Empowering Patients to Get Involved in Research with Patrick Flume, MD

The public has been hearing for months about the clinical trials conducted by various institutions and pharmaceutical companies related to the COVID-19 pandemic, but what does it mean to be involved in a clinical trial, and why would the public want to participate? What is the importance of clinical trials, what are the safeguards surrounding any clinical trial, and what do clinical trials offer the public?

Dr. Patrick Flume is a professor of Medicine in Pediatrics with specialties in pulmonology and critical care medicine at the Medical University. He serves as the Powers-Huggins endowed chair for cystic fibrosis and is the director of the Adult MUSC Cystic Fibrosis Center. Dr. Flume is heavily involved in MUSC’s research enterprise, including the way MUSC manages clinical trial safety and protection of all those engaged in any clinical trial. Dr. Flume, along with many other clinical scientists at MUSC, has been instrumental in several very successful clinical trials, most recently the implementation and success of the COVID-19 trials.

Read The Transcript

[00:00:05] Loretta Lynch-Reichert: Hello once again to our Science Cafe audience. We are thrilled to have you join us from the comfort of your home, or car, or on your walk as we meet the challenges brought about by COVID-19. I am Loretta Lynch-Reichert, Director of Research Communications at the Medical University of South Carolina, and host of MUSC’s Science Cafe.

Today we are speaking with Dr. Patrick Flume, a professor of medicine, pulmonologist, and director of the Adult Cystic Fibrosis Center at MUSC – just some of the hats he wears as a member of our academic and hospital staff. Welcome, Dr. Flume.

[00:00:42] Patrick Flume, MD: Thank you, it’s a pleasure to be here.

[00:00:44] Lynch-Reichert: Let’s begin with an understanding of cystic fibrosis and the variety of ways it manifests in patients.

[00:00:52] Flume: Cystic fibrosis is a genetic disease and it’s what we call a recessive genetic disease, which means that you have to have two abnormal copies of the gene that’s involved with cystic fibrosis. So that means you got one copy from each parent, they were a carrier, and they don’t have cystic fibrosis. So when you have those two abnormal genes, those code for a very important protein which exists in all parts of the body and so typical manifestations of cystic fibrosis include digestive problems – the pancreas is not producing digestive enzymes and it’s often how we make the diagnosis early in life as the child would be failing to grow. But also important in the sinuses and in the airways where it renders the area ripe for infection, and these patients develop chronic infections which then go on to cause persistent problems and then it can affect other aspects of the body as well.

[00:01:54] Lynch-Reichert: It’s quite important in today’s environment with COVID-19 but let me go back to something you just said. When you have two parents who are carriers but do not have cystic fibrosis - how often in nature does that occur?

[00:02:13] Flume: So it varies a little bit based upon one’s race, but in general, about one in 30 will have a CF gene mutation if there’s no family history. If there is a family history, the odds of being a carrier go up and so the odds of two people coming together is about one in 900 and then the chances that they have a child, that that child will have cystic fibrosis, is one in 4. So the average instance is about one in 3,600 births.

[00:02:46] Lynch-Reichert: So that’s not something that you would suggest would be a manner of standard of care for a pregnant woman to be tested or a couple to be tested? It’s such a severe disease, I wonder if it’s worth it.

[00:02:59] Flume: So current recommendations are that the obstetricians will very often offer CF genetic screening to women who are pregnant or considering pregnancy, and then keep in mind that the test that we do doesn’t test for a normal gene, it looks for the most common mutations. So having a negative test doesn’t mean you have a zero chance of being a carrier, it just means the odds are really, really low. We also do newborn screenings, so every child born in the state of South Carolina has a heel stick in which we begin diagnostic testing for cystic fibrosis.

[00:03:32] Lynch-Reichert: Wow, I had no idea. Dr. Flume, as CF therapy has changed quite a bit since you began practicing, what are you most excited about in the standard of care now?

[00:03:42] Flume: When I started in cystic fibrosis back in the early 90’s, there were no approved therapies other than digestive enzymes for the treatment of CF disease, specifically the lung complications. Since that time, we’ve had a number of therapies approved for the treatment and we’ve seen survival in our patients increase dramatically, so when I started in this business, the median age of survival was the early to mid-twenties. That means half of the patients were not expected to survive past their early 20’s. Now that is approaching 50 years of age. Consequently, most of the therapies that have been developed treat the downstream consequences of having cystic fibrosis - treating the infections and the mucus that builds up in the airways to try and prevent decline in lung function.

[00:04:35] Lynch-Reichert: But there’s some new, exciting therapies on the horizon. How did these new discoveries emerge and what are some key issues still needing to be addressed?

[00:04:45] Flume: So we’ve had some very exciting developments in the last few years. Once the gene was discovered in 1989, there was tremendous excitement that we could even see a cure for cystic fibrosis, that we could perhaps replace that gene. Gene therapy’s not here yet, however a lot was learned about the different CF gene mutations and how we might approach them. So in general, you can think about many, many CF gene mutations, and there are over 2,000 that have been identified but they result in either a lack of production of protein - so there’s no protein getting to the cell’s surface where it needs to do its job - or that protein doesn’t function properly and the way that it’s supposed to function is like a channel, a channel by which ions can flow and in the airways to allow for normal fluid layer on top of that airway surface so that things can be cleared out of the lungs.

What we’ve learned recently is that we can use small molecules, drugs, to try and bypass some of those abnormalities. So the first innovation was a drug called Ivacaftor and what this is, is what we call a potentiator, which means it makes the protein work even better. And so the way I like to describe it is, it’s as if the channel is a screen door and you’re putting a rock in that screen door to keep it open so that things can flow out and that study was done in patients who had a mutation that resulted in that gate not opening and the results were amazing – lung function improved by 10 to 12%. That’s a lot for these patients. The problem was that only about 4% of our patients had mutations that were affected by a potentiator like that.

The most common mutation is the delta f508 mutation. What this does is it’s missing one amino acid, so when you build your protein, like putting beads on a string, one bead is missing and that’s all it takes so that protein won’t fold into the shape it’s supposed to be in and they get transported up to the top of the cell, so it gets tossed out as garbage, so those patients don’t have any protein. Well a drug like Ivacaftor won’t work in that setting because there’s no protein for it to work on. So the discovery of other molecules, what we call correctors, they seem to stabilize that folding process and the trafficking of that protein getting up to the cell’s surface, and so the first drugs, Lumacaftor and Tezacafter, these were effective, although not super potent.

You could still combine them with Ivacaftor because if you get some protein up there you can kick it with the Ivacaftor, but we knew even from the beginning that it wasn’t a lot of protein, and so in those patients, their lung function only improved about 3 or 4% but we kind of expected that. And then what was learned is these new regenerations of these correctors, if you use them in combination, this most recent combination is Elexacaftor and Tezacaftor, two correctors to get more protein, and now you’ve got a lot of protein, hit it with the Ivacaftor and that triple combination will result in an improvement of lung function of 14%. That’s huge! But even more important is it works in people who have even just one copy of delta f508.

[00:08:28] Lynch-Reichert: How long did it take them to get to that point?

[00:08:31] Flume: So in the development of medications, it always seems way too slow. You can imagine that if your child has cystic fibrosis, any time it takes for us to develop an effective therapy like that just takes too long. And for companies that are developing these medications, it just takes too long to get it through that preclinical - the cellular and animal studies for safety - and then into phase one, which is safety and dosing trials all the way up to phase 3, those pivotal studies that ultimately lead to the approval of those drugs. Now, in this particular space, because people were so excited about it, the enrollment was actually pretty robust. But it still takes years for us to get to that point and so far, we’ve approved the drug for people 12 and older, we’re currently doing studies in the 6 to 11 and then we’ll move down to the 2 to 5. As you can imagine, if your child was born with CF, you’d want therapy to start as soon as possible.

[00:09:34] Lynch-Reichert: Absolutely. You’re listening to the Medical University of South Carolina’s Science Cafe podcast on cystic fibrosis with Dr. Patrick Flume, director of the Adult Cystic Fibrosis Center. Dr. Flume, I think you and I had spoken before that it’s important for the community to know, the public to know, that we don’t do this research in isolation and that there is a collaboration between basic scientists and clinical scientists. You’re the clinical scientist. Did you... were you part of any of the beginning research to take a look at what’s possible or are you now just taking the drugs that have been discovered and putting them into the clinical trial and how is that going for you?

[00:10:22] Flume: So there’s always been an interplay between those who work at the bedside and those who work at the bench and people at the bedside make observations that can lead to eventual discovery. So for example, the diagnosis of cystic fibrosis was made in the early part of the twentieth century when they were investigating patients who they thought had celiac disease, but who actually had this fibrosis of the pancreas. Back then, cystic fibrosis of the pancreas was the full name of the condition, and it was during a heatwave that happened in New York where all these kids were dying because of heat prostration and being dehydrated and so eventually that led to the discovery of the sweat test and actually it was known years and years before as there was an abnormality of the sweating in these kids because there’s an old German folk song that roughly translates into “the child will die soon if his forehead tastes salty when kissed.”

So the CF protein is important in the sweat gland, so when you sweat you’re trying to get rid of heat, so that initial sweat has salt and fluid, but as that sweat moves toward the surface of the skin, the salt gets reabsorbed because you’re trying to get rid of heat, not salt, and then the salt can evaporate and that’s how you lose heat. But the CF patients are missing that protein so they can’t reabsorb that sweat, so a diagnostic test, what we use for diagnosis of cystic fibrosis, is to induce sweating, put a little bit of medicine on the skin’s surface and collect the sweat and measure the salt in it and it’s quite high. So when people then go to the laboratory and begin to make discoveries about cystic fibrosis and they have a drug that they think would be beneficial, they need to come back to the bedside and work with clinicians who can help figure out, well what endpoints – what clinical measures – make sense because you don’t get a drug approved because you make the sweat less salty, you get a drug approved because it improves lung function, it improves quality of life, it reduces some of the complications and that’s where the bedside has to come back into the picture.

[00:12:40] Lynch-Reichert: Dr. Flume, you indicated that cystic fibrosis is actually a disease of the pancreas and I wonder if it had ever been considered to do a pancreatic transplant rather than the lung transplants that I’ve seen very successfully happen with CF patients.

[00:12:59] Flume: So the protein that’s involved in cystic fibrosis, it does involve the pancreas as well as the lungs – think of it as cells that line things, like ducts. So the ducts of the pancreas, where the digestive enzymes are made, then would flow into the intestinal tract -- they’re all plugged up and about 75% of patients that have CF will have what we call pancreatic insufficiency and most of those, it really occurs at birth, and so to replace the pancreas is quite a big operation. The way we manage the digestive part is we get enzymes from pigs, and they can take them as a supplement with every meal to help digest their food.

Now some of our early studies with these new drugs, what we call the CFT modulators, there is a hint that there may be some improvement in digestive enzymes in children suggesting that maybe it’s not permanent, that they might have some pancreatic function that could be preserved. Now another complication that occurs over time, as our patients get older, is the development of CF-related diabetes. The pancreas is also an endocrine organ, and it has islet cells that produce the insulin and there have been successful islet cell transplants where you can take the islet cells and put them back into the patient and perhaps result in fewer complications related to diabetes.

[00:14:35] Lynch-Reichert: That’s fascinating. It is a whole-body kind of disease, or at least it affects quite a bit of the body. In fact, I believe you shared with me that one of the unfortunate symptoms of CF in men is infertility, and for women, lower fertility, is that correct?

[00:14:54] Flume: So in males the vas deferens, which is the tube that carries the sperm into ejaculate, that is obstructed from early on. About 98% of males are going to be functionally sterile. You can make sperm, but it just can’t get to where it needs to go. In women, there is a perceived reduction in fertility, and it’s been hypothesized that it’s because the cervical mucus is thicker, and it serves as a mechanical barrier. Now with our CFTR modulators, we’re seeing a bit of a baby boom, not just at our center but at other centers, that with these medications, like the triple combination or the Ivacaftor, that perhaps is changing cervical mucus and making these women a little bit more fertile. And so we have already had two babies and I think we have seven more pregnancies on the way.

[00:15:53] Lynch-Reichert: That is so exciting, that’s just incredible. Friends of mine who have CF have had double lung transplants. Are they candidates for this new drug therapy as well, still?

[00:16:09] Flume: So the national history of CF lung disease is one of progression, these chronic infections and the inflammation that comes in to fight that infection is slowly destroying the airways and it’s the main reason that people with cystic fibrosis die and die younger. So lung transplant became a viable option in the last few decades, and it is the last option when a person is nearing the end of their life because of their lung disease. We are pleased with our success rates. We are continuing to hope for better, but our patients with CF do as well or better than other conditions with lung transplantation.

So in terms of the use of CFTR modulators with patients with lung transplant, keep in mind these are systemic drugs – you take them orally, so they’re absorbed in the gut, and they get to all parts of the body. So, what we’re hearing now are reports of improved sinus disease, fewer sinus complications in patients who have CF-related diabetes, we’re seeing better glucose control and perhaps staving off the development of diabetes. I mentioned the increased fertility in women, there also is improved nutrition and weight gain, which is very important in these patients. So even in those folks who have a lung transplant, they still have cystic fibrosis in the rest of their body, maybe not in the lungs, but everywhere else, and so they can still derive benefit from those medications. And then we can even begin talking about potential for benefit in the lung transplant, that the Ivacaftor that’s present in the medication works on normal CFTR, so there is the potential that we can talk about studies involving people who don’t have cystic fibrosis but have a condition for which it still would be beneficial.

[00:18:03] Lynch-Reichert: That’s really incredible, um, and it leads me to ask a question of you. I said in our introduction that you’re a person who plays many roles and wears many hats. Your roles include not only physician, you’re an endowed chair, scientist, you’re a center director, you’re a teacher, you’re a mentor, you’re also the vice provost overseeing research regulatory compliance, you’re a quality improvement guru, not to mention being a husband and a father. I’ve known you for a while now and I still marvel at how you do it all, especially the very compassionate care of your patients. What drives you?

[00:18:43] Flume: Ultimately, it’s being able to have good results and good rapport with my patients. I didn’t get into this training because of the cystic fibrosis and I often say that it wasn’t that I discovered CF, it was that CF discovered me. I was fortunate to go to University of North Carolina at Chapel Hill for my pulmonary and critical care training and it was really there that I got the opportunity to take care of patients with cystic fibrosis, and aside from the fact that the condition is very interesting, it was also a time when we were just starting with lung transplant which was very new, it was a lot of new research – I mentioned all these medications that were being developed- and so I really began to get an opportunity to work with patients who were highly motivated, had a great interest in their health, anxious to try and find cures for their condition at a time when clinical research was really about to burst in the world of CF.

The other parts of CF that I really enjoy is that we work as a team in the clinic, it’s not just a clinician - we have nurses, we have dieticians, respiratory therapists, pharmacists, psychologists, social workers all working together as a team to provide care for our patients. Although I can get up onstage and talk about CF as if everybody’s the same, the fact is everyone’s a little bit different in terms of their manifestations of disease, their severity, what resources they have. And then you bring clinical research into the mix and start to see these exciting results, and as I said earlier, to watch the mean age of survival go from the mid-20's to now we’re going to cross 50, the majority of our patients are in the adult age group so this is no longer a pediatric disease. That’s what makes it exciting and when you can bring a product like that to your patients and see them thrive, and now instead of spending time in the hospital, they can be at work, they can be at school, they can be in relationships, that’s what’s really satisfying.

[00:20:57] Lynch-Reichert: So Dr. Flume, MUSC is one of the leading academic hospitals in the area working on COVID-19 therapies, vaccines, tests. I would imagine that the work you’re doing on CF patients might also have a cross purpose with patients of COVID-19?

[00:21:19] Flume: So at first, at the onset of COVID-19 there was obviously concern about anybody who has a health condition, in particular, a pulmonary health condition, so there was great nervousness about what this might mean for the CF population. I’m happy to say that it has not been a devastation for our patients. Our patients have actually fared quite well, not just locally but across the nation and the world. I don’t think that the medications that they’re taking is providing protection or that their condition is somehow offers some protection, I think though that we have always had a culture of infection control in the CF patients because we worry about passing infection from patient to patient, so the notion of physical distancing and other infection control measures were probably already in practice by our patients, so that was to their advantage.

Now my role with COVID has really been on the regulatory side that from our institution, trying to figure out what would be best for our patients that we serve. We have fielded somewhere north of 50 trials, potential studies, that could be brought to our patients. We obviously can’t do all of them. A committee was put together to vet these trials to find out what would be of the greatest benefit, importance to the people we serve, which are patients, but also our staff. So we’ve launched a few studies, the most important of which has been the convalescent plasma treatment and I’m happy to say that not only are we able to provide that for our patients here in Charleston, but also at our affiliate hospitals across the state, and so it’s very important that we try to find which studies are of the greatest value and likely to be successful.

[00:23:257] Lynch-Reichert: And that takes some time.

[00:23:29] Flume: It takes time.

[00:23:32] Lynch-Reichert: What is the message you would like our listeners to take away from our conversation about CF? What is your dream, what is your hope?

[00:23:41] Flume: So one message I would like to convey is that how important it is to do clinical research and to do it well. It is too easy for people to make claims about some health product on the internet or on television completely untested when the work that we do in clinical research is very rigorous to try and prove that not only does the drug work, but also that it’s safe.

The second thing I’d like to convey to people is that we owe a tremendous debt of gratitude to all of those people who have participated in clinical research. It’s a safe bet for me to say that everybody listening has taken a medicine at some time in their life, whether it’s a prescription medicine or an over the counter medication, and what they should know is that somebody out there volunteered for some part of those studies, and so when we invite people into our studies and when they participate, we always make sure to give them the safest and most positive time with us and we always say thank you, because this work is terribly, terribly important.

[00:24:56] Lynch- Reichert: I could not have said it better. It is very important for our public to understand what it is that we do at MUSC, how it benefits them, and I want to thank you so much for your time today, Dr. Flume, and for all you do for our patients, their families and the MUSC academic and research community. As someone who has known you well for several years now, I want to say thank you to you for the work that you do. It’s always a pleasure to talk to you and I learn so much from you.

[00:25:23] Flume: Well, thank you.

[00:25:24] Lynch-Reichert: Join us next month to hear from Dr. Michael Yost, a professor of surgery and innovator in 3D printing. The future is now. Please stay safe and healthy and thank you for joining us. This is Loretta Lynch-Reichert at the Medical University of South Carolina for MUSC Science Cafe.