Good morning, everyone. So welcome to the Treatment of Cystic Fibrosis in the Age of CFTR Modulators. So just a quick reminder that all sessions can be evaluated through the mobile app or on the online program. And don't forget to evaluate this session and course. So the first speaker is going to be Christina Mangora. She's an assistant professor of medicine from the Medical University of South Carolina. And she's going to speak about the transformative impact of CFTR modulator therapy in the natural history and the future of CF. Hello, everyone. Thank you so much for attending today, and let's get started. So as Leah said, I am an assistant professor from the Medical University of South Carolina, and I do not have any disclosures today. Here are our lesson objectives, which I'll let you take a quick look at, but will not read specifically. And we'll get started. So just a few basic introductory slides just to frame where we're going with the rest of this talk. So CF is an autosomal recessive disorder affecting just over 30,000 patients in the US and more than 70,000 patients worldwide. This is all through the CFTR gene mutation cystic fibrosis transmembrane conductance regular. This was first identified in 1989, and now we know that there are more than 2,000 known variants. What's really important to understand as we go through our talks today and really focus on our modulator therapies is that F508 deletion is the most common mutation, and we'll find that about 44% of our population are homozygous and 41% are heterozygous. And then we still need to remember that there is a substantial, nearly 15%, portion of the population that has neither this mutation or has unknown mutations. And again, as we get into the kind of work of the CFTR modulators, we'll understand why this becomes so important. Here just to review how our CFTR functions, we can see that in our wild type CFTR, everything is going to be working normally. So we are going to make, process, and traffic our protein appropriately. And then across the spectrum of our different classes of CFTR mutations, we see different variation in the amount of protein that can or cannot be made. So in the most severe cases, no protein is synthesized. And in other cases, we'll see impaired trafficking or functionality or even less protein production. And as you can imagine, based on the amount of functional protein that you're able to make, you'll have varying severity of disease. Pathogenesis of CF is most important as we focus on the lungs. Because historically, this is where we're going to see our greatest bids of mortality and morbidity in our CF population. So again, starting with our gene mutations, we can then see that we have changes in CFTR quantity and function. And one of our opportunities to target and fix the pathogenesis of CF lung disease is to target CFTR. We know that when our CFTR is not working properly, we'll see reduced airways surface liquid, impaired mucociliary clearance, and then leads us into this vortex of ongoing obstruction, infection, and inflammation, which ultimately leads to progressive irreversible lung damage and respiratory failure. And this is kind of the other area where we can have therapies focused to treat our patients with CF. And that's where we can target our downstream effects. Historically, this is where all of the initial therapies to target CF began. So when we talk about different aerosolized therapies to assist with mucociliary clearance or to assist with treating chronic infection, we are all targeting the downstream effects. We are not necessarily getting to the heart of the matter, which is targeting the CFTR protein itself. This is just a slide to remind us that while we have all of our focus on the lung because of how it affects both your morbidity and mortality, we also know that CF is manifested throughout the body. And the CFTR receptors are present in all of the organ systems that you can see here, leading to all of these extra pulmonary manifestations of CF. And you'll get to hear about some of these moving through our different talks today. So again, just back to here, we want to see where we're going to be able to intervene upon the pathogenesis of CF lung disease. So again, historically, we are targeting downstream effects when we looked at mucolytics, when we looked at antibiotics, when we looked at other airway clearance therapies. But now, we moved into an era where we felt that we had that pretty well figured out. And we wanted to see how can we target the heart of the problem, which again, is targeting the CFTR protein. We can take different approaches to targeting CFTR. And again, this is just another photo showing you all the different ways that the CFTR protein is having issues with synthesis, production, and trafficking. And what we can do to help that, we can work in two ways. First of these is we can potentiate the effects of CFTR. And what that's doing is that is increasing the time that the activated channels are open at the cell surface. And if that doesn't work, we can go and also work on correcting, which is going to correct and improve the process and trafficking of the CFTR protein. So two different ways that we can help to modulate the protein, either helping again to keep those channels open and traffic, or help to just help the earlier stages of trafficking and processing earlier in the stages of protein synthesis. So the very first time that anyone got into looking at how we can modulate CFTR was with the first modulator, which was called IVACAPTOR. This was a potentiator, again, helping to keep those channels open. And it looked at individuals who had the G551D gating mutation. All of these trials that we're going to talk about focused on including individuals with cystic fibrosis who had lung function somewhere around 40% to 90% and were adult patients. And what we found when we looked at this study was really, really amazing. What we found is that we had not only a significant reduction in sweat chloride, meaning that we were improving the functionality of the CFTR, but we also saw substantial increases in pulmonary function, increased time to exacerbations, improved symptoms scores looking at the CFQR respiratory domain, and improvement in BMI in our underweight patients. You can see in all of these slides that the effects were found as early as day 15 and were sustained throughout the 48 weeks of the clinical trials. These results were, of course, great. But unfortunately, looking at just the G551D mutation, we were really only impacting approximately less than 5% of individuals with cystic fibrosis. So really, you know, it was really awesome, but our work wasn't done. And we needed to figure out how we can get these therapies available to a larger proportion of our CF population. And that's when we decided to not only focus on the potentiation, but see how we can have a dual modulator where we could potentiate and correct. So here, we began to look at two additional studies that were done, looking at lumacaftor ivacaftor, and also tesacaftor ivacaftor in our patients with CF. And this was looking at individuals who are homozygous for the F508 del mutation, which, as you recall, is going to account for approximately 44% of our patients with cystic fibrosis. So now, we have a way not only to kind of tackle this from a slightly different approach, but also to make these drugs available to a larger proportion of our population. So how do our drugs compare? This is just a quick reminder of what we saw in our initial ivacaftor trial. And we're seeing, again, all of these great effects, increased FEV1, reduced pulmonary exacerbations, improved symptom scores, and improved BMI, all of that coming along with a concurrent reduction in sweat chloride levels. And here, we see that in both of these trials, both with lumacaftor ivacaftor and tesacaftor ivacaftor, we did see, again, improvements. But unfortunately, these improvements were not, as you can see, they just were not the same as what we saw with ivacaftor. So while we were finding some improvement, again, it just wasn't at the same level. And we also, again, still were not being able to get this drug out to the largest proportion of our patients with, you know, CF, because we're still under less than 50% of the population that we're targeting now. So again, back to the drawing board, and what can we do? So we decided to add another drug. So this was called alexacaftor, and this is a next-generation corrector. So working similarly to the way that lumacaftor and tesacaftor did, but just a newer iteration of this drug. What came from that is we saw two clinical trials, one which was looking at individuals who were having, again, homozygous for this mutation. So these individuals had previous modulator therapy, and now we're getting the benefit of the third drug. And then there was also another study which was done looking at individuals who were heterozygous for this mutation. So these patients were modulator naive. So what do we see here? What we found was excellent, excellent results. And we can see that in the previously treated modulator population, we're seeing an absolute change of more than 10% in FEV1, again, seeing as soon as day 15 in our clinical trials. What was even more impressive was in our modulator naive population, we saw nearly a 14% increase in FEV1 in these individuals. So really, this was landmark. This was really amazing, and the excitement in the CF community when these results came out was very, very high. So in addition to what we saw now in the pulmonary function, we also saw that in the largest proportion of CF population that was able to be accessed to these drugs, we also found reduction in pulmonary exacerbations, improvement in symptom scores, increases in BMIs, as well as reductions by chloride levels. And all of these were very much in proportion or greater than what we saw in ivacaftor. So again, we're having our most potent modulator therapy that we've seen, and now it has been available to a large, large proportion of our individuals with cystic fibrosis, so nearly 90% of the population. Here are just some graphics to demonstrate all of the benefits that we've seen. So here, we're looking at a study that was looking at some of our registry data, and we can see that our first dotted line is when we're going to have ETI, elixir catechetivic ivacaftor approved in October 2019 for individuals 12 and older. You can see there, there are individuals 12 and older, pulmonary exacerbation in red versus those who are under that in blue, a substantial reduction in pulmonary exacerbations that continue to decline even after the onset of the COVID-19 pandemic. And you can see that in individuals who were not eligible for this drug based on their age when it was first approved, you do not see in that, you know, between those two dotted lines, you do not see that same reduction in exacerbations. Additionally, we see ongoing now, a few years into this, sustained benefit in lung function in individuals treated with ETI. So here, we're looking at both, again, looking at our population who is homozygous and our population who is heterozygous, and we're seeing now that there is sustained improvement in pulmonary function, and we also know that there is a decrease in rate of lung function decline. So again, just really changing the way that we look at our patients with CF and how we can improve and preserve our pulmonary function and change the course of disease moving forward. Going back to this, saying that we know that there are also, you know, CFTR modulators throughout the body, we also know that we've seen reduced sweat chloride levels, improved symptoms of sinus disease, reduced inflammation, improved absorption, nutritional status, motility, and weight gain in our GI tract and working with our pancreas. We also see improved glycemic control, possible improvement in bone density, looking at our endocrinologic disease, and we've seen improved fertility in women with CF. And for me, as a CF provider who is also a woman, this is really one of the most exciting things that I think we've seen. And if we move over to look at registry data, we can see a tremendous increase in pregnancies to women with CF. And this really has been such an important and impactful change, I think, for women with cystic fibrosis. So very important things that have happened with the introductions of these drugs and different ways that we now need to focus on how do we treat our CF population. So here, we know that these modulators have been transformative. If we look here, we're looking at the median predicted survival from our CF registry data, and we can see from all the way back in 1989 when the CFTR gene was first discovered until, you know, the 2016 to 2020 group. You know, now with having a median age of survival over 50 years, this has been so, so impactful and so transformative to our individuals with CF. Unfortunately, though, this therapy does not yet reach every person with CF. So not only do we know that there is a proportion of individuals who have genetic ineligibility, so people who do not have the F508 del mutation or other now available mutations for which we know the ETI is approved, we have this proportion that either have nonsense mutations, splicing mutations, different mutations, where we know that these drugs just don't work. We don't see that same restoration of CFTR therapy. So because of that, you know, we know that we need to have ongoing research, and we do have multiple alternative approaches that are in development. And not to bore you with all of them, but just to say, you know, we're looking at gene replacement, mRNA replacement, read-through technology, and looking at antisense-legal nucleotides. So lots of things in the pipeline and in development, but still not yet ready for prime time. We also know, and I will let our other speakers talk more about this, that we do have adverse effects and intolerances that have limited the use of modulated therapy in all patients. So we know that there has been some hepatic toxicity, particularly in individuals who have baseline abnormal hepatic function. Negative impacts on mental health, which have been a big topic in the CF community. We also have seen increased gastrointestinal side effects, increased weight gain, and some myalgias and joint aches, which have been limiting factors to getting these therapies to patients. The other part of this is age. So over time, and I think mostly with ETI, we have seen such a rapid, you know, increase in eligibility based on age, and now we know we have more experience with modulators, that they are, you know, more available. But still, individuals who are having either one or two copies of F508del, who may be eligible, need to wait up to two years of age to have modulated therapy available to them. Whereas those with Ivacaftor can get it at just four months. So as you can imagine, you know, it's hard to know that this drug is available, particularly if you have a child with CF, knowing that you'll have to wait up to two years where they may be eligible for these drugs. So in conclusion, highly effective CFTR modulator therapy has transformed the world of CF care. The treatment is disease modifying, and it's great, but we need to remember that it is not curative. This is not a cure. We also need to know that this is not available, accessible, or even tolerable by all persons with CF. And in our community, we celebrate these great achievements, but we know that we're not done, and look forward to all the research in the future. Thank you so much for coming today and listening, and I'll take any questions. I believe we have a few minutes for questions. And if we don't get to you, we can obviously catch you at the end of our session, too. I'm Josh Diamond. I'm a lung transplant physician at University of Pennsylvania. So one of the things that we've seen very rapidly is that we no longer have actively listed cystic fibrosis patients on our transplant list. We used to do about 12% of our population every year was patients with CF, and now we do at most one transplant a year. But we have started utilizing it extensively after transplant, so I was wondering if you have any sort of experience or recommendations about the use of Trikafta in the post-transplant phase of care for the treatment of all those extra pulmonary manifestations that you described. Sure. You know, there is data that has been published. It honestly is a bit variable in terms of tolerance as well as possible toxicities with it. But I would say overall, and you know, in my experience, I have found that of our previously transplanted population who would be eligible for modulators, we do often use them, particularly for sinus disease. And I think clinically that's where it's made the most beneficial effect on our patients. I would say it's generally well-tolerated. We do take an approach at our center at least sometimes where we will modify the dosing that we're doing to reduce interactions with different drugs that you may be using, either your immunosuppressants or particularly any antifungal agents where there's major drug-drug interactions. But I think, you know, it's very well-supported that we can use them, again, and I think mostly for the sinus disease and to a lesser extent the glycemic control is where I've seen the most impactful. Great. Thanks. Yeah, that's been our experience as well. Thank you. Yep. Okay. So then we will move on to our next speaker. And I would like to introduce Dr. Leah Cohen, who is an assistant professor at UT Southwest, and she will be here to give our next talk. So I will be speaking about CFTR modulators and the effects on pulmonary exacerbation and airway clearance. And again, my name is Leah Cohen. I'm an assistant professor of internal medicine in the Division of Pulmonary and Critical Care at University of Texas Southwestern here in Dallas, and I have no disclosures. So I did thought we could put a few audience response questions for those who would like to participate, make this talk a little bit more interactive. So you can either navigate within the app or you can point the QR code at the camera. So our elected objectives for today are to define pulmonary exacerbations in people with CF, to discuss updates in the treatment of pulmonary exacerbations, and then we'll discuss how the CFTR modulators affect pulmonary exacerbations and how they're changing the role of airway clearance. So I'll give you guys a few seconds to answer our first question. An acute pulmonary exacerbation must include A, change in symptoms from baselines, B, decline in lung function, C, fever, or D, hemoptysis. So, not unsurprisingly, most people in the room got it right. It's a change in symptoms from baseline, but I'll talk in a second why decline in lung function is not actually considered a cause of a pulmonary exacerbation. So how do we define acute pulmonary exacerbations? Well, the problem is we actually really don't have a true definition. So if you asked, went to different people in different centers or between pediatrics and adult-centered, we would have disagreement on what we might define an exacerbation to be. So there's no consensus criteria. But how we do define it is an acute worsening of symptoms that warrant medical intervention. And the signs and symptoms that we're looking for are increased cough, change in sputum, so volume or consistency, also decreased appetite or decreased weight, or change in their respiratory exam or weight. And it may or may not include a decline in lung function. So it's really the symptoms that drive whether or not we treat an exacerbation. But we do know that it's still a major cause of morbidity that is linked to disease progression. So how do we treat pulmonary exacerbations? Well, we have not updated our guidelines since 2009. So based on those 2009 guidelines, which, as I mentioned, were before the modulator area era, the inpatient treatment was recommended compared to outpatient treatment. They still recommend increased time and frequency of airway clearance. So when you come into the hospital, we're going to make you do your breathing treatments at least at our center three to four times a day. And then we'll usually treat with IV antibiotics as an inpatient. And of course, we're usually going to use anti-pseudomonal antibiotics. And double coverage at this time is still recommended to prevent resistance. And you're usually going to use a synergistic combination. So we usually use a beta-lactam and imidoglycoside combination. And then at that time, the duration of treatment was very unclear. So the CF community at large decided we needed to do a better job of understanding how do we treat pulmonary exacerbation. So we started a observational clinical trial that stands for the STOP trial. And the goal of it was to gather information to define key clinical endpoints, the magnitude of response, and then also what the variance was amongst different centers or clinicians to guide future interventional trials. This was an observational study at 11 UFCS centers from January 2014 to January 2015. So again, Ivacaftor was approved, but most of the other modulators were not. And then to be eligible for the clinical trial, you had to have a CF diagnosis. You had to be admitted for IV antibiotics, so you had to be in the hospital. And then the primary objectives from the physician were lung function recovery and improvement in symptoms. So this was their table one. And I bring it up to show you that it was a pretty diverse population. You had to be 12 to be in the study. So we had some young adults in addition to mostly middle-aged and older adults. Their lung function amongst the group was variable, so you had people with severe disease as well as people with mild disease. And then majority still grew pseudomonas, which is what was to be expected. And then again, this was around the era of Ivacaftor, and so how many patients were on Ivacaftor at the time. So the duration of therapy on average was about 13.8 days. What we found was lung function was less relevant as compared to symptoms. And then the decision to treat with IV antibiotics based on the conclusions of studies was factors in their baseline FEV1, their change in baseline of their lung function, what their baseline severity was, and then experience with prior treatment regimens. What was interesting to note is nearly half of the patients enrolled in the trial were treated for a pulmonary exacerbation in the six months prior to being enrolled in the study. So obviously, these events are recurring. And the other thing was important to mention is nearly half of the population was treated with either oral or inhaled antibiotics prior to admissions. The limitations were, as again, the definition of an exacerbation were defined by the physician or clinician, and then it excluded those patients on outpatient therapy. So we took stop one, and we created stop two. We're very clever at naming our trials in the CF community. And this was a pragmatic pulmonary exacerbation treatment interventional trial to assess duration. This was basically looking at the duration of IV therapy. As most of us know in the general community, we are starting to learn from the IV community that less stays on antibiotics is probably better, less resistance, less side effects, and so forth. And so we wanted to understand how long should we treat our patients with antibiotics. So this was a study looking at adults with CF who had a pulmonary exacerbation on IV antibiotics. And then the antibiotic selection was pretty open, but it was treatment based on the previous sputum cultures for two years prior. They still recommended increased airway clearance and that their chronic treatments be continued. And this actually could be done at either the hospital or home. And then the final comment was steroids had to be used prior to randomization. Steroids as far as treating pulmonary exacerbations is debatable, and depending on which center you go to, as a fellow I don't think I ever gave anybody steroids. And then as a faculty, there are certain patient populations where I may give steroids if they have an asthmatic component or they've responded to steroids in the past. So some of that is anecdotal based on, again, where you trained, hence why we have to do a better job defining how an exacerbation works. So this is actually a very important thing to understand, to understand as how we ran the protocol and how the study works. So the first visit would be basically at enrollment. So if you decided you want to participate in the study, we would get your baseline spirometry We would have you record a symptom diary, and then you would fill out what was called the chronic respiratory infection symptom score. And the higher the score, the worse your symptoms were. And then somewhere between day 7 and 10 of IV antibiotics, you would be randomized. And then before that randomization, we did your spirometry. We had you repeat your symptom diary and repeat the CRIS score. So then people were then randomized, basically categorized to either early responders. That's what the ERR is. So there's an early responder group. And those were people who had a change in FEV1 greater than or equal to 8%. So basically from that first visit to the second visit, if they were in that group, and they had a CRIS score greater than or equal to 11, they were randomized to 10 versus 14 days. So that's where the randomization would occur. And then the people who were not in that group were basically did not meet those criteria, were put into the non-early robust responders group. And they were randomized to either 14 or 21 days. So the thought was is that if you were an early responder and your lung function was improving quickly, that perhaps you didn't need as long of a course. And this was based on a non-inferiority. We were basically trying to say, can you get away with 10 days of antibiotics compared to 14? Versus in those who were slow responders, what's the difference between 14 versus 21? We did do a third visit at the completion of the study. And so this was their findings. So they did an allocation. There were more people in the non-responder arm than the early responder arm. And then the results basically showed for those who were early responders, 10 days is not inferior to 14 days. So shorter course could be possible for some of our patients. And then the patients who were not considered early responders, their overall lung function improvement was less than the early responders' arms, which would sort of make sense that their lung function really didn't really improve very much. But they did find that there was no evidence or no difference in lung function between 14 and 21 days. So how do we interpret this data? If you, again, if you go to different centers, you're going to get different answers. So this has been my experience based on what we do at UT Southwestern. And again, the study did not really comment on the difference between inpatient versus outpatient antibiotics. So that portion really wasn't commented on. But for our site, we still favor inpatient treatment for at least five to seven days. And the reason for that is it allows us, so as many of you may know if you're on an aminoglycoside, you have to check levels. And the levels have to reach an appropriate target. And that actually can take a couple of days to get there. And it's much smoother to do in the hospital where you can draw labs at that specific time than having to do it on an outpatient basis working with home health. And then in addition to that, we then have a good five to seven days to push our patients to do their airway clearance more than they would at home. We know for a fact that when they do go home and do their home IVs, they're not going to be doing their airway clearance as much. Because a lot of the reasons that they're choosing to do home IVs is because they're parents and they have jobs. And so we still encourage people to at least come in for a few days to get them set up and get started. And then we can send them home to finish out their IVs. We still double cover pseudomonas. And then we choose to apply the results for a SOP2 trial depending on when our patients can finish antibiotics. So we'll check a lung function within that five to seven day mark, usually right before they're getting ready to go home if they're going to go home on IVs. Or if they're staying in the hospital, we'll check it in at the one week. And we find that our early responders, a lot of those who are back to baseline or are moving in a positive trajectory, we give them the argument that they could probably get away with 10 days, especially if they're feeling better. Sometimes we will still check an FE. They still like us to check their lung function on the last day. And I think that just gives the patient more confidence. Some of them don't want to know the numbers. And so we go ahead and send them home after 10 days. If our patients decide that they want to go longer, so if their lung function hasn't responded at day seven, we will repeat pulmonary function tests on day 14. And then if they're still not back to baseline or not feeling better, we will extend to 21 days and we will stop. We really don't encourage our patients to go beyond 21 days because, as we saw in the SOP2 trial, there really wasn't data to suggest that you need more than 21 days of antibiotics. And at that point, if your lung function hasn't really returned to baseline, we have to sort of then discuss with the patient other factors. So where are we going next? So we are currently enrolling patients at multiple CF centers, including UT Southwestern is one of the centers participating in the SOP360 trial. So the goal of this trial is to compare one versus two antibiotics. Do we really need to double cover patients? Can we get away with one antibiotics? And a lot of this has to do with, as many of us know, patients are already on inhaled tobramycin or inhaled Cayston. And so are they really going to get a benefit from adding on that IV therapy? We also, again, have to check levels with IV tobramycin. And then, of course, there's risks of ototoxicity and nephrotoxicity. So that's one of the big things we're comparing. We're going to enroll patients who are six years and older. They will be limited to a 14-day course. And then, obviously, because we're looking specifically at treatment of pseudomonas with a double coverage, they have to have at least one pseudomonas culture in the last two years. So this is something that is currently ongoing. All right, so our last question, and obviously, Christina, if you were paying attention to Christina's talk, you should get the answer to this question correct. CFTR modulators such as alexacaftor, tezacaftor, ivacaftor blank the rate of acute pulmonary exacerbations in people with CF. A, decreased. B, did not change. And C, increased. You were all paying attention, or at least have read the press briefings about CFTR modulators. So they did decrease the rate of acute pulmonary exacerbations. And again, so this is the slide from the landmark study that was done in the New England Journal. I just picked the one that showed just those who were not on modulators before. So these are people who were heterozygous for Delta F508. And you can see the rate of pulmonary exacerbations of placebo compared to those on triple combination therapy, how the rate of pulmonary exacerbations changed. So all pulmonary exacerbations dropped, hospitalizations dropped, and treatments with IV antibiotics dropped. And then I did not include this slide. Christina included it because it was already included. But as you saw, even on the long term, we saw a very nice decline in the rate of pulmonary exacerbations after people were started on triple combination therapy. In addition to that, persisted even during the COVID-19 pandemic. So I'm going to briefly talk a little bit about changes related to airway clearance after people have been on Trikafta. And the reason for this is that our patients do airway clearance. We encourage our patients to do their airway clearance at baseline twice a day. But if you're looking at all the medicines that they do, which includes, at least at our center, we push bronchodilators, we push for hypertonic, Pulmozyme, and they may be on an inhaled antibiotic. If you nebulize a medication that takes 10 to 15 minutes, plus you're doing a vest for 20 to 30, that's about an hour for one treatment in the morning. And then you're looking at maybe another hour. So for those of us in our lifestyle, to find two hours out of your day to sit down and take the time to focus on your airway clearance is a lot of time out of your day. And the other thing that's changed post-modulators is a lot of our patients don't have a significant cough or sputum production. And so they don't feel the effects of the therapies that they used to. And so a lot of our patients have actually stopped their airway clearance, and we as physicians and clinicians don't know what to tell them, especially the ones on modulators. And so this was called the SIMPLIFY study. Very lovely name. So it was a two-parallel, open-label, randomized-controlled, non-inferiority-to-trial. Very complicated, but I'll explain it. So subjects who were already on Trikafta, and they had to also be on either hypertonic saline or Dornay's Alpha for six weeks. They had to be on it before. They discontinued either one for six weeks. There were 80 clinics in the US, so in our therapeutics development network, so 80 CF centers that participated. They had, if you were a young adult, you could have higher lung function. So they looked at 12 to 17-year-olds who had lung function greater than 70%. We consider this to be mild lung disease. And then if you were an adult, you could have a lung function that was greater than 60%, so a little bit more range. So the results showed that there were 847 subjects, and the average lung function was actually very high in this population, and I want to point that out. So it was 96.6. So for those who are not familiar with CF, that's very high, very good lung function. And of that group, there were 370 in the hypertonic saline group and 477 in the Dornay's Alpha group. So again, this was a non-inferiority trial, and they looked at their non-inferiority margin. And again, this was only six weeks off therapy, so a very limited amount of time. And actually, at our center, I found it very difficult to enroll some patients, because I do have some that are very regimented and do not, probably less so than others who did not believe in stopping their airway clearance just because they were on Trikafta. And some of that was is they did see that initial, their increase from baseline, and they wanted to maintain that as best as they could. So we actually had a hard time enrolling some of our more regimented patients who might be the ones who would benefit. And basically, what we found is that if you were to stop Dornay's Alpha or hypertonic saline, it was not inferior to continuing. So suggesting that maybe we could consider stopping therapies. There was one little note that I found interesting that they said the Dornay's Alpha group saw actually that there was, I think, less of a decline in their lung function compared to hypertonic, which a lot of us would think is counterintuitive, because Pulmozyme was the airway clearance drug, and it was always the one that if my patients were limited on time that I would push them to do, because it was once a day and timely. So it brings up a lot of questions then about how Dornay's Alpha is actually working in our patient population. So again, discontinuing treatment was not inferior to continuing treatment with respect to absolute six-week change in lung function in both groups. So what do we recommend as clinicians? I'll be honest. I have to work with patients on an individual basis. So because this trial was limited to those patients with mild to high lung function, for my patients who have lung function with severe to moderate disease, so this is people with lung function less than 70% or even less than 40%, I don't know what to tell them. I tell them to continue, because they still have very low lung function, and I want them to maintain that for a lot of time. But we then work together to figure out how best to maximize that. There were also no changes to comment about during exacerbation. So we do have patients who've definitely stopped their airway clearance and have definitely exacerbated. And so then they ask, and we bring them in, and we restart things, and then they ask me afterwards what to do, and there are some of our patients who still will only do their treatments when they feel sick. And then how do we encourage the use? Which one should we encourage the use of? And so those questions are really unanswered. But I think for our patients who have mild lung disease, who have really never been sick and who have done really well, you could make the argument to back off or at least consider just one of the two medications for maintenance therapy. So in summary, we still need a way to define acute exacerbations in people with CF. We are attempting to reduce the time needed to treat with IV antibiotics. Triple combination therapy reduces the annual rate of pulmonary exacerbations in the short term, and then we are starting to see some of those results from the long term as we've had this drug approved now for almost five years. And so therefore, our longitudinal studies looking at the relationship between triple combination therapy and pulmonary exacerbations are needed. And then, of course, the biggest factor is we still don't know who needs to continue airway clearance except when being treated during an acute exacerbation. Thank you. So don't forget to evaluate this session, and I'll take a few minutes for questions. I will ask you a question then. So I would say that at our center, the application of the SIMPLIFY results are very similar. It's very questionable. But in encouraging your patients who have moderate to severe lung disease to continue, how have you addressed maybe some pushback from them if they say, well, I'm not bringing up mucus, or I have decreased tolerance of these therapies now that I do not have such thick secretions now that I'm on modulator therapy? Yeah. So that is actually a lot of what we're hearing from our patients. And that is a really hard thing to dissect. And so I always encourage exercise as a form of airway clearance. I think it's great for them. If you ask our patients before modulators, you go for a jog, they're going to cough up mucus throughout their jog. So I still encourage exercise. I think that's very important as if they're going to not do as much airway clearance. And then I actually do try to simplify their regimen, as the argument is. I try to say, what time do you have and what to do? And I still, despite the results of the SIMPLIFY study, I'm a big pusher of Pulmozyme. And again, a lot of that has to do with it's once a day, and it's 15 minutes. And if they do that with their vest or their aerobica or whatever you're using for 15 minutes once a day, I'm encouraged for that. And I actually have a patient who's a late diagnosis who would qualify for modulators, but his lung function is very, very, very high. And so he does Pulmozyme, he says he does it five days a week, he forgets to do it on the weekends. And we've actually seen still a positive improvement in his lung function even without modulators. So it still works in those individuals. And then the other thing I tell patients is, Pulmozyme has to be refrigerated. So we talk about the logistics of that. So if you're going to do your treatments during your break at lunch at work, and there's not a refrigerator accessible, then maybe hypertonic saline is the one for you. My patients who are, and those are, I very much encourage it in my patients with still moderate to severe disease, because I can tell you, based on experience, we are seeing those patients in the hospital. Our census drops, I mean, we had maybe two to three patients in the hospital at a time after the triple combination therapy came out. And then as we got past the COVID era and people have been coming back, our census is similar to, I think, what it was before the modulators. And those are patients who I know for a fact are not compliant with their airway clearance. And I use that as an example for others, because unfortunately, they're the same players before. The tricab has to stabilize them for a little bit, and we're starting to see. And I think that's, as our next speaker will talk about, while as amazing as this drug is, it is still not perfect. And so I'm going to introduce Ted Liu from University of Utah to talk a little bit about some of the not-so-great parts of the modulators. All right. Thank you very much. I'm really pleased to be here. Yeah, but I get to give you the bad news, or what bad news there is. So there are some challenges. I mean, this drug is like any other drug. It's got some issues. And we're just going to go briefly through some of these. So I'm Ted Liu. I run the CF Center at the University of Utah. We just hit like 500 adult patients this year. So I'm a bit overwhelmed. I started doing CF in 2001, and I had a team of five people and 80 patients. And now I think my CF Center is larger than pretty much every department on campus, except for some of the medical specialties. So we've seen a lot of change over the years. I have a bunch of disclosures, I'm afraid. So I get research support from a variety of places. And most importantly, I get clinical trial support. We participated in basically every major therapeutic intervention on CF over the years. And you'll notice on there that Vertex is on there, and they're the maker of all of these modulators that are licensed. So take that with a grain of salt. I'm a member of the Clinical Research Committee at the CF Foundation. So I review grants, and I'm on the steering committee, at least I think I still am. I'm not sure if they've kicked me off, maybe. OK, I'm going to talk about adverse responses. I'm going to talk briefly about working solutions and alternatives, because there are some adverse responses that you have to deal with. And I'm going to talk about how the modulator-related changes kind of shape the future of treatments for CF. So anytime you have a medication, you hope that the benefits outweigh the harms. And on an individual scale, more patients should receive benefit than receive harm. That seems obvious. And for each individual, this gets to the point of, this is a great therapy, but is it right for me? So a specific individual needs to have benefit from a therapy, and it should outweigh any possible harms. Then there's this other thing called public health, which I've been thinking about a little bit more over the last three years for obvious reasons. There are some public benefits that the public receives when we treat some people, but we don't necessarily give benefits to the individual. So this is, I'm thinking about our recent patients who were incarcerated for six months under our care getting anti-TB medications, because they're a danger to the population. And they may or may not feel like they are a danger, and they definitely oftentimes don't feel like they're getting any benefit, because anti-mycobacterial drugs are really hard to take. And then the other part is that sometimes when you increase public health benefits, even at the cost of benefit to an individual, you reduce the cost of care. So things to think about when we're treating patients. So what are the challenges with modulator therapy? This actually turned out to be a fairly difficult talk to put together, because I thought, well, I kind of know this. But then I went searching to see, well, what have people actually said who thought about this carefully? And the answer is, there's not a lot said. And you kind of have to pick and choose what you want to read about. So the first thing is that not all people with CF have genetics that are treatable. Around 90%, so I guess the latest numbers are slightly less, probably because we're picking up more atypical mutations. A few of those that are left out qualify for theratyping or N of 1 trials, which are exceedingly difficult and expensive, but are worthwhile for those individuals. And it's actually possible that the majority of patients or people with CF remain undiagnosed. So if you think about where the CFTR gene originated, it's the tribal regions of northern Pakistan. The gene spread from that location to all different locations. It came with the Celts west and ended up in Ireland. And that's why there's such a huge population of CF patients there. But it also went other places. So India remains a undiagnosed frontier. There could possibly be hundreds of thousands of patients there. And they're not being identified, because childhood deaths are actually still fairly common. If you die of a lung disease and you're a child, you may not get diagnosed. And I don't know about China. I think the gene mutation is low, but the population is enormous. And there's almost no genotyping going on in China. And again, as one of my friends from China has said, people in China tend to die of their first major illness. And so you don't have people surviving to older ages to be diagnosed later. We've talked about cost. Cost is a major barrier to treatment for this very rapidly changing population. Not changing on the basis of individuals, but changing on the basis of the population. So a drop in 90% to 88% is actually a substantial change in the genetic makeup. That's a lot of genotyping to get that change to go down like that. And then adverse events are an unwelcome but frequent complication. So if you look at the number of patients who've been studied in these modulator trials, it's hundreds, maybe a couple thousand at this point. So I guess I don't think this is really that confidential, but I've read over 5,000 safety letters that are serious adverse events. And most people have several updates. So we're talking about thousands of serious adverse events among just a few thousand patients. And that's just the clinical trials. So that's something to keep in mind. So it turned out that when I was looking for information, one of the chief places is prospective clinical trials. So it turns out I had this naive notion, I'm going to just go ahead and catalog all these mutations and these adverse events and tell you about what these are, and it'll be simple. And of course, it's not. So almost everyone in the trial had some kind of an AE. And every single trial was like this. So over 90% of patients reported some sort of adverse event. Among those, though, it was a small fraction that was judged to be related or likely related to treatment. And the moderate to severe AEs led to a discontinuation of about 1% to 5% across all the trials. So these are really motivated patients. These are really motivated clinicians to keep people on drugs. That's actually a fairly large number for withdrawing from a trial. In the real world, these populations are very different. So clinical trials are highly selected. In the Vertex trials, all of the patients were 40% to 90% on FEV1 and a host of other markers. In the real world, you have people either sicker or healthier. They have other complications. They have strange second mutations sometimes. There's non-systematic data collection. The adverse events just get more diverse. It turns out that within the clinical trials, they were very focused on pulmonary and respiratory system adverse events. And once you get outside of that environment, you start to see more serious adverse events that don't get reported in the clinical trials. The problem, of course, with real world data is that you don't have any controls. So at least within the clinical trials, you have very closely watched controls. And you can tell that, oh, headaches are not really an issue because everybody got them and so forth. But without those controls, it's really hard to take a look at what is real and what's not. So in keeping with the interest of my kids and movies, this is the multiverse of adverse events. And the clinical trials really focused on pulmonary, as I've said. But there are extra pulmonary complications. It's basically everywhere that you see CFTR expression. And this is not a complete list. But it's a list that is maybe a useful list. There's a reference down there that reviews the real world safety of CFTR modulators. And that's actually a great place to start. I would start there rather than go to the clinical trials to look at the list of what's out there. So one of my first attempts, because I rewrote this presentation like five times, was to categorize all the adverse events by anatomy. And I thought, well, that's boring. And I didn't do all that well in anatomy class in medical school anyway. So I don't really like anatomy as an organizing theme. And so I thought, well, let's go with mechanisms. So immune-mediated responses, secretion-related, direct toxicities, because these chemicals are potentially poisons, and mixed mechanisms, and other. And unfortunately, just about every individual, you can classify the specific adverse event maybe according to one of these mechanisms. But among patients, you really can't. It turns out that mixed mechanisms is really common. And so I've kind of gone back to talking about this in terms of anatomy. But even then, there was actually this one other vexing category, which it's not a bug. It's a feature. And so it's like, is it an adverse event? Is it something you should be worried about? Or is it not? Like, should you just take it on the chin and keep going? So we'll get to that in a moment. But the pulmonary adverse events, I think there's a sudden increase in secretions in many patients. It might even be the majority in some groups that require an increase in airway clearance. And that actually can be destabilizing and lead to exacerbations. And you may end up giving up because it's too high a hill to climb to get into stable therapy. We've had a few patients like that. The other manifestation of this are patients who don't take their meds all the time. So people who like to go on and off drugs because of whatever reason, you end up with people who are incredibly destabilized ending up in the ICU. There is a bronchoconstriction issue. It's primarily seen in patients who are post-lung transplant. So for those people who are treating individuals post-transplant for non-pulmonary benefits, the major side effect within the lung is bronchoconstriction. And this turns out to be fairly difficult to treat. There is an increase in massive hemoptysis and pneumothorax among some subset. And it's not clear exactly where this is coming from. It may be that we are removing ancient mucus plugs and unleashing organisms that have been plugged up, literally, for maybe decades. It may also be that we're doing this, and there actually are local increases in inflammation. It's not at all clear, and it's really unstudied. But these events have happened and are quite serious. And then there are non-dramatic decreases in lung function. And people with the lowest FEV1s may not be the most effective. So I'm showing you a little data. This is from the 2016 CF registry. This is unpublished. And what we did was we took a look at patients with some subsets of mutations. So G551D patients are shown in Utah red, and R117H patients are shown in white bars. And you can see that there is actually individual variation. So along the bottom, I've categorized patients as very low-predicted survival, low survival, medium-predicted survival, and very high-predicted survival. And you can see that there's actually variation between the mutation types and also within the different populations. And you can see that among these two minor mutations, the very high survival group tended to have a drop in lung function. This is not exactly good news. And you have to pay attention, basically, is what I'm saying, because individual variation can be quite marked. This is the same four groups from very low to high survival. And this is the number of exacerbations. So overall, the number of exacerbations has dropped dramatically. But it turns out that in patients who have very high survival, there's actually an increase in exacerbations. And so you have to kind of take care and count the exacerbations. But it's difficult to see, because if someone goes from zero to one exacerbation, then it's like, well, is that actually a significant change for that one patient? And it's almost impossible to see. The only way we saw this was by aggregating patients who had been on treatment. And I should add that these patients were on treatment for two years. And that's how we could also look back and look at the counts of exacerbations. So for very high survival, for R117H patients especially, there may not be a huge benefit to ivacaftor treatment. All right, GI complications. So there's this non-alcoholic-related acute pancreatitis, which seems to be increased in a fair number of patients on modulators. And then there's liver disease. Transaminitis was sometimes transient in the clinical trials, sometimes not, hyperbilirubinemia, and then hepatic failure. And in both the real-world data and in the clinical trials, as reported, there were increases in liver disease. And I think it's important to note that in the CF registry, again, this is through 2016. This is every year of data since 2003. The darker the curve, the more recent. And basically, for every age group, for every year, the complication rate at CF liver disease, which is a created variable, has been increasing. So we see more and more CF liver disease, which is basically defined as cirrhosis here. We don't have enzymes in the registry. OK, then there's modified absorption. And that can change diabetes characteristics, but also lead to severe pain. And then I think people have not talked about neurocognitive complications very frequently, but CFTR is expressed in the CNS. There are these neurocognitive issues, and there are some recent publications about this, that these changes can be actually quite difficult. And these involve more than 10% of treated patients. So that is actually quite serious. I think one of the more telling stories was an engineer I take care of who complained that he could no longer add numbers. We had another engineer whose mother took away her driving privileges. She's a young adult. And basically, she said, the mother said, she was never a great driver, but now she's positively scary. So the neurocognitive defects that you see with CFTR modulators can be quite serious and can lead to stoppage of the medication. All right. I'm just going to touch on one more thing. Well, you should think about sleep phase delay, because we've had patients who flipped from being early birds to late night owl types. But let's talk about it's not a bug, it's a feature. So you've heard that it reduces sinusitis, but we have patients who now have constant rhinorrhea. So it's great that it treats sinusitis, but it's also very annoying to have rhinorrhea. And then, yes, there is a surge in pregnancy in CF, but there are some case reports and there's some growing concerns that in utero exposure may not be so beneficial to the fetus. So there have been some false negative newborn screens. So mothers who have CF, whose partners are CF carriers, occasionally have children who have CF, and they're not getting picked up in newborn screening. And so that is definitely a bad thing. And then there are some non-CF infants born to those mothers who have had pulmonary hemorrhage and congenital cataracts. So yes, on the whole, it's great that the fertility rate among women with CF has gone way up, but there are some issues. And then sleep clock inversion, come and talk to me afterwards because we're out of time. The most serious thing on here, which is at the bottom, it's not a bug, it's a feature. So patients are living longer, and we've had some patients who were planning their deaths. And they've had to stop and rethink this and say, you know, I need to do something with my life other than plan to die. So I had a young guy who was about 20, and he was all set to become a beautician. And that was like what he was up to. And he realized he was going to live. So he's now in a college program trying to save the world from climate change. So that's encouraging. All right. I just want to say the therapeutic things are reduce the drug dosing, modify the dose, roll back to an earlier generation if you're able to. And then you can try antidepressants and ADD meds, and you can try psychiatric evaluations for other things. But modulator cessation is probably in the cards for a lot of these patients. So we're waiting for new treatments, and I won't mention too much about that. Basically, just to summarize, many mutationally eligible patients with CF can't take modulators because of adverse responses across the organ systems with multiple mechanisms. There's limited access. The off-label dosing schemes may be helpful. And then we're waiting for genetics agnostic treatments for these patients. All right. I guess I'm out of time. Come up here and give us your questions. Thank you.

Cystic fibrosis

CFTR modulators

CFTR gene

Autosomal recessive disorder

F508 deletion

Ivacaftor

Lumacaftor/ivacaftor

Tezacaftor/ivacaftor

Pulmonary function

Extra-pulmonary symptoms

CF