RIGHT, EVERYBODY.
WELCOME BACK.
I HAVE TO SAY YOU GUYS ARE GOING
NUTS IN THE CHAT BOX.
WHICH IS PHENOMENAL.
IT'S COOL TO SEE ALL THE THINGS
THE QUESTIONS AND THINGS BEING
SENT AROUND.
IN RELATION TO BRONCOSCOPY --
BRONCHOSCOPY IN KIDS TO DEFINE
THE AIRWAY CONDITIONS AND
THERAPEUTIC TARGETS AND LOOKING
AT MODULATORS WHAT'S THE THOUGHT
WHETHER BRONCHOSCOPY COULD BE
HELPFUL.
>> THERE WAS A LOOK AT USING
THIS FOR PSEUDOMONAS AND IS IT
AN INTERESTING TOOL TO ASSESS
THE ENVIRONMENT IN THE LUNG AND
THE MUCUS AND DO THE STUDIES AT
THIS POINT.
THAT'S WHERE I SEE THE
CHALLENGE.
I SEE THE BENEFIT AND IN DOING
THE STUDIES TO BETTER UNDERSTAND
HOW MUCH WHAT IS GOING ON AND
HOW MUCH INFLAMMATION IS LEFT IN
THE SETTING ESPECIALLY EARLY ON.
>> IS THE QUESTION WE'RE ASKING
DIFFERENT THAN WHAT WE WERE
ASKING BACK THEN?
SPECIFICALLY, IF WE'RE WAITING
FOR A TIME WHEN AN INFANT OR A
YOUNG CHILD IS GOING TO BE
ELIGIBLE FOR MODULATORS SO WITH
A DIFFERENT QUESTION OF BEING AS
AGGRESSIVE AS WE CAN TO IDENTIFY
PSEUDOMONAS EARLY.
IS THE QUESTION DIFFERENT?
>> FOR PSEUDOMONAS I WOULD SAY
NO BECAUSE THAT'S THE QUESTION.
AND IF YOU HAVE EFFECTIVE
THERAPY YOU CAN HAVE THIS
DISCUSSION FROM DATA AND FROM
THE STUDY IN AUSTRALIA BUT IN
THE ABSENCE OF CLEAR
INTERVENTION IT BECOMES MORE
DIFFICULT.
>> THERE'S A NUMBER OF THINGS
GOING IN THE CHAT NOTING HIGHLY
EFFECTIVE MODULATED THERAPIES
LOOKING AT MICROBIOLOGY AND
INFLAMMATION AND THERE WERE
ISSUES WITH THE STUDIO THE
INCIDENTS OF PSEUDOMONAS IS
LOWER THAN EXPECTED WHICH LEFT
IT A BIT UNDER POWERED.
IT'S WORTH SOME DISCUSSION.
>> AS A PHYSICIAN I WOULD HAVE
ISSUES TRYING TO CONVINCE MY
PATIENTS TO GO INTO THE STUDIES.
>> JEN, NEXT QUESTION.
>> SURE.
I GUESS THE NEXT QUESTION I WAS
GOING TO ASK IS FOR THE WHOLE
PANEL BUT PROBABLY MORE THE
PULMONOLOGISTS IN THE GROUP.
IS IT TIME TO BRING BACK INFANT
PFDs.
IT WAS USED FOR RESEARCH YEARS
BACK IN THE SAME VEIN SHOULD WE
EXPLORE THE DEVELOPMENT OF
INFANTS LCI.
AS TALKED ABOUT.
>> ON THE PROVIDER SIDE THEY'RE
A PAIN AND VERY CHALLENGING FOR
MANY MANY REASONS.
THE SEDATION IS AN ISSUE.
>>I CAN'T
EVEN GET MRIs ON MY PATIENTS
BECAUSE THEY'RE PATIENTS.
I DON'T WANT TO EXPERIMENT ON
THEM OR TRY TO MAKE THEM INTO A
CASE STUDY.
>> I THINK THE CHALLENGE HAS
BEEN LAID OUT.
THE INFRASTRUCTURE FOR TESTING
IS DWINDLING BECAUSE IT'S HIGHLY
RESOURCE INTENSE AND THE
INFORMATION GAINED IS PROBABLY
NOT AT THE SAME LEVEL.
LCI FOR INFANTS MAY BE MORE
INTERESTING BECAUSE YOU CAN AT
LEAST EARLY ON YOU MAY BE ABLE
TO DO IT WITHOUT SEDATION AS A
GROUP IN SOUTH AFRICA THEY'VE
BEEN ABLE TO DO IT THROUGHOUT
INFANCY WITHOUT SEDATION WHICH
IS QUITE REMARKABLE AND THE
GROUP IN DENMARK IS USING MILD
INTRANASAL SEDATION FOR THAT.
THAT'S SOMETHING TO MOVE FORWARD
THEN IT'S MORE REALISTIC IN
TERMS OF THE BALANCE OF THE
BURDEN AND THE INFORMATION
GAINED FOR THE OTHER
METHODOLOGIES IT HAS BEEN RATHER
CHALLENGING.
>> THE MAIN POINT IS WHAT
OBJECTIVE DATA AND WHAT IS THE
RIGHT MODALITY TO USE TO OBTAIN
THAT.
PFTs ARE NOT IT BUT IS IT LCI OR
MRI.
ARE THERE OTHER THINGS WE CAN
DO.
THAT'S THE RIGHT WAY.
>> THERE WAS DISCUSSION
YESTERDAY IN THE BREAKOUT OF
HIGHLY EFFECTIVE MODULATORS WHO
GET VIRAL INFECTIONS AND MAY BE
ABLE TO CLEAR WITHOUT NEEDING
ANTIBIOTICS IS IT POSSIBLE
HIGHLY EFFECTIVE MODULATOR LEADS
TO UNCOUPLING OF INFLAMMATION
SINCE ONLY SOME IS TRIGGERED BY
THIS.
THAT'S A MULTI-PRONGED QUESTION.
>> I WOULDN'T WANT TO DO THIS
WITHOUT SUFFICIENT EVIDENCE
BECAUSE THERE'S A RISK YOU STILL
HAVE AN ISSUE OF LOSING FUNCTION
DURING EXACERBATION AND I'D HATE
TO SEE THAT BEFORE WE HAVE
ADEQUATE EVIDENCE.
>> I THINK SOME OF MY THOUGHTS
ARE THIS IS WHERE I THINK WE
NEED MORE INFORMATION.
I THINK WE DON'T KNOW WHAT'S
GOING ON DURING THESE VIRAL
EXACERBATIONS.
SO OUR HOPE IS WITH OUR STUDY
AND I KNOW THERE'S OTHER FOLKS
THAT IF WE CAN UNDERSTAND THE
MICROBIAL POPULATIONS OF THE
PROBLEMATIC MICROBES LIKE
PSEUDOMONAS OR THE GENERAL
BURDEN AND TAXA CHANGES.
IF WE UNDERSTAND WHAT'S CHANGING
BETTER IT MAY GIVE HOPEFULLY
MORE INFORMATION TO PHYSICIANS
TO THINK ABOUT WHETHER TO BE
PRESCRIBING ANTIBIOTICS OR NOT
AND WE STILL DON'T KNOW ENOUGH.
>> IF WE LEARN ABOUT MOLECULAR
MECHANISMS AND THINK OF IRON OR
MODULATORS OF METABOLISM BEING
TESTED IN CANCER, CAN WE USE
SOMETHING LIKE THAT MAYBE THE
ANTIBIOTIC IS THE APPROACH BUT
TARGETING SOME OF THOSE
DYSREGULATIONS IS MAYBE
SOMETHING TO CONSIDER.
>> I WAS GOING TO MAKE A COMMENT
ABOUT SOME DATA IN THE SETTING
OF HIGHLY EFFECTIVE MODULATORS
THE BURDEN OF CF PATHOGENS WENT
DOWN.
BEING ON MODULATORS AND
PSEUDOMONAS AND THINGS WE
CONSIDER TO BE CF PATHOGENS THAT
DENSITY DECREASED IF YOU HAVE A
KID ON HIGHLY EFFECTIVE
MODULATORS WHO GETS AN INFECTION
THE THOUGHT IT WILL CAUSE MORE
INFLAMMATION AND DAMAGE BUT IF
THE PATHOGENS THE BURDEN IS
DECREASED THEN MAYBE WE DON'T
HAVE TO USE ANTIBIOTICS IF THOSE
SPECIFIC PATHOGENS AREN'T GOING
TO FLOURISH.
IT WAS VERY INTRIGUING DATA I
DON'T THINK I'D SEEN BEFORE TO
THINK ABOUT WHAT ARE THE IMPACT
OF THE MODULATORS ON THE
TRADITIONAL CF PATHOGENS AND HOW
CAN WE USE THAT TO HELP MAKE
CLINICAL DECISIONS?
WE ARE FAR FROM THAT BUT IT WAS
INTERESTING TO SEE THAT WAS WHAT
WAS PRESENTED.
>> ON THE OTHER HAND THE
PATHOGENS DID NOT GO AWAY.
>> I'VE BEEN USING IT ON THE
OLDER KIDS AND BEEN WILLING TO
DO A PFG AND LET A FEW HAVE
COLDS WITHOUT A COURSE OF
ANTIBIOTICS IF THEY'RE STABLE ON
HIGHLY EFFECTIVE MODULATED
THERAPY AND BEEN ABLE TO SHORTEN
THE COURSES BASED ON THE LIQUID
ANTIBIOTICS ARE ONLY GOOD FOR 10
DAYS.
I KNOW THEY'RE WORKING ON A
PEDIATRIC TRIAL TO KNOW THE
DURATION WE NEED BUT I'VE BEEN
WILLING FOR THE ONES ON
MODULATORS SAYING WE'LL ASSET AT
NINE DAYS OF ANTIBIOTICS TO
FINISH OUT THE PRESCRIPTION OR
DO FOUR MORE DAYS OR ANOTHER
WEEK'S WORTH.
>> I THINK WE ALL AGREE IT'S AN
OPPORTUNITY TO LEARN MORE IN AN
AREA VERY IMPORTANT TO EXPLORE.
>> ABSOLUTELY.
>> JEN, DO YOU HAVE THE NEXT
ONE.
>> SORRY, LOOKING IN THE CHAT.
THERE'S A LOT GOING ON.
>> AS FOLKS CHAT, THEY'RE LOSING
THEIR QUESTIONS BECAUSE THEY
HAVE TO SCROLL FOR THEM.
THAT'S THE DELAY.
APOLOGIES.
>> STOP TALKING, GUYS.
[LAUGHTER]
>> THE ONE QUESTION RAISED IS
THAT GIVEN WE'RE EXPECTING
PATIENTS TO LIVE AT LEAST 50
YEARS NOW ON MODULATORS AND WE
WANT TO ENSURE THEY'RE IMPROVING
IN QUALITY OF LIFE AND GIVING
PEOPLE THE BEST POSSIBLE START,
WHAT SHOULD WE BE DOING IN TERMS
OF I GUESS THE QUESTION IS WHAT
SHOULD WE BE DOING IN TERMS OF
HELP KIDS HAVE THE BEST START?
TERI RAISED GREAT QUESTIONS IN
HER TALK.
>> I THINK FOR ME THAT'S A HUGE
QUESTION.
I THINK THAT'S WHERE MY HEAD
GOES IN TERMS OF THINKING ABOUT
BRONCHOSCOPY AND WHAT TOOLS DO
WE HAVE TO ENCOURAGE OUR KIDS TO
BE ADEQUATELY NOURISHED AND HAVE
AS LITTLE LUNG DISEASE UNTIL WE
START THEIR MODULATOR.
WE MONITOR AND SEE KIDS AND
CULTURE THEM AND TREAT THEM WHEN
THEY HAVE INFECTIONS OR
EXACERBATIONS.
WE DO A LOT RIGHT NOW.
I GUESS MY QUESTION IN MY HEAD
IS DO WE NEED TO PUSH DOWN ON
THE ACCELERATOR FURTHER KNOWING
THAT WE'RE PROBABLY NOT GOING TO
REVERSE ANY ESTABLISHED LUNG
DISEASE WITH THE START OF A
MODULATOR.
SO DO WE NEED TO MAKE SURE WE'RE
IN THE BEST PLACE POSSIBLE AND
ARE WE -- ARE THE PROTOCOLS WE
CURRENTLY FOLLOW, DO THEY PUT US
IN THAT POSITION.
IS THERE SOMETHING ELSE WE NEED
TO BE DOING AND THAT IS A BIG
GAP FOR US AS A COMMUNITY TO DO
THE SAME THING SO THAT OUR
PATIENTS ARE IN THE BEST
POSITION POSSIBLE.
>> I THINK IT'S INTERESTING HOW
YOU RAISE THE QUESTION.
IN A WAY FOR ME THAT WAS ALWAYS
THE STRATEGY WE WERE FOLLOWING
TO KEEP PATIENTS AS HEALTHY AS
POSSIBLE FOR THE FUTURE
OPPORTUNITIES COMING IN.
THAT'S THE WAY I SAW EARLY
INTERVENTION THERAPY WITH OTHER
INTERVENTION SAYING OKAY THIS IS
AN INVESTMENT AND WE CAN THEN
BENEFIT FROM OTHER THERAPIES
THAT MAY BE MORE DRAMATIC.
IT'S INTERESTING BUT ALSO
DIFFICULT FOR KNOW ENVISION HOW
WE WOULD BE MORE AGGRESSIVE IN A
WAY THAT WOULD BE BENEFICIAL
BECAUSE ON THE OTHER HAND WE
DON'T WANT TO BE IN THE
SITUATION WHERE WE THROW THE
KITCHEN THINK AT EVERYBODY AND
ALL DIAGNOSTIC MEASURES IF WE
DON'T KNOW THEY'RE OF BENEFIT.
I FEEL AND THINK IT HAS BEEN
DONE FOR BRONCHOSCOPY AND NEED
TO DO THIS AND BE DILIGENT IN
WHATEVER WE TRY TO IMPLEMENT IS
ACTUALLY PROVIDING BENEFIT TO
THE PATIENTS.
>> THE ONE THING THAT COMES MY
MIND IS NUTRITION AND PUSHING
FAMILIES TO MAKE THE DECISION.
THINKING IN MY MIND THE KIDS
I'VE TAKEN CARE OF OVER THE YEAR
WHO WILL SOMETIMES BE WE'LL GIVE
YOU THREE MONTHS OR SIX MONTHS
AND TURNS INTO A YEAR OR 18
MONTHS AND WE STILL HAVE A KID
NOT GROWING.
AND SPECIFICALLY FOR SITUATIONS
LIKE THAT WHERE WE KNOW HOW
IMPORTANT NUTRITION IS DO WE
NEED TO PULL THE TRIGGER SOONER
AND SAY WHEN YOU TURN 6 YOU'LL
HAVE THIS MODULATOR AND
SITUATIONS LIKE THAT WHERE I
AGREE, FELIX, WE'RE DOING AS
MUCH AS WE CAN TO KEEP OUR KIDS
HEALTHY.
I'M THINKING ABOUT THE SPECIFIC
SCENARIOS WHERE WE TEND TO HAVE
MORE PATIENCE AND MAYBE WE
SHOULDN'T WHEN WE KNOW WHAT'S AT
STAKE.
>> AS A GENETICISTS WE DEAL WITH
DISEASE AND GENETIC DISORDERS
AND I THINK THE DATA WAS
PROVOCATIVE IF YOU START
TREATMENT EVEN IN UTERO YOU CAN
AVOID A LOT OF THE PROBLEMS IN
THE LUNGS THAT OCCUR IN UTERO.
THE REAL GOAL AT THEN OF THE DAY
IS TO START TREATMENT AS SOON AS
POSSIBLE.
CERTAIN PKU THE SUCCESS OF
TREATING THAT DISEASE IS
STARTING FIRST WITH SCREENING
AND THEN STARTING AND FOLLOWING
AS THE KEY INDICATOR OF SUCCESS
AND THERE'S MANY OTHER GENETIC
DISEASES THAT YOU WANT LONG TERM
OUTCOMES YOU HAVE TO START
EARLY.
ALL THE OTHER MEASURES WE NEED
TO DEVELOP BUT WE NEED TO START
CONSIDERING HOW TO DO IT.
IN ORDER TO START EARLY WE NEED
TO CONSIDER RISK BENEFIT.
SO TREATING A CHILD OR A BABY
WITH A DRUG THAT WE DON'T KNOW
LONG TERM OUTCOMES HAS RISKS AND
WE DON'T KNOW WHAT THEY ARE
THOUGH WE'RE STARTING TO SEE
BEHAVIORAL ISSUES AND VISION AND
IN THE LIVER.
WHAT'S THE BENEFIT?
HOW MUCH DO WE KNOW OBJECTIVELY
ABOUT THE BENEFIT.
THAT'S WHAT WE TRY TO PRESENT.
THERE'S CLEAR BENEFIT.
YOU CAN ACHIEVE 25% TO 50%
FUNCTION SHORTLY AFTER BIRTH,
YOU'RE GOING HAVE, WE BELIEVE
NORMAL FUNCTION LIFE TIME.
I KNOW THERE'S A LOT OF CAVEATS
IN THIS.
THERE IS.
THIS IS A HIGH-LEVEL VIEW BUT
TOGETHER IF WE DEVELOP A LOT OF
INFORMATION THAT WE CAN PRESENT
TO PARENTS AND WE CAN PRESENT
THAT THE BENEFITS TRULY IN OUR
BEST ESTIMATE OUTWEIGH THE RISK
AND GETTING TREATMENT TO THE
YOUNGEST AGES OF PATIENTS WITH
INDIVIDUAL CF BECOME A
POSSIBILITY OTHERWISE IT MAY
TAKE A LONG TIME TO GET THERE.
AND MAYBE ONE OF OUR GOALS AND I
CERTAINLY SEE SOME OF THIS
EVOLVING IN THE SESSION AND ALSO
THROUGH THE CONFERENCE ACTUALLY
IS HOW DO WE GET THAT DATA TO
MAKE THE ARGUMENT THE BENEFIT
REALLY DO OUTWEIGH THE RISKS
WHEN WE GIVE THESE DRUGS TO A
2-MONTH-OLD.
THAT'S WHAT I'VE BEEN THINKING.
GREAT IF WE GET IT FROM PFTs OR
OTHER TOOLS FOR INFECTION.
>> I THINK IT'S GOOD.
WE'RE TALKING ABOUT THE
UNCERTAINTY OF LONG-TERM
OUTCOMES OF THE MODULATORS AND
I'VE HAD DISCUSSIONS WITH BOTH
PATIENT WE WILLING TO LET THEIR
PANCREAS SLOWLY OR RAPIDLY DIE
OFF.
THERE IS UNCERTAINTY BUT THERE'S
ALSO WE KNOW WHAT UNTREATED CF
LOOKS LIKE.
IT'S NOT GOOD.
>> AS I SAID, YOU KNOW WHAT A
CARRIER LOOKS LIKE.
AS ANN HARRIS POINTED OUT IT'S
AN IN UTERO MALDEVELOPMENT
PROBLEM AND SOME CHILDREN WILL
RAPIDLY DEVELOP IT AND NEW DATA
IS VERY CLEAR WHAT YOU CAN DO
WITH EARLY APPLICATION OF
MODULATORS.
IT SOUNDS LIKE MORE EVIDENCE
THAT WAY THAN IN OTHER VENUES
WILL HELP.
>> I THINK OF THE CHILD WHO HER
SISTER HAS TO GO TO THE SCHOOL
NURSE TO GET ENZYMES BEFORE
BIRTHDAY PARTIES OR WHATEVER AND
MAYBE THE YOUNGER ONE WILL NEVER
HAVE TO.
IN TERMS OF QUALITY OF LIFE,
IMAGINE THAT.
>> WANTED TO MAKE A COMMENT OF A
MOTHER NOT ON CF TAKING TRIK
TRIKAFTA.
I DON'T KNOW WHAT TO SAY ABOUT
THAT.
THE CONCEPT MAKES SENSE.
THAT'S WHAT GARY WAS SAYING.
IF WE'RE GOING TO -- THAT'S
WHAT'S GOING TO PREVENT A LOT OF
THE SEQUELAE WE SEE BUT WHAT ARE
THE RISKS OF DOING THAT?
I'M PRETTY AMAZED THEY WERE ABLE
TO GET THAT AND ADMINISTER THAT
AND THIS WAS THE SAME KID THAT
HAD THE PALPABLE VAS DEFERENS.
>> WE'RE WATCHING IT EVERY WEEK.
>>
>> THE DATA FROM THE FERRETS AND
THE PIGS THE ANIMAL MODELS
PROVIDE AN IDEAL WAY TO TEST IN
A MORE THOROUGH AND OBJECTIVE
WAY IN UTERO TREATMENT.
WE DO OTHER THINGS TO MINIMIZE
THE LIFE TIME EFFECTS BY WORKING
AS EARLY AS WE CAN WITH THESE
CONDITIONS.
THERE'S PRECEDENCE AND THE IDEA
OF TREATING A MOM MAY NOT BE
THAT SURPRISING.
WE MAY SIT AND PONDER ABOUT IT
FOR SOME TIME AND IF WE CAN FIND
EVIDENCE A CARRIER MOM MAY
BENEFIT FROM TAKING TRIKAFTA BUT
TO TREAT HER CHILD, THIS WOULD
NOT BE COMPLETELY UNHEARD OF
BECAUSE WE TREAT PKU THAT WAY.
WE ALREADY PUT HER ON A
RESTRICTIVE DIET TO PREVENT THE
FETUS AND PROTECT IT AND IT WILL
BE WORTH IT THE EFFECT OF
TRIKAFTA ON MENTAL HEALTH
BECAUSE THAT'S BEEN WELL
DESCRIBED OR TALKED ABOUT A LOT
IN THE ADULT POPULATION.
I THINK MANY OF US HAVE
ANECDOTAL PATIENTS THAT HAVE HAD
MENTAL HEALTH ISSUES RELATED TO
STARTING TRIKAFTA BUT THAT'S
IMPORTANCE.
THAT'S A DIRECT IMPACT
POTENTIALLY OF TRIKAFTA ON A
DEVELOPING BRAIN OR ON CHILDREN.
THAT IS SOMETHING WE HAVE TO
UNDERSTAND IF WE'RE TRYING TO
TALK ABOUT WHEN TO START THE
MODULATORS.
IF WE'RE GOING TO START IT AT
BIRTH, WE HAVE TO HAVE A BETTER
UNDERSTANDING OF WHAT THE IMPACT
IS ON A GROWING DEVELOPING BRAIN
AND MAYBE THE ANIMAL MODEL IS
THE PLACE TO START TO UNDERSTAND
THAT.
THAT'S A BIG ISSUE.
>> I WANT TO JUMP IN AND SAY
WE'RE AT TIME FOR THIS SESSION.
THANK YOU ALL TO SESSION 3
SPEAKERS.
IT SOUNDS LIKE THERE'S MORE TO
BE DISCUSSED.
PLEASE USE THE CHAT AND WE'LL
HAVE DISCUSSION OPPORTUNITY IN
THE BREAKOUTS THIS AFTERNOON.
BUT FOR NOW WE'RE GOING MOVE ON
TO SESSION 4.
WHICH IS CONSIDERATION FOR
MODULATOR USE IN SPECIAL
POPULATIONS.
I WOULD LIKE TO TURN THE MEETING
OVER TO THE SESSION 4
MODERATORS.
>> THE TALKS WERE AMAZING AND I
FEEL WE CAN GO HOURS ON
EVERYTHING PRESENTED.
>> WE'LL HAVE FIVE TALKS FROM A
PROFESSOR OF MEDICINE AND PETE
-- PEDIATRICS AND LOOK AT THE
PERINATAL PERIODS AND CF.
>> THANK YOU FOR THE OPPORTUNITY
TO SPEAK TODAY.
I'LL GO OVER MY DISCLOSURES
BECAUSE I DO CONSULTING AS WELL
AS ACT AS A PRIMARY INVESTIGATOR
FOR OUR STUDIES.
FOR THIS TALK I'LL QUICKLY
DESCRIBE WHAT WE THINK WE KNOW
ABOUT THE IMPACTS OF CFTR
MODULATORS ON SEXUAL AND
REPRODUCTIVE HEALTH AND TALK
ABOUT THE SHORT-TERM OUTCOMES
AND GAPS.
AS MOST ARE WELL AWARE, AT THIS
POINT THE MAJORITY OF PEOPLE
WITH CF ARE AT LEAST VARIANT
ELIGIBLE FOR HIGHLY EFFECTIVE
MODULATED THERAPY IMPACTING
EVERYONE PROFOUNDLY AND THAT
CORRELATES WITH SURVIVAL.
THE REASON IT'S AN IMPORTANT
POINT IS BECAUSE WE'RE EXPECTING
TO SEE OVER THE NEXT 20 YEARS A
SIGNIFICANT INCREASE IN THE
POPULATION OF ADULTS WITH CF.
PEOPLE ARE LIVING LONGER.
THEY'RE FEELING HEALTHIER AND
CONSIDERING THEIR OPTIONS FOR
HAVING CHILDREN.
WHAT DO WE KNOW ABOUT FERTILITY
IN PEOPLE WITH CF?
GENERALLY, FEMALES WITH CF HAVE
REPRODUCTIVE ANATOMY AND THERE
ARE FACTORS THAT CAN AFFECT
FERTILITY.
THICK DE HYDRATED PH IMBALANCED
CERVICAL MUCUS AND IN THE PAST
WE SAW DELAYED PUBERTY AND
OVULATION AND PEOPLE HAD
SUBOPTIMAL NUTRITIONAL STATUS.
MOST FEMALES CAN BECOME
PREGNANT.
COLLEAGUES LOOKED AT FACTORS
THAT MADE IT HARDER FOR WOMEN TO
GET PREGNANT AND SHOW PANCREATIC
INSUFFICIENT AND OVER AT FIRST
ATTEMPT MADE IT HARDER FOR A
SUBSET OF PEOPLE WITH CF
HOWEVER, EVEN IN THE
PREMODULATOR ERA 29% TO 39% OF
PREGNANCIES IN FEMALES WITH CF
WERE UNPLANNED.
WHAT ABOUT THE IMPACT OF
MODULATORS?
I'LL SHOW YOU SEVERAL SLIDES IN
WHICH THE REPRODUCTIVE HEALTH
IMPACT ON THE LEFT AND THE
INDIVIDUAL MODULATOR STUDIED IN
ANIMAL REPRODUCTIVE ANIMALS WERE
ACROSS THE TOP.
IF YOU LOOK AT THE IMPACT ON
FERTILITY, THERE WAS IMPAIRED
FERTILITY WITH TEZACAFTOR BUT AT
NORMAL HUMAN DOSES THERE WAS NO
IMPACT.
WHEN THE PH IS ACIDIC IT'S MAKES
IT DIFFICULT FOR THE SPERM AND
WHAT IS THE EVIDENCE?
THERE'S A LITTLE BIT AT THIS
POINT THIS WOMAN WAS DIAGNOSED
WITH CF AND HAS THICK MUCUS AND
AFTER STARTING IVACAFTOR IT'S
NOT AS THICK AND WE'RE LOOKING
AT WHETHER OR NOT CERVICAL MUCUS
CHANGES WITH THE USE OF THIS AND
THOUGH PEOPLE WITH CF ARE
SUPPOSED TO BE ON CONTRACEPTION
DURING THE IVACAFTOR TRIALS 2%
BECAME PREGNANT WE THINK BECAUSE
THEY DIDN'T THINK THEY COULD GET
PREGNANT AND WITH THE MODULATOR
WERE ABLE TO GET PREGNANT.
THERE WERE CASES OF UNINTENDED
PREGNANCIES WITH AND SEVEN WOMEN
WHO REPORTED INFERTILITY BECAME
PREGNANT WITH IVACAFTOR AND
COLLEAGUES REPORTED 14 FEMALES
WITH CF ACHIEVED CONCEPTION AT
EIGHT WEEKS AFTER STARTING
ELAXCAFTOR AND THE DATE IS SUPER
IMPOSED FOR THE TIMING OF TRIALS
PEOPLE WERE SUPPOSED TO NOT --
AND WE'VE LOOKED AT OUTCOMES FOR
PREGNANCY.
GENERALLY THEY'VE SHOWN PEOPLE
WITH CF WHO HAVE LOWER LUNG
FUNCTION ESPECIALLY IF THE LUNG
FUNCTION IS BELOW 50 OR 60 ARE
LIKELY TO HAVE POORER OUTCOMES
ALONG WITH PEOPLE AND TWO
STUDIES LOOKED AT RETROSPECTIVE
STUDIES IN PREVIOUSLY DONE
STUDIES THAT SHOWED MAYBE THERE
WASN'T AN IMPACT ON SURVIVAL.
GOSS AND COLLEAGUES LOOKED AT
FEMALES WHO BECAME PREGNANT
ABOUT 700 AND WERE HEALTHIER AT
BASELINE AND HAD A BETTER
10-YEAR SURVIVAL COMPARED TO
THOSE WHO COULDN'T BECOME
PREGNANT AND SCHEFTER AND
COLLEAGUES LOOKED AT AN
EPIDEMIOLOGIC STUD AGREE 1994 TO
2005 AND SHOWED FEMALES WITH CF
WHO BECAME PREGNANT HAD MORE
ILLNESS VISITS AND MORE
PULMONARY VISIT AND LOWER
QUALITY OF LIFE BUT DID NOT HAVE
ACCELERATED DISEASE PROGRESSION
AND THOSE FEMALES WHO BECAME
PREGNANT WERE HEALTHIER AT
BASELINE THAN THOSE WHO DIDN'T.
WE KNOW WITH LEXTEZIVA THAN
MAINTAIN THE CONDITION IN THE
LIVER.
WHAT DO WE KNOW ABOUT PREGNANCY
COMPLICATIONS IN FEMALES WITH
CF?
AND WE KNOW WITH DIABETES,
INFECTION, PRE-TERM LABOR AND
GESTATIONAL HYPERTENSION AND
PREECLAMPSIA AND THOSE BORN TO
THOSE MOTHERS HAD INCREASED
RATES OF CARDIAC ANOMALIES,
INCREASED JUANDICE AND PREMATURE
DELIVERY.
ONE OF THESE ARE DIRECTLY
RELATED TO CFTR OR THE HEALTH OF
THE WOMAN OR THE LEGACY DIET
WE'RE NOT SURE AT THIS POINT.
WE SAW DECREASED LUNG FUNCTION
WAS CORRELATED WITH DECREASED
GESTATIONAL AGE AND BIRTH
WEIGHT.
THE LOWER THE LUNG FUNCTION A
WOMAN HAD THE MORE LIKELY SHE
WOULD DELIVER AN INFANT WITH
LOWER BIRTH WEIGHT.
WHAT DO WE KNOW ABOUT MODULATORS
AND PREGNANCY FROM ANIMAL
REPRODUCTIVE MODELS?
LOOKING AT ANIMAL MODELS AND THE
INDIVIDUAL MODULATORS AT NORMAL
HUMAN DOSES WE DID NOT SEE
ISSUES BUT AT HIGH DOSES THERE
WAS DECREASED FETAL BODY WEIGHT
AND DECREASED BODY WEIGHT WITH
TEZ AND DETACHMENT FOR THE EARS
AND EYE OPENING AND DECREASED
FETAL BODY WEIGHT WITH
ELEXACAFTOR AND THAT'S RECENTLY
BEEN CHANGED SINCE 2015 THEY'VE
BEEN USING THE PREGNANCY AND
LACTATION LABELLING RULE.
AND LOOK AT CRITICAL DECISION
MAKING WHEN TREATING PREGNANT OR
LACTATING FEMALES.
THE SPONSOR WAS REQUIRED TO SHOW
WHETHER THERE WAS ADEQUATE AND
WELL CONTROLLED STUDIES IN
PREGNANT FEMALES TO SAY IF
THERE'S A DRUG ASSOCIATED RISK
OF MAJOR BIRTH DEFECT OR
MISCARRIAGE AND IN THE ANIMAL
STUDIES THE SPONSOR HAS TO SAY
HOW MUCH DRUG WAS GIVEN COMPARED
TO THE MAXIMUM RECOMMENDED HUMAN
DOSE.
SO WHAT WE'RE TRYING TO WEIGH IN
TERMS OF THE MODULATORS IN
PREGNANCY IS THE UNKNOWN RISK TO
THE FETUS BECAUSE THERE'S A
PAUCITY OF DATA IN HUMANS VERSUS
IF THE MOM DISCONTINUES THE
MODULATOR WILL VERY HAVE HEALTH
DECLINE OR INABILITY TO MAINTAIN
WEIGHT DURING PREGNANCY AND WHAT
IF SHE HAS A SEVERE
EXACERBATION?
THERE ARE REASONS TO BELIEVE AND
THERE'S A THOUGHT IT CAN CAUSE
SEVERE ISSUES.
THERE WAS A CASE SERIES OF
IVACAFTOR WITHDRAWAL SYNDROME
AND THERE WERE THREE CASES OF
DECLINE WITH WITHDRAWAL
INCLUDING UNFORTUNATELY IN ONE
PERSON WHO DIED AFTER WITHDRAWAL
OF IVACAFTOR.
THERE WAS ADDITIONALLY AN
ABSTRACT PRESENTED IN 2018 THAT
LOOKED AT ADULTS WHO WERE IN THE
PHASE 2 STUDIES OF ELEXACAFTOR
AND PEOPLE EXPERIENCED LUNG
FUNCTION DECLINE AND AND THEY
LOOK AT THE USE AND SUBSEQUENTLY
ELX/TEZ/VA AND WOMAN WHO CHOSE
TO STAY ON THEM.
IN 135 FEMALES WITH CF, USE OF
CFTR MODULATOR RESULTED IN POOR
MATERNAL COMPLICATIONS RELATED
TO MODULATOR THERAPY AND ONE WAS
A PULMONARY EXACERBATION AND ONE
WAS AN INCIDENT OF LEUKEMIA THAT
HASN'T BEEN REPORTED BEFORE OR
AFTER IN ASSOCIATION WITH
LUMAVA.
THE MISCARRIAGE RATE WAS LESS
THAN 10% AND CESSATION RESULTED
IN DECLINE AND INTEREST WERE NO
MODULATOR INCIDENTS.
ALL THE MODULATORS ARE PRESENT
IN BREAST MILK AND WE KNOW FROM
RATS ALL WHO WERE ADMINISTRATED,
IVACAFTOR DID DEVELOP CATARACTS
SO THERE'S A WARNING LABEL FOR
THAT.
ONE WOMAN CONTINUED LUMIE --
LUMIVA AND THERE WERE CASES
WHERE THE INFANT HAD AN INCREASE
IN THE LFTs.
THE SECOND WAS ASSOCIATED WITH
THE MOM TAKING ANTIBIOTICS AS
WELL.
RECENTLY UNC SAW ELXTESIVA CAN
BE MEASURED IN THE INFANT AND 65
INFANTS BREAST FED WHILE
MODULATOR THERAPY DIDN'T HAVE
CATARACTS AND THERE WERE NO
ABNORMALITIES IN THE IFTs.
THERE'S DATA THAT SUGGESTS THERE
MAY BE ADVERSE HEALTH IMPACTS.
WE USED THE U.K. REGISTRY TO
LOOK AT THE QUESTION AND SHOWED
A DECREASE IN LUNG FUNCTION AND
DECREASE IN EXACERBATION AND
THROUGH DATA THROUGH CHART
COLLECTION HAVE ON THE 303
PREGNANCY AND THOSE ON
MODULATORS LOOKED LIKE THEY HAD
AN IMPROVEMENT IN THEIR
POST-PREGNANCY FEV1 AND THOSE
WHO WERE OFF MODULATORS HAD A
DECLINE.
WHAT WE'VE SEEN FEMALES WITH CF
HAVE REPRODUCTIVE ANATOMY ARE
SIMILAR AND AND WE NEED
PROSPECTIVE DATA AND
RETROSPECTIVE STUDIES OF
PARENTHOOD SHOW THERE'S SHORT
TERM HEALTH IMPACTS THAT MAY BE
MITIGATED BY MODULATOR USE.
I THINK WE STILL NEED TO KNOW
ARE THE UNKNOWN RISKS BALANCED
BY THE RISKS OF THE HEALTH OF
THE MOTHER, CLINICAL
DETERIORATION FOLLOWING
GESTATION AND FOLLOWING EXPOSURE
DO WE NEED TO EXAMINE BABY'S
EYES AND DOING LIVER FUNCTION
AND ARE THERE LONG-TERM EFFECTS
OF INFANTS AND DOES PARENTHOOD
IMPACT AND IS IT AFFECTED BY
MODULATOR USE.
THERE'S ONGOING STUDIES IN THE
SESSION AND WITH THAT I'LL SAY
THANKS TO ALL AND THE CF
FOUNDATION AND AGAIN YOU ALL FOR
HAVING US HERE TODAY.
>> THANK YOU.
THAT WAS AN INTERESTING TALK.
PLEASE POSE QUESTIONS OR THINGS
TO DISCUSS LATER ON IN THE CHAT.
DR. CATHY RAMOS IS AN ASSISTANT
PROFESSOR AT THE UNIVERSITY OF
WASHINGTON AND WILL TALK ABOUT
MODULATOR TREATMENT AND THE
TRANSPLANT COURSE.
>> I'M MERE TO TALK ABOUT HIGHLY
EFFECTIVE MODULATORS AND I HAVE
GRANT FUNDING FROM THE NIH AND
CFF AND CHEST FOUNDATION AND
VERTEX.
I REVIEW GRANTS FOR THE CFF AND
AN ADULT PULMONOLOGIST CARING
FOR PEOPLE WITH CF AND LUNG
TRANSPLANT RECIPIENTS.
I'LL TALK ABOUT TRANSPLANT FOR
LUNG DISEASE AND HIGHLY
EFFECTIVE MODULATOR ERA AND GIVE
BACKGROUND AND DATA FROM THE
CONSORTIUM AND THE USE OF
POSTTRANSPLANT MODULATORS AND
SHARE GAPS AND OPPORTUNITIES FOR
THE USE OF MODULATORS BEFORE AND
AFTER TRANSPLANT.
PEOPLE WITH CF AND FEV1 WERE
EXCLUDED FROM THE PHASE 3 TRIALS
OF THE CFTR MILD MODULATORS AND
THE CLINIC BENEFIT WAS SIMILAR
TO THOSE WITH A HIGHER FEV1.
THERE'S BEEN CASE SERIES WITH
PEOPLE WITH ADVANCED CF
CLINICALLY PRESCRIBED AND THE
IMPROVEMENT MAY BE MORE MODEST.
CLOSER TO 7% TO 9% COMPARED TO
14% AND IN RECENTLY PUBLISHED
FRENCH STUDIES THEY DEMONSTRATED
THAT 73% OF PATIENTS WHO WERE ON
LUNG TRANSPLANT WAITING LIST
WERE REMOVED AFTER STARTING ETI
AND THOSE UNDERGOING LUNG
TRANSPLANT EVALUATION NO LONGER
MET THE SEVERITY CRITERIA FOR
TRANSPLANT AND THE EFFECTS OF
ETI PERSIST FOR AT LEAST ONE
YEAR AFTER INITIATION.
IN AN OBSERVATIONAL STUDY THERE
WERE LOWER RISKS COMPARED TO A
COMPARATOR GROUP AND WHILE
DEATHS AMONG TRANSPLANTS STILL
OCCURRED FOR PEOPLE TREATED
WITWITH
IVACAFTOR WERE LOWER AND THIS IS
DATA FROM THE PUBLICLY AVAILABLE
WEBSITE LISTED AT THE BOTTOM.
YOU CAN SEE THE ANNUAL RATE OF
CF LUNG TRANSPLANT WAS BETWEEN
200 AND 300 PER YEAR AND UNTIL
2019 CF PATIENTS WERE
APPROXIMATELY 10% OF THE
U.S. TRANSPLANT RECIPIENTS AND
THE GRAPH ON THE OTHER SIDE HERE
SHOWS LUNG TRANSPLANT FOR ALL
DIAGNOSE AND THE NUMBER DROPPED
TO 78 AND IN 2021 IT DROPPED TO
JUST 43 PEOPLE WITH CF WHO WERE
TRANSPLANTED WITHIN THE
U.S. LESS THAN 2% OF ALL
TRANSPLANTS.
IN 2020 DATA FROM THE PATIENT
REGISTRY SHOWED 29 PEOPLE WHO
WERE TRANSPLANTED WERE ON ETI AT
THE TIME OF THE TRANSPLANT.
29 OF 78 BUT 152 TEAM DIED
WITHOUT TRANSPLANT AND ONLY
ABOUT 4 DEATHS WITHOUT LUNG
TRANSPLANT WERE DUE TO COVID-19
AND THE 2021 DATA FOR DEATH
WITHOUT TRANSPLANT ARE NOT YET
AVAILABLE.
IN SUMMARY OF MODULATOR AND
ADVANCED CF 1 DISEASE SOME
TREATED WITH MODULATOR MAY NEVER
NEED A LUNG TRANSPLANT AND 10%
ARE NOT ELIGIBLE AND 300,000
ALREADY HAVE ADVANCED LUNG
DISEASE WITH A FEV1 LESS THAN
40% OF PREDICTED AND MODULATORS
MAY DELAY LUNG TRANSPLANT BUT
THERE'S AN UNPREDICTABLE
LONG-TERM TRAJECTORY FOR PEOPLE
ON MODULATORS.
THE COMPLEXITY ARE LIKELY TO
INCREASE FOR THE INDIVIDUALS WHO
DO REQUIRE TRANSPLANT AND THE
TIMING OF TRANSPLANT SHOULD RELY
ON FEV1 PLUS OTHER FACTORS
THINGS LIKE OXYGEN AND
EXACERBATIONS AND INCREASINGLY
TRANSPLANT WILL BECOME A
VALUES-BASED DECISION AND MEANT
TO IMPROVE SURVIVAL AND MAY BE
MORE SO QUALITY OF LIFE.
AND PROJECTIONS SHOW EVEN IN 20
YEARS FROM NOW ABOUT 6% OF CFS
WILL HAVE ADVANCED CF LUNG
DISEASE AND BENEFIT FROM THE
TRANSPLANT.
NOW I WANT TO SHIFT TO THE
POST-TRANSPLANT TIME PERIOD AND
GIVE BACKGROUND AND DATA.
SO THIS FIGURE SHOWED THE
INTERNATIONAL SURVIVAL ESTIMATES
FOR ADULTS AFTER LUNG TRANSPLANT
BY DIAGNOSIS AND NOTE THE DATES
INCLUDE TRANSPLANTS DONE IN THE
1990s AND SURVIVAL AFTER LUNG
TRANSPLANT HAS IMPROVED OVER
TIME.
FOR ADULTS WITH CF, THE MEDIAN
SURVIVAL AFTER LUNG TRANSPLANT
IS 9.9 YEARS COMPARED TO 6 YEARS
FOR PEOPLE WITH COPD AND FOR
IDIOPATHIC PULMONARY FIBROSIS
AND THE ONE YEAR MEDIAN SURVIVL
IS LISTED AND PLAD IS THE
LEADING CAUSE OF DEATH POST
TRANSPLANT AND -- CLAD.
SINUS DISEASE AFTER LUNG
TRANSPLANT AND A RESERVOIR FOR
BACTERIAL PATHOGENS AND THERE'S
BEEN CONFLICTING RESULTS IN
SMALL STUDIES OF SINUS SURGERIES
FOR SINUSITIS AND THE OUTCOMES
BUT SURGICAL TECHNIQUES HAVE
EVOLVED AND THOUGHT FOR MORE
EFFECTIVE.
ONE STUDY SHOWED FOR SOME
PATIENTS THERE WAS AN
IMPROVEMENT IN FIVE-YEAR
SURVIVAL THE MODULATOR THERAPY
MAY ENHANCE ACTIVITY AGAINST
PSEUDOMONAS AND WE ALSO KNOW
SINUS DISEASE BEFORE TRANSPLANT
IMPROVED ON ETI.
SO WE DID AN ELECTRONIC HEALTH
RECORD BASED COHORT STUDY
BETWEEN OCTOBER 2019 AND
SEPTEMBER 2020 USING 15 SITES IN
THE LUNG TRANSPLANT CONSORTIUM
AND INCLUDED ALL RECIPIENTS WITH
ETI AFTER TRANSPLANT AND HAD
SEVERAL STUDY QUESTIONS
INCLUDING WHERE THE PATIENTS
WERE PRESCRIBING ETI AFTER LUNG
TRANSPLANT AND IMMUNE
SUPPRESSION DIFFICULT TO MANAGE
BECAUSE OF DRUG INTERACTIONS AND
OBSERVED EFFECTS ON A1C AND
HEMOGLOBIN TESTS AND IS THERE AN
ASSOCIATION WITH ANTIBIOTIC
PRESCRIPTION FREQUENCY AND WHAT
ARE THE REASONS FOR ETI?
SO BRIEFLY 95 PEOPLE WERE PRE
DESCRIBED ETI BUT ONLY 91
PATIENTS STARTED IT.
ONE OUT OF 95 HAD INSURANCE
DENIAL FOR THE MEDICATION BUT 44
OUT OF 95 HAD APPROVAL AND
PATIENTS WERE -- 95 OUT OF 95
HAD APPROVAL AND 39 PEOPLE
STOPPED ETI WHICH AIS A LARGE
PERCENTAGE UNDER TWO MONTHS.
THE INDICATIONS WAS A PRIMARY
OBJECTIVE GIVEN DIRECT LUNG
FUNCTION BENEFIT IS UNLIKELY AND
THE MOST COMMONLY REPORTED
CONDITION THAT FACTORED IN WAS
SINUS DISEASE FOLLOWED BY GI
SYMPTOMS AND DIABETES AND BMI
AND PATIENCE PREFERENCE WAS
OFTEN A FACTOR IN PRESCRIBING
ETI.
THE CLINIC OUTCOMES ARE PRE.
THE LUNG FUNCTION DOESN'T CHANGE
AND THE SIGNIFICANT CHANGES ARE
SHOWN.
THERE WAS A TREND TOWARDS BMI
AND HEMOGLOBIN IMPROVED FOR
THOSE WITH ELEVATED A1C AND HEME
-- HEMOGLOBIN IMPROVED FOR
PEOPLE AND THERE'S CAUTIOUS
INTERPRETATION BECAUSE OF
COVID-19 AND 39 STOPPED WHICH IS
43%.
SEVEN PEOPLE DID RESTART AND 45%
REMAINED OFF ETI.
THE REASONS PEOPLE STOPPED ARE
LISTED HERE AND SOME PEOPLE HAD
MORE THAN ONE REASON AND A
NUMBER STOPPED BECAUSE OF G.I.
SYMPTOMS AND SOME PEOPLE FELT
THERE WAS NO BENEFIT.
SOME HAD INCREASED BMI AND
INCREASE IN HEMOGLOBIN AND
DECREASE IN A1C AND DECREASED
ANTIBIOTICS AND THE LIMITATIONS
WE DIDN'T HAVE ANY SINUS SYMPTOM
DATA OR G.I. SYMPTOM DATA
BECAUSE THESE WERE IN ELECTRONIC
HEALTH RECORDS AND THE COVID-19
PANDEMIC IMPACTED OUR ABILITY TO
GET SOME OF THE DATA.
AND FURTHER STUDIES WANTED TO
DETERMINE WHETHER IT WOULD
REDUCE THE INCIDENTS OF CLAD
WITH CF AND LUNG TRANSPLANT.
THERE'S SEVERAL PITFALLS FOR
MODULATOR USE AFTER TRANSPLANT
INCLUDING NO EFFECT ON THE CFTR
AND THE DRUG INTERACTIONS AND
SIDE EFFECTS OF ETI AND THE
BENEFITS.
HERE I WANT TO SHARE THE
RESEARCH OPPORTUNITIES ON THE
PRE-TRANSPLANT SIDE THE TIMING
OF THE TRANSPLANT IS A BIG
QUESTION.
AND WE NEED TO LOOK AT FEV1
MARKERS OF DISEASE SEVERITY ON
MODULATORS AND MORE SENSITIVE
PHYSIOLOGIC MEASURES AND
FUNCTIONAL STATUS AND AS WAS
DISCUSSED YESTERDAY POSSIBLY
BIOMARKERS.
WE ALSO NEED TO PROVIDE DECISION
SUPPORT FOR PEOPLE CONSIDERING
LUNG TRANSPLANT AND INCREASED
ACCESS FOR PEOPLE WITH LOWER
SOCIO ECONOMIC STATUS OR
NON-WHITE RACE OR HISPANIC
ETHNICITY.
ON THE POST TRANSPLANT SIDE IT
WOULD BE GREAT TO DO SOMETHING
LIKE A PROMISE STUDY AND
EVALUATE IN AN OBSERVATIONAL
STUDY OF ETI AFTER LUNG
TRANSPLANT AND CLINICAL OUTCOMES
AND UNDERSTAND THE IMMUNOLOGIC
EFFECTS AND WHY DO LUNG
TRANSPLANT PATIENTS HAVE MORE
SIDE EFFECTS OR NOTICE BEING
THEIR SIDE EFFECTS BECAUSE
THEY'RE NOT HAVING THE PROFOUND
IMPACT ON THEIR PULMONARY
FUNCTION AND MAY BE ABLE TO
LEVERAGE THE HETEROGENEITY AND
PRESCRIBING PRACTICES FOR PEOPLE
IN TRANSPLANT AND BETTER WOULD
BE A RANDOMIZED CLINICAL TRIAL
AND IN IDENTIFYING THE
POPULATION TO BENEFIT FROM ETI
AFTER LUNG TRANSPLANT AND
FINALLY I THINK IT'S IMPORTANT
TO EVALUATE THE PHARMACO
KINETICS OF ETI IN THE SETTING
OF TRANSPLANT MEDICATIONS.
I WANT TO THANK THE CONSORTIUM
SITES AND THE INVESTIGATORS AND
THE NHLBI.
>> THANK YOU FOR THE TALK
DR. RAMOS.
THE NEXT SPEAKER IS FROM SEATTLE
CHILDREN'S WHERE HE'S A
PROFESSOR OF PEDIATRICS AND
CODIRECTS THE COORDINATING
CENTER.
>> THANK YOU FOR INVITING ME TO
TALK.
I WAS GIVEN THE TALK ON CF
ADULTS AND HEMT ON AGING AND THE
BENEFITS OF GIVING THE TALK
THERE'S NOT MUCH DATA ON I CAN
HYPOTHESIZE PRIMARILY.
THESE ARE MY DISCLOSURES.
I'LL HAVE A FUTURE OF WHAT ADULT
CARE MIGHT LOOK LIKE.
WE'VE SEEN THIS SLIDE BEFORE IN
THE WORKSHOP BUT THIS IS THE
RECENT PUBLISHED PRESENTED
SURVIVAL GRAPH THE USCF
FOUNDATION IN FIVE-YEAR
INCREMENTS THE PREDICTED MEDIAN
SURVIVAL FROM 2016 TO 2020.
IT HAS ACHIEVED 50 YEARS OF AGE
AND THE BOUNDARIES ARE 48 AND 51
YEARS BUT THAT'S AN ENORMOUS
MILESTONE MOST DID NOT THINK WE
WOULD ACHIEVE.
THIS IS THE NUMBER OF CHILDREN
AND ADULTS AND THE PROPORTION
AND IT'S BEEN NOTED IN MANY
REGISTRIES ACROSS THE GLOBE THE
ADULT POPULATION EXCEEDS THE
POPULATION RELATIVELY STABLE
BACK IN THE EARLY '90s WAS
ALMOST 70% CHILDREN AND NOW
ALMOST 60% ADULTS AND 40%
CHILDREN IN THE UNITED STATES.
OUR POPULATION IS CLEARLY
GROWING OLDER.
AND THAT'S A MANIFESTATION OF
THE EXCELLENT CARE PROVIDED BY
PEDIATRICIANS.
THERE'S BEEN ATTEMPTS TO WHAT
THE POPULATION WILL LOOK LIKE IN
THE FUTURE.
EYE NICE ANALYSIS WAS DONE BY A
TEAM IN EUROPE WHICH TRIED TO
ESTIMATE THE NUMBER OF ADULTS
LIVING WITH CF AND WHAT THEY
WOULD LOOK LIKE BETWEEN 2010 AND
2025.
THEY ESTIMATED THERE WOULD BE A
75% INCREASE IN THE ADULT
POPULATION IN THAT 15-YEAR GAP.
>> THIS WAS A HISTOGRAM BASED ON
THE POPULATION AS OF LAST FRIDAY
IN OUR ADULT CF CLINIC.
OUR POPULATION IS UNDER THE AGE
OF 30.
BETWEEN 30 AND 40 AND 15%
BETWEEN 30 AND 50.
ALMOST A THIRD OF OUR POPULATION
IS OVER 40.
WE HAVE OVER 60.
AND WHAT DO WE WORRY ABOUT AS
THE POPULATION AGES.
WE HAVE INCREASED POPULATION AT
THIS TIME LIVING WITH STRUCTURAL
LUNG DISEASE AND CHRONIC AIR
INFECTION.
THIS IS GOING TO BE A MAJOR
ISSUE.
I THINK THE CFTR MODULATION
IMPROVED THE OUTCOME AND LUNG
FUNCTION BUT NOT REVERSED IN
MOST OF THE PATIENTS THE KNOWN
STRUCTURAL LUNG DISEASE THEY
HAVE.
THERE'S THE EVOLUTION OF OBESITY
AND DIABETES IS ALREADY A HEALTH
PROBLEM.
THE NEXT PROBLEM COULD BE LIVER
DISEASE AND G.I. CANCERS.
WE DON'T KNOW A LOT YET.
WE CAN LOOK AT THE IVACAFTOR
EXPERIENCE AND THERE'S
PUBLICATIONS ON THE TOPIC.
WE LOOKED AT FEV1 DECLINE WITH
IVACAFTOR AND DECLINE WAS .91%
IVACAFTOR TREATMENT VERSUS A
GROUP OF HOMOZYGOUS COMPARISON
GROUP.
THE ACUTE IMPROVEMENT WITH
IVACAFTOR WAS STILL ASSOCIATED
WITH A DECLINE.
SO WHAT WILL WE SEE WITH
IVACAFTOR IS UNCLEAR.
WE LOOKED AT THE AGE EFFECT OF
TREATING PATIENTS WITH IVACAFTOR
AND WHAT THEY NOTED WAS
REMARKABLY STABLE OR LACK OF
DECLINE AND ONCE LUNG DISEASE
OCCURS YOU MAY HAVE DISEASE
PROGRESSION DESPITE THESE
THERAPIES.
YOU HAD A HAZARD RATIO OF 2.4 TO
INCREASE HAZARD OF GETTING CKD
WE DEMONSTRATE THREAD PATIENT
POPULATION IS AGE.
THIS IS THE RATE OF STAGE 5, 4
AND 3 OR GREATER THAN 3 CASES
BUT YOU CAN SEE THE POPULATION
BETWEEN 45 AND 55 ARE LIKELY THE
PATIENTS WHO HAD MORE OF OUR
CLASSIC CF NOTING MARKED
INCREASES IN STAGE 3CKD.
THERE WAS A STUDY WHICH NOTED
THE PREVALENCE OF 2.7% AND AND
CKD IS REMARKABLY COMMON AFTER
LUNG TRANSPLANT AND THE TWO-YEAR
RISK OF CKD WAS 35%.
THIS IS THE RISK OF RENAL
DYSFUNCTION IN THE POPULATION
PROPORTION ON THE Y AXIS IN
YEARS POST TRANSPLANT ON THE X
AND THERE'S NOT A LOT OF
FOLLOW-UP BEYOND TWO YEARS OF
TIME BUT STILL DEMONSTRATED
SUBSTANTIAL RISE IN CKD EVENTS.
THE INCREASED RISK IN KIDNEY
INJURY IS LIKELY SOMETHING WE'LL
BE ENCOUNTERING MORE SO THAN
LESS SO.
IF YOU HAZARD RATIO INCREASE BY
AGE, IF YOU ARE 25 TO 35 YEARS
OF AGE IT'S 1.6.
IF YOU'RE OVER 35 YEARS OF AGE
COMMONLY THE AGE OF PATIENTS
WOULD BE TRANSPLANTED AT IS
2.45.
HYPERTENSION IS ONE OF THE KNOWN
ADVERSE EVENTS DESCRIBED IN THE
PHASE 3 TRIAL.
IT'S KNOWN IN THE PACKAGE INSERT
AS ONE OF THE POTENTIAL ADVERSE
REACTIONS TO THE DRUG.
THEY NOTE 10% OF THE PATIENT
POPULATION IN THE TRIAL HAD A
DIASTOLIC PRESSURE OVER 90 AND
CHANGE OF GREATER THAN 5
MILLIMETERS OF MERCURY WHEN
TREATED IN THE SHORT-TERM
CLINICAL TRIAL.
THERE'S ALSO AN INTERESTING CASE
SERIES JUST PRESENTED WHICH IS
IN A CASE OF FOUR PATIENTS IN
JCF NOTING THE ONSET OF SYSTEMIC
HYPERTENSION WITHIN WEEKS OF
GETTING TREATED WITH ETI AND ALL
NEEDED TREATMENT FOR THEIR
HYPERTENSION.
IN THIS CASE SERIES THEY NOTED
COMPLICATED TO SOME EXTENT BY
SALT SUPPLEMENTATION BUT NOT
RESOLVED WITH SALT LIMITATION.
AND THERE'S ANIMAL MODELS AND
NOTE CFTR REDUCTION IN VASCULAR
TONE AND BRINGS OUT UNDERLYING
HYPERTENSION.
SO CARDIOVASCULAR DISEASE IN CF.
THIS IS A POTENTIAL.
I THINK THERE ARE RARE REPORTS
TO DATE OF ASYMPTOMATIC VASCULAR
DISEASE AND THERE WERE REPORTS
OF TWO PATIENTS PRESENTED IN JCF
AND YOUNG WOMEN WITH ST
ELEVATION MIs.
AND WE LOOK AT FIBROSIS AND
DESCRIBED AS AN SINUCITAL
DISEASE AND MAYBE LIVER DISEASE
WILL BE UNMANAGED AND NOTING
ETIs IS ASSOCIATED WITH THE
RATES OF INCREASE ABNORMAL EST
AND ALT.
AND THERE'S RISK OF LYMPHOID
LEUKEMIA AND TESTICULAR CANCER.
WHAT A WINDOW TO THE FUTURE AND
THIS PATIENT WAS HAD
BRONCHIECTASIS AND TREATED FOR
ABOUT 10 YEARS AFTER THE
PRESENTATION.
HE'S PANCREATIC SUFFICIENT AND
STARTED IVACAFTOR TO A POINT
WHERE HE COULD CARE FOR HIS WIFE
WITH PROGRESSIVE DEMENTIA.
HE LOOKS VERY DIFFERENT FROM ALL
THE CF EFFICIENT PATIENTS AND
DIABETES AND TYPE 2 AND AFTER
TREATMENT OF IVACAFTOR HE BECAME
OBESE.
AND I'VE NERVE SEEN A PATIENT
WITH A PATIENT WITH THIS DEVICE
IN THE SETTING OF CF.
WE MAY SEE THIS AS PATIENTS AGE
AND GET MORE COMMON CLASSIC
CARDIOVASCULARS THAN THE NORMAL
POPULATION.
THE MOST IMPORTANT QUESTION IS
WHIL CHRONIC LOWER AIR INFECTION
CONTINUE TO LEAD TO LOWER BUT
CONTINUED LUNG FUNCTION DECLINE.
THEY'RE LIKELY TO HAVE EVOLVING
CARE AND WHEN IT COMES TO
COMPLICATIONS.
AND WHAT ARE MORE --
MORBIDITIES IN -- IMPROVE AND
THANK YOU FOR THE OPPORTUNITY.
>> THANK YOU.
THAT WAS AN INTERESTING TALK.
I THINK THERE'S SO MANY
QUESTIONS WE NEVER THOUGHT WE'D
NEED TO BE ASKING.
SO INTERESTING AND JUST A
REMINDER FOR EVERYBODY, PLEASE
POST ANY QUEST QUESTIONS OR TOPD
NOW TO JOHN BREWINGTON TALKING
ABOUT PERSONALIZED CARE AND
THERATYPING FOR VARIANTS.
>> I DON'T HAVE RELEVANT
DISCLOSURES.
WHEN I STARTED THINKING ABOUT
FOLKS AS PART OF THE CF
COMMUNITY WHO DON'T HAVE ACCESS
TO MODULATOR THERAPY WHICH BY
THE 2020 REPORT SUGGESTS IS 20%
OF THE CF POPULATION.
THE GROUP IS HARD TO
CHARACTERIZE.
IT'S VERY HETEROGENEOUS BUT
THERE'S THEMES TO RUN THROUGH.
GENETICALLY THE GROUP IS
ENRICHED FOR VARIANTS THIS
INCLUDES PRESUMED NONSENSE
VARIANTS AND UNCHARACTERIZED
MISSENSE VARIANTS AND INTRONIC
VAS
VARIANTS AND WHILE THERE'S
THEMES AND INDIVIDUALS HAVE
VARIANCE AND PEOPLE SMARTER THAN
ME ESTIMATED NOT ALL OF THE
VARIANTS CAUSE DISEASE ABOUT
HALF EXIST IN 5 IN 10 PEOPLE
ACROSS THE WORLD.
NOW, AS A GROUP THIS IS
TRADITIONALLY AN UNDER SERVED
POPULATION.
IT'S ENRICHED FOR PEOPLE WHO
DON'T IDENTIFY AS WHITE AND WHO
MAY IDENTIFY AS HISPANIC AND THE
NEXT TALK WILL TOUCH ON THIS SO
I'LL JUST STATE IT AND MOVE ON.
WHILE WE HAVEN'T BEEN TRACKING
THE GENOTYPE IN CLINICAL TRIAL
FOR MORE THAN 15 YEARS THOSE
TRACKED AND REPORTED OFTEN NOTE
WE HAVEN'T AN UNDER
REPRESENTATION OF PEOPLE IN
GROUP AND CLINICAL TRIALS BEFORE
MODULATORS AND INDIVIDUALS MAY
NOT BE UNDERSTOOD.
IT'S LOGICAL TO MOVE FORWARD AND
SAY THERE'S A FINITE PORTION, WE
DON'T KNOW WHAT SIZE BUT A
FINITE PORTION THAT MAY RESPOND
TO TREATMENTS WE ALREADY HAVE.
THEY SIMPLY DON'T HAVE ACCESS TO
THEM.
TO TREAT THE WHOLE GROUP WE'RE
GOING TO NEED AND A TOPIC BEYOND
THE DISCUSSION BIT THINK WHAT
ARE THE THINGS WE CAN DO NOW
WITH THE TOOLS WE HAVE FOR
INDIVIDUALS WHO MAY HAVE
BIOLOGIC BENEFIT FROM THE TOOLS.
PERSONALIZED CARE BECOMES VERY
IMPORTANT.
I'LL FOCUS ON MODULATORS AND I
ALWAYS LIKE TO HIGHLIGHT WE'VE
BEEN DOING PERSONALIZED CARE IN
CF FOR MANY YEARS TREATING
PATIENTS NOT JUST BECAUSE OF
THEIR DIAGNOSIS BUT BASED ON
SYMPTOMS AND SEVERITY OF DISEASE
AND MORE.
I WANT TO FOCUS ON CF MODULATION
FOR THIS TALK.
WE'LL USE THE WORD THERATYPING
WHICH MEANS FOCUS ON A RESULT
OPPOSED TO A MECHANISM.
NOT HOW DOES A DRUG WORK BUT
DOES IT WORK OR NOT.
THIS IS MORE RELEVANT FOR THE
MAJORITY OF PATIENTS AND
CLINICIANS WOULD SAY THE RESULT
IS MORE IMPORTANT THAN DETAILS
OF THE MECHANISM.
THIS CONCEPTUAL FRAMEWORK CAN BE
APPLIED TO MANY TREATMENTS NOT
JUST MODULATOR BUT I'LL FOCUS ON
MODULATORS TODAY.
THE FIRST IS IN VIVO STUDIES TO
IDENTIFY CHARACTERISTICS FOR
RESPONSE AND THOSE SUGGESTIVELY
OF RESIDUAL CFTR FUNCTION OR USE
A PERSON AS THEIR OWN CONTROL
AND THERE'S ALL RIGHT A SESSION
YESTERDAY TALKING ABOUT ANIMAL
MODELS AND MODULATOR STUDIES SO
I WON'T TOUCH ON THAT BUT
THERE'S A POTENTIAL ROLE THERE.
OVER THE NEXT FEW SLIDES WE'LL
FOCUS ON IN VITRO MODELS OF
THERATYPING AND HUMAN AND
NON-HUMAN CELL LINES FOR HIGH
SCALE, HIGH THROUGHPUT
REPRODUCIBILITY STUDY AND THOSE
SMALLER IN SCALE BUT PERHAPS
MORE PRECISE TO AN INDIVIDUAL.
I'LL START WITH THE FIRST WHICH
IS CELL LINES.
OUR PRIMARY EXPERIENCE IS AN
OVEREXPRESSION MODELS WHERE AN
EPITHELIAL ORIGIN CELL LINE
PRODUCES WHAT YOU PUT INTO IT
AND THERE'S A HISTOLOGY SLIDE I
ALWAYS INCLUDE TO REMIND US THE
THYROID IS EPITHELIAL IN ORIGIN
AND SO THERE'S A LOGICAL STEP TO
MAKE.
THE CELLS ARE EASY TO CULTURE
ONCE YOU KNOW WHAT YOU'RE DOING.
AND CREATE A HIGH SIGNAL TO
NOISE RATIO.
AS MOST KNOW THE CELLS HAVE A
GREAT TRACK RECORD FOR
DEVELOPMENT OF DRUG, REGULATORY
APPROVAL AND IN THE CASE OF
MODULATORS EXPANSION OF
REGULATORY ACCESS TO PEOPLE.
THE STUDY IN THE BOTTOM RIGHT
NOW OVER 10 YEARS OLD HAD
STUDIES TO DEMONSTRATE THE
BENEFITS OF IVACAFTOR AND USED
FOR LABEL EXPANSION.
LARGE LIBRARIES OF DATA EXIST
NOT ALL ACCESSIBLE BUT THEY
EXIST AND THEY'RE OUT THERE AND
THE WORK IS ONGOING.
THERE'S A FEW GAPS TO THINK
ABOUT FOR THE APPROACH.
THE FIRST IS WHAT'S THE RIGHT
MODEL AND FRTs HAVE BEEN WIDELY
ADOPTED AND METHODOLOGY FROM LAB
TO LAB MAY VARY AND THERE'S A
NEW STUDY ALMOST 15 YEARS OLD
NOW COMPARING THE CELLS ON THE X
AXIS AND THE HUMAN DERIVED LINE
ON THE Y AXIS.
THE BLACK DOTS ARE COMPOUNDS
THAT GENERALLY AGREE WITH EACH
OTHER AND THE WHITE DOTS THERE'S
DISAGREEMENT.
SO THE LINES DON'T ALL AGREE
WITH EACH OTHER.
IT'S ALSO DIFFICULT TO STUDY
SPLICE EFFICIENCY IN VARIANTS
BECAUSE THE GENIC CONSTRUCT
MEANS THERE'S NO INTRONS IT'S
BEEN SPLICED AND WHAT CHANGE THE
EFFICIENCY OF SPLICING CAN'T BE
WELL REPRESENTED IN THE MODELS.
THE APPLICATION OF THE
INDIVIDUAL IS ALSO SOMETHING OUT
IN QUESTION.
THERE'S LIMITED STUDIES THAT
LINK CFTR DATA TO CLINIC DATA
THOUGH THE LABEL EXPANSION HAS
BEEN SUCCESSFUL AND CLEARLY
WORKS IN BROAD STROKES.
ALSO WHILE FRT LIBRARY DATA HAS
BEEN USED THAT'S A CONVERSATION
BETWEEN THE PHARMACEUTICAL
COMPANY AND FDA.
IT'S UNCLEAR OF INDEPENDENT
GENERATED DATA WITH MODELS
MAKING ITS WAY UP TO REGULATORY
CHANGE OR EXPANSION PICKED UP BY
THE PHARMACEUTICAL COMPANIES.
I'LL MOVE ON TO PATIENT DERIVED
MODELS AND THERE'S A LOT OF
THEM.
SOME DEPEND GEOGRAPHICALLY.
GASTROINTESTINAL MODELS HAVE
BEEN USED IN EUROPE AND SHOW
RESCUES USING IVACAFTOR AND
LUMACAFTOR AND THE TRADITIONAL
USE OF THE CELLS ARE OBTAINED AT
THE TIME OF LUNG TRANSPLANT SO
QUITE INVASIVE AND NASAL CELLS
HAVE MANY CHARACTERISTICS OF THE
BRONCHIAL CELL MODELS AND SEEING
MORE STEM CELL DERIVED MODEL.
THEY GENERAL CAPITALIZE ON THE
TRANSPORT TO QUANTIFY CFTR
THROUGH ORGANOIDS OR ASSAYS.
THEY HAVE HIGHER APPLICATION TO
THE INDIVIDUAL REPRESENTING THE
GENOTYPE OF THE INDIVIDUAL FROM
WHERE THEY CAME BUT THE
THROUGHPUT IS NOT AS HIGH AS THE
FRT MODEL.
THERE'S A NUMBER OF GAPS.
FOR ONE, WHAT'S THE RIGHT MODEL.
THERE'S NO ONE PERFECT CHOICE.
WE SEE A STUDY FROM THE GROUP IN
LISBON AND THEY CORRELATED
RATHER NICELY WITHIN
INDIVIDUALS.
PERHAPS IT'S NOT WHICH IS BETTER
BUT WHICH ONE DO YOU HAVE ACCESS
TO.
AGAIN, GASTROINTESTINAL MODELS
HAVE BEEN WELL ADOPTED ACROSS
EUROPE BUT LESS SO IN THE
STATES.
THERE'S ALSO SITE TO SITE
VARIATION LIMITING THE ABILITY
TO SHARE AND COLLATE DATA AND
YOU HAVE INDIVIDUALS WITH TWO
RARE PHENOTYPES IT BECOMES A
GENETIC FINGERPRINT SO AT WHAT
POINT ARE YOU SHARING PHI IN THE
WORLD?
THERE'S ALSO THE QUESTION OF
FIDELITY OF THE RESULTS OF THE
MODELS AND CLINIC BENEFIT.
IN BROAD STROKES THEY PREDICT
THE BENEFIT HAPPENING IN
PATIENTS THE STUDY IN THE BOTTOM
RIGHT ALMOST FIVE YEARS OLD NOW
CONNECTING NASAL CELL DATA TO
LUNG FUNCTION FOLLOWING
TREATMENT WITH MODULATORS.
THROUGHPUT REMAINS LIMITED AND
REPRODUCIBILITY IS NOT AS
IMPRESSIVE AS WITH RTs.
THEY ARE GAP THAT NEED TO BE
ADDRESSED.
HOW CAN WE TAKE THEM FROM THE
LAB TO THE CLINIC AND CHANGE
PATIENT OUTCOMES?
THIS IS HAPPENING IN VARIOUS
FORM.
FOR FRT-BASED LIBRARIES HAS MADE
CHANGES IN THE LABEL EXPANSION
AND WHEN IT COMES TO PATIENT
DERIVED MODELS THE FOLKS IN
EUROPE ARE ONGOING WITH THE
STUDY LARGE SCALE ENROLLMENT FOR
ORGANOID TESTING AND OUR NEXT
SPEAKER IS LOOKING ATT IVACAFTO
RESPONSE AND THE DATA LIMITED
WITH SMALL CASE SERIES AND THE
NUMBERS ARE RELATIVELY SMALL.
THE FOUNDATION HAS FUNDED OUR
GROUP AS A NATIONAL RESOURCE
CENTER.
AND FROM OUR WORK OVER THE LAST
COUPLE YEARS AND WE'VE
SUCCESSFUL TO GET OFF-LABEL
COVERAGE OF DRUGS FOR 40 OF THE
59.
THE DRUGS THEY RESPONDED TO ARE
SHOWN IN THE BAR GRAPH IN THE
MIDDLE AND SHOWING THE X AXIS
AND MODULATED FUNCTION ON THE Y
AXIS AND THEY'RE TWO DIFFERENT
SCALES BUT ABOUT 50% BUMP IN
CFTR FUNCTION AS A RELATIVE
NUMBER.
IT'S A SIGNIFICANT IMPROVEMENT.
THE IMPACT OF THE DATA ON THE
REGULATORY EXPANSION IS UNCLEAR.
IF WE CAN'T CHANGE THE
REGULATORY IMPACT WE HAVE TO ASK
CAN WE GET OFF LABEL COVERAGE
AND THIS IS VARIABLE DEPENDING
ON THE INSURANCE COMPANY AND
INDIVIDUAL.
WITH TIME AND FAMILIARITY
ADVOCACY MAY CHANGE.
IT'S VARIANCE FROM LAB TO LAB
WITHIN THE INDIVIDUAL MODELS.
TOE RIGHT IS A STUDY FROM LAST
YEAR FOR THE PURPOSES OF THIS
TALK LOOKING AT A SINGLE CHANGE
IN IMMEDIATE COMPOSITION C AND
THERE'S DRASTIC DIFFERENCES IN
HOW IT'S MEASURED AND IT MAKES
IT HARD TO COLLATE DATA AND
COMPARE ACROSS LABS.
DESPITE THE GAPS I THINK THERE'S
A LOT OF PROMISE IN THE FUTURE
FOR NOT JUST MOVING FORWARD WITH
IMPACTING PATIENT CARE BUT ALSO
UNDERSTANDING MUTATION AGNOSTIC
THERAPIES IN THE GROUP.
STUDYING PERHAPS NON-CFTR
TARGETED DRUGS THAT TARGET THE
TISSUE OF ORIGIN AND
UNDERSTANDING THE RESPONSE
VARIANT.
WHY DO SOME RESPOND ROBUSTLY TO
MODULATORS AND SOME DON'T.
I'LL END HERE ROUGHLY ON TIMISH
AND SUMMARIZE PATIENTS WITH
ULTRA RARE VARIANTS ARE A
POPULATION THAT DESERVE MORE
STUDY AND WE'RE PATIENT ACCESS
AND PERSONALIZATION OF CARE WITH
MODULATORS AND I THINK THE
SYSTEMS CAN BE POWERFUL FOR OUR
FUTURE WORK AND SERVING THIS
POPULATION AND THE BROADER CF
POPULATION AS WELL.
A HUGE THANK YOU TO THE
ORGANIZERS FOR LETTING ME SPEAK
AND I'LL INTRODUCE THE NEXT
SPEAKER.
SHE'LL BE THE LAST SPEAKER FOR
THE SESSION AND FROM UC SAN
FRANCISCO AND LOOKING AT HEALTH
EQUITY AT THE POPULATION WITH
CYSTIC FIBROSIS.
>> THANK YOU.
>> CF OCCURS IN PEOPLE WITH ALL
RACES AND ETHNICITY AND THOUGH
IT'S A SOCIAL CONSTRUCT,
VARIANTS DIFFER BETWEEN GROUPS
AND I THINK EVEN MORE SURPRISING
IS THE PERCENTAGE OF POPULATION
HAS NOT FULLY GENOTYPED.
THESE ARE PATIENTS KNOWN TO HAVE
CF THAT HAVE EITHER ZERO OR ONE
VARIANT IDENTIFIED AND ONLY 3%
OF NON-HISPANIC WHITE PATIENTS
BETWEEN 8% TO 10% OF EVERYBODY
ELSE.
THIS IS REALLY IMPORTANT WHEN
WE'RE THINKING ABOUT MODULATOR
THERAPY.
AND YOU CAN SEE THERE'S 40% OF
VARIANTS IN EACH AGENT.
VARIANTS DIFFER BETWEEN GROUPS.
A
AND I RELY ON IDENTIFYING AT
LEAST ONE VARIANT IN ORDER TO
PREVENT HAVING A FALSE NEGATIVE
SCREEN.
FOR THIS STUDY WE LOOKED AT ONE
OF THE COMMONLY USED VARIANT
PANEL AND BASED ON REGISTRY DATA
FOR EACH RACE AND ETHNICITY.
THEN WE TOOK THE CENSUS DATA FOR
EACH STATE AND THE FREQUENCY IS
SO DIFFERENT.
IT REALLY EMPHASIZES THAT WE
NEED THE STUDIES IN DIFFERENT
POPULATIONS.
AND WE DID FULL GENE SEQUENCING
FOR THE PATIENTS AND WHAT WE
FOUND IS THOUGH THE TWO PLACES
WERE SO CLOSE GEOGRAPHICALLY,
AND SO THERE'S FREQUENT VARIANTS
THAT WERE FOUND IN MANY OTHER
HISPANIC AND LATINO POPULATIONS
NOT PRESENT AT ALL IN DOMINICAN
REPUBLIC AND 10% OF PUERTO RICAN
APPRECIATES.
THIS EMPHASIZES WE NEED TO STUDY
POPULATIONS AND ALL PATIENTS
NEED FULLING TO UNDERSTAND.
RACIAL AND ETHNIC MINORITIES AND
PEOPLE ARE LESS LIKELY TO BE
QUALIFIED FOR MODULATORS.
AND YOU CAN SEE THAT FOR THE
DIFFERENT MODULATORS THE
FREQUENCY OF QUALIFICATION BUT
WHEN YOU LOOK AT THE OTHER RACES
YOU CAN SEE THIS IS LESS.
80% AND YOU CAN SEE IT'S JUST
OVER 70% QUALIFIED FOR E-LAX CAF
FOR AND OVERALL THREE-QUARTERS
QUALIFY AND LOWER PERCENTAGE
QUALIFY FOR HIGHLY EFFECTIVE
MODULATORS AND UNFORTUNATELY
EVEN LOWER AND NOT ONLY DO THEY
NOT QUALIFY BUT HISTORICALLY
MINORITIZED PEOPLE ARE NOT
INCLUDE IN THE TRIALS.
AND WHEN WE LOOKED AT THIS
STUDIES THAT REPORTED IT ONLY 73
INCLUDED MINORITY SUBJECTS.
SO ABOUT OVER A QUARTER OF THE
STUDIES HAD 100% CAUCASIAN AND
100% WHITE AND WHEN WE LOOKED AT
THE ACTUAL PERCENTAGES INCLUDED
AT NO POINT DID THEY COME CLOSE
TO REFLECTING THE DIVERSITY OF
THE POPULATION AND UNDERSTANDING
DIFFERENCES IN DRUG RESPONSE OR
SIDE EFFECTS IN THE GROUPS.
SO MORE RECENTLY I LOOKED AT A
MORE UPDATED DATA ON MODULATOR
STUDIES AND IT STILL CONTINUES
TO BE QUITE LOW.
IN THE SMALL PERCENTAGE OF
STUDIES THEY'RE NOT INCLUDING
SUBJECTS.
THIS IS EVEN WHEN YOU'RE LOOKING
AT THE PERCENTAGE OF MINORITIES
THAT HAVE 508 IT'S STILL NOT
REFLECTIVE THE PATIENTS ARE
BEING INCLUDED.
AND I'LL GO THROUGH SOME OF THE
REASONS WHY BUT I'LL START BY
SAYING BESIDE THE FACT
ETHNICALLY WRONG THAT THE
PATIENT POPULATION IS BEING
EXCLUDED.
FIRST IT MATTERS OUR CF
POPULATION IS BECOMING MORE
DIVERSE.
THIS IS A LARGER PROBLEM OVER
TIME.
YOU CAN SEE THE DIVERSITY ON THE
LEFT AND EACH YEAR IF YOU LOOK
AT THE REGISTRY DATA THAT IS
BEING MORE DIVERSE.
THIS IS PROBABLY A REFLECTION OF
THE INCREASING DIVERSITY IN THE
U.S. POPULATION.
IT'S A REFLECTION OF NEWBORN
SCREENING.
THEY'RE NOT SEVERE ASTHMATICS
AND THE PATIENTS BEING DIG --
DIAGNOSED AND THE POPULATION IS
MORE DIVERSE IN THE ADULT
POPULATION OVERALL.
THE SECOND REASON IT MATTERS IS
BECAUSE PRIOR TO MODULATORS,
THESE GROUPS HAVE WORSE
MORTALITY THAN NON-HISPANIC
WHITES.
YOU'LL SEE THEY HAVE 85%
INCREASE RISK OF DEATH AND BLACK
PATIENTS 48% INCREASE OF RISK
COMPARED TO NON-HISPANIC WHITES.
AND HISPANIC PATIENTS WERE DYING
SIX YEARS EARLIER THAN
NON-HISPANIC WHITE PATIENTS AND
IN CALIFORNIA THEY FOUND ONLY
73% OF HISPANIC PATIENTS SURVIVE
18 YEARS AFTER DIAGNOSIS
COMPARED TO 98% SURVIVAL OF
WHITE PATIENTS.
IT ALSO MATTERS BECAUSE HISPANIC
WHITE PATIENTS HAVE AND THERE'S
A DIFFERENCE AND IN OTHER DATA
WE CAN TALK ABOUT LATER IS THAT
NOT ONLY DO THEY HAVE INCREASED
MORTALITY AND DIFFERENCES IN
LUNG FUNCTION AND INFECTIONS ARE
DIFFERENT.
SO INCREASED PREVALENCE OF
PSEUDOMONAS AND STAPH IN
HISPANIC PATIENTS ALSO REQUIRE
PSEUDOMONAS TREATMENT AT A
YOUNGER AGE.
WE'RE EXPECTS THE DISPARITY TO
WI
WIDEN OVER TIME BECAUSE WE DON'T
HAVE DISEASE ALTERING MEDICATION
FOR MANY OF THEM.
WE HAVE ALL SEEN GRAPH LIKE THIS
AND HOW WILL WE INCREASE
RESEARCH DIVERSITY AND A WANT US
ALL TO TAKE A MOMENT AND REFLECT
ON THE PERSON WHO TOOK DECADES
TO BE DIAGNOSED BECAUSE HE
DIDN'T LOOK LIKE THE INCORRECTLY
PORTRAYED PICTURE AS TAUGHT IN
MEDICAL SCHOOL AND REFLECT ON
THE CHILD DIAGNOSED MONTHS OR
YEARS AFTER SYMPTOMS BECAUSE A
NEWBORN SCREENING WAS CREATED
FOR VARIANTS FOR ANOTHER RACE OR
ETHNICITY THAN THEY WERE.
REFLECT ON THE BABIES AND
CHILDREN AND TEENAGERS WHO DIED
YEARS YOUNGER THAN WHITE
COUNTERPARTS AND THOSE WHO ARE
WORSE FUNCTION AND QUALITY OF
LIFE.
THINK ABOUT ALL THE FAMILIES WHO
ARE HAVING -- THEY'RE MORE
LIKELY TO GET SECURITY CALLED ON
THEM TO THAN GET HAVE A TEAM
TREAT THEM THAT AND DON'T SOUND
LIKE THEM OR SPEAK LIKE THEM OR
LIKE THEM CULTURALLY AND THEY'VE
BEEN LEFT OUT OF TRIALS AND
DON'T HAVE THESE DRUGS AVAILABLE
TO THEM AND LEFT WITHOUT
LIFE-SAVING TREATMENT.
WHEN WE TAKE THE HEAVINESS OF
WHERE WE'RE AT FOR THE PATIENTS
AND THINK ABOUT WHAT CAN WE DO.
THINKING OF DIFFERENT LEVELS OF
BARRIERS.
ON THE FEDERAL LEVEL WE NEED ALL
STUDIES INCLUDING MINORITIZED
PATIENTS AND FOR MODULATORS IT
MEANS WE NEED TO BE INCLUDING
VARIANTS THAT ARE IN THESE
GROUPS ALSO WE NEED TO BE
RECRUITING PATIENTS OF OTHER
VARIANTS AS WELL.
ON A SYSTEM AND INSTITUTIONAL
LEVEL, WE HAVE DIVERSE
RESEARCHERS.
WE NEED TO BUILD BACK UP THE
TRUST IN THE MEDICAL SYSTEMS AND
NIH AND FDA.
ON A PERSONAL LEVEL WE NEED
RESEARCHERS TO BUILD
RELATIONSHIPS WITH THE
COMMUNITIES AND PATIENTS.
AND ON THE LANGUAGE REIMBURSE
MANY AND HEALTH LITERACY, HOW
CAN WE CARE IN INDIVIDUAL
RELATIONSHIP FOR THESE PATIENTS.
INDIVIDUAL RESEARCHERS CAN'T GO
TO THE FDA TO GET THESE
MODULATORS APPROVED BASED ON
STUDIES IT HAS TO GO TO THE DRUG
COMPANY.
AND THIS IS A PROBLEM OF ALL
PERSONALIZED MEDICINE THAT IS
GOING TO BE ONLY WHO IS INCLUDED
IN THE STUDIES AND WHO IS
INCLUDED IN THE VARIANTS OR WHO
WILL GET THE DRUGS AND SO THE CF
COMMUNITY CAN BE A LEADER IN
PRESCRIBED MEDICINE AND ETHICS
AND TO THINK ABOUT IF THIS DRUG
WAS AVAILABLE TO EVERYBODY IF
THIS DRUG WAS NOT EXPENSIVE WE
CAN USE IT OFF LABEL OR ONLABEL
FOR EVERYBODY TO SAY WHO
RESPONDS.
AND THE GOAL IS TO CURE CF AND
PROVIDE ALL PEOPLE WITH CF THE
OPPORTUNITY TO LIVE LONG
FULFILLING LIVES.
WITH THAT I'LL OPEN UP THE
DISCUSSION AND THANKS TO THE
SPEAKERS AND NHLBI FOR HOSTING
US TODAY.
>> THANK YOU TO OUR SPEAKERS FOR
GREAT TALKS.
AS WE GET UP TO THE PANEL VIEW
HERE I DID WANT TO LEAD OFF WITH
A QUESTION I ACTUALLY GOT
BRIEFLY MENTIONED IN THE LAST
SESSION AND I THINKING ABOUT
THIS ONE IT WILL BE FOR YOU.
IN THE CONVERSATIONS ABOUT THE
IN UTERO MODULATOR USE AND THE
THE QUESTIONS ABOUT FERTILITY
AND THE QUESTIONS TO BE THOUGHT
OF FOR THE PATIENT THROUGHOUT
THEIR LIFE IS THERE ABOUT ADULT
MALES STARTING OR REPRODUCTIVE
ASSISTED TECHNOLOGIES AND HOW
THAT MIGHT BE CHANGING?
>> FOR THE FIRST TIME IN
SPERM LASTS FOR ABOUT 80 DAYS
KNOW KNOW KNOW IF YOU COULD
TALK MORE ABOUT THE FREQUENT
STOPPING ON THE TRANSPLANTATIONS
AND SOME OF THE SIDE EFFECTS.
>> THANK YOU FOR THAT QUESTION,
SO WE NOTICED THAT THE
DISCONTINUATION RATE OF THE--A
LOT OF PEOPLE WHO STARTED FOR GI
REASONS FOR GI SYMPTOMS ENDED UP
STOPPING BECAUSE OF GI SYMPTOMS
AND I SUSPECT THAT ETI IS NOT
BENEFICIAL FOR TREATING GI
SYMPTOMS FOR LONG TRANSPLANT
BECAUSE THEY MAY BE RELATED TO
CERTAIN IMMUNE SUPPRESSION
MEDICATIONS.
AND THERE'S, YOU KNOW
CONTROVERSY ABOUT WHETHER IT'S
BENEFICIALOT NONTRANSPLANTED
PATIENTS GI SYMPTOMS AS WELL AND
I THINK PEOPLE GOT A LOT OF
ABDOMINAL PAIN AND ABDOMINAL
SYMPTOMS.
AND THERE ARE INSTANCES WHERE
PEOPLE STOPPED IT AND RESTARTED
IT AND IT'S HAPPENED SO IT SEEMS
LIKE IT'S A REAL PHENOMENON
THAT'S HAPPENING AND IT'S
POSSIBLE THAT MAYBE THEY HAVE
HYPER-ACTIVITY OF THEIR CFTR
CHANNELS AND IN THE NORMAL NONCF
LUNGS AND SO THAT WAS A THOUGHT.
THE STOPPING AND STARTING IS
REALLY DANGEROUS BECAUSE THE
DRUG ACTIONS AND SO, PATIENTS
JUST HAVE TO BE REALLY AWARE
THAT IF THEY'RE GOING TO STOP
THERE, THEY REALLY NEED TO TALK
TO THEIR TRANSPLANT TO ADJUST.
>> SO I HAVE A QUESTION FOR ALL
OF OUR PANEL BUT I WILL DIRECT
OUR ADULT PULL MONITORROLOGYIST
IN THE CREW, THERE'S BEEN GREAT
CONVERSATION IN THE CHANNEL
ABOUT TRANSITION AND WHAT DO WE
DO WITH PATIENTS AS THEY'RE
INCREASINGLY HEALTHY, DOES IT
CHANGE OUR PLANS WHICH AREN'T
ALWAYS THE BEST TO START WITH IN
CF CARE AND I WILL ADD ON TOP OF
THAT, MAYBE PARTICULARLY FOR YOU
CATHY, HOW DO WE START THE
TRANSITION AND THE PREPARATION
THAT WE TRY TO HAVE AT SOME
POINT THAT THINK ABOUT WHICH
PROGNOSIS, WHEN DO YOU START
TALKING ABOUT THINGS LIKE THOSE
CONVERSATIONS AND 1 THING THAT
WAS RAISED WAS WHO DO WE
TRANSITION TO IS THERE A
WORKFORCE PROBLEM FOR ADULTS
THAT ARE FOCUSING ON CARE, SO
THERE'S A GIANT BUNDLE OF
QUESTIONS THAT I WILL PASS TO
THE ADULT PULL MONITORROLOGYIST
AND SEE WHAT YOU HAVE TO SAY.
>> I WILL TALK ABOUT PROCINOSEIS
IN THE PEDIATRIC CLINIC, IT'S SO
IMPORTANT TO TELL PATIENTS AND
FAMILIES THAT WE KNOW IS BASED
ON THE PAST AND WHAT'S HAPPENED
IN THE PAST AND THINGS ARE
EVOLVING QUICKLY AND EVERY FEW
YEARS IT SEEMS THERE'S A NEW
VERY EFFECTIVE CF THERAPEUTIC
COMING ON LINE AND TELLING
PEOPLE THAT THE MEDIAN EXPECTED
AGE OF SURVIVAL IS 50 YEARS OLD,
THAT'S NOT OLD FOR LUNG
TRANSPLANTS.
SIXTY-FIVE YEAR-OLDS ARE
FREQUENTLY RANS PLANTED BUT CF
PATIENTS ARE DEFINED GETTING
EVOLUNTEERSUATED OR GOING TO A
TRANSPLANT BECAUSE THEY LIVE
LONG ENOUGH AND THEY FEEL LIKE
THEY BEAT THE ODDS BY LIVING TO
FOIRT SO I WORRY ABOUT THE
MENTAL HEALTH AND TELLS FOLKS
THEY SHOULD EXPECT TO LIVE TO
AGE 50 WHICH IS HOW THEY'RE
INTERPRETING THE STATISTIC.
BECAUSE, THEY MAY LIMIT THEIR
AMBITIONS AS WELL.
DRNCHL.
>> I WILL CHIME IN A BIT ABOUT
TRANSITION BECAUSE IT REMAINS A
KEY IN PROBLEMATIC AND PROBABLY
MORE SO NOW AND THAT'S IF YOU
GET THESE--THE TRANSITION WHEN
YOU'RE TRYING TO STAY ON YOUR
TRI CAFTA ON YOUR THERAPIES, THE
IMPACT THE IMPACT ON GOING OFF
ASK ON HAVING AND IT WILL BE
MORE PRONOUNCED OF SEC AND LOW
MEDICAL LITERACY AND MINORITY,
COMMUNITIES WHO ARE NOT--IT'S
JUST--IT SEEMS LIKE IT'S GOING
TO BE A PROBLEM.
--I THINK A LOT CAN BE LOST IN
THESE PERIODS AND IT'LL BE LOST
IN A PARTICULAR POPULATION
THAT'S VERY PROBLEMATIC.
>> I WAS GOING TO SAY, WE
PROBABLY NEED TO ADVICE THE
TRANSITION PROGRAM WE'RE USING
SO THAT WE EMPHASIZE LONGEVITY
AND THE THINGS THAT WILL ARISE
BECAUSE OF LONGEVITY AND AS WAS
MADE THE POINT IN THE CHAT WITH
GREG THAT WE NEED TO MAINTAIN
OUR DISCUSSIONS ABOUT TALKING TO
PEOPLE WHEN THEY'RE DIAGNOSED,
TO SOME EXTENT, AND THE
POSSIBILITIES OF REALLY HUGE
HEALTH WITH LOSS OF THEY SAID
ACCESS TO CARE OR ACCESS TO
THEIR SURANCE WHICH IS CRITICAL
OBVIOUSLY FOR PAYING FOR
$300,000 YEAR MED, NEXMED IS
JUST EXPENSIVE OR A COMBINATION
OF THEM.
>> YEAH AND THINKING ABOUT
ADHERENCE AND TAKING MEDICATIONS
BEFORE YOU HAVE SYMPTOMS OF THE
DISEASE, YOU THINK ABOUT PEOPLE
WHO ARE DESCRIBED ANTIHYPER
TENSIVES WHO ARE LESS ADHERENT
BEFORE THEY HAVE A HEART ATTACK
OR STROKE AND YOU KNOW REALLY
FOCUSING ON HOW WE CAN PREVENT
LUNG FUNCTION LOSS FOR PEOPLE
WHO ARE EITHER DON'T HAVE
ACCESS, BECAUSE THEY USE THEIR
INSURANCE OR OTHER REASONS THAT
IMPACT THEIR ABILITY TO ACTUALLY
OBTAIN MEDICATION AND PEOPLE WHO
YOU KNOW ARE YOUNG ADULTS AND
DON'T THINK IT'S IMPORTANT TO
TAKE IT YET.
>> I THINK THE OTHER ASPECT OF
THAT IS WE REALLY--THIS IS THE
POINT WHERE WE REALLY, REALLY
NEED TO GET THE ADULT CF
COMMUNITY INVOLVED AND HAVE THEM
HELP US CHANGE HOW WE'RE USING
CF RISE AND WAYS TO TRANSITION
PEOPLE BECAUSE WE REALLY NEED
THEIR INPUT, LIKE WHAT ARE THEY
WILLING TO DO NOW THAT PEOPLE
ARE HEALTHIER, BECAUSE WE CAN'T
JUST DICTATE AND SAY HEY, THIS
IS WHAT YOU SHOULD DO WITHOUT
GETTING THEIR INPUT.
>> AND I WILL HIGHLIGHT A
COMMENT THAT POPPED IN FROM
TRACEY WHERE IT SAID A SURVEY
THAT SAID IN ADULT WOMEN OVER 40
WITH CF, THAT THERE'S NO PC P.
SO REALISTICALLY THERE'S FEWER
COMPLICATIONS OUTSIDE OF WHAT WE
AS PULL MONITORROLOGYIST THRAIN
WITH AND DEAL WITH IN MEDIATE
RICKS, THERE'S MUCH, MUCH, MORE
IN ADULTS SO THAT ACCORD NATION
OF CARE IS A BIG BEAR TO TACKLE.
>> WITH OUR CONVERSATION,
THERE'S BEEN A BUNCH OF
QUESTIONS ABOUT USING NF1
TRIALS, GAINING ACCESS WITH
INSURANCE, THERE'S BEEN THIS
ONGOING DEBATE ABOUT CAN YOU
TAKE SOME OF THESE RESPONSE IN
STEREOTYPING AND REALLY HOW DOES
IT CORRELATE TO FEV1, SO I WAS
INTERESTED YOU TALK ABOUT THOSE
40 PATIENTS THAT YOU DID GET
OFFLABEL USE FOR.
YOU KNOW IF YOU COULD SPEAK A
LITTLE BIT TO WHAT YOU KNOW AND
WHAT YOU FOUND.
DRNCHL--YOU KNOW WE ALL DO THIS
IN PRACTICES AND LOTS OF OTHER
DISEASES SOMEONE IN ASTHMA, I
START THEM ON INHALER CORTICO
STEROIDS, BUT IT'S NOT FINANCIAL
PRACTICAL AND THIRD PARTIES
AGREE SO I HAVE TO HAVE ANOTHER
MECHANISM FOR IT.
THERE ARE STUDIES THAT HAVE BEEN
FUNDED TO DID THIS IN SMALL
NUMBERS SO THEY'RE GETTING THE
DATA PRECISION ON THAT, ERIC AND
HIS GROUP ARE DOING THIS FOR
PEOPLE WHO HAVE EVIDENCE SO THAT
PRECISION IS STILL OUT THERE, AS
FAR AS CONNECTION OF YOU KNOW
STEREOTYPING AND WHATEVER FORM
IT MAY BE TO THE CLINICAL DATA,
THERE'S LOTS AND LOTS OF
DIFFERENT WAYS TO LOOK AT IT.
IT ALL DEPENDS ON THE COHORT AND
OBVIOUSLY NO PERSONAL
CONNECTIONS WITH THE NONCELL
MODELS BECAUSE THAT'S DIDN'T
COME FROM AN INDIVIDUAL OR AN
INDIVIDUAL THAT'S BEING COMPARED
TO.
ALL OF THOSE STUDIES WHEN YOU
LOOK AT THEM, THERE'S A
CORRELATION, BENEFIT IN THE
MODEL DOES CORRELATE WITH
BENEFIT OF THE PATIENT BUT THE
PRECISION OF THAT ISN'T CLEAR
AND THE PORTION IN THE VARIANTS
AND THE DIFFERENT MODELS AND THE
WAY PEOPLE DO IT, IT'S DIFFICULT
TO GATHER THAT TICKET AND GET A
HIGH LEVEL LOOK AT IT AND IN OUR
DATA, MEGAN WE'RE DOING REAL
WORLD TYPING WHERE THE DATA
COLLECTION AFTER PATIENTS ARE
STARTED ON DRUGS IS REALLY
WHATEVER IS GATHERED IN CLINICAL
CARE, ESPECIALLY OVER THE LAST 2
YEARS HAS BEEN HIGHLY LIMITED
AND SCATTERED, AND MAKE ITS VERY
DIFFICULT TO LOOK, IT MIRRORS
WHAT WE SEE IN THE PUBLISHED
LITERATURE WHICH IS THE BROAD
STROKES, DEFINITELY A
CORRELATION BUT IT'S HARD TO
REALLY DRILL IN ON HOW PRECISE
THAT PREDICTION IS.
I WOULD ACTUALLY TAKE IT A STEP
FURTHER AND SAY, THAT YOU KNOW
IF WE ACCEPT AND BELIEVE THE
PREDICTION, WHAT'S THE CUT OFF?
WHAT IS OR ISN'T A RESPONSE?
WHAT'S THE NUMBER THAT MATTERS?
AND AGAIN WITH VARIANTS IT'S
DIFFICULT TO PUT YOUR FINGER ON
THAT.
>> IT'S VERY TRICKY.
WE'VE BEEN DOING OFF LABEL FOR
ALMOST A DECADE NOW AND WE'VE
HAD VARYING SUCCESS WITH
INSURANCE COMPANIES, BUT
ALMOST--WE REALLY MAKE A CASE
FOR BEFORE, LIKE, EXACERBATIONS,
LUNG FUNCTION, DECLINE,
INFECTIONS, LIKE ALL THE
MORBIDITY.
WE WILL SOMETIMES BEG FOR A
MONTH, 2, MONTH, 3 MONTHS FOR AN
INSURANCE COMPANY FOR A DRUG AND
THEN GIVE THEM BACK DATA SO
SWEAT CHANGES, WEIGHT CHANGES,
LUNG FUNCTION AND WE'VE BEEN
ABLE TO HAVE PATIENTS WITH RARE
DE NOVO MUTATIONS GET ACCESS BUT
WE REALLY NEED LIKE A PATH FOR
EVERYBODY FOR THIS, RIGHT?
YOU CAN'T JUST BE IF YOU'RE AT A
CERTAIN CENTER WHERE THE CF
PROVIDER IS MORE LIKELY TO DO
THIS, FOR INSTANCE OTHER
CENTERS, WHETHER YOU GET THE
DRUG OR NOT AND THEN ALSO LIKE
YOU WERE DISCUSSING IT MAKE ITS
DIFFICULT TO PUBLISH
WITHOUT--YOU KNOW WITH KEEPING
THEIR INFORMATION PRIVATE,
RIGHT?
THERE'S JUST A LOT OF
CHALLENGES.
IT WOULD BE REALLY NICE IF WE
COULD COME TOGETHER AS A GROUP
TO COME UP WITH LIKE WHAT ARE
THE THINGS TO MONITOR AFTER
THERAPY.
IF THERE COULD BE SOME UNIVERSAL
LANGUAGE THAT PEOPLE COULD USE
FOR LETTERS FOR INSURANCE
COMPANIES, ADVOCACY FOR
INSURANCE, BUT WE REALLY NEED TO
COME UP WITH A BETTER WAY TO GO
FORWARD WITH THESE PATIENTS.
>> --IT IS INCREDIBLE LOAMACYY
DISAPPOINTING WHEN IT DOESN'T
WORK AS WELL AND I'VE HAD A FEW
PATIENTS WHO WE'VE SENT OVER TO
DR. GREEN'S LAB AND IT'S REALLY
SAD, IT'S SORT OF LIKE COMPOUNDS
THE FACT THAT THEY'RE NOT
ELIGIBLE.
I COMPLETELY AGREE, I DON'T WANT
TO CUT YOU OFF, BUT THAT'S THE
DOWN SIDE OF WORKING FOR
PERSONAL RESOLUTION, THE GOAL
STOCK EXCHANGE UNDERSTAND IS IT
IF THERE'S BENEFIT, AND THERE'S
EXPECTATION MANAGEMENT AROUND
THAT'S VERY DIFFICULT AND I
TOTALLY AGREE THAT HAVING THE
OPPORTUNITY TO HARMONIZE
PRACTICES ACROSS GROUPS FOR
THIS, COULD CERTAINLY HELP WITH
THAT AND WE CAN SHARE THINGS
THAT WORK WELL AND DON'T WORK
WELL.
>> I WAS GOING TO SECOND WITH
WHAT CATHY SAID THAT YOU HAVE AN
EXPECTATION THAT WE AS PROVIDERS
COLLECTION THAT FOR THE TRIAL.
AND I WANT TO COMMENT ABOUT
SENDING CELLS TO YOUR LAB AND
THAT IS I THINK A PATIENT THAT
BECAUSE OF THEIR RESPONSE THE
WHOLE GROUP OF PATIENTS GOT
ACCESS TO THE DRUG AND ANOTHER
GROUP OF PATIENT WHO IS CAME TO
OUR CLINIC WHOSE SIBLING HAD
STUDIES IN YOUR LAB, THEREFORE,
I WAS ABLE TO ORDER TRICAFTA,
PRETTY EASILY IT WAS
REMARKABLYICISMEM.
HOW DO WE MAKE MORE OF THAT
UNIVERSALLY KNOWN AND YOU KNOW
HOW DO WE--I JUST COMMENT ON
THAT, BECAUSE I THOUGHT THOSE
WERE GREAT EXAMPLES OF THERAPY
ANDA TYPING HOW 1 PERSON WAS A
GREAT ADVANTAGE TO MULTIPLE
PEOPLE.
>> YEAH, FOR SURE, CHRIS.
AND I WILL SAY UNFORTUNATELY
THAT'S THE MINORITY OF
OPPORTUNITIES IN THIS SPACE, AND
AT THE END OF THE DAY, A LOT OF
IT COMES DOWN TO WHAT THE THIRD
PARTY PAYORS ARE WILLING TO
ACCEPT AS RATIONAL TO TRY THE
DRUG.
WE HAVE IT IN GREAT SUCCESS IN
SOME GROUPS WITH EXPANDING,
ESPECIALLY IN SIBLINGS AND
THINGS LIKE THAT.
SOME OF THAT COMES BACK AROUND
AND THERE ARE SOME IMPORTANT
QUESTIONS WHICH IS HOW DO YOU
SHARE THESE DATA AND DO IT IN A
RESPONSIBLE FASHION.
YOU KNOW IT'S DIFFERENT FROM
FRTs WHERE YOU'RE SHARING
INFORMATION ABOUT A SIMPLE
VARIANT IF YOU'RE SHARING A
PATIENT GENO TYPE ESPECIALLY
ULTRA RARE AT SOME POINT, YOU
HAVE TO ASK, IS THIS ACCEPTABLE
TO SHARE AND CERTAINLY YOU CAN
GET PATIENT CONSENT AND THINGS
LIKE THAT TO DO THAT BUT WIDE
SPREAD SORT OF COALITION SHARING
DOES BECOME DIFFICULT.
IF WE HAVE INFRASTRUCTURE IN
PLACE WHERE WE CAN TALK THROUGH
AND WORK THROUGH DIFFERENCES
FROM LAB TO LAB AND COAALATE
DATA AND PULL OUT INDIVIDUAL
VARIANTS THAT ARE RESPONSIVE
THEN WE HAVE THE ABILITY TO
BUILD THAT AND SHARE IT IN A
MORE RESPONSIBLEY WAY.
BUT THE--IT'S SOMETHING THAT I
THINK HAS GREAT PROMISE THAT
HASN'T REALLY BEEN TAPPED INTO
AS WELL.
I THINK 1 OF THE BING THINGS
THAT ALL OF US AND I'M
PARTICULARLY GUILTY OF THIS NEED
TO DO MORE AND MAKE SURE THAT
WHEN WE FIND THESE VARIANTS THAT
ARE CONSISTENTLY RESPONSIVE,
MAKING SURE THEY'RE OUT THERE IN
THE LITERATURE AND PEOPLE PICK
UP ON IT AND KNOW THIS IS
SOMETHING TO CHASE AND GO AFTER
DR. MRK GARY DO YOU HAVE
THOUGHTS ON THAT WITH YOUR WORK
IN THIS SPACE?
>> I MEAN, THERE'S JUST SO MUCH
THAT GOES INTO ALL OF THIS,
RIGHT?
THERE'S JUST SO MUCH MORE WE CAN
DO WITH THIS.
ONE OF THE INTERESTING THINGS TO
ME IS THAT YOU'RE THINKING ABOUT
THE NATURAL HISTORY OF CF, AND
HOW WE DON'T--WE STILL DON'T
REALLY UNDERSTAND FULLY THE
NATURAL HISTORY IN CERTAIN
GROUPS BEFORE MODULATORS, AND
HOW IMPORTANT IT'S GOING TO BE
WHEN WE UNDERSTAND THE HISTORY
OF AFTER MODULATORS AS WELL, AND
HOW IT WILL BE GETTING DIFFERENT
GROUPS AS WELL.
SO YOU KNOW THE CHAT, LOTS OF
QUESTIONS ON THE SITE OVER HERE
BUT JUST THINK BEING, YOU KNOW
SOCIOECONOMIC STATUS, HOW THAT
WILL BE AFFECTING DISEASE
TRAJECTORY GOING FORWARD, RACE
AND ETHNICITY, HOW DECEASED AND
DIFFERENT AND THINKING ABOUT
WHEN YOU'RE DESIGNING, SO FROM
THE NIH POINT, WHEN YOU'RE
DESIGNING CLINICAL TRIALS AND
THINKING ABOUT PATIENTS ARE
COMING IN DIFFERENT DEC
TRAJECTORIES AND IN MEASURING A
RESPONSE AND REALLY THE
IMPORTANCE OF LOOKING AT THESE
SUBGROUPS, COLLECTING THE
INFORMATION IN THE SUBGROUPS AS
WELL.
SO AND THEN ENROLLING ENOUGH
PATIENTS TO LOOK AT DIFFERENCES,
RIGHT?
SO I JUST THINK THAT THERE'S A
LOT OF WORK TO BE DONE AND IT
REALLY STARTS WITH AWARENESS AS
WELL.
>> I THINK IT HAS TO BE CRITICAL
THESE STUDIES ARE DESIGNED
REALLY CAREFUL AND WE HAD TO
THINK ABOUT HOW WE'RE FRAMING
THE QUESTION, BECAUSE JUST
ASSUMING THERE'S A BIOLOGICAL
DIFFERENCE BASED ON RACE IS--MY
POOR ASSUMPTION IS WE'VE SEEN IT
WITH PFTs AND OTHER DATA MAYBE
THERE ARE EPIGENETIC PHENOMENA
THAT ARE OCCURRING BECAUSE OF
SYSTEMIC RACISM THAT ARE
IMPACTING OUTCOMES WE CAN'T JUST
SAY BLACK PEOPLE DON'T RESPOND
TO MODULATORS BECAUSE OF XYZ,
BECAUSE RACE IS A SOCIAL
CONSTRUCT AND IF YOU LOOK AT 1
GENE IN AFFRIC ATHERE'S NOT 1
SPECIFIC MUTATION THAT OCCURS IN
EVERY AFRICAN THAT'S NOT FOUND
IN EUROPEANS FOR EXAMPLE, SO WE
HAVE TO BE CAREFUL HOW WE FRAME
THE QUESTION AND HOW WE ASK AND
ANSWER THE QUESTIONS.
YEAH, I THINK THEY WANT A SIMPLE
EXPLANATION AND THAT'S NOT THE
CASE.
IT'S VERY COMPLICATED AND THAT'S
WHY WE NEED TO BE COLLECTING
LOTS OF DIFFERENT INFORMATION
ABOUT THESE GROUPS.
THERE ARE SO MANY TREATMENTS
ACROSS THE LIFETIME MAY BE
DIFFERENT, THAT THERE'S SO MANY
DIFFERENT BIOLOGICAL SOCIAL
FACTORS FROM THE AIR THEY
BREATHE TO THE TREATMENTS
THEY'RE GIVEN THAT'S WHY THESE
ARE SO IMPORTANT IN THESE
STUDIES TO THINK ABOUT THEM AND
ADDRESS THEM.
AND INCLUDING THEM ON THE
PLANNING AND THINKING ABOUT LIKE
WHAT ARE THERE RESEARCH
PRIORITIES LIKE WHAT ARE--YOU
KNOW WE JUST NEED TO BE--IT
NEEDS TO BE A REAL SHIFT IN OUR
PARADIGM WHEN WE'RE THINK BEING
THIS.
SO, YOU KNOW THERE'S BEEN
SOME--IN SOME OF THE LOW HANGING
FRUIT, SO HERE WE ARE AT NHLBI,
SO WHEN WE'RE THINK BEING WHAT
TRIALS ARE BEING FUNDED AND
WE'RE LOOKING AT THE GRANTS AND
LOOKING AT DAT BEING REPORTED
BACK, WE NEED TO THINK ABOUT
WHERE THESE TRIALS BEING
CONDUCTED, ARE THEY IN A PLACE
WHERE THEY HAVE A DIFFERENCE
POPULATION TO RECRUIT FROM WHAT
ARE THEY DOING TO RECRUIT A
DIVERSE POPULATION?
DO WE HAVE MATERIALS TRANSLATED
IN SPANISH FOR EXAMPLE?
DO WE HAVE DIVERSE RESEARCH
COORDINATORS.
IS IT EVEN ON THE RADAR?
IF YOU'RE NOT THINK BEING IT
WHICH I THINK HAS BEEN SORT OF
THE CASE, LIKE ARE WE LOOKING AS
WE'RE GOING ON AND BEING LIKE,
GOSH, WE ARE ONLY ENROLLING
NONHISPANIC WHITE PATIENTS.
IT NEEDS TO BE A PAUSE IN SAYING
WHY, WHAT CAN WE DO TO CHANGE
THAT?
WHAT DO WE NEED TO ADJUST GOING
ON?
WHEN WE'RE THINKING ABOUT THOSE
OF US WHO ARE EDITORS, THOSE OF
US WHO ARE VIEWERS, WHEN YOU GET
THAT PAPER, ARE YOU LOOKING TO
SEE, IS RACE AND ETHNICITY
THERE, I MEAN I WAS SHOCKED WHEN
IT WAS LIKE NEW ENGLAND JOURNAL
OF MEDICINE, NO RACE AND
ETHNICITY AND I WILL SAY THAT I
WROTE IMMEDIATE RESPONSE BACK
AND THE--THE--I WAS TOLD IT
COULD NOT BE PUT IN BECAUSE
THERE WASN'T SPACE FOR THAT
INFORMATION AND THAT MEANS IT'S
NOT A PRIORITY, RIGHT?
LIKE, THAT MEANS THAT THAT'S
CONSIDERED TO BE NONRELEVANT
INFORMATION WHICH IS SO FAR FROM
THE TRUTH.
SO, I THINK ON ALL LEVELS, WE
NEED TO BE KEEPING THIS
AWARENESS, SO, MAYBE IT JUST
NEEDS TO BE--NIH NEEDS TO GO
FROM WELL, YOU NEED TO REPORT
RACE AND ETHNICITY TO WHAT IS
THE BASE LINE OF RACE AND
ETHNICITY OF YOUR OVERALL
POPULATION?
WHERE ARE YOU GOING TO RECRUIT
FROM?
WHAT ARE YOUR GOALS?
WHAT PERCENTAGE DO YOU NEED TO
RECRUIT TO LOOK AT DIFFERENCE IN
BIOMARKERS, RIGHT?
LIKE, BECAUSE I THINK IF
YOU--WHATEVER POPULATION, THAT
YOU'RE CREATING BIOMARKERS FOR,
THAT YOU'RE CREATING DRUGS FOR,
THAT'S THE ONLY POPULATION THAT
YOUR RESULTS WILL BE RELEVANT
FOR.
SO THERE'S SO MANY WAYS WE CAN
ALL MAKE A CHANGE ON THIS.
BUT IT'S GOING TO BE AT TIMES
HARD WORK.
SO--BUT, YOU KNOW, I THINK, YOU
KNOW FUNDING IS A REAL GOOD
INCENTIVE SO, I THINK WE JUST
NEED TO AT ALL LEVELS BE WORKING
ON THIS AND THINKING BIG.
AND YOU KNOW THE CF FOUNDATION,
IS BIG CHANGES GOING ON AND I
THINK THE NEXT NICAC, WE WILL
SEE MORE OF THAT PRESENTED BUT
THERE'S JUST A LOT OF WORK RIGHT
NOW.
>> --1 THAT CAME UP WITH MENTAL
HEALTH DECLINE OR HEALTH ISSUES
ON MODULATOR THERAPY THAT'S OUT
THERE.
CERTAINLY IN THE ADULT
POPULATIONS, AND THEN ALSO TO
TIE INTO THAT WHAT ARE THE
HEALTH CONDITIONS THAT REALLY
NEED GREATER ATTENTION AND THEY
REALLY NEED TO FOCUS CHRIS, I
KNOW YOU MENTIONED RENAL
DISEASE, AND DIABETES, BUT ANY
OF THE THINGS ARE CRITICAL
THINGS WE SHOULD BE FOCUSING ON
ACROSS THE LIFE SPAN TO PREPARE
FOR AN AGING POPULATION.
>> I WOULD HAVE TO--1 OF MY
SLIDES ACTUALLY SKIPPED OVER
WHICH IS MOST IMPORTANT, WHERE
IT WAS, WHERE IT WAS?
IT WAS ABOUT OBESITY AND IT IS
JUST--I HAVE A PATIENT WHO
GAINED 60-POUNDS IN 3 MONTHS ON
TRICAFTA, IT IS THERE, THE
PROPORTION OF CENTERS NOW HAVING
OBESITY AS AN ISSUE IN THEIR
HEALTHCARE SYSTEM, THE INFRANCIS
COLLINS SPHRUCTURE TO ADDRESS OR
THINK ABOUT OBESE IS REALLY,
REALLY, HAS NOT BEEN FROM THE
CENTER, I KNOW FROM TALKS
YESTERDAY, THEY'RE OBVIOUSLY
REDOING THE NUTRITION GUIDELINES
BUT IT'S GOING TO BE A REAL
ISSUE IF YOU THINK OF DIABETES
AND OBESITY TOGETHER AND A
CHRONIC LUNG INFECTION.
IF YOU THINK ABOUT AN
INFLAMMATORY MELUE, THAT WILL BE
CHALLENGING AND THAT COULD BE A
REAL ISSUE LATER IN LIFE AS
PATIENTS AGE WITH CF, SO I THINK
IT'S--I WOULD COMMENT ON THAT
BECAUSE I THINK IT WAS
UNDERREPRESENTED THERE.
AND MANAGING THESE CHRONIC DRUGS
FOR A LIFETIME AND UNDERSTANDING
THEIR LONG-TERM COMPLICATIONS IS
GOING TO BE REALLY IMPORTANT.
>> CHRIS, ARE THEY GOING TO BE
ON IT FOR A LIFETIME OR IS THERE
SOMETHING DIFFERENT AND BETTER?
THAT'S WHAT I TALK TO ALL MY
ADULTS ABOUT.
I DON'T THINK THEY WILL BE ON
TRICAF TA.
>> I DON'T THINK WE WILL BE ON
IT FOR LIFETIME BUT HOPE LOOFULY
GET A LIFETIME CURE, THAT WOULD
BE DIFFERENT WE WILL SEE BUT, I
THINK OUR GENE THERAPY IS THERE
BUT THEY WILL BE ON THESE DRUGS
FOR A LONG TIME OR SIMILAR DRUGS
I ASSUME JUST GIVEN THE
CHALLENGES OF MOVING GENE
THERAPY FORWARD.
>> AND I WANTED TO ADD ABOUT
MALIGNANCY IS ANOTHER THING TO
KEEP AN EYE ON OVER TIME AND
DOES HIGHLY EFFECTIVE MODULATOR
THERAPY REDUCE THE RATE OF
MALIGNANCY OF CFTR IS A TUMOR
SUPPRESSOR AND YOU'RE FIXING THE
FUNCTION THERE, I THINK THAT
POST TRANSPLANT, THIS GETS
POO-POOED A LOT WHEN I TALK
ABOUT IT, SO I DIDN'T INCLUDE IT
TODAY BUT COULD WE START
MODULATORS AND POST TRANSPLANT
POPULATION AND REDUCE THEIR RISK
OF PTLD OR TRANSPLANT
LYMPHOPROLIFERATIVE DISORDER
BECAUSE THEY HAVE SUCH A HIGH
RATE, EVEN ACCOUNTING FOR EBV
MISMATCHING, THEY'RE AT A HIGHER
RATE OF GEYE CANCERS SO WE FIX
IF WE FIX IT POST TRANSPLANT
COULD WE AFFECT THEIR RISK FOR
MALIGNANCY AND I DON'T THINK WE
WILL KNOW THAT UNTIL WE HAVE A
REGISTRY FULL OF PEOPLE ON
VERSUS NOT ON MODULATEDDORS, IT
WILL NOT BE A MULTICENTERRED
TRIAL, I CAN SEE AN IMPACT ON
THAT.
CATHY IT'S A GREAT QUESTION, IT
GOES BACK TO DISCUSSION
YESTERDAY, MATTERS WHEN IN LIFE
THEY WERE INITIATED THEIR
MODULATOR AND HOW IT WOULD
CHANGE THE CANCER RISK.
IT'S DIFFERENT IF YOU START
SOMEBODY WHOSE 40 VERSUS
SOMEBODY WHO'S 4 MONTHS OLD.
, ALL RIGHT.
WELL, I JUST GOT THE MESSAGE
THAT IT'S TIME TO WRAP BECAUSE
LUNCH IS UPCOMING.
BEFORE WE DO, I WANT TO
HIGHLIGHT THERE'S BEEN
INCREDIBLE CONVERSATION IN THE
CHAT THINKING ABOUT ENROLLMENT
OF PATIENTS IN SUBJECTS AND
STUDIES AND HOW DO WE MAKE SURE
THAT WE'RE INCLUSIVE IN THE
STUDY DESIGNS, SO, PLEASE MAKE
SURE YOU LOOK THROUGH THAT,
REALLY GOOD CONCEPTS OF
CONVERSATIONS THERE.
I WILL SAY A HUGE THANK TO YOU
EVERYBODY FOR THEIR ATTENTION
AND TO OUR SPEAKERS, DR. ANY
LAST MINUTE THOUGHTS.
>> I WAS GOING TO SAY, THERE'S
INCREDIBLE RESOURCES, AGREANCE,
DISCUSSIONS IN THE CHAT, THE
CHAT IS BEING SAVED AND WILL BE
AVAILABLE AND TELL BE GOOD.
BUT WE WANT TO THANK OW
SPEAKERS, THIS WAS AMAZE,
AMAZING WORK YOU ARE DOING, AND
JUST FOR EVERYBODY HERE, WE JUST
THANK YOU, IT'S REALLY EXCITING
ABOUT THE FUTURE OF CF, THIS IS
JUST INCREDIBLE THE WORK THAT'S
BEING DONE IT'S AMAZING TO THINK
ABOUT THE THINGS WE DISCUSS NOW,
RIGHT?
PREGNANCY, AGING, LIKE IT'S
JUST--IT'S JUST A WHOLE NEW
WORLD AND IT'S JUST EXCITING
PLACE TO BE, SO WE THANK
EVERYBODY SO MUCH AND WE THANK
THE NHLBI FOR MAKING THIS A
PRIORITY, THANK YOU, THANK YOU
AND I HOPE EVERYBODY HAS A GOOD
LUNCH AND WE SEE YOU IN JUST A
LITTLE BIT.
>>HELLO, I WOULD LIKE TO
WELCOME EVERYONE BACK TO THE
SESSION TODAY.
WE ARE SOPHISTICATED SESSION 5
TITLED ADVANCING CLINICAL CARE
AND OUTCOMES FOR PATIENTS WITH
CF IF THE MOST MODULATOR ERA.
WE WILL HAVE ANOTHER SERIES OF
TALKS FOLLOWED BY A COMMUNITY
MEMBER PERSPECTIVE AS THE LAST
TALK IN THIS SESSION.
I DO WANT TO MAKE A FEW NOTES OF
CHANGE HERE, OUR 2 MODERATORS
FOR THIS SESSION WILL ACTUALLY
BE DR. HAMLET AND
DR. ROSE NFELD AND OUR COMMUNITY
PERSPECTIVE WE HEARD FROM MISS
LAWRENCE TODAY SO WE WILL HAVE
MISS JENNIFER KYLE GIVING OUR
COMMUNITY MEMBER PERSPECTIVE
HERE SO SORRY FOR THAT THE
CONFUSION, THAT INFORMATION
SHOULD BE UPDATED IN THE PROGRAM
BOOK FOR YOU AND WE WILL POST
THAT IN THE CHAT.
AND WITH THAT I WILL TURN THIS
OVER TO THE MODERATORS OF
SESSION 5.
>> THANK YOU.
WELCOME BACK EVERYONE.
IT IS STILL MORNING ON THE WEST
COAST SO WE'RE JUST GETTING
GOING HERE.
OUR NEXT SESSION ADVANCING
CLINICAL CARE AND OUTCOMES FOR
PATIENTS IN THE POST MODULATOR
ERA WE WILL EXPLORE THE NEED FOR
NOVEL OUTCOME MEASURES TO INSURE
OPTIMAL MONITORING AND DISEASE
PROGRESSION AND SERVE AS
CLINICAL TRIALS AND NEW
THERAPEUTICS.
WE HAVE A GREAT LINE UP
DR. ZACHARY CLEVELAND WILL BE
PRESENTING, AND DR. HEATHER BEAN
WILL TALK ABOUT ASPECTS OF CF
HEALTH, DR. NATALIE WEST COULD
NOT BE HERE TODAY BUT SHE
RECORDED HER TALK AND WILL BE
REVIEWING THE CHANGING LANDSCAPE
OF PULMONARY VASCALATIONS IN THE
POST MODULATOR ERA, AND
DR. [INDISCERNIBLE] WILL PRESENT
ON DISEASE MONITORING AND AS YOU
HEARD, WE WILL CONCLUDE OUR
SESSION WITH MISS JENNIFER KYLE
WE ARE THRILLED TO HAVE HER
SHARE HER PERSONAL EXPERIENCE AS
1 OF OUR COMMUNITY CF RESEARCH
PARTNERS AND WITH THAT I WOULD
LIKE TO WELCOME DR. CLEVELAND
WHO IS THE ASSOCIATE DIRECTOR
FOR PULMONARY ENERGY RESEARCH
AND ASSOCIATE PROFESSOR AT
CINCINNATI CHILDREN'S HOSPITAL
AND UNIVERSITY OF SIN SEN
ILLEGALSEN ATY.
>> ALL RIGHT, LET'S SEE IF WE
CAN MAKE THIS GO.
ALL RIGHT, THANK YOU FOR THE
INTRODUCTION, I'M HERE TODAY TO
TALK ABOUT THE ROLE THAT IMAGING
IS LIKELY TO PLAY IN CF LUNG
DISEASE IN THE HIGHLY EFFECTIVE
MODULATOR THERAPY.
I WILL BEGIN BY THINKING ABOUT
MAJOR OPPORTUNITIES GOING
FORWARD, THAT IS WE HAVE THE
ABILITY TO QUANTIFY
PATHOPHYSIOLOGY AND PEOPLE WITH
NORMAL SPIROMETRY, AND TRULY
ABNORMALITIES OF THE LUNGS.
I WOULD ALSO SAY THAT 1 OF THE
THINGS WE MIGHT BE ABLE TO DO IS
IDENTIFY SUBCLINICAL AS WE
PREPARE FOR GERIATRIC CF IN 20
YEARS FROM NOW.
NOW BEFORE I CAN MOVE ON TO
THOSE LOFTY NOTIONS I NEED TO
TALK ABOUT WHAT EXISTS RIGHT
NOW.
AND FOR YEARS PRIMARILY WHAT WE
HAVE THOUGHT ABOUT IS SPI
ROMETRY IN THE CONTEXT OF LUNG
DISEASE, THIS HAS CHANGED AS WE
TALKED ABOUT IN THIS MEETING SO
FAR.
IT'S IMPACTING HOW WE WRITE OUR
GRANTS.
I MADE THIS GRANT 5 OR 6 YEARS
AGO, WHERE WE TALKED ABOUT
DEVELOPING NEW TECHNOLOGY WITH
HYPER CHLORRA SWREEN WHICH I
WILL TALK ABOUT IN A MOMENT AND
AS SAD AS TD CF SITUATION IS,
IT'S ANI DEAL SITUATION TO
VALIDATE NEW TECH AS AN
OBJECTIVE LUNG DISEASE, AND IT'S
UNPREDICTABLE AND TIME COURSE
LIKE SYNTHESIS, COPD.
IF I TOLD THAT STORY, THE
REALITY IS FOR MANY OF OUR CF,
THEY'RE GOING TO BE SPI ROUGH
ATOM METICALLY NORMAL THROUGHOUT
PEDIATRIC CAN AND INTO ADULT
CARE, SO WE NEED A NEW HANDLE ON
CF LUNG DISEASE, SINCE THE
1980S, 1 OF THE IDEAS HAS BEEN
FORWARDED IS WE USE CT IMAGING
WHICH IS SUPERIOR MEASURE OF
LUNG PATHOLOGIES TO SPIROMETRY
AND IT'S EASY TO SEA WHY.
IS MY AUDYE A PROBLEM?
>> SO, WE CAN HEAR YOU.
>> OKAY, SORRY THERE WAS A
COMMENT I SAW, IN ANY CASE
THERE'S A LOT OF CLASSIC
PATHOLOGY THAT'S SEEN IN THE CF
LUNG AIR TRAPPING CAUSED BY
OBJECTIVE DISEASE, IN THE DENSE
STRUCTURE WHICH IS WE CALL
CONSOLIDATIONS OR GRAWND
CAPACITY, AND VARIETY OF AIR WAY
ABNORMALITIES, MUCUS PLUGGING
AND ULTIMATELY BRONCHIECTASIS,
AND HAVE A DILATED AIR WAY THAT
EXCEEDS THE CHEST.
ANOTHER GRAY WAY OF CT,
OOPS--WRONG WAY.
SORRY, TECHNICAL DIFFICULTIES
HERE.
IS IT'S TRULY QUANTITATIVE IN
THE SENSE WE CAN MEASURE RADIO
SENSITY AND THAT TELLS US HOW
DENSE THE LUNG TISSUE REALLY IS,
WE KNOW FROM THE COPD WORLD THAT
IF YOU MEASURE NEGATIVE 950 HU
OR LESS, WE HAVE CLINICAL
EMPHYSEMA AND THAT HAS BEEN
VALIDATED HISTOLOGICALLY FOR
DECADES.
NOW THIS RAISES AN INTERESTING
PROBLEM IN CF BECAUSE IF WE LOOK
AT THIS--THESE--MANY OF THESE
PEOPLE, WE SEE ACTUALLY LOW
DENSITY TISSUE MUCH LIKE WE SEE
IN EMPHYSEMA PATIENTS BUT IT'S
RELATIVE UNRECOGNIZED WITHIN
CLINICAL CARE RIGHT NOW AND
UNDERSTANDING THIS IS
CHALLENGING BECAUSE LUNG DENSITY
CHANGES WITH TIME, AND IF WE
WANT TO UNDERSTAND WHAT IS TRULY
ABNORMAL WE HAVE TO DEFINE
NORMAL WHICH MEANS WE NEED
NORMATIVE EQUATIONS WHICH WE
HAVE FOR SPIROMETRY, ALL THE WAY
DOWN TO THE PEDIATRIC WELL AND
NOT MANY ARE GOING TO VOLUNTEER
THEIR 5 YEAR-OLD TO BE RADIATED
EVEN WITH A LOW DOSE CT PROTOCOL
TO GET NORMATIVE DATA.
EVEN IN PEOPLE WITH CF WHO HAVE
ESTABLISHED LUNG DISEASE BUT ARE
FEELING BETTER BECAUSE THERE ARE
ALL THESE HIGHLY EFFECTIVE
THERAPIES, HOW MUCH CAN WE
REALLY JUSTIFY ROUTINE
DIAGNOSTIC RADIOLOGY TO
UNDERSTAND BRONCH YECT SIS.
AND I SAY THAT BECAUSE I DON'T
FIND THESE PARTICULARLY
MEANINGFUL.
--STANDARD CARDIAC SCAN BUT IF
YOU LOOK AT THE ARROW IN THE
LUNG WHERE THE RUBBER MEETS THE
ROAD PHYSIOLOGICALLY, IT'S
LITERALLY A BLACK BOX AND TO
OVERCOME THIS CHALLENGE WHICH
HAS TO DO WITH THE MAGNETIC
PROPERTIES ALONE ARE CENTERED,
OTHERS AROUND THE WORLD HAVE
DEVELOPED ECHO TIME MRI, THAT IS
RATHER THAN ENCODE THE DATA WITH
THE TIME CONSTANT OF MINIMILLI
SECONDS AND THE SIGNALING IN A
MILLI SECOND IN THE LUNG TISSUE,
WE GO TO 10S OF MICROSECONDS AND
WE'RE ABLE TO GET QUANTITATIVE
RECOVERY OF SIGNAL INTENSITY AND
THIS ALLOWS US TO SEE PATHOLOGY
LIKE MUCUS PLUGGING, AIR WAY
DILATION, ET CETERA.
AND HERE'S WORK BY MY COLLEAGUES
JASON WOODS AND HIS POST DOC
DAVID ROACH WHERE THEY LOOK IN
TODDLERS WITH LUNG ABNORMALITIES
IN CF AND WE'RE ABLE TO SEE THE
SAME SORT OF PATHOLOGIES 1 SEES
IN CT WITH UT MRI AND WHEN THEY
SCORED THESE IMAGES USING THE
STANDARD BRODY SCORE DEVELOPED
BY OUR SIN SUDDEN ATY CHILDREN'S
HOSPITALLAL AN BRODY THEY SAW A
REASONABLY GOOD CORLEAGZ
SUGGESTING WE CAN ACTUALLY GET
DIAGNOSTIC AND PROGNOSTICLY
USEFUL INFORMATION WITH THE
UTSMAZE MRI.
NOTICE IN WAS A NUMBER OF YEARS
AGO, WE PUSHED THE TECHNOLOGY
MUCH FARTHER THIS, IS OUR
STATE-OF-THE-ART RIGHT NOW HIGH
RESOLUTION UT MRI AND I WANT TO
SHOW 1 FEATURE HERE THAT'S
EXCITING TO US THAT IF YOU LOOK
INTO THE PERIPHERY OF THE LUNG
YOU SLEEP APNEA AND OBESITYY
THESE REGIONS WHERE WE'RE SEEING
AIR TRAPPING ON THE IMAGES WHICH
IS SOMETHING THAT WAS VERY
DIFFICULT TO DO PRIOR TO THIS
EVEN WITH UTE.
NOW WHAT'S EXCITING IN TERMS OF
CLINICAL DISSEMINATION IS THAT
ALL OF THE MAJOR MRI
MANUFACTURES RIGHT NOW HAVE
RESEARCH SEQUENCES FOR SOME
FLAVOR OF UT MRI AND I WOULD
SUSPECT IN THE NEXT 5 YEARS OR
SO, WE WILL SEE THIS AS A
CLINICAL SEQUENCE FDA APPROVED
WHICH MEANS A CLINICIAN CAN
ORDER MUCH THE SAME WAY YOU
WOULD A CT PROTOCOL NOW.
SO WHAT CAN WE DO FOR FUNCTION.
THAT IS WHAT DO WE DO TO MOVE
AWAY FROM OUR OLD FRIEND
SPIROMETRY, WE WOULD LOVE TO
IMAGE THE GASES OXYGEN AND CO2,
BUT FOR TECHNICAL REASONS WE
CAN'T SO WE IMCANCER CENTER A
SURROGATE GAS, XENON 129, IT'S
CHEMISTRY INERT, NONRADIO
ARCTIVE AND OBSERVABLE IN MR AND
WE HAVE THE POTENTIAL TO IMAGE
LUNG FUNCTION.
IF YOU DO THIS NAIVELY YOU DON'T
GET MUCH OF ANYTHING USEFUL
BECAUSE THE GASES ARE LOW
DENSITY, ABOUT A FACTOR OF
10,000 LESS THAN WATER.
SO WE USE A TECHNIQUE CALLED
HYDRO CHLORRIZATION, FROM A
PHYSICIST, PREPARED GAS, GET A
SIGNATURES NOX FAMILY ACTIVATOR
INTENSITY INCREASE OF A FACTOR
OF 10,000, PUT THE GAS IN A BAG,
HAVE THE SUBJECT INHALE THE GAS
WHERE IT REACHES THE ALVEOLAR
SPACES AS A CIRCUIT FOR
VENTILATION AND WHEN WE DO THIS,
THIS SIGNAL BECOMES SOMETHING
LIKE THIS.
THIS IS A INHALED BREATH OF
XENON 129 AFTER HIGH
POLARIZATION, AND THE SIGNAL
INTENSITY FOR REGIONAL
VENTILATION AND IF YOU LOOK AT
THE APEX OF THE LUNG, YOU WILL
SEE RAT BITES OUT OF IT AND
THAT'S WHERE THIS SUBJECT OF CF
WE SEE OBSTRUCTIVE LUNG DISEASE
AND THEREFORE NO VENTILATION IN
THAT REGION.
AND BECAUSE THESE IMAGERS ARE
JUST 3D DATA SETS WE CAN
ACTUALLY QUANTIFY THE IMPAIRMENT
FAIRLY EASILY, THAT IS WE PUT A
SIGNAL INTENSITY ACROSS THE DATA
SET AND DEFINE A THRESHOLD WHICH
WE SAY ANYTHING BELOW THAT IS
ABNORMAL INTENSITY AND CALCULATE
THE PERCENTAGE.
NOW IN YOUNG PEOPLE WITH CF, IF
YOU LOOKED AT SPIROMETRY IN 25
PEOPLE YOU WOULD SAY REAL TEF
LIE NORMAL NUMBERS, YOU NEED
MUCH LARGER TO SIGNIFICANCE WITH
HEALTHY CONTROLS.
HOWEVER THE VENTILATION DEFECT
SHOWS STRONG DIFFERENCES IN IN
POPULATION.
THIS WAS PREMODDULATOR BUT THE
STORY IS SIMILAR.
WHAT'S MOST INTERESTING,
HOWEVER, LOOK AT THE PEOPLE WHO
ARE SPIROMETTICRY NORMAL, IF YOU
LOOK AT THE IMAGES YOU SEE
SOMETHING STRIKING, YOU DON'T
NEED TO BE A RADIOLOGIST OR PULL
MONITORROLOGYIST AND SAYING THAT
KID IS ON A DIFFERENT TRAJECTORY
THAN THE KID SHOWN IN C AND D.
SO THIS SORT OF SENSITIVITY THAT
VENTILATION IMAGING CAN PROVIDE
IN THE AGE OF HIGHLY EFFECTIVE
MODULAR THERAPY.
IT'S ALSO NOT THE ONLY CONTRAST
FROM MRI, WHICH IS A STRENGTH OF
MRI, WE CAN MEASURE HOW FAR A
MOLECULE OR ATOM FUSES IN A
GIVEN TIME PERIOD.
THIS HAS BEEN USE INDEED THE
CONTEXT OF EMPHYSEMA, WHEN WE
MEASURE AN APPARENT CO EFFICIENT
WITH MRI IN THE LUNG FOR
EXTENON, WE MEASURE IN THE LUNG
BECAUSE DIFFUSION OF THE GASES
CAN STRAIN BY COLLISIONS WITH
THE ALVEOLAR WALL, BUT IF WE
HAVE THOSE DESTRUCTIONS IN THOSE
WALLS WE SEE A MUCH LARGER CO
EFFUSION, THAT APPROACHES THE
DIFFUSION METHOD, IN THE MODEL.
WE SEE THIS IN COPD AND WHAT I
FOUND WHEN I CAME TO CINCINNATI,
IF YOU DO THE SAME EXPERIMENT IN
A SUBJECT WITH CF, YOU SEE
PATHOLOGICALLY ENLARGED ALVEOLAR
SPACES IN A SUBSET OF CF, PEOPLE
WITH CF AND YOU DON'T SEE IT AT
ALL IN THE CONTROLS AND WHAT'S
FASCINATING IS YOU TEND TO SEE
THIS ON THE PERIPHERY OF THE
LUNG THAT IS YOU HAVE
PATHOLOGICALLY LOW TISSUE
DENSITY OR LOW STRUCTURAL
INTEGRITY NEAR THE SURFACE WHICH
MAY EXPLAIN WHY PEOPLE WITH CF
HAVE THE THORAX THAN THE GENERAL
POPULATION, SO THIS IS AGAIN
SOMETHING WE NEED TO BE AWARE OF
AND LOOK FORWARD TO, LOOK OUT
FOR AS WE MOVE INTO OLDER AND
OLDER PATIENT CARE AND WE CAN
NOW GET AT THIS WITHOUT THE NEED
FOR IONIZING RADIATION.
A FINAL CONTRAST WE CAN GET FROM
XENON MRI AND WE CAN REASONABLY
DETECT GAS EXCHANGE IN THE LUNG
BECAUSE XENON HAS A LARGE
SENSITIVITY TO THE CHEMICAL
ENVIRONMENT SO WHEN IT DESOLVES
IN THE PULMONARY TISSUES WE SEE
UNIQUE FREQUENCIES IN THE RED
BLOOD CELLS, THE TISSUES AND THE
GAS PHASE WHICH WE EXPLORED FOR
VENTILATION IMAGE.
NOW THIS IS WORK DONE BY MY
COLLEAGUE LAURA [INDISCERNIBLE]
WHO PRESENTED THIS AT ACS, WE
CAN GET NORMATIVE DAT WHICH
WE'RE JUST BEGINNING TO DO AND
WHAT SHE HAS FOUND WHEN COMPARED
TO HEALTHY AGE MATCHED SUBJECT
SYSTEM WE HAVE A PATHOLOGICAL
INCREASE IN THE MEMBRANE SIGNAL
IN CF LIKELY DUE TO SUBCLINICAL
INFLAMMATION IN THE ALVEOLAR
SPACES THEMSELVES.
SO WHERE DOES THIS LEAVE US IN
TERMS OF CLINICAL DISSEMINATION?
THIS IS A SLIDE PROVIDED TO ME
BY MY COLLEAGUE [INDISCERNIBLE]
AT POLAREAN WHO MAKES THE
XENONSPADES POLARIZERS.
THE LIGHT BIEW IS THE ABILITY TO
DO THE XE MRI, AND THE PURPLE
SITES ARE POTENTIAL SITES IN THE
COMING YEARS, RIGHT NOW XENON IS
APPROVED FOR CLINICAL USE IN THE
UK.
WE HAVE RECENTLY COMPLETED
SUCCESSFULLY THE PHASE 3
CLINICAL TRIAL FOR XENON MRI IN
ADULTS IN THE U.S.
WE EXPECT FDA APPROVAL FOR
XENON MRI LATE THERAPY AND YEAR,
CANADA FALLS THROUGH SHORTLY
THEREAFTER.
SO THIS NOW LEAVES US IN A
SITUATION WHERE WE HAVE THIS
REALLY INTERESTING TECHNOLOGY IN
A HANDFUL OF SPECIALIZED SITES,
HOW DO WE DISSEMINATE IT MORE
BROADLY AND I THINK 1 TECHNOLOGY
TRANSFER WE CAN DO WITH THESE
VERY SENSITIVE TOOL SYSTEM WE
CAN VALIDATE MORE EASILY
DISSEMINATED TOOLS THIS, IS AN
EXAMPLE OF WORK WITH MY
COLLEAGUE CANNED WHAT WHO MANY
OF YOU KNOW AND HIS TEAM WHERE
HE'S DEVELOPED PROTEOMIC MARKERS
OVER THE YEARS USING SPIROMETRY
TO SEGGREGATE POPULATIONS IF WE
DO THIS WITH XENON IN
SPIROMETRIC POPULATIONS WE CAN
SEE DIFFERENCES IN PEOPLE WITH
SERUM PROTEOMICS THAT HAVE
SPASESSIVE STATISTICAL
SIGNIFICANCE.
SO I THINK WE CAN MOVE THIS
FORWARD AND DO THINGS THAT I
THINK ARE VERY, VERY SIMILAR
WITH YOUR FAVORITE OMICs,
METRICS TAB O LOAMICS
EPIGENOMICS, THOSE SORTS OF
THINGS.
AND A SIMILAR APPROACH COULD BE
USED IN LIVER AND GUT
COMPLICATIONS WHERE WE USE
SIMILAR TOOLS TO DISSEMINATE
BIOMARKERS EARLY IN THE DISEASE.
SO THAT I GUESS I WILL END WITH
MY ACKNOWLEDGMENTS WHICH ARE
KIND OF MY DISCLOSURES, PEOPLE
PAY FOR THE MONEY, ALL OTHER
PEOPLE DO REAL WORK AND I'M A
PHYSICAL CHEMIST BY TRAINING SO
TAKE EVERYTHING I SAY WITH A
GRAIN OF SALT.
THANKS AGAIN FOR THE OPPORTUNITY
TO SPEAK AND I'M HOPING TO
ANSWER ANY QUESTIONS YOU FOLKS
HAVE IF THERE'S TIME REMAINING.
AND I WILL TRY TO STOP
SHARINGING.
IT WENT OFF SCREEN.
>> SO WE'RE ACTUALLY GOING TO
TAKE QUESTIONS AT THE END IN THE
MODERATED DISCUSSION; IN GREAT
AND I WOULD LIKE TO INTRODUCE
DR. HEATHER BEAN.
>> HI, EVERYONE, THANK YOU SO
MUCH TO WILL THE ORGANIZERS FOR
INVITING ME TO PRESENT ON BREATH
ANALYSIS TODAY.
AND MY SLIDES SHOULD BE
MOMENTARILY MY CHRIS CLOSURES
REEL KEEPSAKES STROONT THIS
PRESENTATION IS THAT I'M A
RECIPIENT OF CF FOUNDATION AND
NIH GRAND FUNDING FOR BREATH IR
MARKER RESEARCH.
JUST TO GET US ON THE SAME PAGE
ABOUT EXHALED BREATH, I AM GOING
TO GIVE SOME VERY HIGH LEVEL
OVERVIEW FOR A FEW MINUES BEFORE
I GET INTO DATA.
EXHALED BREATH IS 1 OF THE 3
MAIN WASTE TREMES OF OUR BODY,
WE WILL THINK FEAS FECES, AND
URINE AS WASTE, ALL THE GASEOUS
WASTE THAT IS COLLECTED DIOF
THEALLY IS TRAN PORTED TO THE
LUNG FOR EXKRIEWGZ AND THEREFORE
THE BREATH CONTAINS INFORMATION
NOT ONLY ON THE HELT OF THE
LUNGS BUT IT ALSO CONTAINS
INFORMATION ON THE HEALTH OF ANY
OTHER BODILY SYSTEM.
AND IF YOU ARE COLLECTING BREATH
AND LOOKING FOR BREATH
BIOMARKERS SPECIFIC TO THE LUNG,
VERSUS SPECIFIC TO THE BREATH,
THERE ARE BREATHING MANEUVERS
THAT CAN BE INFORMED ON FOR
THOSE VERSUS BLOOD BIOMARKERS.
NEXT SLIDE.
JUST FOR TERMINOLOGY, I THINK A
LOT OF PEOPLE HAVE HEARD OF
EXHALED BREATH CONDENSATE, BUT
THAT'S ACTUALLY ONLY 1 PART OF
EXHALED BREATH.
EXHALED GREGHT IS GENERALLY
CATEGORIZED INTO 2 MAIN
FRACTIONS, THERE'S THE EXHALE
BREATH CONDENSATE OR EBC AND THE
VOCs ACCIDENT THE EXHALE
BREATH CONDENSATE IS TRACKED
THROUGH A CHILLED TUBE AND THOSE
ARE GOING TO CONTAIN MOLECULES
OF LOWER VOLATILITY BUT HIGHER
MOLECULAR WEIGHT, ALSO GREATER
POLARIZEDARRIZABILITY, AND IN
THAT FRACTION, YOU WILL FIND
THINGS LIKE HUMAN METABOLITES,
MICROBIAL METABOLITES,
XENOBIOTICS INCLUDING DRUGS,
PEPTIDES, VIRUS PARTICLES WHICH
IS HOW WE'RE ALL GIVING EACH
OTHER COVID AND EVEN EPITHELIAL
CELLS CAN BE FOUND IN EBC.
WHATEVER REMAINS AFTER YOU
CONDENSE OUT THE CONDENSATE IS
THE NONCONDENSABLE FRACTION AND
THOSE ARE THE COMPOUNDS, THEY
WILL BE SMALL MOLECULES
TYPICALLY LESS THAN 300 ATOMIC
MASS UNITS AND THEY WILL BE OF
HIGH MOTILITY AND OF COURSE WE
WILL SEE ATMOSHPHERIC AND ROOM
AIR IN THAT FRKS BUT ALSO HUMAN
METABOLITES, MICROBIAL AND EXTEN
O BITE METRICS TAB O LOAMICS AS
WELL.
NEXT SLIDE.
SO GIVE YOU JUST A VERY FEW
EXAMPLES OF BREATH STUDIES THAT
ARE RELEVANT TO MONITORING CF
HEALTH TO SHOW YOU SOME
FEASIBILITY AND CLINICAL UTILITY
EVIDENCE, I WILL GIVE YOU INFECT
YOWZ DISEASE MANAGEMENT, AND I
WILL ALSO GIVE EXAMPLES OF
NONINFECTIOUS DISEASE MANAGEMENT
THAT WOULD BE RELEVANT TO CF, IN
THE UPPER RIGHT HAND CORNER OF
THE FOLLOWING SLIDES YOU WILL
SEE 1 OF THESE 2 SYMBOLS EVEN
VOCs OR EBC, AND THAT WILL
TELL YOU WHICH BREATH WAS
COLLECTED AND STUDIES FOR THAT
PARTICULAR ANALYSIS.
NEXT SLIDE EMPLOY THIS WAS A
STUDY THAT WAS PERFORMED IN A
POPULATION FOR DETECTION AND
DIGITEXTIS OF PNEUMONIA USING PC
R TECHNOLOGY, IN THIS STUDY,
SOME COLLEAGUES COLLECTED
EXHALED BREATH CONDENSATE AND
THEN THEY PERFORM REALTIME PC R
ON THAT CONDEN SITE AMPLIFYING
THE GENE OF SARS COV 2 IN ORDER
TO DIAGNOSE COVID-19.
ON THE LEFT YOU'RE SEEING A PLOT
OF THE VIRAL RNA LOAD AND EXHALE
CONDENSATE AS A LOG TRANSFORM
ATA AND AS A FUNCTION FROM THE
DAYS DISEASE ONSET OR SYMPTOM
ONSET.
AND ON THE LEFT YOU'RE SEEING
THE DATA FOR THE WUHAN STRAIN,
ON THE RIGHT YOU'RE SEEING THE
DATA FOR THE DELTA STRAIN WHICH
IS 2 SEPARATE STUDIES THAT ARE
RECENTLY PUBLISHED IN GENERAL
BREATH RESEARCH.
AND WHAT THEY ARE OBSERVING IS
THAT ON THE LEFT, WE'RE SEEING
JUST THE DATA FOR PEOPLE WHO ARE
SPONTANEOUSLY BREATHING, THIS IS
NOT SHOWING THE VENTILATED
REGIONS.
CAN YOU SEE THERE'S A DECREASE
IN VIRAL LOAD SINCE THE TIME OF
SYMPTOM ONSET, GENERALLY THE
SENSITIVITY AT 2 DAYS WAS 86%,
BUT IT DROPS THEREAFTER, AS THE
VIRAL LOAD IN THE EXHALE BREATH
CONDENSATE DROPS BUT THE LOAD
WAS STRONGLY ASSOCIATE WIDE
SYMPTOMS AND THE NEED FOR
VENTILATION IN ALL OF THEIR
PATIENTS.
FOR THEIR VENTILATED PATIENTS
THE RNA DETECTABLE LOAD WILL BE
HIGH FOR VENTILATION.
THIS WAS A SMALL PILOT STUDY BUT
IT WAS REPLICATED IN THE DELTA
STRAIN, SO IT LOOKS VERY
PROMISING FOR BEING ABLE TO
DETECT VIRAL PATHOGENS AND
ANOTHER SET OF RESEARCHERS, ON,
A COUPLE YEARS AGO DID A STUDY
ON PC R IN AN EXHALE BREATH
CONDENSE 8 TO DETECT BACTERIAL
PATHOGENS THAT ARE THEY
DEMONSTRATED THAT IT'S FEASIBLE
WITH FOLLOW UP WITH LARGER
SAMPLE SIZES TO DETERMINE THE
CLINICAL UTILITY.
NEXT SLIDE.
MY COLLEAGUES AND I, WE HAVE
BEEN CONDUCTING A STUDY CALLED
IMPACT BREATH THAT IS--HOPEFULLY
YOU'RE ALL SEEING THAT AS WELL,
THAT'S OBSCURING YOUR VIEW, SO
IN THIS STUDY, WE ARE
IDENTIFYING AND VALIDATING.
>> WE ARE SEEING THAT.
>> TECHNICAL SERVICES IS RUNNING
THE SLIDE SO THEY'LL NEED TO FIX
THAT.
>> OKAY, GREAT.
SO IN THE STUDY WE ARE LOOKING
TO VALIDATE BREATH BIOMARKERS
FOR DIAGNOSING PSEUDOMOANUS
POSITIVE VERSUS PSEUDOMOANUS
NEGATIVE PATIENTS.
THE OVERALL STUDY DESIGN WAS TO
ENROLL 288 PERSONS WITH CF FROM
4 CLINICAL SITES THAT ARE
PARTNERING WITH US AND WITH HALF
OF THOSE PEOPLE ENROLLED BEING
PSEUDOMOANUS POSITIVE IS THE
GOAL, I WANT TO UNDERSCORE THAT
OUR DIAGNOSTIC CRITERIA IS THE
LEAD CHRONIC PROTECTION,
PSEUDOMOANUS NEGATIVE IS THE
UNINFECTED OR INFECTED COHORT,
SO INTERMITTENTLY INFECTED
INDIVIDUALS ARE EXCLUDED FROM
THIS STUDY.
NEXT SLIDE.
SO IN PRELIMINARY FINDINGS OF
THIS STUDY, AT THIS POINT WHERE
WE HAVE A HUNDRED 56 PERSONs
ENROLLED WE HAVE LOOKED AT THE
DATA FROM 80 SUBJECTS WE THEN
TOOK THOSE BIOMARKERS AND
APPLIED THEM TO DATA FROM AN
INDEPENDENT DATA SET FROM 76
SUBJECTS WHERE THE DATA WERE
ANALYZED OUT OF BRITISH COLUMBIA
AND WE FIND THAT THE ABOUT I O
MARKERS IDENTIFIED AT ASU WERE
GIVING ABOUT 90% SENSITIVITY AND
SPECIFICITY FOR DIAGNOSING
PSEUDOMOAN ISOTOPE IN THE
SUBJECTS WE ANALYZED AT ASU AND
WHEN WE APPLIED THAT BIOMARKERS
WE WERE SEEING SIMILAR RESULTS.
WE HAVE A FOLLOW UP STUDY
PLANNED FOR THE EARLY DEFEKS
THEN USING BIOMARKERS SO LOOKING
AT THOSE INTERMITTENTLY AFFECTED
SUBJECTS AND ALSO SEEING IF
THESE BIOMARKERS ARE USEFUL FOR
MONITORING ANTIBIOTIC TREATMENT.
NEXT SLIDE.
>> ANALYZING BREATH CAN BE
USEFUL FOR MONITORING
CO-MORBIDITIES AND THERAPIES FOR
CF, THIS WAS A STUDY WHERE THEY
LOOKED AT PATIENTS WHO WERE
RECEIVING LUM ACAFTOR/IVACAFTOR
TREATMENT OVER 12 MONTHS.
IN THESE TIME POINTS WHICH
YOU'RE GOING TO SEE BOTH THE
LEFT AND THE RIGHT IS THAT
MEASUREMENT 1 IS BEFORE THE
THERAPY WAS INITIATED,
MEASUREMENTS 2-5 WERE COLLECTED
QUARTERLY AFTER THE START OF
THERAPY.
WHAT THEY OBSERVED IS THAT THEY
SAW SUSTAINED CHANGE IN BREATH
OF EOCs EVEN THOUGH THERE WAS
A TEMPORARY CHANGE IN THE MIKE
ROY BIOME, SO ON THE RIGHT WE'RE
LOOKING AT THE PSEUDOMOAN
ISOTOPE DETERMINED FROM
METAGENOMICS ANALYSIS AND YOU
CAN SEE THERE'S A DECLINE UP TO
ABOUT 6 MONTHS AFTER THE START
OF THERAPY IN GENERAL OVER THE
POPULATION AND THAT LOW
REBOUNDS, BUT ON THE LEFT, WE'RE
LOOKING AT THE PATTERN OF BREATH
VOCs AND YOU CAN SEE THAT ONCE
THEY INITTIAITED THERAPY, THEIR
VOCs HAD A SUSTAINED CHANGE,
EVEN THOUGH THE MICROBIOME WAS
SORT OF REBOUNDING TO PRETHERAPY
LEVELS, AND AN ANALYSIS OF THE
VOCs THAT WERE DETECTED
SUGGESTED THESE ARE ACTUALLY
VOCs RELATED TO HOST
INFLAMMATION ANDOXIDATIVE STRESS
PATHWAYS, THEREFORE NOT DIRECTLY
RELATED TO THE LUNG INFECTIONS.
SO BREATH, MIGHT ALSO BE USEFUL
TO MONITOR THE PHYSIOLOGICAL
RESPONSE TO MODULATOR THERAPY.
NEXT SLIDE.
AND THEN THIS IS A STUDY OUT OF
THE EMORY GROUP TO LOOK AT
METABOLITE BIOMARKERS OF
PULMONARY EXACERBATION, IN THIS
STUDY, THEY HAD COHORTS OF
EXACERBATED PATIENTS, PATIENTS
WHO HAVE STABLE LUNG DISEASE,
AND ALSO PATIENTS WHO ARE IN A
PREEXACERBATION STATE.
ON THE LEFT WE SEE THEIR CROSS
VALIDATED CLASSIFICATION MODEL
PREDICTION OF ACUTE DISEASE AND
THE SENSITIVITY AND SPECIFICITY
FOR THE PEDIATRIC AND ADULT
COHORTS ON THE BOTTOM LEFT.
INTERESTINGLY THEY COULD ALSO
SEE A SIGNATURE FOR
PREEXACERBATION DISEASE WHICH
YOU WILL SEE ON THE RIGHT AGAIN
WAS GOOD WITH SENSITIVITY AND
SPECIFICITY.
SO THIS IS SHOWING SOME PROMISE
AGAIN FOR IDENTIFYING PATIENTS
WHO ARE AT RISK OF ENTERING INTO
EXACERBATION STATE.
AND IN THIS STUDY THIS IS AN
EXAMPLE OF USING BREATH ANALYSIS
IN THIS STUDY THEY WERE LOOKING
AT IEWGING THE ABSORPTION OF
MIXED TRIGLYCERIDES THAT WERE
STABLY ISOTOPICALLY LABELED WITH
CARBON 13 AND WHAT THEY'RE
MEASURING FOR IS THE ABILITY OF
THE PATIENT TO ABSORB THOSE
TRIGLYCERIDES AND TO METABOLIZE
THEM AND MEASURING THE
ABSORPTION OF MONITORING THE
EXHALATION OF THE BREATH TEST TO
THE GOLD STABBED ARD OF CO
EFFICIENT OF FAT ABSORPTION AND
THEY ALSO DID THE SAME THING
WITH THE FECAL ELAST ACE IN
THESE SAME SUBJECTS.
AND THEY SAW THE EQUIVALENT
AREAS UNDER THE RECEIVER
OPERATOR CURVE FOR THE FECAL
ELASTASE, AND SHOWING THAT THE
BREATH TEST WOULD HAVE THE SAME
DIAGNOSTIC SENSITIVITY OR
EFCASEY IN THE CLINIC.
NEXT SLIDE.
THANK YOU.
SO BREATH HAS AMAZING BREADTH,
IT CAN BE APPLIED TO MANY
CONDITIONS, CERTAINLY PULMONARY
CONDITIONS, THAT HAVE BEEN WELL
DEMONSTRATED, FOR MONITORING
INFECTIONS, BUT ALSO MONITORING
TREATMENT AND THERE'S REALLY
BEAUTIFUL PILOT DATA ON
MONITORING EABT BI ATTIC THERAPY
AND LUNG INFECTIONS.
BREATH IS ALSO USEFUL FOR
MONITORING EXTRA MULL MONITORARY
DISEASEs IN HEALTH AND IF
THERE'S A CONDITION THAT YOU
THINK MIGHT BENEFIT FROM BREATH
ANALYSIS AND NOT NECESSARILY IN
CF, BUT POTENTIALLY IN OTHER
SIMILAR SORTS OF DISEASES THAT
WOULD SHOW IT'S POTENTIAL OF
CLINICAL FEASIBILITY.
NEXT SLIDE.
AND I JUST WANT TO HIGHLIGHT
THAT BREATH ANALYSIS IS MOVING
CLOSER TOWARDS APPLICATION IN
THE CLINIC IN APRIL, THE FDA
ISSUED AN EMERGENCY USE
AUTHORIZATION FOR THE FIRST
COVID-19 DIAGNOSTIC BREATH TEST
AND THESE WERE VOC BREATH TESTS
AND YOU SEE THIS SUBJECT HERE
BREATHING INTO A MINIATURIZED
GC, AND THIS INSPECT IR COVID-19
BREATHAALIZER HAD A 91
SENSITIVITY AND 99% SPECIFICITY
FOR COVID-19.
NEXT SLIDE.
LASTLY I WANT TO HIGHLIGHT THAT
HOME COLLECTION FOR THE FUTURE,
THERE'S BEEN NICE PILOT STUDIES
GOING ON FOR THE EXHALE BREATH
CONDENSATE, THIS IS THE SAMPLE,
COLLECTING AND THEN RETURNED TO
THE LAB FOR ANALYSIS BUT DIRECT
HOME TESTING WHERE YOU BREATHE
INTO SOMETHING HOOKED UP TO A
COMPUTER OR A PHONE AT HOME,
THAT'S A LITTLE FARTHER OUT BUT
HOME COLLECTION IS DEFINITELY
FEASIBLE THE NEAR FUTURE.
NEXT SLIDE.
AND THIS IS MY LAST SLIDE, I
WANT TO EYE LIGHT GAPS AND
OPPORTUNITIES IN IN FIELD.
SO, WE'VE SEEN FROM COVID-19
THAT DIRECT DETECTION OF
MICROBIAL DNA AND RNA FROM EBC
HAS BEEN DEMONSTRATED AND I
THINK THE NEXT STEPS WILL BE
WHAT CLEANLY-MEANINGFUL
THRESHOLDS WILL BE ESTABLISHED
FOR CF LUNG DISEASE.
IDENTIFICATION AND VALIDATION OF
INFECTION BIOMARKERS IS RELIANT
UPON ACCESS TO SPUTUM OR LAVAGE.
WE NEED TO BENCHMARK BIOMARKERS
AGAINST CURRENTLY ACCEPTED GOLD
STANDARDS AND WE KNOW WE ARE
LOSING ACCESS TO THESE
SPECIMENS, SO LEVERAGING
EXISTING CF CLINICAL STUDIES
WOULD BE IDEAL, BREATH SAMPLING
IS NONINVASIVE AND THEREFORE
IT'S GENERALLY PRETTY EASY TO
ADD IT TO AN IRB AND THERE'S
NOT--THERE'S A LOW BARRIER OR A
LOW BURDEN FOR PATIENTS TO GIVE
THAT ADDITIONAL SAMPLE.
AND WE COULD ALSO CERTAINLY
STUDY OTHER PATIENTS AND LUNG
DISEASES SUCH AS PERSONS WITH
NONCF BRONCH YECTA SIS, THERE'S
ALSO INTEREST IN NG O AND
BREATH, BUT CURRENTLY
GOVERNMENTALLY THE EFFORTS THAT
ARE FRAGMENTED AND SILOED SO
INTERAGENCY GOVERNMENTAL
COLLABORATION WOULD CERTAINLY
SPEED PROGRESS IN THAT AREA.
AND THAT'S IT FOR ME.
I WANT TO NOW TEE UP A
PRESENTATION FROM DR. NATALIE
ELLIOTT WEST WHO IS AN ASSISTANT
PROFESSOR OF MEDICINE AT JOHNS
HOPKINS UNIVERSITY IS AND SHE'S
GOING TO BE TELLING US ABOUT
PULMONARY EXACERBATIONS IN THE
AREA OF HEMT.
>> GOOD AFTERNOON MY NAME IS
NATALIE WEST AND I WILL DISCUSS
PULMONARY EXACERBATIONS IN THE
HEMT ERA, I WOULD LIKE TO THANK
THE NIH FOR RECORDING THIS
PRESENTATION IN ADVANCE AS I
WILL BE AWAY AT A FAMILY FUNERAL
DURING THIS TALK.
I CURRENTLY HAVE SEVERAL GRANTS
AREYALATED TO RESEARCH AND
PULMONARY EXACERBATIONS THROUGH
THE CYSTIC FIBROSIS FOUNDATION,
WE WILL DISCIPLINARY CUSS WHAT
WE KNOW ABOUT HIGHLY EFFECTIVE
MODULATOR THERAPY, AFFECTS OF
PULMONARY EXACERBATIONS, GAPS
AND KNOWLEDGE, OPPORTUNITIES TO
LEARN MORE AND 2 CLINICAL TRIALS
THAT ARE ONGOING TO HELP US
ANSWER SOME OF THESE QUESTIONS.
SO WHAT DO WE KNOW ABOUT
EXACERBATION.
WE'VE KNOWN FOR A LONG TIME THEY
HAVE OCCURRED FREQUENTLY IN THE
LIVES OF PEOPLE WITH CF.
THEY'RE ASSOCIATE WIDE WORSE
OUTCOMES, LOSS OF LUNG FUNCTION,
INCREASE IN RESPIRATORY
SYMPTOMS, WORSE QUALITY OF LIFE
AND EVEN SHORTENED LIFE
SURVILAL.
THERE'S CURRENTLY NOT A WIDELY
ACCEPTED DEFINITION OF
EXACERBATION BUT GENERALLY WE
THINK OF THEM IN PARTICULAR
SEVERE EXACERBATION AS INCREASED
SYMPTOMS AND/OR DECREASE LUNG
FUNCTIONS COUPLED WITH THE
DECISION TO TREAT WITH THE
ANTIBODY.
SO WE DO HAVE GUIDELINES FOR
TREATMENT OF EXACERBATIONS WHICH
WERE ESTABLISHED IN 2009BIAN
EXPERT PANEL.
AND WHAT THE EXPERTS REALLY HAD
GENERAL AGREEMENT ON IS THAT
DURING EXACERBATION WE SHOULD BE
CONTINUING CHRONIC MEDICATIONS
AND AIR WAY CLEARANCE.
HOWEVER, AT THE TIME THERE WAS
NOT A LET OF THE EVIDENCE TO
GUIDE US ON DURATION OF IV
ANTIBIOTICS, TREATMENT WHETHER
AT HOME OR IN THE HOSPITAL, THE
ROLE OF INHALED ANTIBIOTICS, THE
NUMBER OF ANTIBIOTICS WE SHOULD
USE AND THE DOSING OF EACH OF
THOSE EABT BIOTICS AND HOW
COTTERY CO STEROIDS EXACERBATES
AND GENERALLY FOR MILD
EXACERBATION WE USE MILD
ANTIBIOTICS AND/OR SEVERE, THAT
MAY REQUIRE HOSPITALIZATION.
SO'RESHORTLY AFTER THESE
GUIDELINES WERE PUBLISHED THE CF
FOUNDATION SUNNEDDED AND
SUPPORTED A STOP PROGRAM,
STANDARDIZE TREATMENT OF
PULMONARY EXACERBATION WHICH I'M
A PART OF AND WE ARE TASKED TO
DESIGN AND CONDUCT CLINICAL
TRIALS, TO PROVIDE ECHEDZ TO
START ANSWERING SOME OF THESE
QUESTIONS WE JUST DISCUSSED.
SO THE FIRST THING WE DID WAS
STOP AND THAT WAS ABOUT 220
PATIENTS WHO HAD BEEN ADMITTED
TO THE HOSPITAL NEEDING IV
ANTIBIOTIC THERAPY FOR THEIR
EXACERBATION, AND WE COLLECTED A
LOT OF DAT AND WE USE THAD DATA
TO DESIGN THE FIRST RANDOMIZED
CONTROL TRIAL WHICH WE CALL STOP
2 AND WE EVALUATED THE EFFICACY
AND SAFETY OF DIFFERENT
DURATIONS OF IV ANTIBIOTIC
THERAPY FOR EXACERBATIONS IN
ADULTS WITH CF, IT WAS
RANDOMIZED AND CONTROL AND IT
WAS OPEN LABELED.
AND I WILL WALK YOU THROUGH OUR
PROTOCOL HERE AND SO, ON THE LOW
OF THE SCREEN, YOU WILL SEE THE
DAYS LISTED, SO ON DAYS 0, A TON
OF EXACERBATION OUR PARTICIPANTS
WERE ENROLLED AND AT THAT POINT
WE MEASURED LUNG FUNCTION FEV1
AND WE MEASURED A SYMPTOM SCORE
CALLED THE CRISSAND WE REPEATED
THESE BETWEEN DAY 7-10.
AND IF PARTICIPANTS HAD AN
IMPROVEMENT IN 8%, AND
IMPROVEMENT IN THE CRISSOR
SYMPTOM SCORE BY 11-POINTS SO
THEY WERE FEELING BETTER, THEN
WE DEEMED THEM EARLY ROBUST
RESPONDER.
E. R. R.
AND THAT POINT ANYWHERE BETWEEN
DAY 7 AND 10 THEY RANDOMIZED 10
VERSUS 14 DAYS.
AND OUR HYPOTHESIS FOR THIS ARM
WAS THAT 10 DAYS WAS NOT
INFERIOR TO 14 DAYS.
IF PARTICIPANTS DID NOT MEET
BOTH OF THOSE CRITERIA, THEY
WERE DEEMED A NONEARLY ROBUST
RESPONDER AND NERR, AT THAT
POINT DAY 7-10 RANDOMIZE TO
EITHER 14 VERSUS 21 DAYS.
AND OUR HYPOTHESIS HERE WAS THAT
21 DAYS IS SUPERIOR TO 14 DAYS.
AND THEN VISIT 3 OCCURRED 14
DAYS AFTER ANTIBIOTIC THERAPY.
AND SO HERE'S OUR TOP LINE
RESULTS ON THE X-AXIS YOU SEE AS
FROM THE IV ANTIBIOTIC START AND
ON THE Y-AXIS YOU SEE THE
PERCENT PREDICTED AND YOU CAN
SEE STARTING ON DAY 0 EXPW LET'S
LOOK AT THE E. R. R.OT FIRST.
THERE WAS AN IMPROVEMENT THAT AT
LEAST WITH 8% BY CRITERIA IN
ORDER TO BE IN THE E. R. R. PLUS
THE PROVEN SYMPTOMS AND THEN YOU
SEE THERE'S REALLY NO DIFFERENCE
BETWEEN THE 10 DAY ARM, WHICH IS
HERE IN GRAY, AND THE BLACK 14
DAY ARM AND INDEED THERE WAS NO
STATISTICAL SIGNIFICANT
DIFFERENCE SO WE CONCLUDED THAT
10 DAYS WAS NOT NEAR 14 AND DOWN
BELOW IS THE NONEARLY ROBUST
RESPONDER ARM AND YOU CAN SEE
THEY'RE ALMOST IDENTICAL AND
HERE WE CONCLUDED 21 DAYS WAS
NOT SUPERIOR TO 14.
AND SO HERE WHAT WE INCLUDED
FROM RESEARCH PURPOSES IS THAT
WE CAN USE A 14 DAY STANDARDIZED
DURATION IN ORDER TO START
ANSWERING ADDITIONAL QUESTIONS
IN PULL MANORY EXACERBATION.
SO WHAT DO WE KNOW ABOUT HIGHLY
EFFECTIVE MODULATOR THERAPY AND
INVESTOR RELATION?
SO THIS WAS GREAT, THIS WAS A
PICTURE FROM BACK IN 2018 WHEN
FDA APPROVED THE NEW BREAK
THROUGH THERAPY PARTICULARLY
TRIFACTA, AND IVACAFTA, APPROVED
FOR 90% OF OUR PATIENTS WITH CF,
SO LET'S REWIND A BIT AND GO
BACK TO THE CLINICAL TRIAL FIRST
OF IVACAFTOR, AND THAT'S ALSOA
HIGHLY EFFECTIVE MODULATOR
THERAPY AND THIS DESCRIBED FROM
THE CLIENICAL TRIAL AND
LOOKINGAL DECREASE IN RATE OF
EXACERBATION OVER THE 6 MONTH
TIME TOWARD AND SO ON THE Y-AXIS
YOU SEE THE PROPORTION OF EVENTS
SO THOSE THAT DID NOT HAVE AN
EXACERBATION AND YOU CAN SEE
THIS CLEAR STATISTICAL
DIFFERENCE.
IT WAS ALMOST A 50/60% DROP IN
EXACERBATION, AND SHOWN
DIFFERENTLY IN THE CAFTOR
TRIALS, BUT LOOKING HERE WE SEE
THE REDUCTION OF ALL
EXACERBATION WAS 63% AND THEN
VERY DRAMATIC REDUCTIONS IN
THOSE EXACERBATIONS THAT LED TO
HOSPITALIZATIONS OR THOSE
NEEDING TO BE TREATING WITH IV
ANTIBIOTICS.
AND HERE WE REALLY SEE, THIS IS
GOING TO BE KIND OF IMPORTANT TO
THE GAPS WE HAVE IN OUR
QUESTIONS IS IN 202,020, THE
DRAMATIC INCREASE THAT WERE
ELIGIBLE FOR MODULATORS THAT
WERE ON THEM SO ABOUT 86% OF
2020 WERE ON MODULATORS THAT
WERE ELIGIBLE.
SO WHAT ARE THE GAPS IN
KNOWLEDGE?
SO WHAT IS THE TRUE PULMONARY
EXACERBATION RATE IN PEOPLE WITH
CF ON HEMT?
I JUST SHOWED YOU IN A CLINICAL
TRIAL BUT NOW IN A MUCH BROADER
GENERAL POPULATION, WHAT IS THE
TRUE EXACERBATION RATE?
AND THEN WE'RE USED TO SEEING
BIG LUNG FUNCTION DROP DURING
EXACERBATION IN THE PREHEMT ERA,
IT'S NOW THAT EVERYONE'S ON,
MOST PEOPLE ARE ON HIGHLY
EFFECTIVE MODULATOR THERAPY IS
THAT LUNG FUNCTION THE SAME WHEN
WE'RE DIAGNOSING EXACERBATIONS
OR ARE THEY DIFFERENT?
AND THEN HOW ARE OUR PATIENTS
PRESENTING?
HAS THE CLINICAL PRESENTATION
CHANGED?
WE'RE USED TO SEE SPUTUM
PRACTICES DUKS, COUGH, WEIGHT
LOSS, HAS THAT CHANGED OR THE
PRESENTATION DIFFERENT?
AND WHAT DOES LUNG FUNCTION
RECOVERY LOOK LIKE, WE KNOW THAT
EXACERBATIONS LEAD TO PERMANENT
LUNG FUNCTION LOSS BEFORE MOST
OUR PATIENTS WERE ON HIGHLY
EFFECTIVE MODULATOR THERAPY.
HAS THAT CHANGED?
AND HOW SHOULD WE BE TREATING
EXACERBATIONS AND PEOPLE ON CF
WHO ARE ON HIGHLY EFFECTIVE
MODULATOR THERAPY SHOULD WE
REALLY BE TREATING AS
AGGRESSIVELY WITH IV ANTIBIOTIC
THERAPY, OR ORAL ANTIBIOTICS BE
SUFFICIENT?
SO HERE'S THE GAPS WE DON'T KNOW
THE ANSWERS TO.
BUT WE DO HAVE SOME HINTS TO THE
ANSWERS.
SO THIS IS FROM THE CF
FOUNDATION PATIENT REGISTRY,
PUBLISH INDEED 2021, BUT ONLY
THAT INCLUDES DAILY BASIS THEA
UP TO 2020.
AND THIS IS LOOKING ON THE
X-AXIS FROM THIS YEAR FROM
2006-2020 AND THE PERCENT OF
INDIVIDUALS WHO WERE TREATED
WITH IV ANTIBIOTICS FOR
PULMONARY EXACERBATION, AND THEN
IN ORANGE IS OUR CHILDREN AND
GREEN IS ADLEASENTS AND BLUES
ARE ADULTS, CAN YOU SEE THERE
WAS DRAMATIC DROP AT THE END OF
2019 AND 2020 AND THAT CO
INSIDES WHEN OUR PATIENTS GOT ON
HIGHEE EFFECTIVE MODULATOR
THERAPY.
ANDEE WE LOOKED AT STOP 2, SO
STOP 2 WAS ALMOST A THOUSAND
PATIENT WHO IS HAD AN
EXACERBATION SO LARGE CLINICAL
TRIAL FOR OUR CF COMMUNITY, AND
WE LOOKED AT WHAT LUNG FUNCTION
WAS DOING IN THOSE THAT WERE ON
MODULATORS AND THOSE THAT WERE
NOT.
I WANT TO CLARIFY THOUGH, STOP
2, THE CLINICAL TRIAL ENDED IN
EARLY 2019 SO THIS WAS BEFORE
THE CAFTOR THERAPIES WERE
APPROVED.
SO WE LOOKING AT THE 6 MONTH
AVERAGE BEFORE THE EXACERBATION
COMPARED TO WHAT THE FEV1 WAS AT
THE TIME OF THE EXACERBATION AND
WE COMPARED THE GROUPS, THOSE
THAT WERE MODULATORS AND THOSE
THAT WERE NOT.
THERE WAS NO STATISTICAL
DIFFERENCE BETWEEN THE 2.
IN FACT IT WAS 8.1% PREDICTED
DIFFERENCE.
HOWEVER WE DID SEE A DIFFERENCE
IN HOW PATIENTS FELT.
SO IN THE CRISS SCORE, THE SIGNS
AND SIVENL TOMS AT PRESENTATION,
SO LOOKINGA THE CRISS SCORE
THERE WAS A DIFFERENCE THAT WAS
STATISTICALLY SIGNIFICANT AND
THOSE NOT ON MODULATORS ACTUALLY
FELT WORSE AT THE BEGINNING OF
THE EXACERBATION COMPARED TO
THOSE THAT WERE ON MODULATORS.
AND THEN LOOKING AT LUNG
FUNCTION RECOVERY, SO THIS
GROUP, ANALYZED THE IVACAFTOR
TRIALS IN THOSE PATIENTS IN G551
D SO THIS WAS 1 ABOUT 160
PATIENTS OR SO AND LOOKEDDA THE
THOSE THAT HAD EXACERBATION SO
WHILE WE KNOW THAT THE IVACAFTOR
TREATMENT GREATLY REDUCED
EXACERBATION, THEY LOOKEDDA THE
LONG-TERM RECOVERY WHICH WAS
DEFINED AS WHAT THE LUNG
FUNCTION WAS LOOKING AT THE END
OF THE 6 MONTH CLINICAL TRIAL
AND LOOKING AT SHORT-TERM
RECOVERY SOPHISTICATEDY ANYWHERE
BETWEEN 2 AND 8 WEEKS FOR
TREATMENT DURING EXACERBATION
AND THERE WAS NO DIFFERENT IN
LUNG FUNCTION RECOVER EXPE FROM
THOSE EXACERBATION, WHEN WE
LOOKED AT STOP 2 IT SHOWED MORE
RESULTS.
SO WHAT ARE OUR OPPORTUNITIES?
SO OUR EXACERBATION IN PEOPLE
WITH CF WHO ARE ON HIGHLY
EFFECTIVE MODULATOR THERAPY ARE
THEY MORE SIMILAR TO THOSE WITH
NONCF BRONCH ECTOMYOSIN SIS AND
I THINK THERE'S AN OPPORTUNITY
ACROSS THESE 2 DISEASE STATES IN
ORDER TO BOOST NUMBERS AND TRY
TO COME UP WITH AN ANSWER TO
THAT.
THERE'S ALSO AN OPPORTUNITY TO
NOW DEFINE THE COMMON SYMPTOMS
AND LUNG FUNCTION DECLINE THAT
PEOPLE WITH CF PRESENT WITH AT
THE TIME OF THE EXACERBATION AS
WELL AS EVALUATING FOR THE
EXACERBATION AND THERE'S 2
CURRENT CLINICAL TRIALS THAT I
THINK COULD HELP US WITH SOME OF
THESE QUESTIONS.
SO OUR STOP PROGRAM WE HAVE NOW
DEVELOPED A PLATFORM OF PROTOCOL
THAT CAN BE USED TO CONDUCT
MULTIPLE CLINICAL TRIALS IN
EXACERBATION, WE CALL THIS STOP
360 IN THE FIRST 1 WE WILL BE
RUNNING THAT SHOULD BE UPAND
RUNNING BY THE END OF 2022 IS
WHAT WE'RE CALLING THE AG STUDY
OR AMINO GLYCOICIDE, AND WE'RE
COMPARING TREATMENT OF AN IV
BETA LACTAM, AND HERO 2 WILL OB
STUDY IS A 1 YEAR OBSERVATIONAL
STUDY SYMPTOMS ON THOSE FOR
THE--CAFTORs.
AND BOTH OF THESE CAN BE USED TO
TRACK EXACERBATIONS AND GATHER A
LOT OF THE DATA WE'VE JUST BEEN
DISCUSSING.
I WOULD LIKE TO JUST GIVE CREDIT
TO MY STOP STUDY CO
INVESTIGATORS WHO HELPED RUN THE
STOP 360 PLATFORM TRIALS.
>> THANK YOU VERY MUCH.
VERY SORRY TO MISS YOU ALL LIVE,
I WOULD LIKE TO THANK CHRIS
GOSES WHO WAS OFFERED TO STEP IN
FOR MY BEHALF FOR THE IMRKS & A
SESSION.
THANK YOU.
DID EMPLOY.
>> THANK YOU DR. WEST AND I
WOULD LIKE TO INTRODUCE
DR. MARRING WET ROSEN FELD FROM
THE UNIVERSITY OF WASHINGTON TO
TALK TO US ABOUT REMOTE
MONITORING TOOLS.
>> GREAT, WELL I WOULD LIKE TO
BEGIN BY THANKING THE ORGANIZERS
FOR INVITING ME TO SPEAK WITH
YOU TODAY.
I'M SO RETURN OF RESULTSRY
NATALIE WASN'T ABLE TO JOIN US
TODAY.
NEXT SLIDE.
HERE ARE MY DISCLOSURES.
NEXT SLIDE, SO I WILL BEGIN BY
DISCUSSING OPPORTUNITIES AND
CHALLENGES RELATE TOAD REMOTE
END POINTS.
I AM FOCUSING MOSTLY ON CLINICAL
TRIALS TODAY BUT THERE IS
OBVIOUSLY GREAT APPLICABILITY TO
CLINICAL CARE AS WELL.
SO I THINK WE'RE ALL LEARNING,
THANKS TO COVID ABOUT THE UNIQUE
OPPORTUNITIES AND CHALLENGES OF
ASCERTAINING WHAT USED TO BE
IN-PERSON END POINTSA THE HOME.
FIRST OF ALL THIS DECREASES
BARRIERS TO CLINICAL TRIAL
ENROLLMENT AND CAN PROMOTE
ACCESS TO CLINICAL TRIALS FOR
THOSE HERETOFORE HAD 2 HIGH
BARRIERS TO PARTICIPATE, AND
ETHNIC RACIAL, GEOGRAPHIC, AGE,
ET CETERA.
IN ADDITION, REMOTE END POINTS
FOR NO TOUCH CLINICAL TRIALS,
GREAT WORK IN CONCERT WITH
INCIDENCE HAVING MORE REMOTE
ACCESS, THE IDEA BEHIND THIS IS
TO BRING THE TRIAL DOWN TO THE
PATIENT AND DECREASE
PARTICIPATION, BUT IN ADDITION
IT HAS SOME REALLY IMPORTANT
CONSEQUENCES IN TERMS OF THE
DATA COLLECTED AS WELL BECAUSE
THE MORE FREQUENT GRANULAR DATA
COLLECTION ENABLED BY HOME
COLLECTION FIRST OF ALL ALLOWS
THE DATA TO BE ASCERTAIN INDEED
A REAL WORLD SETTING, ALSO COULD
POTENTIALLY DETECT CHANGES SUCH
AS EXACERBATIONS EARLIER, AND
WE'VE SEEN PLENTY OF EVIDENCE
ABOUT THAL AFTERNOON, AND
POTENTIALLY, MORE INFORMATION
COULD MITIGATE VARIABILITY
THAT'S ASSOCIATE WIDE HOME
COLLECTION AND POTENTIALLY,
POTENTIALLY, I'M NOT A BETTING
PERSON, REDUCE SAMPLE SIZES ARE
CLINICAL TRIALS.
NEXT SLIDE.
HOWEVER, WE HAVE TO BE REALLY
CLEAR ABOUT THE CHALLENGEs AS
WELL AND MAKE SURE WE'RE
DEVELOPING THE REMOTE END POINT
COLLECTION PROCEDURES IN A WAY
THAT IS MEETING THE NEEDS OF OUR
PARTICIPANTS AND OF OUR RESEARCH
COORDINATORS, ABSOLUTELY
CRITICAL SO OF COURSE THERE ARE
ACCESS ISSUES THAT HAVE HUGE
EQUITY AND DIVERSITY
IMPLICATIONS AROUND ACCESS TO
RELIABLE BROAD BAND.
PEOPLE SHOULDN'T BE DRIVING TO
THE NEAREST WAL-MART TO GET
WIMBERLYIFY TO DO ROUGH ATOM
MOTE PROCEED IRBS AND ISSUES
AROUND DIGITAL LITERACY.
ALSO THOUGH, I TALKED ABOUT THE
OPPORTUNITY TO DECREASE
PARTICIPANT BURDEN IRONICALLY IF
WE'RE NOT CAREFUL WE CAN
INCREASE PARTICIPANT BURDEN AS
WELL AS BURDEN ON RESEARCH STAFF
BECAUSE OF HAVING PROCEDURES
THAT ARE DONE PREQUENTLY AND OF
RESEARCH STAFF NEEDING TO TRAIN
PARTICIPANTS IN HOW TO DO THESE
PROCEDURES AND THEN MONITOR
ADHERENCE.
DATA QUALITY IS A HUGE ISSUE.
WE NEED TO BE DOING REMOTE END
POINT COLLECTION AROUND END
POINTS THAT WE ACTUALLY TRUST,
ARE THEY ACCURATE, RELIABLE?
WHAT'S THE VARIABILITY COMPARED
TO IN-PERSON COLLECTION?
ADHERENCE IS A HUGE ISSUE, TOO,
PARTICIPANTS IN CF CLINICAL
TRIALS HAVE BUSY LIVES AND MAY
NOT FEEL THAT IT'S GOING
BENEFITING TO DO BURDENSOME
PROCEDURES TO TOO FREQUENTLY.
ACTIVE VERSUS PASSIVE DATA
COLLECTION, BUT FOR THE ACTIVE
DATA COLLECTION, PEOPLE NEED TO
BE TRAIN INDEED HOW TO DO THE
PROCEDURES APPROPRIATELY AT HOME
AND THEN, WE'RE ALL FEELING THAT
THIS IS SUCH A RAPIDLY EVOLVING
FIELD WITH NEW TECHNOLOGIES
CONDITIONALLING OUT ALL THE
TIME, HOW DO WE VALIDATE THEM,
WHEN WE GET DONE VALIDATING THEM
ARE THEY OUT OF DATE?
AND THE WHOLE ISSUE WHICH I WILL
NOT ADDRESS TODAY BUT COULD BE
ADDRESSED IN THE Q&A OR IN THE
BREAK OUT AROUND FDA CLEARANCE
OF REMOTE CLINICAL TRIALS.
NEXT SLIDE, PLEASE?
SO WE HAVE BEEN FOCUSING SO MUCH
ON THE MULTIORGAN VIEW OF CF AND
I WILL BE AS A PULL
MONITORROLOGYIST FOCUSING ON THE
MULL MONITORARY END POINTS BUT
THEREYA A POSSIBILITY OF REMOTE
SWEAT COLLECTION, OF GI SAMPLES,
AND OF INFECTION PARTICULARLY
RELEVANT TO OUR TO PEOPLE.
SO AS I MENTIONED I WILL FOCUS
ON HOME SPIROMETRY, BUT PATIENT
REPORTED OUTCOMES IN THE CRISSOR
THE DOMAIN FOR EXACERBATION
SYMPTOMS ARE REALLY IMPORTANT
BUT OTHER THINGS CAN BE
EVALUATED ELECTRONICALLY AT HOME
PARTICULARLY RELATED TO MORE
GENERAL QUALITY OF LIFE.
OXYGEN SATURATION COULD BE
HELPFUL.
SAMPLE COLLECTION EITHER VIA
SPUTUM OR EXHALED BREATH, THAT
PART SOUNDS VERY EXCITING, I
LOOK FORWARD TO
FUTURE--POTENTIAL IRB
DEVELOPMENTS THERE AND THEN
THERE ARE MANY OPPORTUNITIES FOR
PASSIVE PULMONARY END POINT
COLLECTION AS WELL.
A DIGITAL COUGH MONITOR EITHER
PLACED BY THE BEDSIDE OR
POTENTIALLY IN AN AMBULATORY
SETTING AND THAT'S A BIT MORE
CHALLENGING BECAUSE OF PRIVACY
ISSUES, ACTIGRAPHY, HEART RATE,
SLEEP SO THESE WILL BE VERY,
VERY RAPIDLY DEVELOPING FIELDS.
NEXT SLIDE.
SO I JUST WANT TO REVIEW A FEW
OF THE STUDIES THAT ARE ONGOING
PARTICULARLY IN A COUPLE
COUNTRIES IN EUROPE.
LOOK FORWARD TO HEARING MORE
ABOUT THESE WHEN WE'RE GOING TO
THE EUROPEAN SOCIETY MEET
NEGLIGENCE A FEW DAYS.
THE FIRST IS DR. [INDISCERNIBLE]
AND COLLEAGUES OUT OF THE
NETHERLANDS ARE PERFORMING THIS
WONDERFUL DIGITAL BIOMARKER
STUDY WHICH IS A COHORT STUDY OF
60 DAYS WITH ASTHMA, 30 WITH CF
AND 128 WITH HEALTHY CONTROLS
AND THE OVERARCHING AIM IS TO
BEGIN CLINICAL VALIDATION OF THE
MARKERS I LISTED HERE.
NEXT SLIDE.
AND THIS IS JUST A--JUST A
TEASER OF SOME OF THEIR RESULTS,
OBVIOUSLY THEY WILL HAVE MORE
RESULTS COMING OUT, BUT HERE YOU
CAN SEE HOME SPIROMETRY ON THE
Z-AXIS AND RESPIRATORY SYMPTOM
SCORE IN PANEL A, AND DAYS OR
AFTER TREATMENT OF AN
EXACERBATION IN PANEL B AND YOU
CAN SEE THE EXPECTED ASSOCIATION
SO IT'S FEV AS RESPIRATORY
SYMPTOMS AS IT GETS WORSE, FEV
SCORE GETS LOWER AND SIMILARLY
FEV 1 SCORE DECLINES PRIOR TO AN
EXACERBATION AND IMPROVES AGAIN
WITH TREATMENT.
SO JUSTA A TEASER OF THE KINDS
OF THINGS WE'RE HOPING TO SEE AS
WE BEGIN TO QUOTE VALIDATE THESE
HOME COLLECTION END POINTS.
NEXT SLIDE.
>> I ALSO WANTED TO POINT OUT
THE CLIMB-CF STUDY AND THE
CONNECT CF STUDY, WE DON'T HAVE
RESULTS YET BUT BOTH WILL ARE
VIED VALUABLE DATA ABOUT HOME
COLLECTION OF VARIOUS DIFFERENT
END POINTS IN CHILDREN AND
ADULTS WITH CYSTIC FIBROSIS.
NEXT SLIDE.
I DID WANT TO CALL OUT THE
WONDERFUL WORK DONE BY ALEX
PAINTER AS WELL AS NICOLE HAMLET
AND OTHERS AT THE TDN, IT'S A
REANALYSIS OF OF THE EICE DATA,
YOU REMEMBER ABOUT A DECADE AGO,
THIS STUDY THAT WAS EVALUATING
HOME SPIROMETRY AND HOME SYMPTOM
COLLECTION AS A POTENTIAL WAY TO
DETECT EXACERBATIONS EARLIER IN
A RANDOMIZED CONTROL DESIGN, I
WON'T REVIEW THE STUDY ITSELF,
BUT THIS PARTICULAR REANALYSIS,
EVALUATED THE 12th MONTH
CHANGE IN FEV 1 AMONG
PARTICIPANTS IN THE TRIAL AND
COMPARING CLINIC SPIROMETRY,
CLINIC IN BLUE, HOME IN ORANGE
AND WHAT YOU CAN SEE IS THAT THE
POINT ESTIMATE FOR THE 12 MONTH
CHANGE WAS ALWAYS A BIT SMALLER
WITH THE HOME COMPARED TO THE
CLINICS BUT NOT ALL THAT
DIFFERENT.
CLOSER THAN WHAT WE HAD FEARED
AND THIS IS WITH OLD FASHIONED
SPIROMETRY, THE TECHNOLOGY HAS
IMPROVED MARKEDLY SINCE THEN BUT
THERE'S MORE VARIABILITY IN THAT
12 MONTH CHANGE WITH THE HOME
THAN THE OFFICE SPIRORDER OF
MICRONSETRY.
NEXT SLIDE, PLEASE.
ANOTHER BIG ISSUE IS WHETHER
HOME SPIROMETRY NEEDS TO BE
COACHED REMOTELY BY A RESEARCH
STAFF NUMBER OR UNCOACHED AND I
THINK WE NEED TO LEARN MORE IN
THIS AREA, BUT THIS IS
PRELIMINARY DATA FROM THE
PROMISE STUDY WHICH SHOWS THAT
BOTH OF THEM GAVE RESULTS THAT
WERE NOT THAT DIFFERENT FROM THE
OFFICE SPIROMETRY AND WITH MORE
VALID AND RELIABLE ABILITY HAS
BEEN SO MAC IT IS MEASUREMENTS
WE ARE COACHED AND OF COURSE AS
WELL.
NEXT SLIDE.
>> SO I WANT TO MOVE NOW TO AN
UPCOMING STUDY IN--THAT I'M
LEADING ALONG WITH OTHER
WONDERFUL COLLEAGUES, THIS IS
CFF SPONSORED STUDY CALLED
OUTREACH AND IT'S A MULTICENTER,
PROSPECTIVE STUDY OF HOME
SPIROMETRY, AS CLINICAL TRIAL
END POINT AND OVERARCHING
OBJECTIVE TO EVALUATE
FEASIBILITY OF REPLACING OR
AUGMENTS OFFICE SPIROMETRY, WITH
HOME AND COMPARING HOME TO
OFFICE, AND THIS STUDY IS SLATED
TO START IN THE FALL OF THIS
COMING YEAR SO STAY TUNED AND
THANKS TO ALL OF YOU WHO WILL BE
SITES IN THE STUDY.
NEXT SLIDE.
AS WE WENT THROUGH THE PLANNING
PROCESS, FOR THIS STUDY, AND AS
MORE AND MORE PUBLICATIONS ARE
COMING OUT ON A REMOTE END POINT
ASKER TAINMENT I WANTED TO SHIFT
TO TALKING ABOUT EMERGING SORT
OF OVERARCHING THEMES.
THE FIRST IS THE IMPORTANCE OF
UNDERSTANDING THE PARTICIPANT
AND RESEARCH STAFF EXPERIENCE.
THIS IS REALLY NEW TERRITORY
WHERE IN A WAY WE'RE ASKING
PARTICIPANTS AND RESEARCH STAFF
TO DO SOMETHING SO DIFFERENT
FROM WHAT WE'VE DONE FOR YEARS
AND WE NEED TO REALLY KEEP IN
MIND THAT WE NEED TO CO PRODUCE
THESE STUDIES AND UNDERSTAND
WHAT THE PARTICIPANT AND
RESEARCH STAFF EXPERIENCE IS,
ARE THESE MEASURES FEASIBLE,
ACCEPTABLE, AND THAT'S GOING TO
BE CRITICAL IN MAKING THESE
TRIALS A SUCCESS RATHER THAN A
FAILURE.
ALSO PARTICULARLY FOR HOME
SPIROMETRY, AND PUTTING TOGETHER
CLEAR APPROPRIATE TRAINING
MATERIALS AND TRAINING
PROCEDURES FOR OUR PARTICIPANTS
AND ALSO FOR THE RESEARCH STAFF.
WE HAD FOR HOME SPIROMETRY SUCH
DISSEMINATION NEXT TO THE
FOUNDATION OF HOME SPIROMETRY,
WE MAY HAVE TO HAVE PATIENTS
UNLEARN PRACTICES THAT DIFFER IN
A RESEARCH SETTING FROM THOSE IN
THE CLINICAL CARE.
>> 2-MINUTE WARNING.
>> AND I CAN'T EMPHASIZE O
IMPORTANT CO PRODUCTION IS,
WE'VE BEEN DOING THIS IN THE
OUTREACH STUDY AND I AM SO
HUMBLE THAT I'VE LEARNED SO MUCH
FROM THE PEOPLE WITH CF AND THE
RESEARCH COORDINATORS WHO VAIOF
THED IN THE OR REALLY LED THE CO
PRODUCTION.
AND FINALLY, I WANTED TO TOUCH
ON THE CHALLENGES PARTICULARLY
IN PEDIATRIC STUDIES.
NEXT SLIDE, SO AS A PEDIATRIC
PULL MONITOR OLOGIST, THERE WILL
BE DIFFERENT ABILITIES FOR THESE
KIDS IN THE AGE RANGES I'VE SEWN
HERE TO BE ABLE TO DO FOR
EXAMPLE, HOME SPIROMETRY OR
OTHER HOME PROCEDURES, SO THEN
THERE'S THE QUESTION OF HOW DO
PARENTS GET INVOLVED, WHOSE
SMART PHONE IS USED?
HOW DO THE PARENTS FACILITATE
THE PATIENT DOING THE PROCEDURE
WITHOUT ELIMINATING THEIR
AUTONOMY OR WITHOUT BEING OVER
BEARING, OR WITHOUT GIVING
RESULTS THAT AREN'T REFLECTIVE
OF WHAT THE KID IS DOING SO
THESE ARE ALL JUST RAPIDLY
EVOLVING AREAS THAT WE'RE STILL
TRYING TO UNDERSTAND.
AND YOU KNOW KIDS MAY DEVELOP IN
DIFFERENT WAYS, DIFFERENT AGES
IN DIFFERENT KIDS BUT WE STILL
HAVE TO PROCEED STANDARDIZED
GUIDANCE OR MAY HAVE TO STRATIFY
AGES SO IT'S COMPLEX BUT REALLY
IMPORTANT TO TACKLE.
NEXT SLIDE.
SO JUST, I'LL BRIEFLY FINISH
WITH A LITTLE BIT ABOUT OTHER
ORGANS, SORRY DON'T MEAN TO THEM
A SHORT EFTHIMIOS, THEY'RE
EQUALLY IMPORTANT, BUT THESE ARE
NOT MY AREA OF EXPERTISE.
>> SLIDE.
SO THERE ARE TANTALIZING NEW
WEARABLES, SWEAT CHLORIDE
DEVICES THAT AREN'T YET READY
FOR PRIME TIME BUT THEY'RE QUITE
EXCITING AND IT MAY BE IN THE
FUTURE WE CAN COLLECT AN AND
EVEN ANALYZE SWEAT CHLORIDE
CONCENTRATION REMOTELY.
SILL A LONG WAY TO GO BUT
SOMETHING TO KEEPOT RADAR FOR
THE FUTURE EMPLOY.
>> NEXT SLIDE.
>> THESE COULD BE USED TO LOOK
AT PHARMA CODYNAMMICS IF
INDIVIDUALS RESPONDING AND IN
TERMS OF CHLORIDE, COULD BE USED
FOR N-1 TRIALS AS WE TALKED
ABOUT EARLIER TODAY,
PARTICULARLY FOR DOSE ADJUSTMENT
AND IMPORTANTLY FOR NEW BORN
SCREENING, PARTICULARLY IN
STATES LIKE WASHINGTON WHERE
NEWBORNS CAN LIVE FAR AWAY FROM
A CFF ACCREDITED LAB, THERE'S A
REAL CHALLENGE GETTING TIMINGLY
SWEAT CHLORIDES AND THIS COULD
BE USED AS A SCREENING STEP TO
MORE RAPIDLY IDENTIFY BABIES WHO
HAVE A POSITIVE NEW BORN
SCREENING WHO ACTUALLY HAVE CF.
NEXT SLIDE.
AND THEN JUST TO END ON ANOTHER
EXCITING NOTE, I THINK WE'RE ALL
FAMILIAR WITH CONTINUOUS GLUCOSE
MONITORING, AND THIS HAS HUGE
PROMISE CURRENTLY BUT ALSO IN
THE HIGHEE EFFECTIVE MODULATOR
ERA.
IT COULD HELP TO ELUCIDATE THE
EFFECTS OF HEMT ON GLYCEMIC
CONTROL.
IT'S ALREADY USED TO EVALUATE
GLYCEMIC CONTROL ON PREGNANT
PEOPLE AND MODULATORS IN THE MAY
FLOW ARES AND COULD BE USED TO
REPLACE FTDDs AND WHEN LINKED
TO AN INSULIN PUMP WHERE THEY
TALK TO EACH OTHER COULD BE A
BIONIC PANCREAS CLOSE SYSTEM FOR
MANAGING CFRD.
NEXT SLIDE.
THIS IS JUST A STUDY BY SKULLY
AND THE GROUP, LOOKED AT CGM
MEASUREMENTS 14 DAYS PRIOR TO
AND FOLLOWING INITIATION OF ETI
AND YOU CAN SEE IMPROVEMENT IN
ALL INDICES AFTER INITIATION OF
ETI, A LOT MORE WORK TO BE DONE
BUT JUST A SUGGESTION OF HOW IT
CAN BE HELPFUL.
NEXT SLIDE.
SO I WOULD LIKE TO END WITH
ACKNOWLEDGES TO MY CO
INVESTIGATORS ON THE OUTREACH
STUDY, THE CFF THERAPEUTICS
DEVELOPMENT NETWORK AND
RECORDING CENTER WITHOUT WHICH
ANY OF THIS WOULD BE POSSIBLE
AND THEN MY SPONSORS, THANK YOU
SO MUCH.
>> NTHANK YOU DR. ROSENFELD, AND
NOW I WOULD LOAMACYIC TO
INTRODUCE OUR FINAL SPEAKER FOR
THIS SESSION, JENNIFER KYLE
COMMUNITY MEMBER PERSPECTIVE?
I AM 57 LIVING WITH CF AND I'M
HERE TO SHARE MY PERSONAL JOWRN
O MODULATOR THERAPY WITH YOU.
SO I WAS A LATE DIAGNOSIS AT 37.
MY GENES ARE THE A455 E, AND THE
R347 H.
EVEN THOUGH I WAS DIAGNOSED
LATE, THE SIGNS WERE THERE FROM
AN EARLY AGE THAT I HAD CF.
THERE WERE MULTIPLE
HOSPITALIZATIONS FOR INFECTIONS.
AT AGE 11 I HAD A FULL SPINAL
FUSION WITH A HERRINGTON ROD AND
AFTER THAT I STARTED
EXPERIENCING MY FIRST GI ISSUES
AND BECAME VERY NUTRITION
CONSCIOUS LEARNING WHO TO EAT IN
ORDER TO FEEL BETTER.
FROM MY LATE TEENS INTO MY EARLY
50S I HAD A TOTAL OF 6 SINUS
SURGERIES.
IN 20 FLEAN I WAS FIRST
PRESCRIBED COLIDECO, I WAS ON IT
NEAR 9 DAYS AND EXPERIENCED
SEVERE DEPRESSION WITH SUICIDAL
THOUGHTS SO MY CF DOCTOR FELT IT
WAS IMPORTANT TO STOP TAKING THE
MEDICATION.
IN FEBRUARY OF 2021, I STARTED
ON TRICAFTA, BUT DUE TO MY
ISSUES WITH COLIDECO, WE DECIDED
TO START ON THE 2 ORANGE PILLS
FOR THE FIRST 2 WEEKS.
DURING THAT TIME I DID
EXPERIENCE A SLIGHT PUDGIER AND
AN INCREASE IN MY LUNG FUNCTION
WHICH I THINK THEY'RE CALLING
THE BUMP, AND I WAS NORMALLY
AROUND A 70 AND I WEPT UP TO AN
82 AND THEN I PLATEAUED AT A 79.
FOR THE FIRST TIME IN MY LIFE,
MY SINUSES WERE CLEAR WITH NO
INFECTION, AND MY SPUTUM
CULTURES WERE COMING BACK CLEAR.
DURING THAT FIRST 2 WEEKS I ALSO
NOTICED AN INCREASE IN MY
EXERCISE RECOVERY AND TOLERANCE
WHICH WAS REALLY FUN.
SO AFTER THE 2 WEEKS WE DECIDED
TO START THE EVENING DOSE, BUT
ABOUT A MONTH INTO THAT, I DID
START EXPERIENCING DEPRESSION
AGAIN, SO WE THOUGHT IT BEST TO
STOP THE EVENING DOSE SINCE IT
SEEMED THAT I WAS GETTING THE
FULL BENEFIT FROM THE 2 ORANGE
PILLS IN THE MORNING.
I DID NOTICE THAT I HAD MANY
FRIENDS WHO HAD EXPERIENCED
EXCESSIVE WEIGHT GAIN ON
TRICAFTA, AND I DID NOT WANT TO
HAVE THAT EXPERIENCE SO I WAS
QUITE STRICT WITH MY DIET AND
EXERCISE WHILE ON TRICAFTA, I
DID NOTICE THAT I WAS
EXPERIENCING A FORM OF BRAIN
FOG, SLEEP DISRUPTION AND
INCREASED JOINT PAIN WHICH ALSO
SEEMS COMMON WITH THE FRIENDS
THAT I SPEAK TO.
IN THE FIRST 6 MONTHS ON
TRICAFTA, I FELT THE GOOD
OUTWEIGHED THE BAD.
OT EIGHTH MONTH I WENT FOR MY
BLOOD WORK AND THIS IS WHERE THE
SITUATION CHANGED.
WHILE MY PROVIDER WAS NOT OVERLY
CONCERNED WITH MY LAB RESULTS I
WAS SINCE THIS WAS OUT OF MY
NORM FOR MY BODY AND IN OCTOBER
OF 2021 MY CHOLESTEROL SHOT UP
TO A 224 WITH MY LDL COMING IN
AT 124.
MY GLUCOSE WHICH FORMALLY HOVERS
IN THE LOW 40S, WENT UP TO A 75
AND MY HEMODPLOABIN WENT UP TO
5.3.
I DECIDED TO GO COMPLETELY VEGAN
TO TRY TO COMBAT THE CHOLESTEROL
ISSUES AND AFTER SPEAKING WITH
MY DOCTOR, WE BOTH AGREEN CELLED
TO LOWER ME TO 1 ORANGE PILL
WHICH I THEN STARTED TAKING IN
THE EVENING.
IN NOVEMBER OF 2021, I WENT TO
SEE MY RHEUMATOLOGIST FOR
INCREASED OFTIO ARTHRITIS PAIN
AND ISSUES AND SHE ALSO RAN A
WHOLE BUNCH OF BLOOD WORK ON ME.
AT THAT TIME MY GLUCOSE HAD
CLIMBED TO 110 AND I HAD A
C-ANKIO SCORE OF 1.40.
A WHITE BLOOD CELL SCORE OF
6-10.
AN AST SCORE OF 51, ALT SCORE OF
36.
AND AN ANTIU1 RNPSPOIZ SCORE OF
20, ALL SIGNS THAT SOMETHING WAS
CHANGING IN MY BODY.
I DID REPORT THESE FIND I GUESS
TO MY CLINIC BUT AGAIN THEY WERE
NOT OVERLY CONCERNED.
BUT I WAS.
IN JANUARY OF 2022, MY CLINIC
REPEATED MY BLOOD WORK.
MY CHOLESTEROL DID DROP TO A
176, NOT SURE IF WAS DUE TO THE
DECREASE IN TRICAFTA OR THE
VEGAN DIET BUT I WAS HAPPY IT
CAME DOWN, BUT MY GLUCOSE
CONTINUED TO CLIMB AND IT WAS
NOW AT A 122 AND HIGH HEMOGLOBIN
WAS STILL HOLDING UP AT A 5.3.
SO IN FEBRUARY I MADE THE
DECISION ALONG WITH MY DOCTOR TO
STOP TAKING TRICAFA.
I WILL FOLLOW UP WITH MY NEW
CLINIC IN JULY AS I AM MOVING
TOMORROW TO KENTUCKY AND SO I
WILL BE ATTENDING THE VANDERBILT
CLINIC IN NASHVILLE, TENSE
CONTINUOUS, SO HERE'S WHEY WOULD
LIKE TO TELL YOU THAT THE GOOD
NEWS, IS AFTER COMING OFF
TRICAFTA IN FEBRUARY, MY SINUSES
HAVE REMAINED ABSOLUTELY CLEAR.
I SAW MY ENT LAST WEEK, THEY
SCOPED ME AND EVERYTHING WAS
BEAUTIFUL.
MY LUNG FUNCTION HAS HELD AT A
79 WHICH I AM ABSOLUTELY
THRILLED ABOUT.
AND I FEEL LIKE MYSELF AGAIN.
I HAVE TO SAY I AM HAPPY THAT I
AM OFF TRICAFTA, ALSO MY
OSTEOARTHRITIS PAIN AS GONE AWAY
SO NOW I LOOK FORWARD TO THE
MRNA THERAPIES AND GENETIC
THERAPIES THAT ARE COMING DOWN
THE ROAD, I HOPE 1 DAY THAT I
CAN BE IN A CLINICAL TRIAL FOR 1
OF THESE AND ARE LOOK TO WHAT
THE FUTURE WILL HOLD FOR US AS
WE FIGURE OUT THE ROAD TO THESE
MODULATOR THERAPIES A LITTLE BIT
BETTER.
SO I WOULD LIKE TO THANK YOU FOR
LISTENING TO MY STORY TODAY AND
AT THIS TIME, I WOULD LIKE TO
OPEN IT UP TO THE QANDA SESSION.
>> THANK YOU SO.
>> THANK YOU THAT WAS INCREDIBLY
HUMBLING AND IT SHOWS US HOW
EVERY STORY IS UNIQUE AND
IMPORTANT AND WHY WE ARE ALL,
ALL HERE AND GOOD LUCK ON YOUR
MOVE.
>> WE'RE HAPPY TO HAVE EVERYBODY
HERE.
I THINK WE ARE READY TO START
WITH THE QUESTIONS.
I WILL PULL THEM UP.
I FOR 1 THINK WE HAVE TO BE
PATIENT.
I AM SO ANXIOUS FOR ALL OF THESE
OUTCOMES TO BE READY FROM MY
PERSPECTIVE, BOTH FROM, YOU KNOW
NEEDS OUTCOMES FOR OUR STUDIES
BUT ALSO OF COURSE FOR, YOU
KNOW, JUST ADVANCING OUR
KNOWLEDGE ABOUT HOW THIS DISEASE
IS ACTUALLY PROGRESSING FOR
EVERYBODY WHETHER OR NOT YOU'RE
ON MODULATORS OR NOT.
OUR FIRST QUESTION, ACTUALLY
FIRST I WANT TO INTRODUCE
DR. GOSS WHO IS JOINING US.
HE SUFFICIENCY 1 OF THE MULTIPLE
PIs ON THE STOP STUDY AND WE
HAVE A LOT OF QUESTIONS FROM
DR. WEST TO TALK ABOUT THE STOP
STUDY AND EXACERBATIONS AND HE'S
GRACIOUSLY JOINING US TO BE ABLE
TO ASK THOSE QUESTIONS AND ON
THAT NOTE LET ME THROW THE FIRST
QUESTION YOUR WAY, CHRIS, CHRIS
WE A HARD TIME AGREEING ON THE
DEFINITION OF EXACERBATION IN
THE PREMODDULATOR ERA, HOW WILL
WE AGREE NOW.
>> YEAH, WE--WE WENT, I THINK--I
THINK BRUCE MARSHAL CALLED FOR A
DEFINITION, I THINK HIS PAPER
WAS 1999.
WE ALL COME TOGETHER AND AGREE
ON A DEVELOPMENTAL ENDOCRINOLOGY
MISSION AND AS YOU CAN SEE WE
ARE 2022 WITH NO CLEAR
DEFINITION.
I THINK IT'S VERY CHALLENGING,
AND I THINK THERE'S A BROAD
PHENOTYPE OF EXACERBATION.
I THINK WE SETTLED FOR THE
PURPOSE OF CLINICAL TRIALS TO
DEFINE IT BASICALLY ON THE
PHYSICIAN DEFINED DEFINITION OF
INITIATION OF TREATMENT WHICH IS
SORT OF CIRCULAR.
DEFINED BY THE UT COME, I MEAN
BY THE TREATMENT YOU GIVE.
HOWEVER, I THINK IT HAS BEEN
USEFUL AND I DON'T--I DON'T
KNOW, I THINK WITH THE CHANGING
DYNAMIC OF EXACERBATION, IT MAY
BE MORE CHALLENGING TO COME TO A
DEFINITION.
WE DO COLLECT STANDARD
INFORMATION ABOUT EACH
EXACERBATION WHICH HELPED US AT
LEAST DESCRIBE THESE DIFFERENT
VARIETIES AND THERE'S AN ONGOING
PROJECT RIGHT NOW TO FIGURE OUT
IF DIFFERENT PHENOTYPES OF
EXACERBATION, BUT I THINK, IT'S
BEEN CHALLENGING AND I THINK
THAT THERE ARE MANY REASONS WHY
WE HAVEN'T COME DO A STANDARD
DEFINITION.
ALTHOUGH, NONCF BRONCHIECTASIS
HAS.
WE CAN ALSO TRY I THINK I STILL
REMEMBER MARGARET ROH
SENFELLED'S GREAT SLIDE WHERE
SHE SHOWS A SLIDE AND SHE KNOWS
WE KNOW 1 WHEN WE SEE 1.
I THINK WE ARE ATA CHALLENGE
THERE SO USING THESE DATA WE
HAVE, MIGHT HELP IN THAT
DEFINITION PROCESS.
>> I WOULD LIKE TO FOLLOW UP AND
SAY,Y HAVE A UNIQUE EXPERIENCE
OF YOU JOINING US BOTH BEING AND
OFF A MODULATOR DO YOU RECALL
HAVING AN EXACERBATION BEFORE
HAND AND AFTER HAND AND HOW THAT
MAY HAVE DIFFERED?
I WOULD LOVE TO HEAR YOU KNOW
THAT EXPERIENCE?
>> THIS WILL BE AWESOME BECAUSE
I JUST HAD AN EXACERBATION.
SO THAT'S WHY I WENT TO MY ENT.
SO BEFORE WHEN I WOULD HAVE AN
EXACERBATION, I WOULD ABSOLUTELY
BE IN THE HOSPITAL GETTING MY
CENTRAL LINE PUT IN AND WOULD BE
ON OF COURSE A 14 DAYS OF IV
ANTIBIOTICS.
SO AT THIS TIME WHEN I STARTED
THE EXACERBATION, I CALLED MY
CLINIC AND I SPOKE TO MY DOCTOR
AND I SAID, I FEEL LIKE I SHOULD
BE IN THE HOSPITAL BUT I'M GOING
TO GO SEE MY ENT FIRST.
LET'S SEE WHAT THEY SAY, IF THEY
TELL ME THIS IS BAD, I WILL CALL
YOU AND WE'LL GET ME IN, SO SHE
AGREED AND THEY TOLD ME MY
SINUSES WERE BEAUTIFUL AND THAT
THE ORAL ANTIBIOTICS HIALREADY
BEEN TAKING WERE WORKING, I
THOUGHT, THIS IS--I ACTUALLY
STARTED CRYING BECAUSE YOU DON'T
EVER HEAR THAT SO I BURST INTO
TEARS WHICH THE NORMAL WAY TO
HANDLE THAT NEWS.
AND I WAS SO HAPPY THAT I DIDN'T
HAVE TO GO IN THE HOSPITAL, I
DIDN'T HAVE TO GO ON IVs AND I
KNEW I WAS GOING TO BE OKAY AND
FOR THE FIRST TIME EVER I COULD
FIGHT AN INFECTION WITH JUST
ORAL ANTIBIOTICS, THAT WAS
CRAZY.
IT WAS ABSOLUTELY CRAZY.
SO I AM OVER THE MOON.
WORDS CANNOT EXPRESS WHAT THAT
DOES FOR ME.
>> THANK YOU FOR SHARING THAT
EXPERIENCE.
>> NICOLE CAN I ASK A QUESTION,
TO CHRIS AS WELL, CHRIS THIS IS
MEANT TO BE A BIT PROVOCATIVE,
BUT WITH THE DRAMATIC DECLINE IN
EXACERBATION, RATES RELATED
SOMEWHAT TO COVID AND SOMEWHAT
TO HEMT, DOES THAT PUT THE STOP
360 PLATFORM OUT OF BUSINESS?
OR LESS JOKINGLY, HOW ARE YOU
REVISING YOUR ANTICIPATED TRIALS
BASED ON A MUCH LOWER RATE OF IV
ANTIBIOTICS?
>> YEAH, THAT'S A GREAT
QUESTION.
I THINK WHAT WE'VE LEARNED IN
THE CLINICS IS AN ADULT UPTAKE
IN INFECTIONS IN, SINCE
EVERYONE'S WONDERING OUT IN
PUBLIC AGAIN AND GET RESPIRATORY
VIRUSES AND THOSE ARE PRETTY
IMPORTANT IN WHATEVER--SOMEONE
WHO HAS A CHRONIC LOWER
AEOINFECTION, SO WE DID USE DATA
FROM 2020 FOR WHAT WE CAN DO IN
THIS THERE, SO THAT'S BEEN
HELPFUL TO ANTICIPATE WHAT'S
GOING TO HAPPEN.
BASED ON SOME OF OUR DATA ANYWAY
FROM WHAT WE KNOW OF PEOPLE ON
MODULATORS AND THAT MEANS
PRIMARILY IVACAFTOR, WE DO THINK
THE DROP FOR EXACERBATION IS
SIMILAR AND WE WILL SEE IF THAT
CONTINUES WITH TRICAFTA, BECAUSE
IT'S CERTAINLY BETTER THAN
IVACAFT, ON R, ALONE AND THEN
MAYBE THEY COME LESS OFTEN BUT
THEY STILL REQUIRE INTENSIVE
THERAPY BUT ONLY TIME WILL TELL
BUT WE INCREASE, WE HAVE LOTS OF
SITES AND WE HAVE A BIT MORE
PROLONGED ENROLLMENT PERIOD FOR
THE TRIAL.
SO I THINK WE WILL BE OKAY BUT
TIME WILL TELL.
>> THANK YOU.
GO, AHEAD.
>> GO,A HEAD, YOU CAN TELL IT'S
HARD TO REHEARSE IT, OUR NEXT
QUESTION IS FOR HEATHER THOUGH
EVERYONE CAN CHIME IN, DO OTHERS
IN THE FIELD FEEL IT'S IMPORTANT
TO CONSIDER WHETHER CANDIDATE
BIOMARKERS OF INFECTION ARE HOST
DERIVED OR OF MICROBIAL ORIGIN,
OR IS THIS AN AREA OF
CONTROVERSY?
>> I SAW THAT QUESTION CAME IN
FROM LUKE, FEEL LIKE WE'VE HAD
THIS DISCUSSION IN THE PAST.
I THINK THAT IT DEPENDS ON WHAT
YOU'RE USING THE BIOMARKERS FOR.
SO IF YOU'RE USING IT FOR
DIAGNOSIS ISSUING I THINK THAT
IT DOESN'T REALLY MATTER, IF YOU
ARE DIAGNOSING AN INFECTION
BASED ON A BIOMARKER THAT'S
DERIVE FRIDAY THE PATHOGEN OR
THE HOST OR THE HOST PATHOGEN
INTERACTION, THE--SO LONG AS IT
HOLDS UP WHEN YOU ARE LOOKING AT
CONTROLLING FOR SENSITIVITY AND
SPECIFICITY, AND IT MEETS--IT'S
MEETING A NEED FOR TAKING A
CLINICAL ACTION, I DON'T BEING
THAT IT REALLY MATTERS.
IF YOU ARE USING THAT
INFORMATION TO HELP YOU CHOOSE A
THERAPY, THEN IT MIGHT BE MORE
IMPORTANT TO KNOW IF THAT
PARTICULAR MICROBE WILL BE
SENSITIVE TO THAT PARTICULAR
ANTIBIOTIC AND THEN IT MIGHT BE
MUCH MORE IMPORTANT TO
UNDERSTAND THE BIOLOGICAL
ORIGEIGE OF THAT BIOMARKER SO I
THINK IT MATTERS ON HOW YOU'RE
USING THAT INFORMATION.
>> THANK YOU.
>> GREAT.
QUESTION FOR ZACH.
LOT OF ACRONYMS IN.
>> CURRENT TIME REQUIRED TO
REQUIRE UTE MRI AIM KNOWLEDGES
AND RESPIRATORY MOTION AFFECT
IMAGE QUALITY ESPECIALLY IN
YOUNG CHILDREN WHO CAN'T HOLD
THEIR BREATH AND HAVE HIGH RR?
>> REZONING PIRATTORY RATES.
>> YES.
>> SO I THINK THE BEST IMAGES WE
SHOW YOU WE CAN GET DOWN AND
AROUND 5 MINUTES PLUS OR MINUS.
THERE ARE--THERE ARE MECHANISMS
WITH WHICH YOU CAN ACCELERATE
THAT, IT'S CALLED COMPRETIONZED
SENSING AND IT'S THE INVERSE OF
A JPEG WHERE YOU--AND THAT
YOU--IN A JPEG YOU HAVE A HIGH
RESOLUTION IMAGE AND YOU THROW
AWAY REDUNDANT INFORMATION AND
SHRINK IT DOWN, AND YOU SAY, YOU
KNOW WHERE THOSE REDUNDANT
SPACES WILL BE SO YOU ONLY
REQUIRE THE DATA YOU NEED TO
MAKE SOMETHING FAITHFUL TO THE
EDGES IN YOUR IMAGE, SO THAT CAN
SPEED IT UP FURTHER.
ONE OF THE STRENGTHS OF THESE
UTE TYPE SEQUENCES I DIDN'T GO
INTO IS THEY'RE INTRINSICALLY
ROBUST MOTION.
JUST YOU CAN ACTUALLY MAKE A
DESEBT LOOKING LUNG IMAGE
COMPLETELY UNGATED, SO IF THE
KID IS TURNING CIRCLES THAT WILL
BE A PROBLEM, BUT IF IT'S JUST
NORMAL WIGGLING IT'S PRETTY
ROBUST.
ANOTHER INTERESTING THING IS WE
ACTUALLY DID THE SIGNAL DISEASE
MODULATED BY THE RESPIRATORY
WAVE FORM IN AN UNDERSTANDABLE
WAY SO WE CAN DO OUR IMAGE
RECONSTRUCTIONS THAT MINIMIZES
THE IMPACT OF MOTION.
SO WE--WE ROUTINELY MAKE UT
IMAGES OF 5 YEAR-OLDS AND MY
COLLEAGUES JASON AND NORA,
REGULARLY DONYONATAL IMAGING AND
THEY ARE VERY SQUIRMY, SO, IT'S
NONTRIVIAL BUT IF YOU HAVE TECHS
WHO ARE USED TO DOING IT THEY
CAN MAYBE IT HAPPEN.
>> GREAT, OKAY, THIS IS FUNDY,
THE NEXT QUESTION FOR HEATHER IS
FROM ME, SO IN YOUR EVALUATION
OF EXHALED BREATH TO CORRECTLY
CLASSIFY PA POSITIVE VERSUS PA
NEGATIVE PATIENTS WHICH WAS
SUPER EXCITING DID YOU CLASSIFY
THEM AS PA POSITIVE VERSUS PA
NEGATIVE EXCLUSIVELY ON THE
PACEIS OF SPUTUM SAMPLES OR OP
ORAL PHARYNGIAL SAMPLES.
>> NO, FOR THAT STUDY WE WERE
RELYING ON SPUTUM CULTURE BUT
NOT JUST ON THE DAY OF
COLLECTION, BUT ALSO HISTORICAL,
SO IN ORDER TO ENROLL, THEY WELL
TO MEET THE LEADS CRITERIA SO
THAT MEANT THEY WERE GOING TO
HAVE A HISTORICAL POSITIVE
RECORD.
WE ALSO ARE CONSIDERING WHAT
HAPPENS IN THEIR CLINICAL RECORD
UP TO 6 MONTHS AFTER WE
COLLECTED THAT BREATH SAMPLE
JUST IN CASE, IN PARTICULAR,
SOMEONE WHO WAS CLASSIFIED AS
PSEUDOMOANIS NEGATIVE GAME
POSITIVE AT THE TIME OF
COLLECTION, WE SEE REALLY GOOD
CONCORDANCE BETWEEN OUR
CLASSIFICATION OF PSEUDOMOANUS
POSITIVE VERSUS NEGATIVE AND
THEN THERE ARE OVERALL CLINICAL
RECORD BECAUSE OF THOSE
ENROLLMENT CRITERIA, WE DON'T
SEE AS GOOD CONCORDANCE IF WE
TRY TO LOOK AT STAFF, I THINK
SOME OF THAT IS CHALLENGING
BECAUSE OF INFECTION VERSUS
COLKNOWIZATION AND THAT'S WHY WE
DIDN'T TACKLE STAFF, RIGHT OUT
OF THE GATE.
BUT ALSO, I THINK IF WE TAKE A
BROADER PICTURE AND LOOK MORE IN
THEIR CLINICAL RECORD AND NOT
JUST THEIR DAY OF CULTURE,
HISTORY AT THE DAY OF BREATH
COLLECTION, IT WILL CRYSTALLIZE
THAT INFORMATION A LITTLE BIT
BETTER.
WE DID NOT USE OP SWABS, WE KNOW
THE PROBLEM OF OP PER DETUCTING
PSEUDOMOANUS AND THIS STUDY IS
DESIGNED TO LOOK AT THE
SUPERIORITY OF BREATH OVER OP TO
SEE IF WE CAN AT LEAST DO BETTER
THAN OP IN THE ABSENCE OF
SPUTUM.
>> THANK YOU VERY MUCH.
I CAN DO THIS TOO BECAUSE IT'S
ANOTHER QUESTION FOR YOU.
DO WE KNOW ANYTHING ABOUT VOCs
FROM NONCF NORMAL VOLUNTEERS?
CAN VOCs DETECT PA BELOW THE
LEVEL OF DETECTION FROM A NORMAL
CLINICAL APPROACH WITH SPUTUM OR
THROAT SWAB?
>> SO I TOUCH OFFICE OF
DIVERSITY THE SECOND PART OF THE
QUESTION A MOMENT AGO THAT WHAT
WE'RE LOOKING FOR IS A BREATH
TEST THAT CAN OUTPERFORM OP SWAB
AS FAR AS SENSITIVITY GOES.
BUT WE ARE HAVING TO USE SPUTUM
PRIMARILY AS OUR CLINICAL GOLD
STANDARD SO THERE'S SOME TRICKY
CONSIDERATIONS AS WE'RE DOING
OUR STUDY DESIGN THERE.
WE DON'T KNOW, IT'S A GREAT
QUESTION OF LIKE HOW LOW CAN YOU
GO AS FAR AS PSEUDOMOANUS
INFECTION IS CONCERNED BEFORE WE
DETECT.
REALLY THE NEXT PHASE OF OUR
STUDY WILL ADDRESS THAT, WHERE
WE'RE GOING TO SEE IF WE CAN
PICK UP INFECTIONS USING BREATH
EARLIER, FOR SOMEBODY WHO'S
GETTING A NEW ONSET INFECTION
AND NEW DIAGNOSIS, IF WE CAN DO
BETTER THAN OP SWABS FOR PICKING
UP THOSE INFECTIONS EARLIER ON.
SO THAT'S AN OPEN QUESTION, WHEN
IT COMES TO PSEUDOMONUS
VOLATILES AND POPULATIONS, THE
STUDY WE'RE CONDUCTING IS NOT
ENROLLING ANYBODY WHO IS DOES
NOT HAVE CF, THERE ARE OTHER
STUDIES THAT HAVE BEEN PERFORMED
OUTSIDE OF THE CF POPULATION
THAT SHOWS THAT YOU CAN USE IT
TO DIAGNOSE VENTILATOR ASSISTED
PNEUMONIA FOR INSTANCE BUT
THERE'S NOT BEEN A STUDY THAT
TRIED TO BROADLY IDENTIFY BREATH
VOCs FOR PSEUDOMOANUS
DIAGNOSIS REGARDLESS OF WHAT THE
CAUSE OF INFECTION WAS, THE ROOT
CAUSE AND THEN LOOKING AT VOCs
IN THE HUMAN POPULATION MORE
BROADLY.
MOST OF THE STUDIES ARE ON THE
SCALE OF MAYBE UP TO 50
SUBJECTS.
THIS STUDY THAT WE--WE--YOU
DOING WITH IMPACT BREATH IS A
COUPLE HUNDRED AND THAT'S VERY
MUCH ON THE LARGE SIDE AS FAR AS
OUR FIELD GOES.
REALLY WHAT WE NEED TO DO IS GET
TO THE THOUSANDS OF SUBJECTS AND
THERE'S AN INITIATIVE BREWING
THAT WILL BE LAUNCHING SOON TO
ADDRESS THAT.
AND I CAN'T TALK ABOUT DETAILS
BUT IT WILL BECOME PUBLIC IN A
FEW WEEKS.
>> FANTASTIC.
I HAVE A QUESTION FOR YOU
MARGARET AND AWLTS IN THINKING
ABOUT MELANIE'S COMMENTS
YESTERDAY IN TALKING ABOUT
REMOTE VERSUS IN PERSON, AND I
WOULD LIKE TO HEAR JENNIFER'S
PERSPECTIVE ON THIS AS WELL AS
YOU COMPLETE OUTREACH, HOW DO
YOU EVALUATE AND WHAT THE RIGHT
BALANCE EVEN THOUGH WE COULD
ACHIEVE PERHAPS REPLACE, YOU
KNOW SOME OF OUR CLINIC VISITS
WITH REMOTE VISITS FOR RESEARCH?
>> THANK YOU FOR THAT QUESTION,
JENNIFER DO YOU WANT TO ANSWER
BEFORE I DIVE IN, I WOULD LOVE
TO HEAR YOUR PERIS SPECTIVE?
>> SURE.
YEAH, BECAUSE MY CLINICS ARE SO
FAR AWAY FROM ME I CAN SEE IT
FROM BOTH SIDES.
THERE ARE TIMES WHEN I KNOW IT'S
IMPORTANT TO GO INTO YOUR CLINIC
WHEN YOU START TO HAVE SOMETHING
CHANGE AND YOU WANT TO HAVE THE
DOCTOR RIELT THERE SO YOU CAN
FIND OUT WHAT'S GOING ON BUT
THERE ARE MANY TIMES WHEN I'VE
DRIVEN MY HOUR TO MY CLINIC
GOING WHY WOULD I DO THIS AND I
WOULD LOVE TO HAVE THE REMOTE
APPOINTMENT FROM HOME AND KNOW
DONE WITH THE VISIT IN ABOUT 20
MINUTES OR SO.
SO I SEE THE BENEFITS TO BOTH.
I REALLY DO.
AND I SEE ALSO THE DOWN SIDE TO
BOTH.
I THINK THERE'S NO HARM IN
REPLACING YOU ROUTINE CLINIC
VISIT IF SOMETHING'S CHANGED
WITH THE PATIENT, WHY GO?
WHY NOT JUST HAVE IT DONE
REMOTELY, IT MAKES MORE SENSE
FOR EVERYBODY, YOU'RE SAYING THE
DOCTORS TIME, STAFF'S TIME, AS
WELL AS YOUR OWN TIME.
SO I THINK THERE'S NOTHING BUT A
GOOD BENEFIT AND THE MORE WE
DIVE INTO HOW TO DO THESE THINGS
FROM HOME LIKE THE SPIROMETRY
COLLECTION, SPUTUM COLLECTIONS
AND WE GET VERY SAVVY AT IT.
I JUST SEE IT BEING MORE OF A
PLUS THAN ANYTHING.
WE COULD GET TO THE BOTTOM OF
ISSUES A LOT FASTER AND QUICKER
THAT WAY.
I'M ALL FOR IT, I THINK IT'S A
WONDERFUL THING AND I'M GLAD
YEAR GOING IN THAT DIRECTION
EMPLOY.
>> THANK YOU SO MUCH, SO NICOLE
ENGEAJ NOTHING THE CO PRODUCTION
PROCESS HAS LEGALLY BEEN SUCH
A-HIV DON'T MEAN TO SOUND
SACCHARANT BUT IT'S BEEN
HUMBLING AND SUCH A POSITIVE
EXPERIENCE SO I WOULD HIGHLY
RECOMMEND IT, IF NOT THINK WE
SHOULD REQUIRE IF FOR ALL
STUDIES BUT AT ANY RATE WE BEGAN
WITH FOCUS GROUPS WITH PEOPLE
WITH CF AND THEN SEPARATE FOCUS
GROUPS WITH RESEARCH
COORDINATORS AROUND BARRIERS AND
OPPORTUNITIES FOR HOME
SPIROMETRY, AND THAT HELPED US
TO DEVELOP INITIAL MATERIALS AND
THEN WE'VE BEEN DOING THIS VERY
INTENSIVE 6 MONTH PROCESS OF CO
PRODUCING ALL OF THE EDUCATION
AND TRAINING MATERIALS AND
PROCEDURES FOR TRAINING AND HOME
SPIROMETRY WITH A GROUP OF 6
INDIVIDUALS, 3 WITH CF AND 3 WHO
ARE RESEARCH COORDINATORS 1 OF
WHO AM IS A RESPIRATORY
THERAPIST BECAUSE IT HAS BEEN
AMAZING BECAUSE PEOPLE COME UP
WITH IDEAS THAT NO 1 INDIVIDUAL
MIGHT NECESSARILY HAVE THOUGHT
OF AND THEN IT KIND OF BECOMES A
SYNERGISTIC DISCUSSION.
IT'S A LOT OF WORK WE HAVE A LOT
OF WORK STILL TO DO ON THESE
MATERIALS BUT I TRULY BELIEVE
THEY'RE GOING TO BE SO MUCH
BETTER BECAUSE OF THIS
EXPERIENCE, AND AGAIN I CAN'T
REITERATE HOW MUCH I LEARNED.
THE THING I WOULD SAY IS WE
FOCUSED VERY NARROWLY ON HOME
SPIROMETRY AND ON HOW TO DO IT
APPROPRIATELY.
BUT I DON'T KNOW THAT THERE'S
BEEN ANYONE WHRO'S ENGAGE INDEED
A PROCESS OF CO PRODUCTION MORE
GENERALLY AROUND CLINICAL TRIALS
OF THE FUTURE AND WHAT ARE THE
KIND OF HOW DO YOU TAKE THE BEST
OF HOME VISITS OR HOME ASKER
TAINMENT VERSUS CLINIC AND WHAT
FEELS LIKE THE RIGHT BALANCE AND
WHAT ARE THE QUESTIONS AND I
THINK THAT WOULD BE JUST SUCH AN
IMPORTANT OPPORTUNITY ON MY TO
DO LIST IS TO REACH OUT TO
MELANIE FROM YESTERDAY AND GET
HER PERSPECTIVE AND I THINK THAT
THAT MORE BROAD QUESTION,
THERE'S VALUABLE CO PRODUCTION
WORK.
I ALSO HAVE TO CALL OUT THE CF
COMMUNITY VOICE HAS JUST BEEN
AMAZING IN FACILITATING ALL OF
THIS.
>> GREAT.
ZACH, QUESTION FOR YOU IN YOUR
TALK YOU MENTIONED USING
IMCANCER CENTERING TO STUDY ALL
THR ACTIVITIES AND PROJECTSYS
WHICH HAS BEEN A TOPIC
THROUGHOUT THE CONFERENCE, WHAT
ARE YOUR THOUGHTS ON THE TIME
SPAN NEEDED TO EVALUATE THAT FOR
THIS END POINT ESPECIALLY IN
RELATION TO YOU KNOW TEASING OUT
WHAT'S RELATED TO THE
[INDISCERNIBLE] VERSUS PERHAPS
PICKING UP ON WHAT COULD BE
RELATED TO NATURAL DISEASE
PROGRESSION?
>> OH BOY.
HIT ME WITH AN EASY 1.
I WILL TAKE A SLIGHT STEP BACK
FROM THAT.
I THINK THERE'S A COUPLE OF
THINGS WE CAN KIND OF LEARN WITH
IMAGES THAT WILL ASK US TO
BETTER ASK THE QUESTIONS IN
GENERAL BUT WE SEE THESE LARGE
FEV1 IMPROVEMENTS IN THE
CLINICAL TRIAL, AND HOW MUCH OF
THAT IS A RESOLUTION OF A MORE
ESTABLISHED PATHOLOGY, BUT WE
JUST CLEARED OUT A BUNCH OF
MUCUS PLUGS, THAT'S SOMETHING WE
CAN GET AT, THAT SORT OF,
UNDERSTANDING IS THAT JUST A
FIRST PASS CLEARANCE ISSUE OR
ARE WE ACTUALLY REMOVING AIR WAY
INFLAMMATION AND THINGS LIKE
THAT?
I THINK WE HAVE TO ASK THOSE
QUESTIONS IN A MEANINGFUL WAY
BEFORE WE CAN REALLY START
THINKING MEANINGFULLY
THROUGHOUT, LIKE WHAT ARE WE
FIXING WITH THE THERAPIES WE
HAVE RIGHT NOW AND IF WE ASK
THOSE QUESTIONS BETTER AND I
THINK IMAGING CAN HELP, THEN WE
CAN ASK MORE PRECISE QUESTIONS
GOING FORWARD.
MEANING IF THERE'S NO MUSIC WITH
PLUGS LEFT, WE CAN BE MORE KAF
CLEAR ABOUT REMOVING SOME OF THE
PHYSIO THERAPY.
SO, I THINK I SIDE STEPPED YOUR
QUESTION A BIT BUT I THINK THE
THERAPY WITHDRAWAL QUESTIONS,
WE'RE GOING TO DO IT ANYWAY AND
THE PATIENTS ARE DOING IT
THEMSELVES BUT I THINK IT
MIGHT--THE SCIENCE OF IT NEEDS
TO HIT 1 STEP BACK.
>> CHRIS WHAT DID YOU LEARN MORE
ABOUT THE DIFFERENCE BETWEEN
HIGH AND LOW RESPONDERS IN THE
STOP 2 STUDY PARTICULARLY IN
REGARD TO WHAT WE NEED TO TREAT
BEYOND INFECTION AND
INFLAMMATION?
>> YEAH, THAT'S A GREAT
QUESTION.
IT'S VERY INTERESTING, THE LUNG
FUNCTION WEB CONNECTED POSITED
THAT THE LUNG FUNCTION WOULD BE
VERY DIFFERENT AT A RIVAL BEFORE
THE EXACERBATION THAT THOSE THAT
HAD A POOR RESPONSE WOULD HAVE
MORE ADVANCED DISEASE BUT THE
FEV1 ON AVERAGE IS ABOUT THE
SAME.
THEY WERE OLDER, WHICH SORT OF
SUGGESTS SORT OF MORE ADVANCE TD
DISEASE ALTHOUGH LUNG FUNCTION
CLASSICALLIER THAT HAD A DELAYED
RESPONSE OR A NONEARLY ROBUST
RESPONSE, THEY HAD MORE
DIABETES, SO, THAT HAD THE
DELAYED RESPONSE SO MAYBE, MAYBE
GLUCOSE CONTROL, CRITICAL
GLUCOSE CONTROL IS REAL REALLY
IMPORTANT IN MODULATING CF
EXACERBATIONS STEROID USE WAS
VERY SIMILAR IN BOTH, SO YOU
THINK ABOUT IT, BUT WE DIDN'T
REALLY--THE QUESTION STILL IS
OUT THERE, WHETHER STEROIDS WITH
MODULATION WITH STEROIDS LIKE
COPD HAS A BENEFIT.
WE DO KNOW THAT SIGHT OF CARE
MATTERS AND THAT'S AND THAT'S A
TOPIC OF ANOTHER STUDY THAT
WE'RE SORT OF TRYING TO DEVELOP
IN THIS CO MANAGEMENT THING OF
WHAT WE CAN DO BETTER FOR
PATIENTS WHO CHOOSE TO GET IV
ANTIBIOTICSA HOME BECAUSE WE
CLEARLY, THE EVIDENCE IS SORT OF
PILING UP THAT AS ADULTS AND
CHILDREN IF THEY GET TREATED AT
HOME, MAYBE THEY DON'T DO AS
WELL, IT'S MUCH MORE COMMON IN,A
DULT CENTERS TO USE HOME
CELTINGS SO THEY'RE BOTH SORT OF
SOME BIOLOGIC THINGS MAYBE BE
PLAYING A ROLE THAT WE
DON'T--THERE'S NOT A--THERE'S A
STUDY FOR ANALYSIS JUST ABOUT TO
START OR REALLY RAMP UP WHICH IS
UNDERSTANDING WHETHER STEROIDS
PROVIDED ANY BENEFIT, THERE IS A
CLINICAL TRIAL IN EUROPE, SORRY
IN CANADA STUDYING IMPACT
STEROIDS TO LATE POOR RESPONDERS
IN THESE EXACERBATIONS SO THEY
WILL HAVE THAT ANSWER IN THE
NEXT YEAR OR SO.
SO THOSE ARE JUST IDEAS BUT I
THINK THERE'S--THERE ARE
BIOSPECIMENS IN THIS STUDY, SO
THERE ARE WAYS TO LOOK AT
BIOMARKERS, THAT HAVE NOT BEEN
DONE YET TO THINK ABOUT IT.
THERE'S--THOSE RESOURCES
HOPEFULLY CAN LEAD TO BETTER
UNDERSTANDING OF THE BIOLOGY OF
EXACERBATION SO CAN YOU SEE WHAT
WE'RE MISSING BUT I DO THINK, I
THINK THE PHENOTYPE EXACERBATION
IS HELPFUL BECAUSE TREATMENT MAY
BE DIFFERENT BASED ON YOUR
PHENOTYPE.
>> NEXT QUESTION, IS NOT FOR A
SPECIFIC PERSON, IS THIS IS
RELATED TO JENNIFER'S EXPERIENCE
IN TERMS OF HER IVACAFTOR
EXPERIENCE AND HOW YOU STARTED
TRICAF TA ANTICIPATING WHAT
COULD HAPPEN DID WE ANTICIPATE
MENTAL HEALTH COMPLICATIONS WITH
HIGHLY EFFECTIVE MODULATORS AND
TRICAFAND ARE THE CURRENT
APPROACHES FOR MANAGING THESE
SIDE EFFECTS?
I DON'T KNOW MAYBE CHRIS AND
MARGARET CAN TACKLE THIS FROM A
PEDIATRIC AND ADULT PERSPECTIVE.
>> I THINK MOST OF THE WORK IS
ON THE ADULT SIDE.
WE DID NOT ANTICIPATE THIS.
NO.
AND THERE'S CLEAR EVIDENCE THAT
MENTAL HEALTH ISSUES ARE
EEMERGENCYING POST TRICAFA.
THE MECHANISTIC LINK IS SOMEWHAT
UNCLEAR BUT ALL OF US HAD THAT
EXPERIENCE WITH OUR PATIENTS AND
WE DON'T HAVE A STANDARDIZED
APPROACH EXCEPT FOR CO DECISION
MAKING AND OFTEN TIMES STOPPING
IT UNTIL THE DEPRESSION HAS
HOPEFULLY IMPROVED AND THEN
THINKING ABOUT STARTING UP AGAIN
IN A SLOWER WAY, BUT THERE'S NOT
A STANDARDIZED APPROACH IN AN
AREA THAT'S BEGGING FOR
RESEARCH.
>> I WOULD SECOND TO SAY BEGGING
FOR RESEARCH IS REALLY WHAT IT
NEEDS AND WE DO ENCOUNTER THIS
NOT TOO INFREQUENTLY AND WE WORK
WITH PATIENTS LIKE JENNIFER, WE
DO A LOT OF DOSE ADJUSTMENT
WHICH HAS NO PHARMA COBASIS AND
IN TRIALS AND PHARMACOKINETICS
BUT IT SEEPS TO WORK.
WE FLIP MORNING DOSES TO EVENING
DOSES, TO HOPE THAT YOU SLEEP
THROUGH THIS PERIOD WHERE YOU
MAY NOTE THIS EFFECT IN YOUR
COGNITION, SO THAT WE DO A LOT
OF AD LIB WITHOUT KNOWING AND
THERE COULD BE DIFFERENCES IN
BLOOD LEVELS, WHAT IF SOMEONE'S
JUST DIFFERENCES IN METABOLISM
AND IF THE DRUG LEADS TO THE
SIDE EFFECT.
SO I THINK THAT THERE'S WORK
ONGOING, WE KNOW CFTRs IN THE
BRAIN, WE DEEPT KNOW WHAT IT
DOES AND I THINK THERE'S A LOT
OF THINGS THAT TURNING ON A
PROTEIN THAT'S BEEN OFF MIGHT DO
THAT WE HAVE TO BE JUST
COGNIZANT AND AWARE, THIS IS A
DISCOVERY PERIOD, WE HAVE TO
LISTEN TO OUR PATIENTS AND SAY,
HMM, THAT'S VERY ODD.
AND AGAIN THE ACTUAL TREATMENT
RESPONSES AND WHAT WE'RE DOING
ON THE GROUND IS JUST, I THINK
WE'RE ALL INVENTING A PATH WITH
PATIENTS AND IT'S--I HAVE
PATIENT WHO IS TAKE TRICAFTA 3
TIMES A WEEK, IS THERE A ARM
ANYWHERE IN THE CLINICAL TRIAL
THAT SAYS DOSE, MONDAY,
WEDNESDAY, FRIDAY, 1 PILL,
MONDAY, WEDNESDAY, FRIDAY, MUCH
LIKE JENNIFER IF THE PATIENT
SAYS, MY LUNGS ARE CLEAR, I FEEL
GREAT, MY SPIROMETRY HASN'T GONE
DOWN, THERE MAY BE SOME--IT
WOULD BE NICE TO HARNESS FIRST
OUR UNDERSTANDING OF SOME OF
THESE UNINTENDED EFFECTS OF THE
DRUG, BOTH GOOD AND BAD, AND
REALLY HAVE A GOOD CATALOG TO
EDUCATE PATIENTS BEFORE
THEY--YOU KNOW HELP THEM MAKE
DECISIONWHAT TO DO.
>> WELL, PROVOCATIVE QUESTION, I
WILL ALSO I THINK INSPIRED BY
JENNIFER'S EXPERIENCE, WHAT DO
WE THINK ABOUT CYCLING ON ANDAVE
OF MODULATORS?
IS THERE A BENEFIT TO REDUCING
EXACERBATIONS AND REDUCED SIDE
EFFECTS?
FIRST OF ALL LET ME ASK
JENNIFER, WOULD YOU EVER
CONSIDER GOING BACK ON TRICAFTA
AND UNDER WHAT CIRCUMSTANCE?
>> DURING MY RECENT
EXACERBATION, I WENT ON DURING
THAT WEEK TO HELP ABSORB THE
ANTIBIOTIC BETTER SO THAT WAS
THE WHOLE PURPOSE OF TAKING IT,
BUT I ONLY TOOK 1 PILL, 1 ORANGE
PILL IN THE MORNING WITH THE
ANTIBIOTIC AND YOU KNOW I DON'T
KNOW, DID IT HELP?
I CAN ONLY ASSUME MAYBE IT DID?
AS SOON AS I FINISHED THE COURSE
OF ANTIBIOTICS I STOPPED THE
TRICAFTA BECAUSE WHAT HAPPENED
AS SOON AS I WENT BACK ON IS MY
OFTIO ARTHRITIS FLAIRED RIGHT
BACK UP AGAIN.
SO I'M A BIG RUNNER, I WENT OUT
FOR A RUN NEAR THE TAIL END OF
THE EXACERBATION BECAUSE I WAS
FEELING BETTER AND HAD TO LIMP
MY WAY HOME DUE TO HIP PAIN.
SO NOW THAT I'VE BEEN OFF OF IT
FOR ABOUT A WEEK, I WENT OUT FOR
A RUN THIS MORNING, PAIN FREE.
ABSOLUTELY PAIN FREE, ABSOLUTELY
FINE.
SO THERE IS SOME LINK THEIR ALSO
TO THAT BUT YES, I HAVE BEEN
TALKING ABOUT CYCLING ON AND OFF
FOR MONTHS NOW, THAT I THINK
THERE'S A BENEFIT TO DOING THIS
AND THAT'S SOMETHING ELSE THAT'S
PROBABLY GOING TO NEED TO BE
STUDIED DOWN THE ROAD.
>> AS A PEDIATRICIAN I ALSO NEED
TO THROW OUT A WORD OF CAUTION
BECAUSE IF OUR GOAL EVENTUALLY
WILL BE ABLE TO INITTIAIT
TRICAFTA BEFORE THAT HAS BEEN
STRUCTURAL AIR WAY DAMAGE AND
WHILE THE PANCREATIC DAMAGE IS
STILL EVOLVING AND REALLY
INTERVENING EARLY, EVEN MAYBE IN
UTERO AS THE DOCTOR WAS
DISCUSSING THIS MORNING, I THINK
THERE ARE POTENTIAL LYE
SIGNIFICANT RISKS IN CYCLING OR
STOPPING AND STARTING IN WHICH
THERE COULD BE DAMAGE THEN
COULDN'T BE REVERSED THINKING
FOR EXAMPLE OF A FERRET MODEL.
SO IT'S JUST SUCH A TRICK EXPE
HUMBLING SITUATION WHEN
OBVIOUSLY PEOPLE ARE HAVING CLER
CUT INTOLERABLE OR TOLERABLE
SIDE EFFECTS THAT RAISES ISSUES
AROUND DOSING AND SO FORTH, BUT
IF WE ARE TRYING TO PREVENT
DAMAGE IN THE FIRST PLACE, IT
COULD BE A SCARY THING TO DO.
>> COULD I THOUGHT OUT A THOUGHT
EXPERIMENT, DEPRESSION IS A
COMMOFLICATED THING, I WONDER IF
WE COULD LOOK AS A FIELD IS
DEPRESSION THAP HAPPENS WHEN
PEOPLE GO INTO RETIREMENT, HAVE
YOU A GROUP OF PEOPLE WHO HAD
THEIR DAILY LIFE NOW COMPLETELY
DISRUPTED, A LOT OF PEOPLE WITH
CF, THEIR JOB IS STAYING ALIVE
AND NONAPOPTOTIC THAT'S NOT
THERE IN THE SAME WAY I WONDER
HOW MUCH THAT MASSIVE CHANGE IN
LIFE COURSE IS CONTRIBUTING TO
DEPRESSION?
>> YEAH, STEVE MADE A NICE
COMMENT IN THE--YOU KNOW OUR
UNDERSTANDING OF WHETHER
DEPRESSION AND ANXIETY ARE
CORRECTLY CAUSEALLY LINKED IN
THE DRUG IS CHALLENGING, PATIENT
GOES ON DRUG, EXPERIENCES
SYMPTOMS, TAKES OFF DRUG,
SYMPTOMS GOES AWAY, STARTS DRUG
AGAIN, SYMPTOM COMES BACK.
BUT WE DON'T HAVE MUCH OF A
COLLECTIVE UNDERSTANDING OF
THAT.
AND IT'S VERY MUCH AN INDIVIDUAL
PATIENT DECISION THAT'S BEEN
ANYTHING ON ACROSS THE COUNTRY
WITH UNUSUAL AND ELABRATIVE
SOLUTIONS FETAL COMPARTMENT THE
PROBLEM.
SO IT DOES AFFECT, YOU KNOW
COMING OUT OF 2 AND HALF YEARS
OF PANDEMIC, MOST OF US ARE NOT
HAPPY BUT THERE'S A GOOD POINT
TO WHETHER WE HAVE THE CAUSAL
LINK SQUARED AWAY AND WHETHER
THESE RMENTS THAT MANY OF US AS
CLINICIANS HAVE BEEN DOING ARE
REALLY--BUT I WOULD SORT OF
CAUTION THE IDEA OF GOING ON AND
COMING OFF ENTIRELY, WE'VE HAD A
BUNCH OF ADMISSIONS THAT HAVE
BEEN DUE TO RUNNING, BEING
DISCONTINUED FROM TRICAFTA DUE
TO INSURANCE PROBLEMS, SO, THERE
IS A DOWN SIDE PARTICULARLY
PATIENT MODERATE TO SEVERE
DISEASE COMING OFF CAN BE QUITE
PROFOUND EFFECTS ON LUNG
FUNCTION.
>> AND IMEAN AN AREA IN OUR
ANIMAL MODELS MIGHT BE ABLE TO
LOOK AT AS WELL, AND I DO WANT
TO ACKNOWLEDGE THE WORK OF THE
CF FOUNDATION'S MENTAL HEALTH
CONSORTIUM THAT IS TAKE A DEEP
DIVE INTO MANY OF THESE
QUESTIONS INCLUDING TAILORING
NEW MENTAL HEALTH QUESTIONNAIRE
SPECIFIC FOR CF, SO MORE, YOU
KNOW RESEARCH TO COME WITH THE
HELP OF THIS GROUP.
THERE'S A QUESTION FOR ALL,
COULD ANY OF THE SPEAKERS
COMMENT ON THE POTENTIAL ROLE OF
ELECTRICAL INDEPENDENCE
SOMOGRAFY ON THE ASSESS OF OF
EARLY TO MILD CF LUNG DISEASE.
>> NO.
THERE ARE A NUMBER OF
NONINVASIVE EASY MEASURES THAT
NEED TO BE MORE FULLY STUDIED,
ISOOMETRY IS BUT IMPEDE ENSEL IS
DEFINITELY ANOTHER 1 AND I THINK
WE DON'T NEED TO PUT ALL OF OUR
EGGS IN THE LCI AND MBW BASKET
THERE, SOME OF THESE ARE EASY
BREATHING, SIMPLE MANEUVERS THAT
COULD BE READILY INCORPORATED
INTO THE CLINICAL SETTINGS AND
NEED MORE EVALUATION.
>> AND I WOULD SECOND THE
COMMENT THAT IF YOU LOOK AT THE
CATEGORIZATION OF LUNG FUNCTION
IN THE CF FOUNDATION REGISTRY
REPORTS EVERYONE TOOK A JUMP OUT
OF CATEGORIES.
SO, WE CLEARLY NEED TO BE ABLE
TO FOLLOW CLINICALLY A MILD
DISEASE AND MILDER DISEASE AS
MORE AND MORE PEOPLE GET ON
THESE DRUGS EARLIER AND EARLIER
IN LIFE.
AND HOW DO WE--AND OUR ABILITY
TO DETECT CHANGE AND HAVE CHANGE
LINKED TO A TREATMENT THAT HAS
BENEFIT WILL BE REALLY
IMPORTANT.
SO I DO THINK WE HAVE TO AS
BROADLY THINK ABOUT DIFFERENT
WAYS OF MEASURING AND THINKING
ABOUT LUNG FUNCTION JUST LIKE
NRI, IN WAYS TO DETECT CHANGE
AND UNDERSTAND WHAT A MEANINGFUL
DIFFERENCE IS IN ALL OF THESE
INSTRUMENTS.
IT TAKE ACE LOT OF WORK TO
CREATE THE MEANINGFUL DIFFERENCE
IN ANY OUTCOMPREHEND MEASURE,
MEANING CAN YOU TAKE--WE'VE
BEEN, YOU KNOW LCI HAS HAD A
TREMENDOUS AMOUNT OF ENERGY PUT
IN AND IT'S CHALLENGING TO DO
AND WE'RE GETTING THERE BUT
AGAIN, I THINK WE CAN'T JUST
STEER TOWARD 1 OR 2 OUTCOME
MEASURES AND WE HAVE TO EVOLVE.
>> GREAT.
WE HAVE TIME FOR 1 MORE QUESTION
IN THE FULL CIRCLE MOMENT WE
STARTED WITH EXACERBATIONS, WE
WILL END WITH EXACERBATIONS,
CHRIS OR ALL IF YOU CAN COMMENT
ON THE ROBUSTNESS OF THE FIES
DEFINITION OF EXACERBATION BUT I
WOULD BROADEN THAT JUST TO BE
WITH, YOU KNOW CURRENTLY USING
THE FUKs, THERE'S 5
EXACERBATIONS DEFINITIONS OUT
THERE, WHICH WE DO IN THE MEAN
TIME SHOULD WE CONTINUE TO USE
THEM?
>> I'LL JUST COMMENT A LITTLE
BIT.
I THINK THIS IDEA OF A SYSTEM
THAT LOOKS AT VALUES AND LUNG
FUNCTION VALUES AND PATIENT DATA
TO SUGGEST TO PATIENT/PROVIDER
THAT THEY MAY BE HAVE AN
EXACERBATION MAYBE OF REAL
VALUE, I THINK WANE MORGAN HAS
BEEN VERY CONCERNED FOR A LONG
TIME THAT THERE ARE EPISODES
WHERE LUNG FUNCTION GOES DOWN
WHICH ARE EXACERBATIONS THAT ARE
MISSED THAT MAY HAVE IMPACTS ON
PATIENTS LONG-TERM OUTCOME.
SO I THINK--I THINK THEY'RE ALL
DIFFERENT TOOLS, THEY ALL HAVE
THEIR STRENGTHS AND WEAKNESSES,
IF WE HAD A BIOMARKER THAT SAID
YOU HAVE AN EXACERBATION AND IT
WAS INCREDIBLY ACCURATE AND
PREDICTIVE, THAT WOULD BE
WONDERFUL BUT WE DON'T, WE HAVE
A COLLECTION OF PATIENT REPORTED
SYMPTOMS AND FEELINGS WHICH ARE
REALLY IMPORTANT BECAUSE OFTEN
THAT'S WHAT DRIVES THE PATIENT
CALL TO OFFICE AND THEN
OBJECTIVE MEASURES THAT MAYBE
INFLUX.
SO I THINK 1 THING WE HAVE TO BE
CAREFUL OF IS IF EXACERBATIONS
ARE CHANGING AS JENNIFER NOTED
WE HAVE TO BE VERY RESPONSIVE IN
LOOKING AT THE DATA AND SEE IF
WE SHOULD ADAPT TO CHANGING
TIMES.
>> WELL, THANK YOU EVERYONE.
THIS IS THE CONCLUSION OF OUR
Q&A SESSION BUT WE ARE READY NOW
TO TRANSITION SO I WILL HAND IT
BACK OVER TO [INDISCERNIBLE].
>> SO THOSE WHO WEREN'T HERE,
WE'RE GOING TO OPEN UP THE BREAK
OUT ROOMS MOMENTARILY AND THERE
WILL BE A SMALL BOX ON THE
BOTTOM OF THE ZOOM WINDOW WITH 4
GRAY BOXES, THAT YOU CLICK AND
YOU CAN SELECT THE BREAK OUT
THAT YOU'RE INTERESTED IN.
SO WE HAVE THE INFORMATION HERE
BUT YOU ALSO MAY WANT TO CHECK
THE PROGRAM BOOK FOR MORE
INFORMATION.
AND THE MODERATORS WILL BE MOVED
INTO THAT BREAK OUT ROOM
AUTOMATICALLY.
AND SO WE HAVE MODERATORS IN THE
ROOM TO GUIDE THE DISCUSSION.
THERE WILL BE A PERIOD OF OPEN
TIME FOR DISCUSSION AMONGST THE
ROOM, AND THEN, WE'RE GOING TO
BE USING A CROWD SOURCING WHITE
BOARDING TOOL WHICH WILL ALLOW
YOU TO VOTE AND VOTE YOUR
PRIORITIES FROM THE DISCUSSION
TOWARDS THE END OF THE
BRAINSTORMING SESSION, SO WE'RE
GOING TO BE IN THE BREAK OUT
ROOMS FOR ABOUT AN HOUR.
AT THE END OF THE BREAK OUT HOUR
WE ASK THAT THE ATTENDEES LEAVE
THE BREAK OUT ROOMS FOR A 15
MINUTE BREAK AND THIS WILL ALLOW
THE MODERATORS TO COLLECT THE
THOUGHTS AND CLOSE OUT THOSE
BRAINSTORMING
BRAINSTORMING BOARDS WE WILL
WORK OFF OF SO AT THIS TEEM WE
WILL CLOSE OUT THE ROOM AND YOU
CAN MAKE YOUR SELECTIONS.
WELCOME BACK.
WE ARE GOING TO HAVE A REPORT
FROM EACH OF THE BREAKOUTS,
ABOUT 10 MINUTES EACH AND
THEN
WE ARE GOING TO SHOW THE
BOARDS FROM EACH OF THE
BREAKOUT ROOMS
INDIVIDUALLY ALLOWING THE
MODERATORS OF THAT SESSION
TO REPORT OUT.
AND THEN WHAT WE HAVE DONE
WITH THE TOP THREE-FIVE AREAS
THAT WERE MOST UPVOTED FROM
EACH OF THE THREE ROOMS, WE
CONSOLIDATED INTO A FOURTH
BOARD
THAT WE WILL USED TO HAVE A
GENERAL DISCUSSION
FOR THE LAST 30 MINUTES OF
THE
MEETING
SO THE GENERAL DISCUSSION
WILL
BE MODERATED
BY OUR WORKSHOP COCHAIRS,
BUT WE ARE ALSO WELCOMING
THE SPEAKERS
AND BREAKOUT SESSION
MODERATORS
TO PARTICIPATE IN THAT
DISCUSSION AS WELL.
SO WITH THAT I AM GOING TO
ASK
THAT WE PULL UP THE
FIRST PAGE FROM THE BREAKOUT,
ON BREAKOUT SESSION 1.
APOLOGIZE. SOMEONE MESSAGED
THAT YOU CANNOT SEE ME.
-- --
AND THEN I WILL TURN IT OVER
TO THE MODERATORS FROM
SESSION
1.
>> HI EVERYONE.
I'M JESS PITTMAN.
I WILL TRY TO SUMMARIZE WHAT
WE TALKED ABOUT IN OUR GROUP.
WE TALKED ABOUT STARTING OR
NOT STARTINGAGMT WITH
PATIENTS WITH MILD DISEASE
WITH A RELATIVELY HEAVY FOCUS
ON PEDIATRIC PATIENTS,
PARTICULARLY YOUNG PEDIATRIC
PATIENTS.
WE INITIALLY STARTED OFF
TALKING ABOUT OFF LABEL
DISCUSSION ABOUT HOW YOU
MIGHT
INITIATE THERAPY IN INFANTS
WITH TRICAFTA (PHONETIC)
FOR INSTANCE AND WHEN
PATIENTS
ARE AGE ELIGIBLE,
PARTICULARLY IF THAT AGE
CONTINUES TO GO LOWER
WHAT WILL BE THE FACTORS THAT
DROVE US TO
EITHER ENCOURAGE INITIATION
OR CONSIDER DELAY.
THE BIGGEST PART OF OUR
DISCUSSION, WITH SORT OF
TOGGLED
BETWEEN IF YOU DELAY THERAPY
HOW WOULD YOU MONITOR IT
TO MORE OF A PRO THERAPY
DISCUSSION ABOUT WHY YOU
WOULD
DELAY THERAPY AND THERE WAS A
LOT OF DISCUSSION ABOUT THE
PRIMARY PREVENTION ASPECT,
CAN
WE PREVENT THE EARLIEST LUNG
DISEASE?
CAN WE HAVE A CHANCE ABOUT
RECOVERING OR MAINTAINING
PANCREATIC FUNCTION.
CAN WE MAINTAIN VASTDEFIN
(PHONETIC) CAN WE AVOID
(INDISCERNIBLE),
CRITICALLY LINKED TO LUNG
FUNCTION.
SHOULD WE BE DOING EVERYTHING
WE CAN TO ENCOURAGE ADEQUATE
GROWTH,
OPTIMAL HEIGHT IN THIS
PATIENT'S WHICH WE WOULD
PRESUME THAT MODULATOR
THERAPY
WOULD DO AND WE HAD A LOT OF
DISCUSSION THAT JUST BECAUSE
WE CANNOT FIND THE DISEASE,
WE
DO NOT HAVE THE TOOLS, DOES
NOT MEAN THAT THEY ARE NOT
THERE YET.
ONE PERSON COMMENTED
SUCCINCTLY THAT THE RISKS OF
EARLY THERAPY ARE DWARFED BY
THE KNOWN RISK OF EARLY CF.
WE ALSO HAVE A LOT OF UNKNOWN
RISK OF CF AS OUR PATIENT
CONTINUES TO BE HEALTHIER AND
LIVE LONGER AND ARE LIVING
INTO SORT OF SENIOR YEARS AND
WHAT THAT LOOKS LIKE.
---
WE DID HAVE A LOT OF
CONVERSATION ALSO ABOUT
LONG-TERM RISKS OFHEMT,
SPECIFICALLY THINKING ABOUT
THE LONG-TERM IMPACT IN YOUNG
CHILDREN, CHILDREN WHO ARE
RAPIDLY GROWING AND HAVE A
LOT OF NEUROCOGNITIVE
DEVELOPMENT IN PARTICULAR.
SO THERE WAS A DISCUSSION
ABOUT HOW WE MIGHT GET BETTER
SAFETY AND EFFICACY LONG-TERM
AND THINK ABOUT MONITORING
SOME OF THOSE NEUROCOGNITIVE
IMPACTS OR POTENTIAL
NEUROCOGNITIVE IMPACTS,
PARTICULAR THINKING ABOUT HOW
INITIATION AT DIFFERENT AGES
AND DEVELOPMENTAL STATES
MIGHT
IMPACT SIDE EFFECT PROFILE.
---
ANOTHER TOPIC THAT WAS
EMPHASIZED WAS THE USE OF
SWWEAT CHLORIDE AS A USEFUL
BIOMARKER,
WE HAD CONFLICTING DATA ABOUT
OLDER PATIENTS PARTICULAR
WITH
RESPONSE, PART OF THIS
CONVERSATION THAT WE HAD WAS
HMMM THIS MIGHT LOOK
DIFFERENT
IF YOU DID NOT HAVE EXISTING
LUNG DISEASE.
MIGHT YOU SEE A TIGHTER
CORRELATION BETWEEN SWEAT
CHLORIDE RESPONSE AND
PRESERVATION OF LUNG FUNCTION
AND NUTRITIONAL IMPROVEMENTS
IN PATIENTS WHO HAD NOT
DEVELOPED SIGNIFICANT LUNG
DISEASE OR WHAT WE PERCEIVE
AS
PERMANENT LUNG DISEASE.
---
THERE WAS SOME CONCERN AND
PERHAPS MAY ALREADY BE
HAPPENING THAT SWEAT CHLORIDE
HAS TO BE USED AS EITHER A
MEASURE OF WHETHER THE
PATIENT
HAS AN ADEQUATE RESPONSE TO
BE
WILLING TO PAY FOR MODULATOR
THERAPY OR TO MONITOR
ADHERENCE AND THIS WAS
BROUGHT
UP AS A PROBE POTENTIALLY OR
AT LEAST THESE POTENTIAL
USEFUL MODALITY IN TERMS OF
PATIENTS WHO DON'T SEEM TO BE
DOING WELL ON MODULATOR
THERAPY.
IS IT WORTH GETTING SWEAT
CHLORIDE TO SEE EITHER
RESPONSE OR APPEARANCE AS
OPPOSED TO LAYERING ON OTHER
THERAPIES.
---
SPECIFICALLY TALKING ABOUT
SOME OF THE MODIFIED DOSING
REGIMEN MENTIONED IN THE
PREVIOUS SESSION, IN THE
QUESTION BLOCK,
IS SWEAT CHLORIDE USEFUL TO
MONITOR FOR A MINIMAL
THRESHOLD RESPONSE TO
LOWERING
YOUR DOSE TO GET WHAT YOU
WERE
GETTING BEFORE IN TERMS OF
EFFICACY?
---
AND THE FINAL THING WE TALKED
ABOUT AS I MENTIONED EARLIER
WAS THE NEED FOR EFFICACY
AMONG LONG-TERM DATA IN
YOUNG
CHILDREN AND INFANTS AND
THERE
WAS SOME DISCUSSION THAT SOME
OF THE ONGOING LONGITUDINAL
STUDIES AT LEAST BEGIN TO
ANSWER THESE QUESTIONS BUT IF
WE ARE TALKING ABOUT
INITIATION AT INFANCY, THAT
DATA DOES NOT EXIST YET.
---
LOOKING SPECIFICALLY AT
REDUCING RISK OF INFECTION
AND
LUNG INFECTION DECLINE,
THINKING MORE ABOUT REAL-TIME
EFFICACY DATA,
LONGER, LARGER LONGITUDINAL
STUDIES
AND THEN AS I MENTIONED
EARLIER
WITH ALL OF THE CONCERNS
ABOUT
MENTAL HEALTH IN OLDER ADULTS
WE ECHOED THESE CONCERNS IN
CHILDREN AND THE POTENTIAL
COGNITIVE IMPACT
IN THINKING ABOUT HOW WE
COULD
OR SHOULD
BE PROACTIVELY MONITORING
FOR CHANGES IN DEVELOPMENT.
AND DO WE NEED TO THINK ABOUT
ALTERING OUR CLINICAL MODEL
THINKING ABOUT OUR NICU
FOLLOW-UP CLINICS.
IS THAT A MODALITY THAT WE
NEED TO CONSIDER?
---
WE HAD A LOT OF CONVERSATION
ABOUT WHAT THE -- MAY BE
DOING
IN THE BRAIN AS WELL.
AND THERE WAS SOME DISCUSSION
ABOUT DRUG LEVELS AND WHETHER
OR NOT WE REALLY KNOW WHAT IT
THERAPEUTIC DRUG LEVEL IS
WHETHER MOST DRUG LEVELS ARE
BASED PRIMARILY ON SAFETY AS
OPPOSED TO EFFICACY.
WHILE MAINTAINING SAFETY,
DO WE EVEN HAVE THAT DATA FOR
OUR PATIENTS?
---
IN THE LAST QUESTION WHICH
SORT OF LINKS TO THINKING
ABOUT DISCONTINUING OTHER
THERAPIES, DO WE HAVE OTHER
DATA ON HOW MUCH THERAPIES
MAY
INTERACT OR IMPACT THE
RESPONSE TO OTHER CF
THERAPIES?
DID I MISS ANYTHING?
>> THAT WAS AWESOME.
>> YOU DID REALLY WELL JESS,
THANK YOU.
>> ALL RIGHT GREAT.
THANK YOU.
WE CAN MOVE ON TO THE REPORT
OUT FROM BREAKOUT 2.
PULL UP THE BOARD FOR THAT
ROOM NOW.
-- --
>> SO OUR TOPIC WAS
ADVANCING
CLINICAL CARE AND OUTCOMES IN
THE POST MODULATOR AREA.
WE TALKED A LITTLE BIT AT THE
START ABOUT WHETHER THERE
WERE
THINGS WE COULD LEARN ABOUT
NON-CF BRONCHIECTATIC
PHENOTYPE,
DEFINITIONS OF EXACERBATION
AND WE THOUGHT THERE MIGHT BE
WORKING TO JUST TO GET THOSE
THINGS DONE BEFORE WE COULD
GATHER A WHOLE LOT OF LESSONS
THAT COULD BE APPLIED TO CF
BRONCHIECTASIS,
AND TO GET THE NUMBERS NEEDED
FOR GOOD EFFECTIVE TRIALS.
---
WE MOVED TO WHAT WAS NEEDED
TO
UNDERSTAND DISEASE AND
FORWARD
IN THIS ERA.
WE TALKED ABOUT THE NEED FOR
WAYS TO MEASURE MICROBIOLOGY,
MAY BE WAYS TO ASSESS
MICROBIOLOGY BETTER.
YOU HEARD SOME THINGS ABOUT
EXHALED BREATH THAT MIGHT BE
USEFUL FOR THAT.
WE TALKED ABOUT THE NEED TO
REALLY
EXPAND OUR MEASURES ACROSSTHE
LIFESPAN.
SO LOOKING AT EVERYONE FROM
MIDTEENS ALL THE WAY TO OLDER
FOLKS
NOW THAT THE LIFESPAN IS
EXPANDED AND HOW TO DO THAT
AND HOW, WE CAN MEASURE, AND
WE HEARD ABOUT IMAGING AND
EXHALED BREATH THAT MIGHT
WORK.
---
ONE PROBLEM THAT GET
DISCUSSED
A LITTLE BIT WITH SOME OF
THESE PATIENTS CAN'T
EXPECTORATE SPUTUM ANYMORE.
WE TALKED ABOUT THE
POSSIBILITY AND NEED FOR
INITIATIVES FROM EACH OF THE
IRS, AND SEE IF THERE WERE
SOME OF THESE MONITORING
METHODS.
---
WE GOT INTO BIOMARKERS A LOT
AND THE BIG THING THAT CAME
OUT OF OUR DISCUSSION WAS THE
NEED TO KIND OF DEVELOP THESE
NEW BIOMARKERS WHILE AT THE
SAME TIME NOT THROWING OUT
SOME OF THE OLD BIOMARKERS IN
THE THINGS WE HAVE COME TO
DEPEND ON.
SO PARALLEL DEVELOPMENT,
USING
MEASUREMENTS WHILE AT THE
SAME
TIME TRYING TO DEVELOP NEW
ONES.
AND SOME OF THESE
MEASUREMENTS
THAT WE ARE USED TO ARE GOING
TO HAVE CEILING EFFECTS WHERE
THEY MAY NOT BE SENSITIVE
ANYMORE AND WE NEED TO DECIDE
AND PRIORITIZE TRYING TO FIND
WAYS TO WORK AROUND THAT OR
YOU INSTRUMENTS TO WORK
AROUND
THAT.
---
WE TALKED A LOT ABOUT THE
FACT
THAT THERE ARE BANK SPECIMENS
FROM SOME OF THESE STUDIES
THAT HAVE BEEN PUT AWAY AND
MAYBE PEOPLE ARE NOT AS AWARE
OF THEIR AVAILABILITY AND
THAT
THEY MIGHT BE A BIG RESOURCE
FOR PEOPLE THEY KNEW ABOUT
THEM AND COULD ACCESS THEM,
AND THE FOUNDATION IS WORKING
TOWARDS DOING THAT, AND
TRYING
TO MAKE THOSE RESOURCES
AVAILABLE.
---
AND THAT THERE MIGHT BE A
NEED
FOR SOME FUNDING MECHANISMS
THAT WOULD LET PEOPLE GET IN
THERE AND USE THOSE SAMPLES
INTO SECONDARY ANALYSIS ON
SOME SAMPLES WE GATHERED.
---
WE HAD SOME OF THE SPECIFIC
STUDIES LISTED THERE.
WE WERE WONDERING ABOUT HOW
ACCESSIBLE THE SAMPLES WERE.
---
WE TALKED A LOT ABOUT THE
NEED
TO DEVELOP NEW BIOMARKERS AND
CORRELATE THEM.
A LOT OF THE BIOMARKER
DISCUSSIONS CAME BACK TO THE
IDEA THAT
IT WAS A GOOD IDEA TO PURSUE
THESE THINGS. WE PROBABLY
NEED
TO SPREAD OUT OUR EFFORTS AND
NOT JUST FOCUS IN ONE
DIRECTION, NEED SOME TIME TO
DEVELOP THOSE BIOMARKERS
WITH THE DATA THAT IS OUT
THERE SO WE KNOW WHAT THEY
ACTUALLY MEAN.
---
WE DID HAVE SOME DISCUSSION
ABOUT A TRIAL DESIGN, MORE
FLEXIBLE TRIAL DESIGNS,
PRAGMATIC TRIALS AND THERE
WERE PROS AND CONS AND HOW
USEFUL THAT WOULD BE FOR
DEVELOPING NEW THERAPIES.
I THINK ONE THING WE TALKED
ABOUT IN DEVELOPING SOME OF
THE SURROGATES WE NEED TO
INVOLVE REGULATORY AGENCIES
BECAUSE AT THE END OF THE
DAY,
THEY WILL MAKE THE DECISIONS
ABOUT WHAT THEY CONSIDER TO
BE
GOOD SURROGATES IN TERMS OF
GETTING APPROVAL FOR DRUGS.
SO THEY REALLY NEED TO BE
INVOLVED FROM THE BEGINNING
OF
THAT.
---
WHEN I DID IT CAME OUT THAT
STUCK WITH ME IS THAT WE
WOULD
EVENTUALLY NEED A
(INDISCERNIBLE) OF DIFFERENT
INDICATORS,
TO PURSUE ANY NEW THERAPIES
AND I THINK THAT IS BEEN A
GOOD THEME THROUGHOUT CF
RESEARCH AS WE HAVE DEVELOPED
SOME OF THESE BIOMARKERS THAT
OVER THE YEARS HAVE LET US
ESTABLISH MECHANISMS ACROSS
WHEN TESTING A THERAPY.
---
BONNIE AND RHONDA, WHAT DID I
MISS?
LACKING IN RESPONSE, THING
THAT IS A PRETTY GOOD SUMMARY
OF WHAT THE GROUP DISCUSSED.
>> I WANT TO THROW OUT TIM,
THAT IF PEOPLE WANT TO LOOK
AT
THE 1ST, 2ND, 3RD, 4TH
QUESTIONS, WE DID IT.
>> THANKS FOR LETTING ME KNOW.
I DIDN'T REALIZE THE HEADERS
WERE MISSING.
>> SORRY I WAS MUTED.
TIM, I THINK YOU DID A GREAT
JOB OF SUMMARIZING, WHICH WAS
A VERY ROBUST DISCUSSION. I
DO
THINK THAT WHEN WE WERE
TALKING ABOUT DIFFERENT
OUTCOMES IN BIOMARKERS, NOT
ONLY DO WE WANT TO SEE YOUNG,
MILD PATIENTS BUT WE ALSO
HAVE
TO THINK ABOUT THE AGING
PATIENTS, SO BOTH EXTREMITIES
OF THE LIFESPAN.
AND ALSO, THAT WE REALLY WANT
TO THINK ABOUT ALL ORGANS.
SO I THINK SOMEBODY SAID
ABOVE
AND BELOW THE DIAPHRAGM, EVEN
LIKE HOW DO WE DO BETTER
IMAGING, EARLY PANCREATIC AND
LIVER DISEASE?
---
AND FOR EXAMPLE THE CFQ IR
(PHONETIC), IF WE LOOK AT
MANY
TRIALS EVALUATED.
WHY ARE WE NOT USING OTHER
SCORES ARE MUCH MORE GLOBAL?
SO THOSE ARE A COUPLE OF KEY
THINGS.
-- --
>> THANK YOU BREAKOUT ROOM 2.
SO WE CAN PULL OUT THE ROOM
SLIDE FOR ROOM 3.
AND I INVITE THE MODERATORS
TO
GIVE THEIR REPORT OUT.
>> THANKS MAURA.
I CAN SEE OUR BOARD IS UP.
THANK YOU TO EVERYBODY WHO
WAS
A BREAKOUT ROOM 3, I'M TRACY
-- WE HAD A VERY BROAD
DISCUSSION ACROSS A RANGE OF
TOPS AND YOU WILL SEE THAT AS
I START THIS REPORT OUT.
JUST BUILDING ON WHAT
BREAKOUT
SESSION 2 JUST TALKED ABOUT,
WE HAD A ROBUST DISCUSSION
ABOUT AGE-RELATED DISEASE AND
COMORBID CONDITIONS IN CF AND
WHAT WAS GOING TO BE UNIQUE
TO
CF AND DIFFERENT FROM THE
GENERAL POPULATION, AND THAT
MORE RESEARCH WAS NEEDED
HERE.
---
WE REALLY TALKED ABOUT
INCORPORATING SCREENING FOR
DISEASES OF AGING, OR
COMPLICATIONS OF AGING.
AND REALLY THAT EXPERTISE
NEEDED TO TREAT SUCH ISSUES.
AND I THINK THAT WHAT WAS
BROUGHT OUT IN THE DISCUSSION
WAS THAT IT IS REALLY NOT
CLEAR TO AS WHAT IS A
COMPLICATION OF AGING OR A
COMPLICATION OF HIGHLY
EFFECTIVE MODULATOR THERAPY,
OR JUST SOMETHING THAT IS
ASSOCIATED WITH RENEWING CFTR
FUNCTION.
WE TALK SPECIFICALLY ABOUT
CARDIOVASCULAR DISEASE
HYPERTENSION, OBESITY AND
DIABETES, AND SCREENING FOR
CANCER WHICH INCLUDED G.I.
CANCER, TESTICULAR CANCER,
CERVICAL CANCER.
AND I WILL GO IN THE ORDER OF
THOSE DOWN THE COLUMN SO WE
WILL JUMP AROUND A LITTLE
BIT.
WE DID TALK ABOUT THE USE OF
HIGHLY EFFECTIVE MODULATOR
THERAPY IN UTERO AMONG
PREGNANT PEOPLE WITH CF.
OR PREGNANT PEOPLE WHO ARE CF
CARRIERS, PREGNANT WITH THE
CHILD WITH CF.
---
THERE WAS A ROBUST DISCUSSION
IN THE Q&A BEFORE AND EARLIER
IN THE CHAT, AND THAT
CONTINUED A BIT DURING OUR
BREAKUP.
---
THE NEXT THING THAT GARNERED
A
GOOD PORTION OF THE VOTE IN
THE DISCUSSION, AND WE TALKED
ABOUT, IS HOW DO WE PARTNER
WITH PRIMARY CARE PROVIDERS
AND PROVIDE THEM WITH
SUPPLEMENTAL OR ADDITIONAL
EDUCATION AND TRAINING ABOUT
WHAT MODERN CF LOOKS LIKE?
AND HOW DO WE SUCCESSFULLY
ADD
THEM INTO THE CF CARE MODEL
AND PARTNER WITH THEM?
---
WE TALKED ABOUT WITH EMERGING
DISEASE MANIFESTATIONS, WHAT
OTHER PARTNERSHIPS WITH
SUBSPECIALTY PROVIDERS DO WE
NEED AND WHO NEEDS TO BE
BROUGHT TO THE TABLE IN THE
CHANGING DEMOGRAPHICS IN CF?
THIS WAS BROUGHT UP
SPECIFICALLY WITH THE GROWING
FREQUENCY OF PREGNANCIES AND
THE NEED TO PARTNER WITH
OBSTETRICIANS.
BUT REALLY IT RANGES ACROSS A
LOT OF DISEASE MANIFESTATIONS
AS SUMMARIZED ABOVE.
---
WE TALKED ABOUT TRANSPLANT
AND
WE TALKED ABOUT HOW MORE
RESEARCH TO ECHO DR. RAIMOS
FROM BEFORE IS NEEDED IN THE
TIMING OF TRANSPLANTS AND
INCREASED ACCESS AS WELL AS
THE NEED FOR OBSERVATIONAL
STUDIES OF USE OF HIGHLY
EFFECTIVE MODULATORS, POST
TRANSPLANT OR IN CONJUNCTION
WITH TRANSPLANT MEDICATIONS.
---
IN THE LAST TWO THINGS IN
THIS
COLUMN THAT WE TOUCHED UPON
WERE THE NEED FOR ROBUST
TRANSITION PROGRAM AND AN
EVIDENCE-BASED TRANSITION
PROGRAM RELATED TO THE MOVE
FROM PEDIATRIC TO ADULT
FACING
CF CARE.
AND THE FOCUS ON LIFESTYLE
BEHAVIORS TO PREVENT SOME
DISEASES ASSOCIATED WITH
AGING
THAT WAS SUMMARIZED ABOVE.
---
IN THE SECOND BUCKET,
WE REALLY HAD A GREAT
DISCUSSION ON PERSONALIZED
MEDICINE AND THERATYPING.
AND REALLY THE NEED TO
MAXIMIZE OPPORTUNITIES FOR
BANKING PATIENTS BIOSPECIMENS
A BIG EXAMPLE WAS EXPLANTED
LUNGS,
AND ASSESSETI RESPONSE IN
SELF-CONTAINED MUTATIONS
MORE COMMONLY FOUND IN PEOPLE
OF COLOR AND WE DISCUSSED
RESEARCH ALIGNED WITH THE NEW
DEMANDS IN AN AREA OF HEMT:
ADHERENCE, MENTAL HEALTH AND
SUBSTANCE ABUSE.
---
AND JUMPING BACK THIS IDEA OF
REALLY MORE ROBUST
PHARMACOGENETICS STUDIES TO
BETTER UNDERSTAND VARIABLE
RESPONSES TO HEMTS.
---
AND IN THE LAST COLUMN WE
SPENT A GOOD PORTION OF OUR
TIME TALKING ABOUT ADDRESSING
RACIAL AND ETHNIC HEALTH
DISPARITIES INCLUDING
PARTICIPATION IN CLINICAL
TRIALS.
WE TALKED ABOUT ADDRESSING
TRUST AND PROVIDER BIAS, AS
BARRIERS TO PARTICIPATION IN
CLINICAL CARE AND CLINICAL
RESEARCH.
REALLY THE NEED TO RAISE
AWARENESS IN THESE
POPULATIONS
FOR SWEAT TESTING, GENE
TESTING AND MONITORING TO
IMPROVE RECRUITMENT
STRATEGIES
REALLY TRAIN OUR CF CLINICAL
AND RESEARCH TEAMS AND BE
PROACTIVE ABOUT DIVERSITY,
EQUITY AND INCLUSION.
---
TO BE INTENTIONAL ABOUT
INCLUDING BIPOC, PREGNANT
PEOPLE AND THE INTERNATIONAL
COMMUNITY IN OUR STUDIES AND
TO ADDRESS THE RELUCTANCE TO
PARTICIPATE IN STUDIES THAT
MAY NOT HAVE DIRECT BENEFIT
FROM THE RESEARCH
DEVELOPMENT,
AND THE USE OF RECRUITMENT
TARGETS
THAT ARE REPRESENTATIVE OF
DISEASE PREVALENCE.
---
WE SPECIFICALLY DOVE INTO HOW
THESE POPULATIONS WERE LESS
LIKE IT TO BE REFERRED FOR
TRANSPLANT.
SO REALLY SOME ATTENTION PAID
TO THE REFERRAL PROCESS, AND
WE TALKED ABOUT SOME ONGOING
INITIATIVES FROM THE CFF LUNG
TRANSPLANT CONSORTIUM AND
PROGRAMS TO IDENTIFY PATIENTS
WITH RARE MUTATIONS AND TO
MAKE SURE THAT THEY WERE
BEING
REFERRED IN A TIMELY AND
APPROPRIATE WAY.
---
AND LASTLY WE TALKED ABOUT
THE
REALLY DID NOT FIT IN A
BUCKET
BUT I THINK IT IS SOMETHING
WE
ALL RECOGNIZE, IS THAT WE
HAVE A VERY POWERFUL TOOL IN
CF, WHICH IS THE CF
REGISTRATION WHILE BALANCING
THE FACT THAT DATA ENTRY CAN
BE BURDENSOME WE MAY BE ABLE
TO LEVERAGE THIS RESOURCE TO
TRACK ALL THE PHENOTYPES
USING
THIS TOOL AS WELL AS
PARTNERING WITH THE TDN.
---
SO THAT IS BREAKOUT 3 IN
SUMMARY AND I WANT TO HAVE
COLLYN, GABRIELLE AND
KATHERINE TO FILL IN THE
BLANKS IN THINGS THAT I
MISSED.
>> THAT WAS A GREAT SUMMARY.
I DON'T HAVE ANYTHING OTHER
THAN TO REMIND THE COMMENT
THAT PAUL MADE.
THERE IS AN OPPORTUNITY TO
INTEGRATE THE REGISTRY WITH
DMRS, AND THAT SEEMS TO BE
UNDERUTILIZED AND THAT MAY BE
SOMETHING WE WANT TO LOOK AT
TOO.
>> I AGREE.
I THINK IT WAS A GREAT
SUMMARY.
-- --
>> GREAT, THANK YOU SESSION 3
FOR YOUR REPORT OUT.
NOW WE ARE GOING TO BRING UP
THE BOARD FOR
THE SUMMARY OF THE DAY.
WHAT YOU WILL SEE HERE IN
THIS
SLIDE IS THAT IT WILL HAVE
THE
CATEGORIES THAT RECEIVED THE
MOST VOTES FROM EACH OF THE
THREE BREAKOUT ROOMS.
AND SO I WILL INVITE THE
WORKSHOP CO-CHAIRS TO TURN ON
THE CAMERAS AND HELP MODERATE
DISCUSSION ON SOME OF THE
THEMES.
ALSO WE ARE NOT SHOWING
YESTERDAY'S TOPICS BUT FOR
THOSE THAT WERE HERE, WE
SHOULD THINK ABOUT WAYS SOME
OF THE TOPICS HERE MAY
OVERLAP
OR HARMONIZE WITH SOME OF
THOSE DISCUSSED YESTERDAY AS
WELL.
---
AND WE WILL INVITE ANYONE TO
PARTICIPATE WITH COMMENTS OR
QUESTIONS IN THE CHAT AND
THEN
ALSO IF ANY OF THE BREAKOUT
MODERATORS OR TODAY'S
SPEAKERS
WANT TO WEIGH IN, YOU ARE
WELCOME TO COME OFF OF MUTE
AND PARTICIPATE AS WELL.
>> MAURA, I WOULD LIKE TO
BOTH
COLLIN AND I ARE UNABLE TO
TURN ON OUR CAMERAS.
>> YEAH I DID MESSAGE OUR A/V
TEAM.
THERE WE GO, I CAN SEE YOU
NOW!
>> I WANT TO THANK EVERYONE
FOR PARTICIPATING, IN SINCE
WE
ARE GETTING TOWARDS THE END
OF
THE MEETING, THERE'S SO MANY
GREAT TOPICS BROUGHT UP IN
THE
LAST TWO DAYS IN THE SPEAKERS
AND THE BREAKOUT SESSIONS AND
SINCE WE ARE WINDING THIS
DOWN,
ONE THING WE SHOULD MAKE SURE
IS THAT IF THERE ARE ANY
TOPICS PEOPLE FEEL WE HAVE
NOT
TALKED ABOUT THAT ARE WORTH
HAVING A FEW MINUTES TO
DISCUSS, I REALLY APPRECIATE
IT.
THINK IT WAS THE LAST
SESSION,
THE LAST BREAKOUT THAT
MENTIONED UNDERSTANDING WHY
THERE ARE VARIABLE RESPONSES
TO HEMPT.
WE DID NOT TALK ABOUT THAT
TOO
MUCH TODAY. WE TALKED ABOUT
PEOPLE NOT BEING ELIGIBLE.
IT IS A REALLY INTERESTING
QUESTION.
SO MANY OF OUR PATIENTS HAVE
RESPONDED TO TRIPLE THERAPY,
BUT IF WE BACK IT UP A SEC,
WHEN WE HAD (INDISCERNIBLE)
WHICH MOST OF US AGREE DID
NOT
HAVE A PROFOUND EFFECT ON THE
PATIENT'S WE DID HAVE A
HANDFUL OF PEOPLE WHO HAD
THOSE THERAPIES THAT WERE
HIGHLY EFFECTIVE SO THERE ARE
DIFFERENCES IN THE WAY
PATIENTS' RESPONSES THAT WAS
ONE TOPIC WE HAVE NOT TALKED
ABOUT, IS THERE AN
OPPORTUNITY
TO BETTER UNDERSTAND AND
OPTIMIZE THESE THERAPIES?
I DON'T KNOW IF THERE ARE
OTHER TOPICS THAT PEOPLE
WANTED TO BRING UP THAT WERE
LESS DISCUSSED.
-- --
RON MENTIONED THAT THEY
TALKED
ABOUT IT IN BREAKOUT 1 AS
WELL
AND THE DOSE SUGGESTIONS AND
PHARMACOGENETICS SUGGESTIONS
AS WELL.
WHAT IS THE RIGHT DOES OF
THIS
MEDICATION?
FOR ADULTS AT LEAST THERE IS
ONE GUIDELINE, AND IN OUR
CLINIC WE ARE THINKING TO
TINKER WITH THAT MAY BE, TO
ORANGE PILLS ONE BLUE PILL
MAY
NOT BE THE BEST FOR ALL,
UNDERSTANDING THAT ONE SIZE
DOES NOT FIT ALL, THAT COULD
BE SOMETHING WE CAN
INVESTIGATE MORE.
JOHN?
>> I WANT TO RESPOND TO YOUR
FIRST COMMENT ABOUT THE NEW
PHENOTYPES.
I THINK THAT AS A FIELD
WE NEED TO GET COORDINATED TO
THINK
10 YEARS FROM NOW WHAT IS IT
WE WISH WE HAD DONE NOW.
ONE OF THE THINGS I THINK
ABOUT,
AS PULLING GENOME INFORMATION
IS GOING TO BE EASIER AND
EASIER,
THE PROCESS AND UNDERSTAND
POLYMORPHISMS OR CHANGES IN
GENE FUNCTION ACROSS
INDIVIDUALS. SOME OF THE
THINGS THAT I THINK WE
TALKED
ABOUT IN THE SESSION I WAS IN
IS HOW TO COORDINATE THE NEW
PHENOTYPES TO THE TDM WHILE
NOT MAKING IT OVERLY
CUMBERSOME.
ARE WE BANKING DNA FROM
PATIENTS THAT ARE YOU GOING
TO
THE TDN OR GOING TO THE
CLINIC
TO GET CARE.
>> I DON'T IF YOU GUYS
DISCUSSED THIS, BUT IF
ANYBODY
WANTS TO DISCUSS THE LEVEL OF
BANKING DNA BECOMES HIGHER
LEVEL OF ISSUE OF CONSENT
WITH
REGULAR SPECIMENS, AND I
DON'T
KNOW IF THAT WOULD COMPLICATE
THINGS.
IF ANYBODY WANTS TO WEIGH IN
ON THAT.
-- --
>> I THINK --
POST-COVID COUGH THERE --
I THINK THAT GROWING UP WITH
THAT SAME GENERAL IDEA,
WHETHER OR NOT WE NEED TO HAVE
MORE PROTOCOLS IN PLACE
TO DO
SORT OF TARGETED COLLECTION
FOR CERTAININFORMATIVE
COHORTS.
FOR INSTANCE, WE HAD A LOT OF
CASE REPORTS OF PEOPLE GOING
OFF OF MODULATORS.
CASE REPORTS, DO WE REALLY
NEED TO DOUBLE DOWN AND START
BUILDING A COHORT?
SHOULD WE BE DOING SOME
COLLECTION OF SAMPLES?
WE COULD BE DOING CASE
STUDIES
IN LOOKING BACK AT SOME OF
THE
MARKERS TO INFORM WHO IS
TOLERATING AND WHO IS NOT.
THAT IS A MORE GENERAL
QUESTION.
>> GARY MIGHT SPEAK GENETICS.
>> IT IS SOMETHING WE HAVE
BEEN TALKING ABOUT FOR SOME
TIME, WHETHER WE SHOULD BANK
DNA.
WE HAVE ADDRESSED THIS ISSUE
ALREADY SEVERAL TIMES WITHIN
THE FOUNDATION.
THERE ARE AGREEMENT TO BE SET
UP WITH DIFFERENT
INSTITUTIONS
BETWEEN UNIVERSITY OF
WASHINGTON, HOPKINS AND
UNIVERSITY OF NORTH CAROLINA,
5000 INDIVIDUALS HAVE GONE
GENOME SEQUENCING AND THERE
HAVE BEEN QUITE A BIT OF NEW
REVELATIONS WITH MODIFIED
GENES, INDIVIDUAL RARE
VARIANTS APPEARED TO BE
INTERESTING IN THESE DATA
SETS
HAVE MADE AVAILABLE TO
EVERYONE WHETHER
IT IS USEFUL TO COLLECT
ADDITIONAL DNA, FOR EXAMPLE
THE CHECK ON THE C STUDY
WILL
BE INTERESTING BECAUSE YOU
CAN
LOOK AT THE ISSUE OF
PHARMACODYNAMICS,
INDIVIDUALS WHO HAD A GOOD
RESPONSE IN SWEAT CHLORIDES
VERSUS POOR RESPONSE IN
RESPONSE TO THE TRIPLE
COMBINATION.
---
GENETIC MARKERS OF DRUG
METABOLISM CLEARLY WELL
WORKED
OUT FOR A VARIETY OF
DIFFERENT
COMPOUNDS.
I WOULD THINK THAT FOR
(INDISCERNIBLE) AND THE OTHER
MODULATORS THERE ARE LIKELY
TO
BE A VARIANCE THAT HUMANS
CARRY THAT WOULD CHANGE THE
RATE OF METABOLISM AND WE
COULD DO THE STUDY IF WE
WANT,
WE JUST NEED HIGH-QUALITY
PHENOTYPING.
OBTAINING THE DNA SIMPLER,
JUST KNOWING WHEN THE PATIENT
WAS ON THE DRUG, OFF THE DRUG
OR HAD A PROBLEM WITH THE
DRUG. AND IT WOULD COLLECT
THE
DATA WE COULD ADDRESS A
VARIETY OF OTHER THINGS
REGARDING NOT ONLY CF ITSELF
BUT THE OTHER GENES THAT
CONTRIBUTE TO THE VARIATION
BUT INCOMING FROM THE POINT
OF VIEW AS A MEDICAL
GENETICIST SO ADMIT MY BIAS,
I
DO LOOK THROUGH THE LENS OF
THE GENOME BUT IT IS
SOMETHING
THAT WE COLLECT IS NOW WE
WILL
DO THIS FROM THE PERSPECTIVE
OF BEING AVAILABLE TO THE
STUDIES.
CHINA?
>> THANK YOU GARY.
ARE YOU SPEAKING ON THE
SPECIFIC ISSUE?
>> YES I AM.
I THINK THAT WE PROBABLY NEED
TO THINK BIGGER THAN DNA
BECAUSE YOU KNOW THERE'S BEEN
A FANTASTIC AMOUNT OF
INFORMATION THAT HAS COME OUT
OF THE DNA SEQUENCE.
WHAT WE REALLY NEED TO BE
LOOKING AT, TRANSCRIPTOMIC,
MAY BE EPIGENETIC CHANGES. WE
WON'T GET THAT INFORMATION
JUST BY BANKING DNA.
TESTING MORE BROADLY
ABOUT WHAT ARE THE QUESTIONS
WE ARE ASKING,
AND REALLY WHAT ARE THE
MOLECULAR AGENTS WE NEED TO
ASK.
>> THAT WAS SOMETHING THAT
CAME UP IN OUR GROUP AS WELL.
IT IS ONE THING TO FREE
SAMPLES,
BUT DO WE WANT TO PUT THEM IN
RNA LATER SO WE CAN DO
(INDISCERNIBLE) -- DO WE NEED
TO LOOK AT CELLS?
>> YOU CANNOT BUY BIOPS THE
LIVER, ONE OF THE MOST
IMPORTANT ONES. THAT ARE
PRACTICALITIES
TO WHAT WE ARE ABLE TO DO ON
THE COST BUT WE NEED TO START
SOMEWHERE AND I THINK HEARING
THE CF PATIENTS, PEOPLE WITH
CF TALK ABOUT WHAT THEY'RE
GOING THROUGH, I THINK
ESPECIALLY THE ONES THAT ARE
HAVING PROBLEMS IN THE UNIQUE
PHENOTYPES AND MODULATORS
WOULD BE MORE THAN HAPPY TO
FILL OUT DETAILED PHENOTYPIC
DATA, OR ASSIST IN GETTING IT
ENTERED AND ACCURATE.
BECAUSE I KNOW IT IS A BURDEN
FOR THE DOCS.
>> I THINK WE MIGHT MISS THE
KEY FEATURES. OBVIOUSLY DNA
IS
EASIEST ACCESS AND IT WILL
TELL US ABOUT CERTAIN THINGS
IN OLD TISSUES,
GOES BACK MANY YEARS.
THE CFTR GENE WOULD NOT BE
FOUND IF WE WERE NOT WORKING
ON THE GENES THAT EXPRESSED
IT.
SO IF WE ARE WANTING TO LOOK
FORWARD 10 YEARS,
WHAT WOULD WE WISH WE HAD
DONE?
I THINK THAT WILL BE A VERY
IMPORTANT THING.
>> I'D LIKE TO GIVE GOSHAN
(PHONETIC)
A CHANCE TO TALK.
HE HAS BEEN PATIENTLY
WAITING.
>> THANK YOU FOR THIS
WONDERFUL SYMPOSIUM.
PROBABLY WHAT IS MISSING IS
THE IMMUNE EFFECT.
APPARENTLY PATIENTS CAN BE
INFECTED.
AFTER THE INFECTION THE
INFORMATION TYPICALLY IS THE
IMMUNE DEFECT.
SO SINCE WE ARE TALKING ABOUT
A FUTURE RESEARCH.
THIS PROBABLY IS ONE OF THE
MOST IMPORTANT AREAS AND AN
UNDERSTUDIED AREA.
WITHOUT A GOOD, STRONG,
COMPETENT IMMUNE SYSTEM, THE
PATIENTS WILL HAVE HIGHLY
INFLAMMATORY RESPONSE AND
MANIFESTATION.
AND APPARENTLY NEUTROPHILS
AND
MONOCYTES, MACROPHAGES OF THE
MOST IMPORTANT DEFENSE IN THE
LUNG.
THEY ARE THE PREDOMINANT
NUMBERS IN THE DISEASE TO
LUNG.
I WOULD ADD THIS POINT.
HOPEFULLY WE WILL DRAW SOME
ATTENTION TO THIS AREA.
>> THANK YOU FOR BRINGING
THAT
UP.
DO YOU WANT TO SPEAK TO IF
YOU
THINK SOME OF THESE IMMUNE
DEFECTS WILL BE CORRECTED BY
MODULATORS?
>> THAT IS A COMPLICATED
ISSUE.
WHEN THE IMMUNE CELLS RECRUIT
TO THE LUNG AND THE DRUG
LEVELS OR ACTION MODE MAY BE
DIFFERENT AND THEY ARE NOT AS
EFFECTIVE AS IN THE BLOOD.
SO THEREFORE, THAT IS WHY THE
MODULATOR SEROTY ARE NOT
COMPLETELY EFFECTIVE LEAVING
THE IMMUNE CELLS OUT, THAT IS
A PROBLEM FOR THE FIELD.
>> SINCE WE ARE SPEAKING OF
IMMUNE CELLS, I DON'T KNOW IF
JAY COLES ONCE ARGUE THAT
T-17
CELLS OF THE MOST IMPORTANT
CELLS FOR THE RESPONSE. I
AGREE. I AM A NATIVE INDIAN
PERSON AND I THINK THAT
UNDERSTANDING HOW IMMUNE
CELLS
CONTRIBUTE TO INFLAMMATION IS
IMPORTANT BUT THERE ARE MANY
IMMUNE CELLS. THAT WAS A
TOPIC.
INFORMATION CAME UP MANY
TIMES, I THINK IN THE LAST
TWO
DAYS, SPECIFICALLY DISCUSSING
MEDIATORS OF INFLAMMATION AT
A
CELLULAR/MOLECULAR LEVEL WITH
NOT TALK ABOUT IT AS MUCH BUT
AN IMPORTANT AREA.
>> THANK YOU.
>> ONE OF THE HOT TOPICS HERE
IN TERMS OF THE LONG-TERM
RISKS OF AGMT, TRYING TO POST
OR UNDERSTAND THE QUESTION
OF,
DO WE REALLY HAVE THE RIGHT
TOOLS IN PLACE TO MONITOR
THESE RISKS?
THAT TO ME POINTS TO A MORE
OF
AN AP-SURVEILLANCE TYPE OF
DATABASE, SOMETHING WE HAVE
NEVER DONE BEFORE AND THERE
ARE CHALLENGES OF COURSE
SORTING OUT WHAT IS RELATED
TO
TRIKAFTA VERSUS THE DISEASE
ITSELF BUT IF YOU STEP BACK
COLLECTING THE DATA COULD BE
A
VERY IMPORTANT RESOURCE,
AS WE ARE DEVELOPING THE
GENETIC THERAPIES AND WE ARE
GOING TO NEED SOME REALLY
GOOD
COMPARATIVE DATA TO COMPARE
SOME OF THE LONG-TERM RISKS
OF
THE GENETIC THERAPIES.
AND WHAT TYPES OF OUTCOMES
SHOULD WE BE CLOSELY
CAPTURING,
AND HAVE DATA ON IN OUR
PATIENTS TO SET US UP FOR
THAT
AS WELL.
---
IF I COULD PIGGYBACK ON THAT,
THINKING ABOUT IF WE ARE
MOVING TO TRIKAFTA IN THREE
MONTH OLD AND WHETHER OR NOT
WE SHOULD HAVE MORE EMPHASIS
ON NEUROCOGNITIVE EVALUATION
OR THINGS OF THAT NATURE,
DEVELOPMENTAL ASSESSMENTS; I
KNOW THAT WE HAD CFTR QUALITY
OF LIFE ASSESSMENTS BUT THAT
IS DIFFERENT THAN THINKING
ABOUT EITHER MENTAL HEALTH OR
COGNITIVE/BEHAVIORAL IMPACTS
THAT I THINK A LOT OF US
EXPRESSED CONCERN FOR IN OUR
BREAKOUT SESSION.
>> THIS IS BONNIE.
CAN YOU HEAR ME?
>> YES.
>> WE HAVE THE WHOLE ISSUE OF
SAFETY WHICH IS INTERESTING
BECAUSE WE WERE PLANNING
BEGINNING WITH YOUNGER KIDS,
WE ARE NOT LOOKING AT THE
SAFETY OF THE DRUG,
SPECIFICALLY NOT COLLECTING
ADVERSE EVENTS FROM THE DRUG
BECAUSE IT WOULD BE A VERY
DIFFERENT APPROACH WE STARTED
TO DO THAT AND SO WE ARE
GETTING HISTORY.
BUT IN THE PAST WE HAVEN'T
REALLY THOUGHT ABOUT DOING
THAT
BUT I THINK IT IS VERY
INTERESTING THAT YOU BRING IT
UP.
WE DID DISCUSS THE
NEUROCOGNITIVE A LOT, WE
LOOKED INTO IT AND INTO THE
FEASIBILITY OF IT.
THE PROBLEM IS YOU HAVE TO
HAVE TRAINED PSYCHOLOGISTS
DOING A LOT OF THESE TESTS.
IT IS INCREDIBLY IMPORTANT
BUT
IT WOULD HAVE TO BE A
SUBGROUP, REALLY
UNDERSTANDING
WHAT TESTS, AT WHAT TIME AND
WHO IS GOING TO DO IT.
SO I THINK IT IS PROBABLY
WORTH THE INVESTMENT BUT IT
IS
NOT LIKE GETTING
(INDISCERNIBLE).
>> SUE?
>> THANK YOU VERY MUCH.
I WANT TO POINT OUT SOMETHING
THAT I NOTED IN THE
CONVERSATIONS YESTERDAY AND
TODAY, THE IDEA THAT NEW CF.
THERE WAS AN ANALOGY MADE TO
PULMONARY DYSPLASIA,
TRANSITIONING FROM THE OLD TO
THE NEW. I THINK IT WAS A
GOOD
ANALOGY. I WANT TO SAY THAT
WHAT WE KNOW ABOUT CF IN THE
PAST HAS BEEN BASED ON
ANALYSIS OF LUNG EXPLANTS.
AND WE ARE NOT RECEIVING
THOSE
THESE DAYS, THAT IS A GOOD
THING.
BUT IF WE'RE GOING TO
CHARACTERIZE WHAT I ALLOW
MYSELF TO CALL THE NEW CF, WE
NEED A SOURCE OF CELLS AND
TISSUE.
AND HOW WE CAN COLLECT THE
SAMPLES
I THINK SHOULD BE SOMETHING
THAT SHOULD BE PUT ON THE
LIST
OF TO-DO'S.
AND AGAIN THERE WAS A LONG
DISCUSSION ABOUT THINKING
(CORRECTION) BANKING DNA,
BANKING CHROMATIN,
COLLECT CELLS FROM DIFFERENT
REGIONS OF THE AIRWAY, AND
ALSO OTHER TISSUES SO WE CAN
REALLY UNDERSTAND WHAT IS
GOING ON WITH CF IN THE AGE
OF
HTMT.
THANK YOU.
>> THANK YOU SUE.
ARE THERE OTHER TOPICS THAT
PEOPLE FEEL MAY HAVE BEEN
MISSED TODAY OR YESTERDAY?
THIS IDEA OF BANKING HAS BEEN
-- LIKE WHAT JOHN SAID, IN 10
YEARS WHAT WOULD WE THINK OF
WE SHOULD HAVE DONE?
REPOSITORIES OBVIOUSLY THERE
IS A FUNDING ISSUE.
THE ONE THING THIS COMMUNITY
IS SO GOOD AT IS WORKING AS A
TEAM.
OBVIOUSLY, THERE ARE PATIENTS
ALL OVER THE COUNTRY, AND IN
ORDER TO DO A LOT OF THE
CLINICAL TRIALS WE HAVE HAD
TO
WORK AS A TEAM AND IT SEEMS
THAT THESE NEW STUDIES
WHETHER
CLINICAL TRIALS ARE USING
SAMPLES TO DISCOVER NEW
BIOMARKERS AND NEW END POINTS
SOMETHING WE CAN DO WELL AS
TEAMS, AND THIS CAME UP
YESTERDAY DURING THE FINAL
DISCUSSION AS WELL BECAUSE
PART OF THE TEAM IS THE BASIC
SCIENTISTS, AND THIS IS WHAT
HAS BEEN GREAT ABOUT THIS
MEETING PEOPLE WHO CAN SAY OH
I CAN DO THIS IN MY -- MODEL
OR IN MY IN VITRO MODEL,
PEOPLE WHO CAN MODEL UNDER
THE
STATISTICS AND WITH
CLINICIANS.
AND THE IDEA THAT WE ARE
TALKING ABOUT, NEW GUIDELINES
AND PARADIGM SHIFTING ABOUT
HOW WE THINK ABOUT A LOT OF
THINGS.
THAT WAS A LOT OF TOPICS I
THROUGHOUT AT ONCE.
I DON'T KNOW IF ANYBODY ELSE
WANTS TO EXTRAPOLATE FURTHER.
JOHN, YOUR MICROPHONE IS
LIVE.
I THOUGHT MAYBE YOU HAD
SOMETHING TO SAY.
>> I WAS READING THE CHAT AS
YOU WERE TALKING TOO ABOUT
THE
BANKING OF SAMPLES AND HAVING
NASAL EPITHELIUM EASY TO GET.
AND IN MY HEAD, HAVING HEARD
SOME OF THE STORIES, HOW
CELLS
IN VITRO THAT MIGHT BE
POLARIZED FROM THE NOSE, HOW
THOSE AIRWAY EPITHELS WORK,
MODERATORS.
IS THAT GOING TO INFORM WHITE
PERSON HAS MIGRAINES OR THEIR
LIVER FUNCTION TESTS WERE UP?
WHAT I STRUGGLE WITH IS THAT
THE HIGHLY EFFECTIVE
MODULATORS ARE AFFECTING THE
ENTIRE BODY,
AND A LOT OF ORGANS AFFECT
CF,
SOME DOING BETTER AND SOME
WORSE.
HOW DO YOU COORDINATE
THINKING
ABOUT THAT MULTIORGAN
COMMUNICATION AND SO FORTH TO
UNDERSTAND WHAT IS AT THE
ROOT
OF THAT AND HOW CAN YOU
PREDICT IT IN A PARTICULAR
PATIENT?
NOT TOTALLY EXACTLY IN
RESPONSE TO WHAT YOU WERE
SAYING KATIE.
I DON'T KNOW THE ANSWER BUT
STARTING WITH ORGANIZING WHAT
THE PHENOTYPES ARE, AND AS
MUCH CLINICAL DATA FOR THE
BASIC RESEARCHERS TOO SO THEY
CAN THINK ABOUT THE QUESTIONS
AND FORMULATE HYPOTHESES THAT
HOPEFULLY WILL BE CLINICALLY
RELEVANT WHEN TESTED IN
ANIMAL
MODELS.
I AM STRUGGLING WITH THAT.
I DON'T FEEL IT CAME OUT WITH
THAT LIST AFTER THIS ENTIRE
MEETING.
I THINK IT IS MAINLY BECAUSE
PEOPLE LIKE CHRIS
THAT WERE TALKING ABOUT
YOU KNOW THE VARIOUS CASE
STUDIES, IT IS NOT BEING
ORGANIZED
IN SOME SORT OF WAY
INDEFINITELY
THIS IS WHERE THE CF
FOUNDATION SHOULD BE ABLE TO
HELP.
>> SO YOU ARE SAYING IN TERMS
OF ADVERSE EFFECTS OR OFF
TARGET POTENTIALLY WE HAVE
BEEN SEEING CASE REPORTS AND
IF WE COULD AGGREGATE THAT
DATA?
>> YEAH.
THAT INCLUDING PATIENTS THAT
ARE DOING BETTER WHEN THEY
COME OFF.
IT IS AMAZING TO KEEP LUNG
FUNCTION.
THERE ARE A LOT OF QUESTIONS
ABOUT HOW THIS CAN BE TACKLED
I THINK IN A NUMBER OF ANIMAL
MODELS THAT HAVE ALREADY BEEN
MADE.
I AM HAVING TROUBLE
FORMULATING WHAT IS MOST
CLINICALLY PRESSING
FOR THE COMMUNITY.
>> I WOULD SECOND THAT.
IF THE ANIMAL MODELS ARE
GOING
TO KEEP PACE WITH CLINICAL
EXPERIENCE WE HAVE TO HAVE
SORT OF
REGULAR CONVERSATIONS ABOUT
WHAT CLINICAL EXPERIENCE IS.
OTHERWISE I AM AFRAID THAT
THE
ANIMAL SPACE WILL BE ASKING
OLD QUESTIONS, OR NOT THE
MOST
RELEVANT QUESTIONS.
>> GOOD POINT.
COMMUNICATION AND DIALOGUE.
OBVIOUSLY WE HAVE OUR
SCIENTIFIC MEETINGS BUT
MAYBE,
A MORE CENTRAL REPOSITORY OF
THESE CONCERNS.
>> AND IS A WHITE PAPER COMES
OUT OF THIS RFA, LISTING
THOSE
QUESTIONS AND THE PRESSING
AREAS WILL BE VERY IMPORTANT.
JP YOU HAVE YOUR HAND UP.
>> THIS IS A NEW PARADIGM
WHERE ALL OF A SUDDEN THE
CLINICAL CARE HAS SHIFTED
INDEPENDENTLY OF THE ANIMAL
MODELS.
ALL OF A SUDDEN THE
INFORMATION FLOW HAS TO GO IN
THE OTHER DIRECTION.
IT SHOULD GO IN BOTH
DIRECTIONS. OH, WE ARE SEEING
THIS IN THE CLINIC.
HOW CAN OUR ANIMALS HELP US
UNDERSTAND THIS BETTER?
IT CREATES A NEW PARADIGM.
IT IS EXCITING BUT IT
REQUIRES
THINKING ABOUT ENSURING THAT
THOSE DIALOGUES HAPPEN IN THE
WAY THAT THEY NEED TO.
>> I DO THINK THAT ONE THING
-- LOOKING AT THE CHAT -- ONE
THING THAT WE ARE LOOKING
ABOUT IS WE HAVE THE
REGISTRY.
IT DOES TAKE HUMAN
EFFORT TO ADD IN NEW
CATEGORIES AND NEW DATA,
IT IS HEAVY LIFTING TO GET
EMRS TO TALK TO THE REGISTRY
BUT I THINK
MOST CENTERS HAVE AN
INDIVIDUAL DEDICATED TO THAT.
MANY OF THE
CENTERS HAVE AN INDIVIDUAL
DEDICATED TO DATA ENTRY,
NOT TRIVIAL TASK THAT WE HAVE
INFRASTRUCTURE BUILT IN.
DO WE WANT TO ADD MORE
CATEGORIES TO WHAT IS IN THE
REGISTRY SO WE CAN HAVE AN
IDEA OF ARE THERE ADVERSE
EFFECTS?
ARE THERE PEOPLE WHO HAVE HAD
BETTER OR WORSE RESPONSES?
AND THAT IS IN THE REGISTRY
FOR STUDY.
>> I WAS GOING TO SAY, THAT
IS
THE OTHER VISA WAS GOING TO
WEIGH IN, BUT I SHUT UP.
THE DECISIONS ABOUT WHAT GETS
ADDED TO THE REGISTRY,
CAREFULLY THOUGHT OUT BECAUSE
THERE'S ALWAYS A RISK OF
DIMINISHING RETURN WHEN YOU
HAVE TOO MUCH INFORMATION.
THAT BEING SAID THERE HAS
BEEN
SOME SUCCESS USING SOME
ENHANCED REGISTRY COLLECTION
AROUND SPECIAL EVENTS IN
POPULATION.
I THINK THAT IS GREAT
FEEDBACK
THAT CAN BE TAKEN BACK TO THE
REGISTER TEAM.
>> JOHN?
>> ONE OTHER THING WITH HIS
AUDIENCE.
IT WOULD BE GOOD TO MENTION
--
SHIFTING GEARS A LITTLE BIT
--
AT THE NIH CFRD WORKSHOP
SIMILAR TO THIS, AFTER
HEARING
THE PATIENT TALK ABOUT HER
EXPERIENCE, I CAME AWAY --
MOST CAME AWAY WITH THE
MEETING -- THAT THE CLINICIAN
THAT WE NEED TO TRYING TO
TAKE
CARE OF CF PATIENTS, IN THAT
PARTICULAR AREA THERE WAS
POOR
COMMUNICATION BETWEEN
PULMONARY, INTERNAL MEDICINE
AND ENDOCRINE FOR EXAMPLE.
AND AS I HEAR ABOUT ALL THE
OTHER PHENOTYPES THAT ARE
EMERGING, OBESITY, MENTAL
ILLNESS, THAT IS SOMETHING
THAT WE MAY WANT TO TRY
TO EMPHASIZE COMING OUT OF
THIS MEETING.
THAT THE TYPE OF CLINICIAN
THAT NEEDS TO BE TRAINED TO
PROVIDE SPECIALIST CARE OF CF
PATIENTS NEEDS TO BE
RETHOUGHT.
I DON'T KNOW WHAT THAT MEANS
BECAUSE I AM NOT A CLINICIAN
BUT THE CF FOUNDATION HAS
SOME
REALLY GOOD PROGRAMS AND
FELLOWSHIPS THAT MIGHT BE
HELPFUL.
>> WE HAVE -- IS EVERYONE
ABLE
TO TURN UNDER MIC?
OR JUST THE SPEAKERS?
>> EVERYONE.
>> BECAUSE WE HAD SOMEONE IN
CHAT TO JOIN US TO TALK ABOUT
THE SUBJECT.
ELIAH? (PHONETIC)
>> I CAN TALK BUT I CANNOT
SHOW MY VIDEO. SORRY.
THANK YOU FOR LETTING ME
TALK.
I CAN SHOW MY VIDEO.
HI.
SO, I'M A PEDIATRIC
GASTROENTEROLOGIST FROM THE
UNIVERSITY OF IOWA AND
COLLABORATE WITH JOHN
ENGELHARDT ACTUALLY FOR SOME
OF THE BASIC SCIENCE STUDIES
IN FERRETS AND PIGS.
I'M THE MAIN PI OF THE
(INDISCERNIBLE) STUDY, GOING
ON FOR OVER 10 YEARS, SO WE
HAVE A COHORT OF CHILDREN
WITH
ACUTE AND CHRONIC
PANCREATITIS.
WE HAVE OVER 800 CHILDREN
THAT
WE HAVE BEEN FOLLOWING FOR A
WHILE.
AND ABOUT 1/3 HAVE CFTR
MUTATIONS; SOME HAVE CF, SO
THEY HAVE TO BE PANCREATIC
SUFFICIENT OF COURSE TO
CONTINUE TO HAVE PANCREATITIS.
IT IS A VERY IMPACTFUL
DISEASE.
SO THEY HAVE -- PANCREATITIS
AND OVERTIME IT WILL TURN
INTO
CHRONIC PANCREATITIS.
WE HAVE PEDIATRICS AND ADULTS
AND OF COURSE IT IS PANCREAS
FOCUSED LOOKING POSSIBLY FOR
BIOMARKERS AND PANCREAS IS AT
A DISADVANTAGE IN THAT WE DO
NOT HAVE VERY GOOD END POINTS
TO DECIDE WHAT IS EXACTLY THE
RIGHT THING TO REALLY DECIDE
WHAT IS THE BEST WAY TO SEE
HOW THE PANCREAS DAMAGE
OCCURS
AND THAT IS ONE OF THE RECENT
BEEN INVOLVED WITH A PIG
MODEL
AND THE FERRET MODEL.
IF SOMETHING COMES UP I WILL
BE HAPPY TO SHARE WITH THE CF
COMMUNITY.
WE ARE IMPRESSED WITH THE CF
FOUNDATION AND HOW THE CFTR
MODULATORS HAVE EVOLVED.
THERE ARE OF COURSE GREAT
CASE
REPORTS IN PEDIATRICS AND
ADULT HOW CFTR MODULATORS
HAVE
BEEN SUCCESSFUL IN DECREASING
THE NUMBER OF PANCREATITIS
ATTACKS IN PATIENTS, AND
BEING
PANCREATIC SUFFICIENT.
UNFORTUNATELY THAT HAS NOT
HELPED US INSPIRING THE
PHARMA
IN GETTING THIS FOR THE
PEDIATRIC PATIENTS.
BUT PEDIATRIC PANCREATITIS IS
MOSTLY A GENETIC DISEASE, 1/3
OF THE PATIENTS OUT OF THE
800
PATIENTS THAT WE HAVE IN THIS
COHORT HAVE A CFTR MUTATION.
SO THOSE PATIENTS ARE
DESPERATE FOR TREATMENT.
AND WE ARE HOPING THAT WE CAN
AT SOME POINT MAKE THAT
AVAILABLE TO OUR PATIENTS.
THANK YOU FOR LETTING ME
TALK.
>> THANK YOU FOR THAT
PERSPECTIVE.
>> WE HAVE ABOUT THREE
MINUTES
BEFORE THE MEETING IS
SUPPOSED
TO CLOSE. I INVITE TO
PARTICIPATE IN THE AUDIENCE
IF
YOU HAVE ANY COMMENTS YOU
WANT
TO RAISE PUT THEM IN THE
CHAT.
OBVIOUSLY WE WILL NOT GET TO
THEM THE LAST THREE MINUTES
BUT WE ARE COLLECTING THE
CHAT
TOGETHER WITH THE INFORMATION
WE HAVE BEEN TAKING
THROUGHOUT
THE MEETING AND WE WILL
RECONVENE THIS WORKSHOP
PLANNING TEAM TO DISCUSS IT.
AND ALSO WE MAY END UP
CALLING
ON SOME OF YOU ALL OLD AS
SUBJECT MATTER EXPERTS, WE
MAY
NEED ADDITIONAL INFORMATION
FROM A COMMUNITY PERSPECTIVE
ABOUT WHAT WE NEED TO DO AND
THE OPPORTUNITY TO MOVE
RESEARCH FORWARD IN THE
FIELD.
I WILL LEAVE THE CHAT OPEN
HERE FOR THE NEXT COUPLE OF
MINUTES AND THEN DEFER BACK
TO
OUR WORKSHOP COCHAIRS TO SEE
IF THEY HAVE ANY CLOSING
REMARKS, THEY WOULD LIKE TO
ADD.
>> I WILL JUMP IN.
FIRST OF ALL WE NEED TO
THINK
EVERYBODY FOR THIS 2-DAY
INCREDIBLE MARATHON.
WE HAVE A LOT OF WORK TO DO.
WE NEED EVERYBODY.
WE NEED A NEW PIPELINE.
WE NEED YOU RESEARCHERS TO
COME INTO THE PIPELINE SO AS
MUCH AS YOU CAN INSPIRE AND
EXPAND THAT WILL BE ONE OF
OUR
CHALLENGES MOVING INTO THE
FUTURE.
I REALLY WANT TO THANK THE
NIH, AND YOU IN PARTICULAR
MARRAH FOR ENVISIONING THIS
CONFERENCE AND THANK YOU FOR
BRINGING US TOGETHER AND WE
LOOK FORWARD TO THE NEXT
STEPS.
THIS IS A CONTINUATION OF
JUST
A WHOLE NEW WORLD AS WE MOVE
FORWARD WITH OUR RESEARCH.
I AM INSPIRED AND I HOPE
EVERYBODY ELSE IS TO CONTINUE
THIS IMPORTANT WORK.
>> YEAH AND I WILL PIGGYBACK
ON THAT.
AS I MENTIONED TO YOU ALL IN
OUR EARLY CONVERSATIONS, THIS
WAS A BIG TASK.
THERE ARE A LOT OF TOPICS
THAT
WERE COVERED.
THERE ARE SOME THINGS THAT
MAYBE WE DID NOT SUFFICIENTLY
COVER, BUT THAT IS WHAT WE
HAVE ALL OF THESE RESOURCE
MATERIALS THAT WE WILL LOOK
AT
AND I THINK THERE IS
POTENTIAL
FOR ADDITIONAL PROGRAMMING
THE
FUTURE.
THAT CAN BE A LOT OF
DIFFERENT
THINGS.
IT CAN BE STATEMENT PAPERS
FROM YOU IN THE COMMUNITY,
FUNDING OPPORTUNITIES THAT
OUR
ORGANIZATIONS THINK ABOUT
HERE
AT THE NIH OR THE CYSTIC
FIBROSIS FOUNDATION,
IT COULD ALSO BE ADDITIONAL
WORKSHOPS OR EVEN FORMING NEW
PARTNERSHIPS AND
RELATIONSHIPS
THAT WE NEED TO HAVE IN ORDER
TO ADDRESS SOME OF THESE
GAPS.
WE ARE GOING TO BE THINKING
ABOUT THESE CREATIVELY AND AS
I MENTIONED BOTH DAYS, MY
EMAIL BOXES OPEN TO ANYBODY.
IF YOU WANT TO EMAIL ME AND
YOU HAVE IDEAS
OUT-OF-THE-BOX,
IN THE BOX I AM HAPPY TO HEAR
IT.
>> I WANT TO THANK ALL OF THE
SPEAKERS AND ATTENDEES FOR
THIS REALLY INTERACTIONAL
MEETING.
ALL OF THE CONTRIBUTIONS OF
THE CHAT AND THE QUESTIONS
AND
THE BREAKOUTS REALLY MADE
THIS
A REALLY INFORMATIVE MEETING.
THANK YOU TO EVERYBODY.
>> I ECHO ALL THE COMMENTS.
IT HAS BEEN GREAT.
THANKS TO EVERYBODY.
>> ALL RIGHT. THANK YOU.
ONE LAST THING BEFORE
EVERYONE
LEAVES. OUR WORKSHOP SUPPORT
TEAM
IS DROPPING IN A SURVEY FOR
THIS WORKSHOP AND WE WOULD
LIKE YOUR FEEDBACK AND YOU
WILL ALSO RECEIVE THIS VIA
EMAIL AND IF YOU WOULD ANSWER
THE SURVEY IT WOULD HELP US A
LOT AND HELP US STRUCTURE
FUTURE WORKSHOPS HERE AT THE
NHLBI.
AND ONE MORE THING I WANT TO
GIVE TO THE CYSTIC FIBROSIS
FOUNDATION, THE NIAID AND
NIDDK ARE IN THE PLANNING
TEAM
AND WOULD NOT BE ABLE TO DO
THIS WITHOUT YOUR
PARTICIPATION SUPPORT. THANK
YOU,
AND I REALLY APPRECIATE THE
PARTNERSHIP THAT WE HAVE AND
WITH THAT I WILL LET EVERYONE
GO AND WISH EVERYONE A HAPPY
WEEKEND.
THANK YOU.