Chapters Transcript Video Breathing Hope: Advancements in Pediatric Cystic Fibrosis Care So today it is my pleasure to introduce our own Doctor Elizabeth Gibb, um, a pediatric pulmonologist who serves the needs of our community here at UCSF Benioff Children's Hospital, Oakland. Uh, prior to joining us, she completed her medical training at Harvard School of Medicine, followed by pediatric residency and then a pediatric pulmonology fellowship at UCSF. She specializes in treating a broad range of chronic lung disease such as asthma, bronchopulmonary dysplasia, interstitial lung disease, sleep apnea. And respiratory conditions related to neuromuscular disease and the highlight of this talk, cystic fibrosis. Um, so please join me in welcoming Doctor Elizabeth Gib. I'll hand it over to you now. Thanks, Sarah. Thanks for having me. Um, let's see. Here we go. Um, I was asked to talk about cystic fibrosis today. Um, it's a really exciting time to talk about cystic fibrosis in 2025, so hopefully this is new. I know that Doctor Huang talked about GI cystic fibrosis manifestations really recently, so hopefully you're all super excited to hear more about CFTR modulators and changing landscape and pediatric CF. Um, my disclosure certainly have nothing to disclose, unfortunately. Um, so we'll talk a little bit about genes and, um, you know, the basics for CF, but we're gonna really focus on what CF is looking like in 2025 and CFTR modulators, which have really changed the landscape of CF, um, but we'll talk a lot about the future of CF therapies too, so there are patients who do not have a highly effective modulator and really what the future of CF therapies is, um, going to look like. So we all learned in medical school that you have two parents who are carriers and um mom passes on one gene to the child, the dad passes the other gene to the child, and there's a 25% chance that you have an affected patient, affected child, 25% that they didn't inherit either gene, um, and 50% would be carriers. Um, of course, it's a lot more um complicated than that. In real life, we have families that have multiple children and they might have different phenotypes, might be different severity. So it's really more something along this model where you have allele 1 from one parent, allele 2 from the other parent, and then there's all these modifier genes, environmental factors and outcomes um a phenotype. There, uh, the gene was discovered in 1989, um, and there are over 2000 mutations, um, in the CFTR2 database, which is a great place to look if you ever get a newborn screen and you're like, oh, I've never heard of that one before. Um, I do that all the time, look it up, has it been described in other cases. But it's pretty complicated, you know, for just a single single gene, you have all these different mutations and they can act very differently. Um, we have to go back a little bit to our biochemistry class just to understand how modulators work. So, looking back at the model of having your DNA, right, so we have our mutation, it's going to be transcribed into mRNA and then it's going to be translated into a protein that needs to be folded. And modified and then it needs to be inserted into the membrane because the CFTR protein is a salt transporter. It's present in all the cells in our body. Um, and so in order to have a functional one, it needs to go through all these steps in the right way and then be inserted into the membrane. So in different cells, the transporter can be facing different directions, um, for a lot of the pathology with sticky mucus being like cough and sinus infections and clogging up pancreatic ducts, we're thinking about sticky mucus clogging things up and how the fluoride is not able to come out of the transporter, and then the water can't follow the salt, and so you end up with this really what they say dehydrated airway surface liquid, that's that brown mucus over on the side. But we also take advantage of this for the sweat test. So in our, um, the cells in our skin, the, we are taking advantage of the fact that you get too much chloride and so a sweat test for an affected CF patient is usually over 60, but for a lot of the severe mutations, about 100, um, whereas for a carrier, it would be about 30, and a lot of us who don't carry any CFTR mutations, it would be probably under 10. CF can affect all the um cells in the body. Um, we think a lot about lungs. Of course, I think a lot about lungs, but also nutrition, um, but it can also affect other things, um, like the bones and arthritis and um fertility. So really affecting everything. Um, I don't know if you guys have all been watching the Bob Dylan movie. My son's super into it these days, so the times they are changing, and, um, back in the old days, this would be sort of the typical child that would present with cystic fibrosis. Um, somewhere along the line, we lost the messaging and it became this is a white person's disease, which is definitely not true, um, but you'd have this very malnourished child with really wasted. Remedies, a big belly, and severe lung disease already at a young age. Um, that is not what I see in CF. Thankfully these days, what I see are healthy babies who are referred with abnormal newborn screens, and this is how you do a sweat test with this little watch-like thing here. And, um, patients with CF come from all races and ethnicities. So, um, we wanted to include some of that here. And then really now that um people with cystic fibrosis are living longer, um, I wanted to add this person here who is a parent with cystic fibrosis, um, and, uh, that's been a really exciting part of the recent history with CF. So, um, as I mentioned, most patients with cystic fibrosis are now diagnosed on the newborn screen. Um, the CF Foundation, um, and Doctor McCauley, um, in Chicago has been really looking at the time of first CF event, which could be your first visit at the CF center, your sweat test, um, and trying to improve that because there's a lot of evidence that treating CF earlier, um, particularly for those, um, with severe mutations where malnutrition very early on. can set you up um for poor outcomes. It's really important to get into the CF center early. Um, interestingly enough, so the average across the country is in the 20s, but, um, California, we have, I'd say a good newborn screen, but we have a slow newborn screen. We're going to be working on improving that, but, um, a lot of the positive newborn screens that we will find or you'll find in your clinics are coming at about 2 months. So we're, um, actually about 1 month later than almost the, the median of the rest of the country. Um, so, as I said, some are diagnosed prenatally, but most are diagnosed on newborn screen now. Um, the California CF newborn screen currently has three steps. The first is an IRT, which happens on the blood spot, um, in the hospital. We have a fixed cutoff to um refer to the panel, the CFTR panel, if you're in the top 1.6%. Interestingly enough, of course, there's like racial differences in IRT. You can also have a high IRT if you've had a stressful um delivery, so sometimes we see a false positive um there, and then um a patient will get our California specific panel which has over 70 variants. We started um in 2007, um with uh 30 mutations. So if you come up positive with 2 on panel, you get a mailer and you probably get that in around 20 days. Um, if one variant is identified, then we go to a third step in California, which is sequencing. And this is what is currently really slow and adds a month to our um diagnosis time here in California. So if you end up finding a second variant, um, you'll get a mailer with a positive newborn screen. Um, and if you got one variant, you will get a mailer that says, um, negative newborn screen. So if you think about that model, there are some ways still to that you can be missed on the newborn screen, and that's really important for pediatricians just to know, um, it's How the newborn screening works where you live, um, and California's is very different. There are some states that are still just looking at Delta 508 and they're working right now on a bunch of QI projects to sort of improve newborn screening across the country. Um, you won't be surprised to hear that there are disparities um within who is diagnosed by the newborn screen. Um, I've been really involved with our California newborn screening program, um, over the years, and we've done a really good job of increasing, um, detection for Hispanic, um, children, but we are still finding that we are missing, um, Alaska Native American Indian, Asian and black um children at much higher rates than Um, the other than white and Hispanic, uh, children. So just really important to think about that as you're seeing patients in your clinic about who is still likely to be missed on your newborn screen and if you ever have clinical suspicion, you should always refer to us to figure it out for you. Um, so in 2025, this is really, um, you know, an awesome slide is looking at survival and we're looking at the median survival, so 50% will die before this, 50% after this age, but we are up to um 61, which is really, really exciting. Um, you'll see these are birth cohort years, so like depending on when people were born. So in for people who are born in sort of the more recent cohort expecting a median survival of 61. Again, looking at that slide, which is really cool. So what does this mean? It means that now we have more adults with cystic fibrosis than children. Um, you know, it used to be only a pediatric disease because everybody would die in childhood. Um, and that's really not the story now. Um, our population is staying about the same, but the adults are just being inundated with, um, people living longer and longer. And there's a huge need for adult providers for cystic fibrosis. Um, the story of increasing diversity is because we are looking for it, so it was never a white person's disease. The actually the original case reports of cystic fibrosis were in um non-white children, but it's just really important to know that we are now looking for it and that's why we're finding it in a diverse population. It was always there, it was us that we were telling the story wrong. So just looking at UCSF, um, we put this together for our site visit last year and so I had the adult population at UCSF too, but this is our pediatric population broken down by um Oakland and San Francisco, just looking at our payer mix, and um we have a much higher um medical population or um than In other places, and we also tend to serve a more diverse population. So this every year, the CF Foundation gives us a little report comparing us to the national values and we have, you know, lower rates of white children, lower rates of black as well, um, but much higher uh uh Hispanic population than the rest of the country. The adults are over here, kind of a different story, but. Not our story today. And I would say that just the UCSF, um, CF team, we are really dedicated to diversity and underserved populations, which I think is really one of our strengths. We've been um involved in advocating for those who are not eligible for CFTR modulators, advocating for improving. Um, detection on the newborn screen for all races, um, trying to improve access to CFTR modulators, um, outside of the US, um, the, the company that makes these amazing drugs has done some bad things and they actually, um, you know, bought up the patents in India, so you can't make any, um, generics in India, and so a lot of like European countries and the rest of the country really does not have this. Um, highly effective modulator therapy and um they're really monopolizing it. So there's a great story to go with the CFTR modulators, but it's also really important to know that some of the practices that are also not so great and really continuing to increase disparities in the CF um world. If you have time, um, it would be awesome if you wanted to look at some of our Spanish language videos that we put together for CF Mental Health, um, and CF Healthcare, um, because we found that we were caring for really this population of monolingual Spanish families and the resources from the CF Foundation until very recently really were very focused in English. Um, they're doing a much better job recently, but we made some videos that you can look and watch which are cool. Um, so in 2025, again, a lot of looking at birth cohorts just because things have improved over time, but if you look in all ages, FEV1, which is the, the measure of lung function that we use most usually, um, to measure the lung function. Has improved in all age, age ranges. And if you look at our children, these are normal numbers, normal, normal. So, um, I'm usually handing off normal lung function to my adult colleagues for most of our patients, which is really exciting, and in the adult population, they are also seeing improvements. Um, nutrition, uh, is also improving, um, and along with that, the CF population is really looking like the US population with increasing levels of obesity. Um, and so in the CF world, we've always really focused on nutrition. We have a, um, multidisciplinary team. We work really closely with our awesome dieticians because lung function is correlated with nutrition. So in the CF world, you're always aiming for a BMI of about 50th percentile because lung function is correlated with um with your BMI. So we're aiming for a normal BMI, we're aiming for normal lung function. But while that has happened, we are seeing increasing rates of obesity, and, um, you know, when I was a resident and rounding on CF patients in the hospital, they would have plates of bacon, um, for breakfast, and that was sort of what we were teaching in the CF clinic is high fat, high calorie diet, and we didn't really mention vegetables or anything healthy at that time, it was just get as many calories in and um, Now in the era of modulator therapy, when um malabsorption has decreased, we're seeing, you know, that is of course causing problems and obesity, and we've really had to shift how we discuss weight um and nutrition in the CF clinic, so that's been really a, a big change. Um, I talked to residents, so I, I think, you know, Doctor Bletcher introduced me as being from Oakland. I am, um, working in both sides of the bay and the CF director for Oakland and San Francisco for pediatric CF center, um, and both the residents on both sides of the bay always tell me, oh, they, the patients were stolen to the other side of the bay, and I just wanted to tell you that nobody stole your patients. The patients got better because something happened in 2020. What happened in 2020? Your first answer would be there was a pandemic, um, which would be correct, but really what happened in the CF world is that CFTR modulator therapy, highly effective therapy, ETI, the triple combination medicine, triafta. It was released um in October 21, 2019. So the really the big change here of um decreasing IV exacerbations or exacerbations requiring IV therapy was because of CFTR modulator therapy. Some of it was related to shelter in place and you've seen a little bit of like going up again, finding a new normal, but really this was modulator therapy. Lung transplants used to be a huge thing um in the CF world. They are um really, really decreasing in CF. So, modulators, the first one came out in um 2012, um it's called Ivaca or, uh, Kaleidoco is the brand name in the US um it was uh only for people, about 5% of the CF population who had we call a dating mutation, um, the one that the mutation that they did in the studies was called G551D. Um, and then again here at the end of 2019 to 2020, you'll draw your attention to the green here. This is the increasing numbers of green and lexica Tezica Ivicaftor, which we call tricata, um, in this country, or ETI for short, um, is a highly effective modulator and that's really what has changed the CF landscape. So if you look at um this blue group over here of who's ineligible, so it started in 2012, only 5% of patients were eligible by their genotype, but now we're down to about 5 to 10% of the population that is ineligible for um a modulator based on their genotype. Now, how does CFTR modulators work? Again, this is where we need to go back to that biochemistry that we were talking about. So for the G551D gating mutation, here's your CFTR transporter inserted into the membrane, and the chloride is supposed to go through it, but in this mutation, The protein is OK except the gate doesn't work. And so it's not letting the chloride through. And you add this medication, the IV catheter in, and it helps the gate stay open so the chloride can come, and then the water follow lifts the salt and you don't have the dehydrated um airway surface liquid. So that doesn't work for all mutations. It only worked for ones that had the skating mutation problem. The next modulator that was developed um was Luma after Ivicaor or Orkambi, and this was developed for patients that had two copies of Delta 508. And so what happens in Delta F 508 is that you end up, so you've got your DNA, making mRNA, you end up making a protein, but the protein fold, it's wrong. And so it doesn't, this is in the normal case, it should be trafficked to the membrane inserted into the membrane. But in Delta F508, the protein gets made and it's, it's an OK protein, but it's not perfect. And so your body recognizes that it's misfolded and actually degrades it and doesn't put it into the membrane. And what the um the, so that's a two medicine, Lumica oribica or, um, you find that this protein, they can make it so the protein, even though it's not quite normal, still doesn't get degraded and gets inserted into the membrane. And it turns out you don't have to have a totally normal amount of CFTR. You just have to have enough so you can get enough salt and enough water, so your airway surface liquid is not dehydrated. Um, The next one that came about because Lumo after Ivacater was only for Delta 508 homozygous. Tesica Ibicafter was for more. It also had a better safety profile and you could take it with like birth control. Um, now, ETI lexic after Tezic after Ivica is the triple combination, and that's the one that's really changed the landscape here. Anybody who has one copy of Delta 508 or another eligible mutation, um, 2 and up is eligible to take this medication and it's been really life changing for lots and lots of people. This one is a pill that you take in the morning and the night. They package it with like orange in the morning, blue for nighttime pill. Um, and then recently, very recently, we had Vancia or Tesica dutifiaor and that one is called Olive Trek. It's a once a day pill, so we've gone from having, you know, only supportive care with um mucus clearance, hypertonic saline, azithro Monday, Wednesday, Friday, to having very specific genetic mutations which are highly effective and can normalize this, um, the sweat chloride can normalize lung function. Um, so most of our patients now, over 90% are eligible for one of these modulators. And you can look up the genes on a little table on Up to date, or you can go to the website um for Vertex, and you can enter the mutations and how old your patient is and find out if they're eligible for any of these therapies. Um, it is a lot of uh alphabet soup with the names of the mutations, and obviously, I do this every day, so I know the mutations off the top of my head, but you should definitely, you know, feel comfortable entering them into a calculator. Um, learning about them, finding out if you're eligible that way. So what do the modulators do? Um, they decrease your sweat chloride and so for Ivicador, which is kaleidoco or for ETI, um, they actually normalize the sweat chloride below the level of even carriers often. Um, decreasing pulmonary exacerbations. We saw that slide that's been a crazy change since the time, you know, I was a resident and had lots of CF patients in fortune-ups all the time. Our patients, if you want to see CF patients, you have to come do pulmonary rotation with us and see them in the outpatient clinic because that's where they are. Living their life, um, improving lung function, improved quality of life scores, improvements in weight gain for the highly effective modulators again with Ica or or ETI. And then because we have now CF adults, they're going to school, they're having jobs, and they're having babies. So one of the first things that started happening when um when Tricata came about is that people who were having trouble getting pregnant before or thought they couldn't become pregnant, all of a sudden there was a huge baby baby boom. Um, so pregnancies went from like the 100s to over 600. And so now we have moms and dads with cystic fibrosis. One of the other cool um treatments that have become available, it's not FDA approved, so I have to um say this is off-label, but there have been case reports of prenatal treatment of cystic fibrosis in utero. So, as you know, one of the complications that you can have is meconium ileus, so in utero bowel obstruction due to the inspeated um meconium. In the fetus. And so there was this mom who was a carrier of Delta 508, and she had actually had previous children with cystic fibrosis, and they had had the complication of meconium ileus. So this wasn't the first time. Um, and they noted that the fetus had, um, ecogenic bowel and concern for meconium ileus. They started, um, ETI therapy on the treating the mom orally. At 32 weeks, um, gestation. And after a month of therapy, they repeated the imaging and found that the meconium ileus had resolved. Um, so they, they did a stool elastase on the infant once the infant was born, and it was 240, which is in the sufficient range. So normally you would expect, um, a Delta 508 homozygous infant to have a stoulastase less than um 15. Um, so in the normal range, and a sweat fluoride of about 60, which normally I would expect a Delta F 508 homozygous child to have a sweat test of about 100. What's important to know in these cases is that the, um, the IRT, which is our first level of screening on the newborn screen, it can be falsely um low in these infants who are, are these fetuses who are receiving um ETI therapy in utero. So we have to kind of monitor our Population of pregnant moms, um, and make sure that if they are getting treated with ETI that we know that we need to send genetic testing even if um the IRT is, is in the normal range. So again, this is not something that is ready for prime time. Um, there are some trials uh going on and hopefully will be funded for um doing a project here at UCSF in the fetal treatment center for, for doing an in utero study, but um we haven't heard yet and who knows what's happening with that. Um, also important just again to say that there are huge disparities in race and ethnicity by for who's eligible for CFTR modulators, and basically for every modulator, um, minoritized patients have a higher risk of not being eligible just based on their their mutations, because these are genetic therapies and you have to have the mutation. So, um, if you are from Asian, black, um, Patient, they are more likely to not have their genes understood and not identified um fully. So some patients still, we send them off to um additional testing through the CF Foundation called the MAP program to get um to see if they have a second mutation and try to understand that, but there's definite disparities and that really is increasing disparities in CF care at this juncture. And these disparities happen um really across the board for many reasons, and it, some of it is based on genetics and um so incomplete genotyping, as I was mentioning, um, rare mutations that are not well described. Um, but minoritized patients are also less likely to be participating in clinical trials, um, and There's a lot of policy issues, newborn screening, not identifying patients, um. Lots of barriers to participating in in studies, um, and, you know, differences in how minoritized patients are treated in the clinic and how they feel about, uh, healthcare, and we really have to um make sure that we are trying to intervene and improve um access to CFTR modulators and, you know, of course, outside of CF care, other care um because we want to improve these disparities really across the board. So that's something that we can all um be working on, even if you're not participating in the trials directly. Um, now turning sort of to the last part, right? So we have these patients who are not eligible for modulators for various factors. Um, and the first therapy was this skating mutation where we just used one medication. The 2nd The second is um the Delta F508 um and the other protein mutations looking at the triple combination with ETI um and using that to kind of get over this threshold of having enough CFTR function around. But if you have nonsense, um, mutations where you're not making any of the um CFTR protein, you really can't, um, use any of these modulator therapies. You need to have a protein that gets inserted into the membrane. And so, this is a little bit more complicated. So we kind of have these therapies now, but trying to figure out how to get the rest of these patients eligible for having a highly effective therapy um is really the next, the next step here and it's turns out to be much more uh challenging. So we'll go through some examples of what um research is going on to try and um help these patients who have nonsense or um splicing mutations, deletions, duplications. um and the goal um ultimately is to have mutation agnostic therapies where a patient with any mutation identified could be eligible for, um, for these, these treatments. So again, this is kind of looking at the different types of mutations that we've talked about with the block and the regulation for the um G551D with the gating mutation, Delta F508 falls into this block and processing. Um, but no synthesis, that's what we're gonna talk about now is where somebody has a mutation where you don't make, it's a stop coat on and you don't make any protein. So nothing gets into the membrane, so you have nothing for the modulator to work on. So, um, one of the thoughts was we could do something called translational read-through. So basically, here we've got our ribosome, you've got your MRNA, and you are putting little pieces of protein together, translating it from mRNA to protein, and if you come across a stop code on, usually the ribosomes gonna disconnect and you stop making protein. But what you need here is to bring sort of a um a near match. Uh, TRNA instead of the stop codon TRNA, and so you can bring some protein. So it might be like the wrong amino acid, it's a little bit wrong, it's not a perfect protein, but you end up making a protein, um, with the translational read through, and then you can use the modulator on that protein to make it work better. So you kind of trick the body to bringing a near cognate. Amino acid and near cognate tRNA, you bring it over, and so instead of a stop coat on, you can still elongate this chain and keep making protein, even though it's not exactly the one that was um that was in the mRNA. And then they add the, the CFTR modulator to it and you can actually improve the CFTR function um above that threshold, which can be functional. So, pretty cool, um, biochemistry stuff happening there. These are kind of early preclinical trials in animal models, so they're doing a lot of oops. They're doing, you know, a lot of pipehetting and things with, with mouse models of non-CF G 542X is a stop code on. This is another stop code on, and then adding the, the, the modulator to that. Um, again, this is looking at non-CF versus stop codons and then adding the VX 770, which is adding those CFTR modulators to it. So a little bit of a wrong protein, but you get it into the membrane anyways and then you use your modulator therapy to make it work better. Another um place where you can run into trouble with this is that is something called nonsense mediated decay. So your body also, every step is trying to um be efficient. So if you have a an mRNA that is coding for something that is not gonna lead to a functional protein, um, they will, your body is gonna degrade it at a higher rate. And so what we want to do is make more mRNA of these sort of imperfect mRNAs, so then we can use the translational read through and put it into the membrane and then use our modulator. So, they're using these nonsense mediated decay um. Things, SMG 6 was an example of one where they added it to the MRNA and so they don't decay at the same rate, so you have more of that bad MRNA around, then you can make more of the imperfect protein and then you can use your um You can use your modulator to restore function. Um, so again, that's for sort of nonsense, um, proteins or when you're making stop codons, so you're using your translational read through together with more mRNA and then adding the modulators on top of that to get to a functional um CFTR protein. Next we look at um splicing mutations, stellations, duplications. And using something called an ASO or anti um oligonucleotides. And again, here, what happens is you have a mutation in a spice site. So normally there's splicing that happens to process the MRNAs, um, and getting it translated to the protein. And so if you have a mutation in one of these slice sites, the processing can't happen, you can't translate the protein correctly. Um, so what you wanna do is use these ASOs, um, to try and sort of block that, uh, that spice site, change it back to something that you, the splicing can still occur, and even if the splicing isn't exactly perfect, that you have an mRNA that's functional enough that you can use it to make a protein that's Functional enough, and then you can use your CFTR modulator to make it work better. So again, it's kind of cool, again, they're putting the the modulator on top of the um ASO and you can improve the function. Getting it to above this threshold. So then the next big thought is, um, you know, gene therapy, and there's a couple of different um ways of approaching it. So what I'm gonna talk about today are um mutation agnostic, but looking at MRNA um replacement. So basically delivering the right um gene, uh in an MRNA nebulizer. And delivering it into the lungs. So, this is mutation agnostic, it doesn't matter, you just start nebulizing the therapeutic mRNA in a nebulizer. There's a lot of different um companies, Vertex, which is the one that makes the CFTR modulators. Recode arduous, and they are using lipid nanoparticles um to deliver in a nebulized multiple times a day to deliver correct um mRNA to the lungs so you can make correct um CFTR proteins which can move salt and water and um improve your function. So if you look at the CFT the CF Foundation website, they have a whole um drug pipeline thing where they look at different like modulators, they have different nutritional medications, but this is their pipeline for genetic therapies, and we're seeing these phase one, phase two trials now which are coming to be. Um, this 4 DMT company is based in Emeryville and they're doing um a trial phase one trial right now, um, and we're actually participating at UCSF recruiting, um, adults with CF for this um inhaled MRNA therapy, um. Which is just really exciting that it's happening right down the street from us. Um, so, you know, we'll see what comes from all of these different ones. There's also a lot of discussion about like CRISPR and doing other sort of gene editing, um, uh, treatments which will be kind of also in the future a little bit more tricky. We had a great talk at the CF Foundation meeting last year with from um Somebody in sickle cell, and I know you guys have had a lot of experience here with doing the sickle cell, um, bone marrow transplant therapies, but, um, you know, obviously, our patients are not getting bone marrow transplants. So figuring out how to deliver the appropriate gene and the correct gene to our patients is a little bit um trickier. Um, but this 4 DMT one just down the street in Emryville, we, we're recruiting um for it now using um an adeno. virus vector um to deliver the, the medication. So they presented a poster where they had um dosed some patients with this and they're actually um staining for delivery of the appropriate um CFTR normal. So, you know, unfortunately, the early data is looking like these improvements. If you think of like CFTR modulators, which are highly effective therapy, leading to normal sweat tests and improving um our lung function, we usually see a bump of about 15% in FEV1. Some of these early trials look like 5%, so maybe not huge um improvements, but these are early days and, you know, we'll kind of see what the What the rest of this will, will look like down the road as we improve the, the therapies. Um, but really exciting stuff sort of on the horizon that can treat any mutation for cystic fibrosis. So that is a quick rundown looking, um, you know, at the future of CF care and where we are now, but just important to know um that there's over 2000 different mutations um in the CFTR gene. Um our patients are living longer and we're handing off, you know, generally healthy adults to, um, our adult colleagues and there's a huge, um, increase in adult population, cystic fibrosis, um, when you're thinking about your newborn screen. Just, you know, feel free to reach out if you have any questions cause it can be confusing and definitely don't think that because you had a normal newborn screen, you can't have cystic fibrosis. We um have had over 70 missed cases since we started newborn screening in California. Um, since 2007, so think about those patients, keep referring them. Um, understand that there are disparities in the newborn screen and the modulators are great therapies, but also significant, um, racial and ethnic disparities in who is eligible for these therapies. Um, and lastly that new therapies are coming and um hopefully gonna be mutation agnostic therapies down the road. So, um, this is my CF team, and I wanna thank all of them for helping me every day and taking care of our patients and Yeah, that's us. The OR is also calling me. Thank you so much, Doctor Gibb. Um, we do have some questions if you, but you may need to speak to the OR first. I might have, um, yeah, Doctor Betts is wanting me. Hold on, I'm just gonna text them back and say finishing this up, but go for it. Um, so I'll just remind the group to take the survey that's in the chat in order to get um EME credit, um, and we have a number, um, of excellent questions coming up, some of which are, I think, just a quick review, um. So, um, the first question that we had gotten was, what are the next steps after you get a mailer saying that somebody has a positive newborn screened for for cystic fibrosis? Um, so usually the pediatrician, OK, so the way it's supposed to happen is that the pediatrician gets a call, and then the pediatrician, um, can make a referral, you know, discusses the result with the family because it's better to have it come from somebody who knows them rather than a cold call from somebody who doesn't know them. Um, and then with discussion with the family, you decide where you want to refer, what CF center. Um, There are definitely times when this is not what's happening, um, but in general, that's what's supposed to happen is that the pediatrician will get the mailer certainly if you guys ever feel uncomfortable and not sure quite what to say cause it can be super confusing and we often are finding mutations that, you know, are not delta F508, so you might not know like, oh, what does this mutation do? Is this a severe mutation? Um. You know, you can always start with introducing to the family, like, you know, this is a screening test and we need to refer you for additional testing because it's just a newborn screen and what they need to come is have sort of an assessment where we would do like their stool elastase, we're gonna do a sweat test, um, assess for symptoms, and then Depending on what the genotype is, we often are starting um enzyme therapy right away if we expect this even without having the stoolastase back if we're expecting this to be a severe mutation with pancreatic insufficiency. But often you're gonna get something that is not a like clearly positive newborn screen. You're often gonna get like this was a high IRT but no mutations were identified or um some a carrier screening mailer and that can also be confusing, so feel free to reach out to us about that. Wonderful. Thank you. We also have a question also about the newborn screen about why California particularly screens for 72 variants. How are those particular ones selected? Are they just the most common ones that we see? Yeah, so what we did was we kept on going back and adding the variants that we were seeing in California. So we looked in the cases that were missed and then we added them to our panel. So we've actually gone back many times and added additional variants over time to make our um our screening better. So our, yeah, our, ours is very different. I think that we will be moving to next gen sequencing and we will probably end up moving to having all of the variants and CFTR2 sort of uncovered. So everybody will end up getting, if you had a positive IRT, everybody will get next gen sequencing and then we'll kind of unblind it, which hopefully will make the, um, it will make it faster for us to get those results to positive families and babies so they can get started on therapy faster. Awesome. So many, so many things changing so quickly in such a positive way. It's very exciting. Um, we also have a question from the group about the cost of modulator therapy and if you've had good success having, um, insurance pay for it, if families have been burdened by the cost of that therapy, just sort of. Who's responsible for that financial burden. Um, so yes, it's super expensive, um, on the positive side for our families, most of them really are paying, um, pretty much nothing because it's covered by Med CCS. Um, we have had some, even our private insurance patients actually, most everything has been really covered and it's been less of a problem than expected. What happened in the last year is that Um, vertex, which is the company that makes the modulator therapy, and the insurance companies, the private insurance companies. I know you're shocked to hear this, they've had sort of a um power struggle of cost sharing and pushing it back um at each other, and so a lot of our uh private insurance families were caught in the crosshairs there and they've ended up having high um Co-pay issues and um in the thousands and thousands of dollars, there are some assistance programs and it's made it kind of complicated depending on what some of those private insurances are and what um Their insurance uh companies are doing for those modulator therapies, but some of them have had to kind of like meet a deductible and then mid-year they can um they can go on to a different assistance program, but it does require like knowing what's going on, monitoring their um their copays and how much it's costing and that is really a, you know, a barrier and I Problem for a lot of people, but most of our patients, cause we have 70% medical actually are not paying anything. Great. Thank you. Um, We have a more specific question about the possible treatments um that involve increasing defective mRNA and if that's specific to the CFTR gene and what the side effects could be and this commenter was um referring to um trichohepatoenteric syndrome where the mechanism of abnormality is possibly the MRNA hanging around too long and if that's a concern with some of these newer treatments. Well, I've never heard of that before, but um, I think there's a lot of concern, um, that people are worried about various things with, you know, gene therapies and um. I think that What we are facing now is that we have a really small population, you know, CF is a rare disease to begin with and then you now have 5 to 10% of the patient population that's either ineligible or intolerant of currently available modulator therapy. So we have a really small and to do trials on. So the original trials with CFTR modulators, you know, we were able to recruit, it's pretty easy to take a pill, you know, obviously there have been There have been actually a lot of concerns about the side effects of those medications, which I didn't go into today, but um. There's definitely more concern of like how are we going to recruit this population, which generally, as I said, is like a very underserved population that has traditionally not participated in trials, and how do we get them to participate in what are maybe seen as like more high risk, you know, genetic therapies where things are not Quite as clear um what the side effects might be in long term. So I think there's a lot of concern about that and there's a very thoughtful, um, you know, approach from the CF Foundation of how to engage these patients, but also, um, we're doing like a reach, it's called a reach trial where we're Making a sort of a, it's almost like a control group where patients who are currently not eligible or not treated with modulator therapy, using them as um a big control group for the whole country, knowing that each of these individual genetic trials is going to be very small. We're looking at like trials with like 3 to 10 patients currently. Um, so I think there's a lot of concern, um, and I don't know yet all of those potential side effects, um, cause we haven't really You know, been dosing patients ourselves. These are all for 12 and up, you know, adult sort of adult patients at this time, but um. Looking forward to hearing more about it. I'm sure that that will be a big focus, you know, in the coming years at NACFC which is our CF Foundation meeting. Definitely, thank you. Um, we have a question about if there is a lower age limit for sweat testing or if it can be done in all ages accurately. No sweat tests inpatient, no sweat tests on failing to thrive infants who are dehydrated on IV fluids. Thank you. Um, you are supposed to be, you know, a couple of weeks old. There is a weight limit. Um, you know, the, the thing is, is that we get a lot of QNS and so, um, where we don't get enough sweat. the baby. So you can't sweat a premature baby. They have to be over 2 kg. They're supposed to be over a couple weeks old, but I can tell you that our rates of getting enough sweat from small dehydrated failure to thrive babies is very low. And in the era of where we can get genetic therapy very quickly, it's almost You know, we, we can help you figure out who's the, what's the best test for your patient, um, but We shouldn't be doing it on like NICU babies. We used to like sweat inpatient Nikki babies all the time and that's just not a, it's not an effective way for us to diagnose CF. Gotcha. So it can be troubleshooted on a more individualized basis of what might be more appropriate. Always order a stoolastase, a throat culture, and we can order the genes, and they come back in like 3 weeks. And in the meantime, if there was clinical concern, we can always start modulator therapy, I mean not modulator, sorry, enzyme therapy in the meantime if we were concerned that this was a male absorption um problem. So it's, it's not a. It's not something that needs to be done that day. There's almost always a better way. Um, so sweat test, of course, has its role, but there's actually patients that have CF who don't have a positive sweat test. Um, there are patients that have a positive newborn screen and have a negative sweat test, and we monitor their sweat test yearly over time. Um, and it can be in the, the normal range for years and years, and then maybe it transitions to over 60 when they're 8 years old. So it's just not, you know, in the er of of where we have genetic testing, it's not always the best test really. Definitely. Thank you. Um, We have a question with more pregnancies, are families getting genetic counseling? Um, That's, you know, updated with the um kind of newer, you know, life span information and the available treatments um for people with cystic fibrosis, you find that people who are, have a family history are getting appropriate counseling on this. Well, I would, I think that we are seeing in some populations that people are doing a lot more genetic testing and perhaps not always continuing pregnancies with CF or choosing to do IVF and um prenatal genetic reimplantation genetics, um, where they will do testing on embryos and only decide to implant embryos that are not um affected CF. Thankfully the um Uh, the genetic testing in the adults is getting better. We have also had some families that were caught off guard because they thought they had genetic testing for CF and then had IVF and had a child that has a positive newborn screen. Um, so there's also some cool new tests that I've seen where they're doing, um, So like the, the cell-free DNA testing that you can get for like trisomies, there are some genetic mutations that they can actually do cell-free DNA testing, so without doing an amnio on um pregnant moms and so we've been getting some referrals for prenatal um like concern that this is maybe an affected um fetus just based on self retesting. Um, so we're definitely seeing a shift, and I think with the interest in potentially treating um fetuses, we're seeing really interesting ethical questions coming up about treating carrier moms or, um, who have, who are carrying CF affected fetuses, um, and, you know, the potential side effects for the mom and Um, a lot of, you know, really interesting thoughts there, but, you know, not just treating meconium ileus, but there's some thought you could actually reverse the male infertility with in utero treatment of male fetuses because the vas deference is very sensitive to CFTR function and is usually obliterated um prior to birth. Um, so there's a lot of talk about this, but it's also like in a very gray ethical area. Definitely. Um, on a similar note about sort of families, um, how do you counsel families now that parent and child might both have CF since the, the teaching used to be to keep CF patients away from each other. Um, well, I mean, for, uh, inside, outside of families, I think, you know, there have been CF siblings for years and years, and I remember in my residency going into rooms where brother and sister were sharing a room, getting their tune-ups together. Um, and obviously, you know, we get them separate nebulizers and stuff, but they're sharing an environment. So, yes, like the movie 6 ft Apart, we still recommend that and we don't send them to camp together. We have them wear a mask in the clinic even before COVID. Um, we wear gowns and gloves to protect our patients because we're seeing many patients, um, and with CF and we don't want to transmit, um, their infections from one to another, um, but in families, um, you know, we don't separate them or any way. We encourage families to be together. And then just a couple more questions about the CFTR modulators. Um, one question is about, is there a particular optimal time of day in which to take it? And another question is, what are the most common side effects that you see from those medicines? Um, so, like most of them have been like a morning and a nighttime pill, um, they just, you know, as I said, released the Olive Trek, which is a once a day pill, um, they you can take it any time of day. Um, so most people have been tolerating them really well, but there is definitely, um, so we monitor for something, um, we, we monitor for cataracts. They were in the in utero studies and um ferret models, there were some uh cataracts that came. About, um, so a year an eye exam every year. We also monitor LFTs, um, and there have been some, um, unfortunately like bad uh LFT elevations or drug-induced liver injury. So they recommend monthly testing for 6 months and then every 3 months for a year, which is pretty tough for a child. Um, there are some other things that we've seen like rashes and um, Uh, unfortunately, some mental health concerns with like brain fog, um, depression, anxiety, suicidality, um, which seems to be kind of an emerging. It it seems like it's definitely real, you know, and I think it, it, this came out at the same time as COVID happened, and so we were hearing these case reports of these terrible cases of a patient getting started on modulator therapy and having, um, you know, a suicidal. situation, um, and it was sort of unclear, right? Like these were our teenagers, this was during COVID. Um, I think it's, you know, it is becoming clear that it is, there's something happening there, and I don't really understand all of it, um, but some people are intolerant of modulators and that's another group of patients that, you know, needs a different therapy type. Um, so, you know, in younger children, there was maybe like hyperactivity, ADHD symptoms that might come about, um, and it's something that we're just kind of monitoring. Um, and, you know, letting families know about and kind of helping shared decision making. I would say most, the vast majority of our patients tolerate everything really well and are like they undergo what they call a purge where lots of mucus comes out and then their lung function improves by 15%, their weight is improved, they are stopping doing their mucus clearance. And they feel great, and they don't want to come to clinic anymore. They certainly aren't coming to the hospital anymore, and that's the main side effect that we've seen, but we really do have to be, you know, um, monitoring for these other side effects and making sure that our patients are tolerating things OK. Excellent. Well, thank you so much for answering all of these questions and for this talk in general. I think it's um a really fun time to be, you know, working with patients who have cystic fibrosis and with many more things on the horizon, it's just an exciting time. So thank you for updating us on all of that. Um, a reminder to. Definitely, uh, and remember to take the, the, uh, survey in the chat to get CME credit by this Friday, um, and thank you all so much for being here. Thank you. Thanks, doctor G. All right. Created by
