>>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 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.