Focus on Cystic Fibrosis - Transcript

[00:00:59] GR Scott Budinger, MD: Okay, we will go ahead and get started. Good morning for those of you here in the United States, and to those of you in Europe, good afternoon. We have people registered for this conference from more than 10 countries across the globe, and I want to extend a warm welcome to everyone that is here. My name is Scott Budinger for those of you that don't know me, I'm Chief of Pulmonary and Critical Care Medicine at Northwestern University, and I'm director of the Simpson Querry Lung Institute for Translational Sciences. And on behalf of Northwestern University, the German Centers for Lung Research or the DZL, and the University of Pittsburgh, I want to welcome you to the inaugural session of this new series, Global Voices in Patient-Centered Research. We are so pleased you can join us here. This new international series is built around a simple but powerful idea, that discovery-based research that starts in the lab and is driven by the curiosity of investigators can truly transform lives, and that the most meaningful research is grounded in the experiences and voices of patients. The series will feature patients with lung disease, researchers, and clinicians who care for them, and patient advocacy groups who support them, and will be hosted by institutions around the world. Today's session focuses on cystic fibrosis, a condition that over the past few decades has gone from being a uniformly fatal childhood disease to one where many individuals now live full adult lives. This progress has only been possible because of substantial and sustained investments in basic science research, and the dedication of clinicians and researchers in academia and pharma and the unwavering partnership of patients and families. You'll hear today from leaders in the field, Drs. Manu Jain and Susanna McColley, who care for adults and children with cystic fibrosis at Northwestern, and JP Clancy, who is the Senior Vice President of Clinical Research at the Cystic Fibrosis Foundation. But much more importantly, you will hear from someone living with cystic fibrosis whose perspective reminds us of why this work matters so deeply. Once again I want to thank you for being here and for your commitment to advancing patient-centered science. Drs. Melanie Königshoff, Werner Seeger, Iasha Sznajder, and I, who lead this effort, hope this series sparks new ideas and new collaborations between our groups and groups around the world. But most of all, we hope it provides renewed energy to continue our collaborative international efforts to drive discovery research that will improve the lives of patients with lung disease. Just to start with a couple of housekeeping items, we will be taking questions in writing, and those will be at the end of the program. Please post the questions in the chat, and if you're interested in hosting a session at your own institution, please reach out to me or Dr. Seeger, Sznajder, or Königshoff, and we'd be happy to discuss putting that together with you. Finally, just a note to everybody, this meeting is being recorded, and we will send a link to the recording to everyone that has registered for the meeting. So without further ado, I will turn this over to Dr. Manu Jain, and thank you again for all being here.

[00:04:06] Manu Jain, MD: Thank you, Scott, for that very, very nice introduction. We're gonna start with Dr. McColley, who is going to share her perspectives on how the care of children with CF has evolved over time, and then I will talk about the adult care of people with CF, and then we'll have one of my patients, who is a new mom and about to be mom for a second time, sharing her perspective on what's happened in CF care and raising a family. And finally, we'll finish with Dr. Clancy from the CF Foundation, who will sort of bring this all together in terms of linking the basic science research that's been done in the past to the clinical care that we've been able to deliver to our people with CF. So, Dr. McColley, would you please get us started.

[00:05:00] Susanna McColley, MD: Yes, thank you, Manu, and welcome everyone. It's such an honor to be here with you today to talk about this important issue of how basic science has led to clinical advancements, and I will tell you that I am a clinician. When I was doing my training I started my pulmonary fellowship in 1988, at Johns Hopkins. I wanted to do clinical research in cystic fibrosis. I was told by my very first mentor that there was no such thing as that, because there hadn't been enough fundamental science discovery to create a career on that. I kind of didn't take that advice. But nevertheless, I think it's really important to go back and then look forward in history to understand how fundamental science is so important to the advancements that we have today. So I am going to start very early in the history of CF care. I had the great privilege of giving the Carl Doershuk Lecture at Rainbow Babies and Children's Hospital at Case Western University a couple of months ago. And we all know that cystic fibrosis treatment started well before we knew what caused cystic fibrosis. And so in the early days of cystic fibrosis in the United States, a group of families started the Cystic Fibrosis Foundation, and they quickly recognized that they needed to have care centers where physicians and other team members who were interested in caring for their children could give them good care and could advance their life expectancy and quality of life. And so this is a paper published in 1964. I was three years old in 1964.

[00:07:28] So 1964. This was a hallmark paper in the Journal of Pediatrics, and this was a report from Rainbow Babies Hospital. It was one of two of the first cystic fibrosis centers accredited in the United States, and I have highlighted the advancement here. None of the deaths occurred before five years of age, because at that time it was rare that a child actually lived to be in kindergarten.

[00:08:21] So what has NIH funded that has enabled the advancement of survival and quality of life in cystic fibrosis. Well, lots and lots of foundational research, including mucus rheology, including systemic and airway inflammation. Discoveries related to pancreatic physiology and immunoreactive trypsinogen being elevated in the bloodstream were foundational as well. Airway microbiology, incredibly important. And then, of course, ion transport abnormalities. So when I was doing my fellowship, people were looking for the chloride channel that was defective in cystic fibrosis, because there was a hypothesis that a known chloride channel caused the abnormality that causes elevated sweat chloride, lung disease, pancreatic disease, and other organ system dysfunction.

[00:09:25] But during my time of training, the gene that causes cystic fibrosis, is defective in cystic fibrosis, was discovered. And what I really like about this image is that this gentleman sitting here in 2009 is the same as this child who was on the cover of Science magazine in 1989. And so you see here not only the discovery being celebrated, but the increased life expectancy that came out of this, not because we had CFTR modulators in 2009, but because clinical research really ramped up after this discovery.

[00:10:20] And so in the perspective of a pediatric pulmonologist who studied cystic fibrosis for many years, there is no question in my mind that the two major impacts that have driven survival are the advent of newborn screening and discovery science that led to CFTR modulators, and I want to point out that when I was a younger doctor, CF newborn screening was quite controversial, because it really was not clear whether that early diagnosis with early treatment could be life changing and increase longevity in cystic fibrosis. We used to see kids who were really sick. Most of them got much, much better with the treatment that we could give, and it was a randomized, controlled trial sponsored by the National Institutes of Health in the United States. To Dr. Philip Farrell that really gave conclusive evidence about how health prolonging and by extrapolation, survival prolonging, newborn screening is. And then the CFTR modulators all came from discoveries in basic science laboratories, Michael Welsh and Alan Berkman being very prominent in this that led to a company coming out of the University of California, San Francisco, that was purchased by Vertex Pharmaceuticals, and all of this also had a lot of funding through the Cystic Fibrosis Foundation. I want to acknowledge that as well. But without this NIH funding we would not have these advancements.

[00:12:14] And so, since we started newborn screening in the United States, and this, for those of you in Europe, this is done on a state level and not on a country level, that's true in similar constructs in some European countries as well. But there is definitive evidence that lung function has increased. So newborn screening was fully implemented in the United States in 2010, and you see here how much better lung function is being maintained in childhood than it had been in previous birth cohorts.

[00:12:56] And we also have significant expansion in CFTR modulator use to people with rarer as well as common CFTR variants. We continue to do studies in young children, and I'm involved in many of those. There is still an ineligible population, but this has made a huge difference.

[00:13:20] So we continue to have unmet needs for children with cystic fibrosis, just as their unmet needs for across the lifespan of this disease. So one of the things that I've worked on a lot is just overcoming disparities because we have unequal outcomes based on socioeconomic and racial and ethnic features in the United States and in other places in the world. There are also missed and delayed diagnoses, some of which are related to, some of which are disparity driven, but for other reasons as well. There are a lot of people who can't benefit from modulators and those not receiving them. Basic science work has allowed for clinical trials in new areas. And then globally, there are countries and full continents that don't have diagnostic or treatment capabilities. And we want to spread the impact of CF therapies worldwide, diagnosis and therapies. And then we want to optimize health across the lifespan. And I think that as a pediatrician there's a lot of interest in fetal treatment, so treatment of mothers with modulators particularly. We know that cancer and cardiovascular disease that occur in adulthood have origins in childhood in the general population, and we want to be able to understand and reduce risks. We want to improve mental health. We need new epidemiology and standards of care in the modern era of treatment. So there's a lot to do, and much of this needs NIH funding here.

[00:15:03] So all of the babies, thank you for your attention. We've had a lot of progress. We've got a lot of new horizons. And thank you very much for your attention. I will turn it back to Dr. Jain.

[00:15:56] Manu Jain, MD: So I'm going to take the baton from Susanna, as I sort of do when she transitions her patients, her pediatric patients, to our adult clinic. And I'm going to talk about this new era of care and possibility from survival to thriving, how CF care has evolved and is continuing to evolve, and the continuing challenges we're going to have to take care of our growing adult population. So these are my disclosures.

[00:16:23] And the objectives I'm going to have in my 7 minutes or so is just to demonstrate the growing adult CF population and the challenge that's going to create for CF, adult CF caregivers, how the care for people with CF has gone from a crisis management to more of a chronic disease management approach, talk a little bit about the burden, how the burden of day-to-day care has diminished, allowing people with CF to have more flexibility in their day-to-day activities. As time passes, I think we're going to need a more comprehensive, multidisciplinary adult care approach as we don't really know what CF in your fifties, sixties, and seventies is going to bring. And so we're going to continue to need to learn about that. Then finally, at the end, I'll talk a little bit about family considerations. I have invited one of my patients I mentioned, who's going to talk to us about what it's like to plan a family.

[00:17:25] So what I'm showing you here is the changing face of CF. And depicted here is a growing change in the CF population, and where data from the CF registry from 2024, but it goes back to the year 2000. As you can see, the pediatric population representing more than 60% of all the people in the US CF registry at that point, and there's been a continual increase in the proportion of adults that are represented in the registry. And this just is because of the improved survival that we've seen continuously for the last 50 to 60 years, and sometime around 2012 in the US there were actually more adults in the CF registry than pediatric patients, and as you can see, based on the projections, by the year 2030 there will be more than 60% of the people with CF will be adults in the US.

[00:18:27] As I alluded to in my objectives, the care of CF patients has changed substantially for adults. When I started in 1998, it was managing one crisis to the next. There were frequent hospitalizations, people developing respiratory failure, needing lung transplantation. A picture on the left sort of depicts that, that's a scene from a movie called Five Feet Apart, that represents a person living with CF, and this was often the life of a person with CF. Contrast that with today on the right, you can see a physician talking to their patient on a telehealth visit, which is happening more and more frequently, talking about sort of their day-to-day management, which is often a report that things are going well, nothing needs to be changed, no crisis is occurring. Obviously this is not everyone's experience as an adult with CF, but it does happen more and more than it used to. Sort of to quantify this a little bit, I've shown you a graph from the CF registry looking at the percent of people who are having a pulmonary exacerbation over time, and you can see back in 2015, about 40-45% of people with CF would have at least one pulmonary exacerbation a year, and contrast that to now 2024, where less than 20% of people will have a pulmonary exacerbation. Pulmonary exacerbations are severely morbid events and reducing them is a very important clinical outcome, and I think this sort of depicts the improved outcome we've been able to have with people with CF.

[00:20:14] At the same time, when we're seeing these improved outcomes, one of the other things that has occurred is that we've been able to reduce the day-to-day burden that people with CF have to go through to manage their disease. It used to be that people would spend one to two hours in the average day doing their daily treatments, but what we've been able to do is reduce our use of dornase alfa, as you can see on the top graph, which is a mucolytic. And then we're using less inhaled antibiotics. Inhaled tobramycin is depicted on the bottom graph. And so we're seeing these improved outcomes as we're starting to use these chronic historical symptomatic based therapies less and less, sort of allowing people more time in their day-to-day to be able to do the things that are important to them besides managing their CF.

[00:21:08] Now, as I alluded to earlier, I think that the care for the whole person is going to need to change as patients get older and older. On the left I've shown you what a typical care team might have consisted of for an adult with CF, you would have a pulmonologist, nurse, dietitian, perhaps an endocrinologist if they had CF-related diabetes, respiratory therapist, and social worker. But as time passes, and Susanna alluded to some of the chronic diseases that may develop with aging, I think we're going to need to recruit more subspecialists in the care of people with CF, and this would include obviously gastroenterologists, obstetricians, that I'll talk about in a little bit. But as people get older, you know, cardiology, geriatrician, there is a higher risk of cancer in people with CF, so we're going to need to engage oncologists more as well, and other subspecialists. So we're in a transition phase where we're evolving our care of people with CF, and this is going to continue to require research going forward to engage people to learn more about what happens with aging and CF.

[00:22:21] But looking ahead, you know, the future is bright, based on everything that I've talked about, and also what I'm showing you in this slide on the left is a graph of the number of lung transplants that are done, have been done annually in people with CF, and you can see, it was around 200-250 until about the year 2019, which is when ETI or Trikafta was approved, and you can see the substantial decrease following the approval and uptake of ETI. And now there's fewer than 100 lung transplants that are done in people with CF in the US on an annual basis, and almost none in pediatric patients with CF. And then, if you look at predictive models of survival, this is data, this is a graph from a recent publication that modeled what life expectancy might be in using ETI. And you can see that now the predicted survival is nearly 70 years of age, with continual daily use of ETI, substantially different than in the pre–modulator era, which was in the mid-[1930s], better than it was historically but clearly a big jump with ETI.

[00:23:31] And then finally, there's been a baby boom in the CF world. Again, 2020, there's a big jump, more than doubling of CF pregnancies reported in the registry, and this has continued for the subsequent annual basis as well. And this brings up the question of why are we seeing this? And then I thought it would be really the best to hear a perspective from a CF mom who has experienced the beneficial effects of Trikafta.

[00:24:19] With that I'd like to welcome my patient, Anna Kramer. Anna, welcome. It's really wonderful that you're able to share your perspectives with us. So thanks for coming.

[00:24:31] Anna Cramer: Of course. Thank you for having me.

]00:24:33] Manu Jain, MD: So, Anna, I wanted to start having you comment about how you feel like basic science has changed your life before you even knew the word research. Can you explain what that's meant to you?

[00:24:45] Anna Cramer: Yeah, absolutely. So, I was born in 1987. I am now 38 years old, and really it took my parents a little while to settle in. They were told that I would only live to about 15 at that time, and so it was about a year and a half later, in 1989, that, as Dr. McColley said, the CF gene was discovered, and my parents, like so many in the CF community, could finally see that light sort of like, okay, a cure is possible. Treatments are possible. We just found the gene. Now, the options are going to start unrolling, and really over the course of my life. That is exactly what we've seen. So my family started heavily fundraising for the CF Foundation at that time in 1989, over the course of my life we personally have raised, like $750,000 for the foundation, and it was for this exact reason to pour that money through the foundation into research that would present therapeutic options for people like me with CF. To have the future that I am now living. So it really started working in my life before I even realized you know what it was going to mean for me personally.

[00:26:09] Manu Jain, MD: So was having a baby, pregnancy, something you considered as you got older, came into adulthood?

[00:26:18] Anna Cramer: So, yes and no. I think, you know, as college age and into adulthood it was definitely something that was always on my brain, you know, would I have a family someday? I had always dated through college, but during that time, when I kind of started going out on my own, and living like a normal college student might, is when my health really started to decline. And throughout my late twenties, as I settled down with a serious partner, my health really started to decline. And it was actually the day that I got engaged that I was told at CF clinic that I would need a double lung transplant if my health continued to decline the way that it was. So the year leading up to our wedding, instead of having the talks that many people are probably having when they're planning to get married, we were discussing the fact that kids were not a part of our future, and that realistically, we didn't really even know what the future would look like. So yes, it was a dream of mine. But I like to consider myself a realist, and if you had asked me on my wedding day, would we have children? I would have said, absolutely not.

[00:27:33] Manu Jain, MD: So when did you realize that maybe the future would be different than what you realized at that point that having children was actually a possibility?

[00:27:41] Anna Cramer: So, ironically enough, the FDA approved Trikafta approximately two weeks before Mike and I were married, and it was very surreal, like I said, I'm a realist, and I never, I had heard about this new treatment that was going to be available, but I truly never believed or wanted to believe that it would help me, because I was so convinced that it wasn't. But about six weeks after returning from my honeymoon, so right around the first of the year 2020 is when I started Trikafta. I was inpatient over Christmas, because I was so, so sick at that time, and I started Trikafta and immediately felt the effects working. By the time I went home I was like, oh my gosh! Is this really happening? And you know not many, I'm sure many CF patients can now say this, but not many people truly get the beauty of hindsight, and it was only once I felt so good after being on Trikafta that I realized truly how bad I had felt, and that everything in my life before Trikafta was difficult. I couldn't cook dinner. I couldn't walk my dog. I was sort of working at the time, but it was hard, and you sort of just do it, because that's your normal. But then Trikafta came along, and suddenly all those things that were once impossible were now easy. So during COVID, when everyone was like, this is terrible, we're stuck inside, I'm like, I can cook dinner, and I can, like I had this new life. It was truly incredible. So it took me about six months of living that new reality. I was very used to getting bad news, particularly in a medical setting, and so I did sort of have that six-month period of like, there's no way this is going to last, the rug is going to get pulled out from under me, when is my lung function going to go back down to where it was. Luckily, knock on wood, five years later I am still in an incredibly healthy spot, so it was probably about six months in that I was like, okay. With the help of my social worker through the clinic I was able to speak with her and my husband. And we were like, we're ready to actually start planning our future at this point.

[00:30:10] Manu Jain, MD: So women with CF historically have faced, you know, some relatively unique fertility challenge.

[00:30:17] Anna Cramer: Yes.

[00:30:17] Manu Jain, MD: How do you feel like the research around CF has helped sort of help you in that perspective?

[00:30:23] Anna Cramer: Definitely. It was a twofold help for me, I guess you could say. The first step that my husband and I took in exploring having a family was to get him tested for the CF gene. He does, in fact, carry the CF gene, as fate would have it. So our options at that time, and we elected at that time, after speaking with the geneticist, to explore IVF. So on the CF front, my health was in such a good place that my CF team approved me to physically carry a baby because I was healthy enough at that time, and then on the IVF front, we were able to do pre-implantation genetic testing on the embryos that were created, and then only elect to use the embryos that were carriers of the CF gene, because I, of course, carry down both copies, but they are not, they do not have CF. So we were fortunate to be able to go that route, like Dr. Jain said. We have a two-year-old, and we are expecting our second in October.

[00:31:35] Manu Jain, MD: So one of the one of the things that has happened to CF, there's been lots of clinical trials over the last 20-25 years or so, leading to the approval of many of these medications.

[00:31:44] Anna Cramer: Yes.

[00:31:44] Manu Jain, MD: Tell me your perspective on joining trials. Why do you think they're important?

[00:31:49] Anna Cramer: Absolutely. They're definitely daunting. You know, everyone has a life, and you know, signing up for a trial, there are certainly a range of trials that you can be eligible for, some don't interfere with your life that much, because they're already treatments that you might be on. Others are taking a big leap of faith and trialing this new medication. But without those trials that would have been in place, these drugs that have drastically changed my life, you know, would not have made it to approval. And so now I feel that it's our job, and especially being pregnant, you know. I know there's studies that are starting to study Trikafta in pregnancy and the safety and efficacy of that. And you know, the effect on our children, also the effects of a mother who doesn't have CF, but whose child might have CF, and her taking Trikafta. And it's really only through these studies that the future generation can have the same outcomes that I've been fortunate enough to have.

[00:33:00] Manu Jain, MD: Great, great. So what's life like now with your balancing and managing your CF, and then raising a toddler and about to have a second child?

[00:33:09] Anna Cramer: Yeah, I would say that it's as close to like, normal and boring, as boring in like, the least boring way I'm living. You know, CF used to be top of mind all the time. I couldn't get away from it, because I was constantly struggling to breathe. I was coughing. I was doing hours and hours of treatments a day. When I traveled anywhere I was lugging cases of medication with me, and now I really have the freedom of, it's still a part of my life, but it's like fifth on the list of, you know, I'm a mom, I'm a realtor, I'm a wife, and there's all these other things that have moved to the top of the list, which is such a luxury. I've been one of the fortunate ones where my treatments have been able to go way, way down. I, of course, take pills every day, but I have been able to maintain my lung function without doing a lot of airway clearance. Not every CF patient has that same luxury. But you know hopefully, with new treatments and medications everyone can kind of get to that that point because it is incredibly freeing.

[00:34:30] Manu Jain, MD: Great. Now, pregnancy and parenting can be taxing emotionally. How does the modern care CF care sort of help with that?

[00:34:41] Anna Cramer: Yeah. So we have always been fortunate. Through our, through the CF center at Northwestern, we, and I believe every CF center, we are fortunate enough to have a social worker. During the time that I was really, really struggling through all of these things that CF brings about, I leaned so heavily on my social worker, and she really helped me get through this. But sort of as the CF population is aging and our needs are changing like Dr. Jain had spoken about, you know, so are the needs of mental health, you know. I'm dealing with still the chronic effects of CF. I have cystic fibrosis–related diabetes. There's still insurance. There's still these medications that cost a lot of money, et cetera, et cetera. And so social work and mental health still really plays a big role. And I think it's important that, you know, the foundation and the centers kind of evolve as the adult population evolves. And as our needs change, the options that we have through clinical care is changing with us.

[00:35:57] Manu Jain, MD: And then finally, I want to ask you, what would you tell a teenage girl with CF now, who dreams of having children?

[00:36:03] Anna Cramer: Oh, so I would say, twofold, one, to take care of yourself, you know, when you're a teenager or 20-something, it's sometimes hard to look beyond into the future. But if you can take care of yourself and listen to your doctors, which I know we all struggle with at times, you know, you never know what therapy is going to be around the corner, and so, if you are in a lucky enough and healthy enough spot to be eligible for those treatment options, they could really, truly change your life. And then the second thing would be to be your own advocate. So, especially in CF, but I'm sure through many illnesses out there, we can't always rely on this, another patient to have the same experience as us. We are so unique, and me especially, I've always been sort of a unique CF patient with the needs that I've had, and so, being your own advocate becomes so important. Relying on your care team along with your own advocacy to really find the best options for you personally and not just, you know, what works for the whole CF population might not be the best thing for you. It can really help you have success, in my opinion.

[00:37:33] Manu Jain, MD: So, last question, Anna. You know clearly there's been a lot of progress, but we still have a long way to go. What can the average person of the public do to help accelerate this process, in your opinion?

[00:37:45] Anna Cramer: Absolutely. So, my family, when we started fundraising, and they would put me up on that stage at like four years old to give the little speech to tug at all the heartstrings, it was quite literally for this reason. My parents dreamed that I would one day go to college, have a career, raise a family, and the only way to have that outcome for all CF patients, not just patients like me, with the most common mutation, is to continue to fund research, in my opinion. We have to keep fundraising, putting that money towards research that matters so that every single CF patient can have the success and the outcomes that I have, and that we can continue to support the chronic condition that we now have, that as we age will continue to evolve and have needs. The second thing is absolutely clinical trials. Like I said, without the trials that were done before me, though, I would not be where I am today. And so it's our job, as a, you know, CF population now, adults and kids, to really encourage participation in those trials that can help future CF patients, and hopefully they get less and less, but help future ones have these successful health outcomes. And then just access. So not every CF patient is from the same socioeconomic background. Some of them are far away from CF centers, so just getting the same access that someone like me is afforded because I live in one of the best cities in the world, with access to several amazing CF centers, allowing this outreach so that everyone can have access to the same resources that someone like me has.

[00:39:45] Manu Jain, MD: Thank you, Anna, for incredibly articulate advocacy for CF, really appreciate it. Thanks again. And then, now I'd like to introduce Dr. JP Clancy from the CF Foundation. He's the Executive Vice President of Clinical Research, and Dr. Clancy is going to sort of wrap this up, sort of providing a context linking the history and research of CF to where we are today and going forward. So welcome, JP.

[00:40:14] JP Clancy, MD: Thank you, Manu, and thank you, everyone. And it's a pleasure, and thank you again for this invitation, this opportunity to be part of this inaugural meeting. And it's really, really exciting. And I've had the opportunity to work with Manu and Susanna for more years than I would like to count, but first as a CF clinician and researcher, but now, with the foundation for the last seven years. And I'm going to try my best to sort of tie in some of the sort of incredibly important basic science work that really informed these improvements that we've been discussing in the first part of the presentation.

[00:41:04] So the overall topic I'll just give you a brief history of CF for those who aren't fully aware and how sort of moving, how we kind of were able to move from symptomatic to really personalized care, based on CF-causing mutations, how important the lab discoveries were to this work, and really how this is now beginning to pave the way for genetic-based therapies. And I just wanted to highlight that none of this would have happened without basic research that really helped us understand what causes CF, and in large part this was the NIH. Certainly CF Foundation has been a big contributor, but no way that any of this work could have happened in the absence of NIH funding and other governmental agencies.

[00:41:45] So CF was first formally described in 1938, it obviously has been around for millennia, but was really first described in 1938 by Dorothy Andersen, and she was a pathologist. And the reason I bring that up is she basically described a series, a case series of children who had died very early in life, with certain characteristics kind of highlighted here at the left side, and the bar graph shown on the bottom right is age at which these children and infants essentially had died. And the point I wanted to make is, these infants were all dying in the first months to years of life, and just a reminder that untreated CF is a fatal disease in early childhood, I mean in very early life, and also I want to highlight that work, too, what she originally described was this. Characteristics were found in a multiracial and multi-ethnic background. It wasn't limited to a white population, it was described in black, and Hispanic infants, too.

[00:42:56] And we look at the early days of CF, it was really around developing diagnosis, monitoring, and some of the basic treatments which are highlighted here. And this really went on from sort of the [1950s] to [1960s] and into the [1970s], really starting to focus on some of the symptoms, and how we might be able to address them. At this time, though, it was really relatively unstandardized, and over time it did become coordinated, and the development of the concept of a multidisciplinary care team to take care of people with CF really became the standard, but it certainly took a few decades before that was established.

[00:43:32] Things changed dramatically in 1989. This is a picture, excuse me, of Francis Collins sitting in a barn in Michigan, holding a needle, sitting on a haystack. And conceptually, this was really with some of the very earliest work of using the currently now standard genetic tools and capabilities to identify genetic diseases and characterize them. And the CF gene was identified in 1989. I happened to be a third-year medical student, and I was working in a CF lab, so very serendipitously, I saw CF become something that we were sort of struggling to understand all of a sudden understanding the genetic basis. And I just wanted to highlight that this foundational event really began the transformation that we're really talking about today.

[00:44:23] Fast forward about three-ish decades. Basic science has helped us really understand how abnormalities in CFTR cause CF, and the first is, we know what it is. It's a chloride channel. It's a member of this protein family called traffic ATPases. They have these characteristic domains. They sit in the cell membrane. And CFTR is very unique among all of these, in that it is the only one that actually functions as a chloride, as a channel. The others are pumps, and this kind of works in a very different way. And I just highlight two in red. It has this thing called the regulatory domain that's only found in the CFTR among this protein family, and that helps regulate how it opens and closes.

[00:45:07] And basic science was actually critical in helping connect how that chloride transport defect causes disease. And I know this is very much a cartoon we're looking at. But on the left, we're really looking at a cartoon of the airway surface, looking at on the left side epithelial cells with cilia and an overlying mucus layer, and if you look on the right side, this is just a cartoon of what the CF airway under a microscope looks like. It has very thick, sticky, dehydrated mucus. It has chronic infections, all of which over time contribute to progressive lung disease.

[00:45:52] Basic science really helped drive these, first of all, improvements in symptomatic care that Susanna talked about before. And I've sort of highlighted over time, we're looking back as far as 1986, all the way up to about 2013 very steady progress in outcomes. We're looking at sort of median predicted survival and sort of the introduction of different type of symptomatic therapies, treating malabsorption, thick mucus, inflammation, infection, another hydrating therapy for mucus. All of these were associated with steady improvements in CF outcomes. But things really changed dramatically when we started treating the cause of CF, which is CFTR.

[00:46:24] So, what are modulators? Well, basically, these are small molecules that help CFTR work better. And although there are 1,700 known CF-causing mutations, there are only a handful that are super common. And when we think about what a modulator does, it really sort of addresses one of three fundamental factors that are important in any chloride, or excuse me, any channel in how it performs, and that includes, one, the size of the channel, and that's G, which stands for conductance. To the number of channels available, how many are actually sitting in the cell membrane to do the job, that's N. And then Po just stands for open probability, or how much of the time the channel spends open. And basically, if you multiply these together, that really gives you the total available chloride transport. And modulators basically work on sort of these fundamental aspects of any type of channel, but obviously uniquely serving CFTR.

[00:47:16] So how did modulators come to be? Well, in the very, very early 2000s CFF [Cystic Fibrosis Foundation] partnered with a company, Vertex, who many of you may know, who's doing quite well now, but they screened hundreds of thousands of compounds in a very standardized way, using a standardized cell system that expressed one of two different CFTR mutations. One is the G551D. It has a problem with opening and closing. And the other is deltaF508. And that is one that has problems with trafficking and also opening and closing. And basically through this really iterative screening process, they were able to identify compounds which were then tested in human bronchial epithelial cells derived from people with CF with these type of mutations. And what really sort of is exciting here is there was really very little animal model work. Honestly, almost all of this work came to be using this type of system to determine the effectiveness of these different drugs.

[00:48:14] And the first drug that really crossed the finish line, it was originally known as VX-770, now known as Ivacaftor, and it was again identified in the screen for the G551D CFTR mutation. This is the third most common cause of CF mutation. It's a problem with opening and closing. And if, see this structure down on the left, you could have made a lot of money if you could figure out what that was back in the day. But this is just an experiment that shows how it fundamentally works. What we're looking at is a sheet of airway cells derived from a person with a G551D mutation. And we're basically looking at activation of CFTR by different stimuli. This little FSX is basically a way to raise cyclic AMP, and normally, that should cause a big upswing representing chloride transport. But you see, there's just a little blip. And then you see these other arrows. These are increasing concentrations of VX-770, and you can see increasing chloride transport, which represents activation of G551D.

[00:49:16] And what we found is when this was translated into clinical trials that were completed in 2011 and ’12, there were dramatic improvements in lung function as measured by FEV1, and reductions in sweat chloride, which are shown on the right side below the diagnostic capability. And really, this set the stage and really set a benchmark of what could be accomplished if you restored CFTR function by using these small molecules.

[00:49:43] Another sort of approach, that sort of grew out of this, was really to look at the ability of Ivacaftor or VX-770 to activate other channels that had similarities, but weren't exactly the same as G551D. And what we're looking at here is a screen of 54 CFTR missense mutations in a common cell line. And the black is basically activation, the normal way. And the white is the additional activation you get with Ivacaftor. And what they found is that there's a large chunk of these that you can actually activate in the laboratory. And this type of research in a test tube or in a dish was actually able to allow label expansion to a number of rare mutations in CFTR, that honestly would be almost impossible to include in a clinical trial, just because they were so rare within the general CF population. And this concept has been adapted to more and more mutations over time.

[00:50:41] Now fast forward about ten more years. Additional modulators were developed that are able to actually address the most common cause of CF, the F508 mutation. This is a problem in trafficking, in which, when phenylalanine is missing from the position 508 of the protein, it misfolds and never gets to the cell membrane to do its job. And what these drugs do are really sort of bind to the CFTR, the deltaF508, and help it get in the right shape so it can find its way to the cell membrane and then be activated.

[00:51:15] And when we look at the impact of these drugs, this is a triple combination therapy that was just alluded to by the prior presentation, we see this dramatic improvement in lung function above, and reduction in sweat chloride down below, by this triple combination of two correctors and one potentiator. And this was in people who had one copy of F508 in the second mutation that had minimal function, unresponsive. There's actually been a next-iteration improvement upon this. And this has just even raised the bar higher of what can be achieved with these types of CFTR-activating drugs.

[00:51:55] So what is this translated to? Through clinical trials and theratyping, that sort of testing of rare mutations in the laboratory, roughly 200 CFTR mutations now can be treated with modulators, we've seen as already highlighted. This has been associated with the transformation from a pediatric to an adult dominant disease, a dramatic drop in transplants, and a doubling in the pregnancy rate, and also an improvement in outcomes. Now that median predicted survival is now up to 65 years, which is amazing.

[00:52:28] Now, not everybody can benefit from a CFTR modulator. This is just a bar showing us in purple a large population of people treated with modulators. And then there's a subgroup here at the top, roughly 10% who either have mutations that are not responsive, or they just can't tolerate the drugs for a variety of reasons. And the point is, most of these represent biosynthetic defects. There's just no protein for a modulator to work on. And when we look more carefully at the population of people in the US represented here, if we're thinking about developing new therapies, the number of people available for these studies is ultra rare. We're talking about 1,600 adults. And from that group, looking at them a little more carefully, only about 1,100 have lung function over 40%, which is usually an inclusion criteria. It is highly overrepresented for people of black and Hispanic heritage, and about only 25% or less of these people actually have clinical trial experience. So it's really taking this new development into a brand new population.

[00:53:38] Currently, there are a large number of CFTR genetic-based therapies in the current pipeline, and we call them nucleic acid–based therapies or NABTs. And you can see some that are mRNA-based and approached using allele-specific oligonucleotides, gene additions, and potentially some small molecules. And the point is, how do you really advance any of these programs through such an ultra rare population? And the point is, we need a different playbook. We have to go at this in a very different way compared to how we develop modulators.

[00:54:12] And so, what we're working on right now is trying to build that ecosystem for therapeutic development for those who are not modulator eligible. It includes a lot of work with regulators. I highlight a couple of sort of important events to consider. One is the RISE workshop that is going to be sponsored by the FDA in September of 2025, development of guidance documents trying to cooperate globally, assess new endpoints, and also something called the REACH initiative in which we're trying to take, really develop the ecosystem that we could use pooled controls across a variety of programs rather than each program having its own placebo-controlled approach. And please pardon me, I live in Cincinnati, but I had to sort of do a shoutout to Joe Burrow. But point is, we're really trying to go on offense to really drive this different approach to drug development.

[00:55:07] So just to finish up, I just wanted to highlight, I hope you can appreciate that we are seeing, we are just living through a radical transformation for CF, and this is the direct result of basic and translational research to understand the fundamental causes of CF. Modulators are transformational, but they're not available for everybody, but they really do bring the idea of matching a medicine to a mutation, which is really what we think about personalized care. And finally, the pathway to genetic cures is a brand new territory. And we are really laser focused on helping to bring those therapies to those who are currently not benefiting from modulators. So, thank you, I will stop sharing and happy to answer or be part of any remaining time for discussion.

[00:55:53] GR Scott Budinger, MD: Great. You know, I really want to thank particularly Anna, and to thank Susanna, JP, and Manu for a really wonderful discussion around CF. I'll ask a question, since we don't have a lot of time. I wanted to ask Anna and JP, really, you know, having been involved in sort of advocacy and successfully involved in advocacy for research. You know, I think one of the challenges we have in the lab is actually telling people about what we do, and why it’s important for patients, especially when we're looking at timelines of 20 years. And I'm wondering, as a foundation or as a patient advocate, how you frame those discussions with friends and family.

[00:56:41] JP Clancy, MD: Anna, do you want to tackle, or do you want me to try?

[00:56:43] Anna Cramer: I'll give my own personal response, and then, happy to have you follow it up. I think it's really through sharing these personal stories. My parents would always say, by putting a face to the name of a disease, that's really the way to get people involved, and to show them that it really works. You know, it's sort of rare that you get to actually see the success of a drug like Trikafta in people's lives. And it's such, I mean, it could be a movie, all of us CF patients who have been so fortunate to experience being literally so close to death and then having this whole new life in front of us. And it's a direct result of the research. So it's through sharing those stories I really believe that people will want to be involved in funding the research that is still needed to, you know, to help more of the CF population have the same results.

[00:57:49] JP Clancy, MD: Yeah, I couldn't agree more. Nothing speaks louder than the voice of the people affected by the disease. And that goes at all levels, fundraising, interacting with regulators, certainly advocacy work by organizations is a critical part of the equation. But if you don't walk with the people affected by a given disease, you're not going to be affected in the same way. You just, the impact of those stories at the personal level can't be overstated.

[00:58:17] Anna Cramer: Yep.

[00:58:20] GR Scott Budinger, MD: Anna, I want to thank you for sharing your story. It certainly was really impactful for everybody that was here today. And I want to thank everyone for attending today. I think this is a real, great example of how we can move forward, walking with the patient across different lung diseases, and leading with CF, it makes total sense. Just the success story here is just wonderful to see. So I will, we will end the conference to be respectful of everyone's time. If you have additional questions, please send them to me by email, and we'll get responses to you from Susanna or Manu or JP. So thank you so much, and have a great day.

[00:59:03] Anna Cramer: Thank you.

[00:59:04] JP Clancy, MD: Thank you, everybody. I appreciate the invitation.