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Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie Cole (Host): As the journey to end cystic fibrosis isn't a straight line, it really is an evolving map with many paths and unique challenges. Welcome to UAB MedCast. I'm Melanie Cole. We're exploring new research and clinical trials for CF patients with Dr. George Solomon. He's an Associate Professor in the Division of Pulmonary, Allergy and Critical Care Medicine at UAB Medicine.

Dr. Solomon, it's always a pleasure to have you join us. Start with a little bit of the evolution of the research for CF patients and where we are now. Tell us what we know that we didn't know say 20 years ago.

Dr George Solomon: Sure, Melanie. That's a great question and one that we're working on extensively here at our institution and across the country and really across the world to care for patients with CF. So there have been some major advances for the care of patients with cystic fibrosis in the last decade or more. Maybe the greatest advance that has been the development of drugs we call CFTR modulators, which essentially is a term that means small molecules that are taken orally, which activate defective CFTR protein. The CFTR protein is the protein that's sort of the business end of cystic fibrosis. And when it malfunctions, it causes essentially all of the pathology and the morbidity and results in mortality in patients with cystic fibrosis.

So in the last decade, we have developed these protein modulators, which activate defective protein in a large number of patients. And in 2019, there was a landmark approval of a combination of these modulators we call Trikafta now. And that drug activates the most common mutated protein called F508del CFTR. Now, that means that we have access for effective to highly effective drugs, which help with the basic problem in CF for many patients with cystic fibrosis, but it doesn't mean all. And unfortunately, many of the patients that are in the remainder 15 or so percent of patients that are not covered by these types of medications have extremely severe mutations and resulting protein defects in that CFTR protein. So as a result, they have very severe disease. And as a result of that, many of them are suffering still and feel a bit left out. And so our center here at UAB, as well as centers across the country and across the world has embarked on an initiative called the Path to a Cure, which is really looking at the next stage of development of molecules that would activate protein and/or replace defective gene that's known as genetic therapies of various sorts to work on those remaining 15% of patients who are not treated by these protein modulators, and maybe even more importantly to effect eventually a one and done cure for cystic fibrosis for everyone that's affected by the illness.

Melanie Cole (Host): What do you feel, Dr. Solomon, makes cystic fibrosis research so unique? As you're telling us what you need to figure out and the plan as far as the CFTR proteins, tell us some of those strategies and expand a little more on really how you're figuring out the underlying cause and how that's all coming down.

Dr George Solomon: That's a great question. I think one of the unique things about cystic fibrosis is, and the research realm is that, first of all, we act as truly a research collaborative across the world for this condition; that research initiatives, especially this Path To A Cure initiative, are intentionally made to be collaborative so that the best minds in the field and the best clinicians and the best clinical and basic science researchers are being put together really to make sure we're doing this the right way and because there's a lot of challenges in doing this kind of research.

When you talk about delivering genetic material to human beings, there are ethical and other concerns and safety concerns, which are unique to that type of therapy. And so myself along with others in our center and across the country and actually across the world have convened a genetic therapies working group, which has innumerous committees on it, trying to think about how we conduct this type of research, how we consent patients, how we develop models, like animal models, and imaging and other techniques to see if these therapies are effective and how that integrates into the right type of clinical trial designs to help pharma sponsors who are developing these types of therapies to try to move them forward to the marketplace. And I believe that this initiative is maybe the most collaborative that even the CF Foundation has sponsored in doing this kind of work. And so I believe that's a unique situation.

Now, the reason it was done is because, as I've mentioned a few moments ago, there are a lot of challenges with doing it. The safety ethical concerns and the access to the right types of patients who are not as common in cystic fibrosis at our centers makes this a much more challenging type of research to do, not to mention the long-term implications of giving genetic material to a human being as an exogenous therapy. And so that group is sort of leading the charge along with many other folks across the world to try and make sure we're doing this the right way and we're not taking it lightly. And so that means that we know the gravity of the situation and the challenges of getting those therapies developed to patients, but also conducting the studies the right way. And so I think we'll be seeing a lot more innovative designs of clinical trials, innovative designs of collaborations for referral of patients and new methodologies for understanding how the cystic fibrosis protein works and how we can deliver genetic materials to humans and to we call preclinical models like animal models, which may model the condition and help us understand how the treatments work in a better way in the future.

Melanie Cole (Host): Fascinating really. As you're really trying to figure out the underlying genetic mutations to address that root cause of CF, what other clinical trials and research are you doing at UAB that you would really like to mention for other providers that may not know about these things?

Dr George Solomon: So that's a great question. So part of this Path to a Cure, there's a second initiative in the Path to a Cure besides working on developing genetic based therapies to correct the basic CFTR defect. And the point of those genetic-based therapies really is to not have to worry about the gene mutation as long as we can correct and give normal CFTR genetic material, which would make normal CFTR protein and supersede the genetic defect. But as you can imagine, it's extremely challenging to deliver that genetic material to the lungs or to the rest of the body in a way that's safe. And so we understand this is going to take some time.

As a result, a second initiative within that Path to a Cure is to open up the doors for more patients to have access for those protein modulators than initially were intended by the original sponsoring pharmaceutical companies that develop them. And so our center here is sponsoring several studies looking at we call access trials, looking at access for these modulators to patients that heretofore have not had an FDA-labeled indication. What that means is the FDA has not approved the drug for those particular patients, because they have a mutation that's not been studied. So we hope to study those and novel ways of doing that. And we're looking at two populations right now on a study that we're conducting along with a couple of other institutions across the country. One of those is looking at patients that have the types of mutations that result in a milder type of condition, which usually presents later in life, we call adult or later-onset cystic fibrosis. And those patients usually at presentation have a milder disease phenotype than patients who might have more severe mutations, like the F508del mutation we talked about earlier. However, the mutations over time, the environmental responses infections, inflammation can cause these patients to have very severe illness. We want to help them because they have significant morbidity and a risk for early mortality as well.

In addition to that population, we're looking at a mutation called N1303K. It's important because the molecular mechanism by which the protein is defective is almost identical to what's happening with that more common mutation called F508del. And what we have learned from laboratory investigations in our center here in my laboratory and other laboratories we collaborate with, again, I want to highlight that Path to a Cure is highly collaborative, we've learned that the drug combination called Trikafta may actually activate that defective protein as well and result in some functions. So we're gonna actually going to be testing that in human beings, starting next month with a trial that would enroll patients throughout the country who would come here to receive the drug for a period of time and have observations and clinical investigations conducted on them to see if the drug is actually working or not on them with the goal of motivating a next step study to try to get access for those types of patients for this drug up to the FDA, that would have coverage for these highly expensive medications and perhaps have a better outcome for themselves short term, while we're working on the genetic therapies, which are coming around the pipe in the next few years.

Melanie Cole (Host): And that's really the crux, isn't it? To translate these findings into treatment strategies and adding to your promising pharmacologic approaches that you're developing and testing. How do you see this playing out in the future? And what do you hope to see happen as we wrap up, Dr. Solomon? And you're such a great guest and a passionate educator. Please give us your wrap-up and what you'd like other providers to know about Path to a Cure and the initiatives that you're doing there at UAB Medicine.

Dr George Solomon: Well, I think the answer is that there's a couple of take homes from this. One is we want to make sure we have not missed anyone with cystic fibrosis for two reasons. One is we want to understand diagnosis. As a corollary to this Path to a Cure, there are a lot of initiatives looking at better ways to diagnose and improve the diagnosis of cystic fibrosis, that we identify everyone who has this condition, because if we don't know you firmly have the condition we can't very well treat you for it with these advanced therapies.

In addition to that, we want to make sure that we have developed strategies to offer therapies, which are meaningful to the level of the CFTR modulators are for everyone with the condition once we've diagnosed it. And so what I would encourage outside providers who are listening to this is beyond hopefully being interested and inspired by the research is to think about if you have a patient that you think could have cystic fibrosis, please refer them to us, so we can try to make that diagnosis and work through that strategy, so we can get these patients into clinical trials if they qualify for them and get new therapies down the line, which may help and have significantly meaningful outcomes for them in the future.

Melanie Cole (Host): One hundred percent. And I certainly hope that you will join us again many times and update us as you learn more and there's new exciting advancements in the world of cystic fibrosis. Thank you, Dr. Solomon, as always. And a physician can refer a patient to UAB Medicine by calling the MIST line at 1-800-UAB-MIST or by visiting our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. For updates on the latest medical advancements, breakthroughs and research, follow us on your social channels. I'm Melanie Cole.