RARE Daily

Considering the Unfinished Work in Cystic Fibrosis

August 31, 2023

Cystic fibrosis is a rare disease that has been an area of significant innovation. New therapies have provided life-changing treatments for most patients, but about 10 percent of people with the condition don’t benefit from these treatments because of the specific mutations underlying their condition. We spoke to Jamie Chang, senior medical director at the contract research organization Rho, about the advances that have been made to treat cystic fibrosis, the treatment gap that remains, and what’s working its way through the pipeline that may change that.


Daniel Levine: Jamie, thanks for joining us.

Jamie Chang: Good afternoon.

Daniel Levine: We’re going to talk about cystic fibrosis, Rho, and how it leverages its clinical expertise in this area to help drug developers advance their candidates into development. Let’s start with cystic fibrosis. For listeners not familiar with the condition, what is it?

Jamie Chang: Sure. it is a genetic condition where patients would inherit two copies of a gene that leads to a protein not functioning and that essentially leads to all the different manifestations of cystic fibrosis, which include lung disease and other organ systems as well. It is the most common autosomal recessive disorder in Caucasians, about one in 3000 or so. That means that it’s actually a fairly common rare disease.

Daniel Levine: This is a pulmonary disease, but the effects go well beyond the lungs. How does it manifest itself and progress?

Jamie Chang: Yeah, sure. So, I think that’s a really important thing that you bring up. In cystic fibrosis the main organ system we think about are the lungs and that’s obviously because of their huge role in day-to-day life, exchanging gases, breathing, all those things are obviously things that patients will feel if they’re not working correctly. But because this [is] the condition that leads to a protein that’s in different tissues, it’s in your GI tract, it’s in your pancreas, in lots of different places. So, in addition to the lung manifestations, which could be shortness of breath or maybe they can’t exercise as much, they may have other things. They may have trouble getting the normal nutrition because they can’t digest fats and proteins for, for like people who, who don’t have the, the condition or they may develop diabetes because the pancreas is involved not only in digestion, but also involved in controlling energy metabolism, so insulin and those things as well. So, it is for sure a multi-system disease that really requires a lot of attention. But for the patients and their families and the care teams that they’re involved.

Daniel Levine: It’s one of these diseases where people who have the condition can look quite normal from the outside, and people can be quite unaware of the fact that they have this. What’s it like to live with cystic fibrosis? What impact does it have on someone’s day-to-day life?

Jamie Chang: Yeah, as I sort of mentioned, because it impacts on all these potential different body systems, cystic fibrosis patients really, they spend a lot of their time that they need to dedicate to routines, whether that’s taking the medications that help them digest food better or wearing one of these vests that helps break up a lot of mucus in their lungs. Part of the routine of their day-to-day life is making sure that they’re attending to all the things that will keep them well and keep them feeling well. So, it used to be, and this is part of what we’ll talk about, but it used to be that this would really limit even extracurricular activities and sports, and there’s just been so much f progress in this field in the last couple of years. Those those things are becoming less and less common.

Daniel Levine: Well, this is an area where there has been significant therapeutic advances that have benefited many people with cystic fibrosis. As a physician who’s treated patients with the condition, how has the landscape changed for people with cystic fibrosis and how have new therapies changed the natural history of this condition?

Jamie Chang: Yeah, thanks for that question. It’s been pretty amazing just to see, even the last 10 years or so, some of the advances and probably one of the biggest advances has been in the development of medications called CFTR modulators. Just to step back just a little bit, CFTR is the protein that I referenced in the first question. This is the protein that doesn’t quite work the way it’s supposed to in cystic fibrosis. And that results in all the different manifestations that we talked about, the lungs and the pancreas and the gastrointestinal system. These modulators essentially are medications that help this protein that’s not quite functional function better, and they do so in such a way that they improve the quality of life. They reduce that degree, like how they feel short of breath and the loss of lung function as well. And the modulators have really, I think, made some really incredible benefits in terms of quality of life for the cystic fibrosis patients as well. And that, combined with some of the other therapies, you know, average lifespan 20 years ago was for cystic fibrosis was in the thirties. It’s now solidly in the fifties and even older now. So, it’s been an incredible journey and it’s just amazing how much progress has been made in the last couple of years.

Daniel Levine: There are some 2000 known mutations that underlie the development of cystic fibrosis. One of the challenges with genetic targeted medicines is that they may work on one or more mutations, but not others. What gaps exist in treatments for cystic fibrosis today?

Jamie Chang: Yeah. That number of mutations in any genetic condition can seem overwhelming from the outside, I think. In the traditional paradigm, we think for each sort of mutation, there’s going to be a gene therapy, right? Something that repairs or replaces that gene that has that mutation in it. And that may be the way, that may be the future. But the gene therapy technology is not there yet for developing like mass, like just being able to afford to develop a gene therapy for a specific mutation right away. The gene editing, that’s certainly coming down the pike, and that could certainly be a possibility. But the one thing about cystic fibrosis, which is interesting, is that a lot of those mutations that you mentioned, 2000, all sort of have the same end product. They all result in this protein that I’ve mentioned, the CFTR, not functioning totally correctly. So, a lot of the gene therapy approaches now are actually working toward, well, you may have a particular mutation, but at the end of the day, you need a functional copy of this gene. So, basically having gene therapies that target that and regardless of the mutation—I’ll qualify that in a second—they will attempt to insert a gene, a CF CFTR gene, that will actually work, regardless of that mutation. Now back to the gaps or the challenges, that approach is not necessarily going to work for all mutations in cystic fibrosis. And that’s part of probably why you’re asking the question. And that gets to this eight to 10 percent of the cystic fibrosis patients for which these modulators, these therapies that I’ve talked about, don’t work and they don’t work because these patients don’t make any protein at all, so that you can’t really act on it if you don’t have that. So, the gap here is that there’s eight to 10 percent of cystic fibrosis patients who not only don’t have access to these modulators but that the gene therapies that are being developed are not particularly applicable to them. So, that’s one of the big gaps, I think, in terms of cystic fibrosis—the final 10 percent who don’t have any available therapies, disease modifying therapies available to them.

Daniel Levine: In the world of rare disease, this is one of the relatively larger indications which has made it attractive for drug companies to pursue. As we dig down into the mutations with unmet need, is there some point at which the indication becomes too small to be attractive to pharmaceutical companies?

Jamie Chang: Yeah, that’s such a great question. I think cystic fibrosis has been, and really what I want to say, just really very lucky in the sense that there is so much energy and advocacy for it, and we’ll talk about the Cystic Fibrosis Foundation a bit more, but that this [too small to be attractive] hasn’t really manifested in the cystic fibrosis field. And just to give an example of that, some of the ultra-rare mutations that I’ve mentioned—that eight to 10 percent—there is a company actively developing a therapy for this. And this is a very small portion of the cystic fibrosis patients. And I think to answer the question more directly, there it might be this very rare mutation in a few patients. But part of this is that the technologies that are being used and are being developed may have broader applicability maybe within that therapeutic area, but also outside the therapeutic area. So, whatever technologies are being used to target these very rare mutations, they may be more applicable to other areas. and I also just want to take it, for the regulatory authorities, the FDA and the EMA, they’re the orphan drug designation. These programs, there’s a lot of incentives for companies to invest time, energy, resources in developing these therapies. That can be a win-win, certainly for patients and for the companies alike.

Daniel Levine: Rho is a contract research organization that works in many areas, but it has developed strong capabilities within cystic fibrosis. What’s it done in this area and what does it offer a drug company client?

Jamie Chang: Yeah, thank you for that. If I could just step back a little bit and say, Rho started in the cystic fibrosis field probably about 2012 or so, and that actually was with some of the digestive therapies. That was our first foray into this community and this is an incredibly amazing advocacy network. A few people who still are at Rho actually proactively reached out to the Cystic Fibrosis Foundation, which, again, for any listeners who are not aware of this or who are looking at or building advocacy groups, they have a great formula for building a very strong advocacy network. So, we reached out to them and we’ve communicated with them since to know what’s going on in the space, what’s going on with the patients, and also have learned of the therapeutic development network, which is called the TDN. This a scientific body that essentially reviews all the proposed research in the cystic fibrosis field to make sure that the research that’s being done is really progressing things forward as well. So, we’ve had a nice communication with them on a regular basis outside of our work with clients, but also with clients just navigating how things work as well. So, I think that with the knowledge of the space of cystic fibrosis and the TDN, I think that we bring a lot to the table in terms of clients starting thinking about developing therapies in the cystic fibrosis space. I think that’s probably one of the main contributions where we can assist. The other part is because of our work with the foundation and with patients and sites, we understand the patient experience, which includes the family. Like any rare disease, you have to think about the family when you’re thinking about how do we make this as convenient as possible for the patient and the families who already are very busy and all. You have to have these things to go on too. So, we think when clients come [down] the road, they’ll have that experience with the advocacy groups and the scientific body that governs the research, but also understanding the patient and the family experience, for anyone going into a clinical trial for cystic fibrosis.

Daniel Levine: You mentioned the Cystic Fibrosis Foundation, which has really been a powerhouse in the drug development side and brought a lot of resources to bear. But to what extent when you’re designing a trial are you working with the client and really getting that kind of input from a patient organization like the Cystic Fibrosis Foundation?

Jamie Chang: Yeah, thank you. So, quite often, as I said, we have interactions, communications with the CF Foundation and about the therapeutic with the TDN, so they know who we are. We’ve worked through with other clients, we’ve worked through them getting their programs out there. So, we work very closely with the Cystic Fibrosis Foundation, the TDN, and bring what experience we’ve had from prior projects to the clients. Hopefully we’re giving them that much more upfront that they can get that much ahead of the game when they hit the ground running. We’re really making an effort to actively engage with the Cystic Fibrosis Foundation for many of the reasons we’ve already talked about.

Daniel Levine: And I think there are well-known challenges to developing a therapy for a rare disease. Given the small populations, the heterogeneity of these conditions, and the fact that populations may be geographically dispersed, are there any particular challenges to clinical development in cystic fibrosis than what most people might think of? Are there challenges that are particular to the condition itself?

Jamie Chang: Yeah, and this is a good thing. There’s so much research going on in cystic fibrosis that making sure that there will be patients that would want to participate, that would be available to participate, is a big thing. And that’s a good problem to have from the patient’s perspective, but it’s something that really [you] keep in mind given how active this space is and just how much energy there is. Sponsors entering this space just have to have an idea that there oftentimes is a lot going on at a given time and we have a pretty good sense, like I said, from our communications, what’s going on at a given time. One thing that’s also very specific to the cystic fibrosis space, as I maybe mentioned or didn’t mention earlier on, one of the manifestations is you produce a lot of mucus or sputum and a lot of times that sputum is something that sponsors and companies want to collect because it tells a lot of what’s going on inside the patient’s lungs. You know, are you decreasing the infections? Are you decreasing the inflammation? All things that are very important to understanding might the therapy actually work in these patients. And then again, this is a good thing, but with the modulators a lot of cystic fibrosis patients can’t produce sputum anymore. And so, because of this, we had to think things outside the box like, how do you collect this sample when they might show up to the clinical site and they say, we need to sample this, and we can’t do it. So, Rho has worked with a lot of sponsors to work at home collection. How on their own terms, patients collect it, make sure it’s taken care of and shipped and the quality is good and it makes it to the lab safely. So, that’s one thing that I would just point sponsors to is that if you’re interested in sputum as a biomarker and you’re looking at that, as well as there may be some challenges in terms of getting those collections, but we certainly have some ideas on how you might do that if that’s part of your program.

Daniel Levine: You talked a little about the possibility of gene therapy and gene editing, but as you look at the development landscape, where do you see therapies for cystic fibrosis going and are there things that particularly excite you?

Jamie Chang: Yeah, I think the eight to 10 percent, those that we’ve talked about that I’ve referenced a few times. There is a lot of energy in a specific company. I think company’s name is Splisense, I think, but they’re working to actively find a way to get a therapy for these patients who don’t have the modulators, who don’t have other treatment options as well. There is a lot of activity for sure within gene therapy, whether that’s DNA, whether that’s mRNA, whether that’s using viruses or liposomes to deliver. There’s a lot going on here. And it’s a single gene disorder, I think there’s a great potential here for cures. There’s still a lot to learn about the gene therapies in a lot of ways. And in the meantime, I think, we can’t lose sight of, you know, we need to develop other therapies that can address ongoing issues whether it’s the digestion and the potential malabsorption nutrition issue, whether it’s developing more antimicrobials or antibiotics to help fight the infections that these patients have. As we’re figuring out what gene editing or what gene therapy technology is going to work, we really have to keep our eye on developing some of these therapies that are going to bridge these patients until these therapies are available. And if I may do one more plug for the Cystic Fibrosis Foundation, they have, if you Google cystic fibrosis pipeline it will list all the therapies that are being developed in cystic fibrosis by category. So, you’ll see gene therapy, you’ll see absorption, you’ll see fighting infections. It’s a wonderful, wonderful resource to know what’s out there. On that same page is also where patients can find out where to sign up for these or where to find out more information about these studies. So, lots coming down the pike. The gene therapy is super exciting for sure. In the meantime, just thinking about what kinds of therapies we can also develop to bridge until we really understand this technology and really embrace it.

Daniel Levine: Well, as a physician who’s treated patients at a time when there were fewer therapeutic options, and now involved in clinical development, what’s it been like to see all the activity in this area?

Jamie Chang: Yeah, I think you probably can guess my answer. It’s beyond exciting and I mean, you can look at the statistics in terms of just quality of life and lifespan as well. But just to see, I think, the overall improvements in quality of life and the ability to participate more activities that I think from any perspective, any healthcare providers, is probably what you can’t ask for more in terms of that. So, as I mentioned, this is such a dynamic and energetic community. The resources and focus are just really something to model if you’re looking for organizations and how to model their foundations and their advocacy groups.

Daniel Levine: Jamie Chang, senior medical director for Rho. Jamie, thanks so much for your time today.

Jamie Chang: No, thank you. I appreciate the time.

This transcript has been edited for clarity and readability.


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