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Hello, and welcome to the intestinal failure webinar. I'm Pravin Chaturvedi. I'm the Chair of the Scientific Board and Chief Scientific Officer of Napo Pharmaceuticals, a Jaguar Health Company. It is my pleasure to welcome all of you to this webinar. I wanted to set the stage for defining what is intestinal failure. Intestinal failure was first defined in 1981 by Fleming and Remington as a reduction in the functioning gut mass below the minimal amount necessary for adequate digestion and absorption of food. Since then, the definition has been revised and nowadays, according to the guidelines, in adults, intestinal failure is defined as a decreased absorption of macronutrients and/or water and electrolytes due to the loss of gut function and the need for parenteral nutrition, and they both should be simultaneously present to define intestinal failure. intestinal failure derives from several diseases needing parenteral nutrition. And in children, in particular, it also requires parenteral nutrition that would guarantee 75% of caloric requirements for not less than a month or at least 50% of the requirements for not less than 3 months. Intestinal failure in adults and in children is a devastating disorder. And intestinal failure in infants and children, which is broadly defined as the inability of the gastrointestinal tract to sustain life without supplemental parenteral nutrition. The most common type of intestinal failure is short bowel syndrome with an estimated incidence of between 3,000 to 5,000 or 100,000 births per year. Intestinal failure is classified according to its onset metabolic and expected outcomes into 3 types. Type 1 is a short-term acute and usually self-limiting condition. This refers to intestinal failure that lasts for less than 28 days, and it can be related to postoperative ileus or acute intestinal obstruction. Type 2 is a prolonged condition intestinal failure, that's considered to be duration greater than 28 days and requires artificial nutrition. It tends to involve medically unstable patients who may have suffered sepsis or metabolic or nutritional complications as a result of major bowel surgery. And type 3 intestinal failure is a chronic intestinal failure that requires long-term parenteral support. Type 3 intestinal failure may be irreversible and occurs as a consequence of the loss of the length of small bowel. In the United States, in children alone, there are about 16,000 children on home parenteral nutrition and the economic burden of intestinal failure of just the pediatric population is substantial with estimated individual medical charges exceeding $500,000 in the first year of life alone. And so the prevalence of children with intestinal failure has waned with the use of parenteral nutrition, but it is by no means a medical need that has been addressed fully. Today, we have the pleasure of listening to 6 key opinion leaders for both adult and pediatric intestinal failure. You will hear first from the pediatric intestinal failure experts. From there, we will switch to adult intestinal failure. We now speak with Professor Mohamad Miqdady, the Division Chief Pediatric Gastroenterology, Hepatology and Nutrition at Sheikh Khalifa Medical City in Abu Dhabi, United Arab Emirates.

Thank you very much for the nice introduction. Next year, will mark our 10th annual Elite Pediatric Gastroenterology Congress. The reason I started this actually about 12 years ago was to increase the awareness about pediatric gastroenterological disorders. I'd like to elaborate more about intestinal failure. In very simple words, intestinal failure, when the intestine fails to do its own job. And the primary job of the intestine is actually to absorb water and electrolytes and nutrients to maintain the body. This is important throughout life, but probably it's even more important in young children because in young infants and children, it's important not only to maintain life but to allow them to grow and develop throughout the different stages of their life. If the intestine fails to do its job, then there will be not enough water or electrolytes and no nutrients to allow the body to grow. In children or in young infants, we are talking mostly about short bowel syndrome and congenital diarrhea. Short bowel syndrome when somebody had to have surgery early in life when they remove part of the intestine. And if they remove a lot of that intestine, the body cannot survive. They will spend a long time in the neonatal intensive care units or they were required to have total parenteral nutrition. And what it means in simple terms, and instead of getting all the food and the electrolytes and the water through the mouth, we do it through the vein by having a central vein, a major vein that we go through to give them enough fluid, electrolytes and nutrients for them to survive. Then it becomes the issue of how long can you keep them in the hospital. Obviously, the shorter the admission to the hospital, the better outcome that will be. At some point of time, after a few months of being in the hospital, we managed to send most of these patients in home parenteral nutrition or home TPN. Staying in the hospital is still a big hazard for the parents. Because -- let me walk you through like a daily routine of a trial with short bowel syndrome who needs home PN and if you compare it with a normal child. A normal child will woke up in the morning, brush their teeth and get their breakfast. A child with parenteral nutrition, unfortunately, does not have that luxury of eating. And eating and drinking fluids, unfortunately, these children, they don't have that luxury. Although we sometimes take it as a granted, they are hooked up to the TPN includes having a central vein with all the tubing and the bag and the pump that infuses the parenteral nutrition to them. They have to be hooked up to this equipment most of the day, anywhere between 16 to 24 hours a day. And the younger you are, the longer the duration. The central line, which is a line that goes into a major vein usually somewhere in the upper chest or in the neck, this central line is really a precious line and a very sensitive, if you will. Precious because it's going into a major vein, goes directly to the blood stream. And it has to be totally aseptic. It should be totally super extra clean because any type of contamination can result in a blood infection with its all known complications and trouble. If the infection is severe, unfortunately, it might affect other organs in the body, vital organs like the heart, the kidneys, the brain and so on and so forth. And there is a certain mortality i.e., certain percentage of people might die from that. And obviously, because these kids, they have this central line throughout their life, so the risk is always there. If the child is in a school age. He needs to go to the school, carrying a bag with the fluids, the pump and pipes. Typically, any simple child were required to have 2 pumps carried with them. The smallest will be around 400 grams, which is another pound. So 2 of them, that's 2 pounds. So he has at least 5 pounds, he is carrying on his bag throughout the day. And unfortunately, he cannot take it off. More importantly, they have deprivation from the normal social activities they have, so they cannot eat while the kids are on break at school and so on and so forth. And becomes a challenge if they go out or attend birthdays or other holidays, Christmas or Thanksgiving or others. If there is any medication on earth that will allow them to use less of this TPN to become less dependent on this home parenteral nutrition, if there is any medication that will allow them to taste the food or eat even a little bit of food, that will be a big achievement. For example, at least they can participate in social events, they can taste some food, hopefully there, and that makes them more normal. My group here in Abu Dhabi, in the United Arab Emirates, we care for such a group of patients with this disorder, whether it's a short bowel syndrome or congenital diarrheas. We feel with the parents when they talk about how important for them if there is any light at the end of the tunnel that hopefully can improve their physical health as well as their mental and social health. I think we put our target as 25%, but probably the real achievement hopefully, will be more. I cannot tell you like how many times the parents are asking me about any new medications. I would say any improvement would be an acceptable improvement. Obviously, I'm more passionate about short bowel syndrome in children more than adults because this -- if I see an infant today with a short bowel syndrome, I'm hoping and that he will live life expectancy of 70 years. If there is any chance we can improve their outcome, this will have a long impact of the days and years they have to live. This is a bit different than if you have like a 50- or 60-year-old man or a woman. [Audio Gap]

So how many do you take care of an annual basis, just short bowel or both congenital diarrheas disorders and short bowel?

Thank you for asking this question. Every year, let's say, we get more than 12 patients. When you read about short bowel syndrome and congenital diarrheas, the phenotype is very different from one patient to other. One of the options of treatment is there a small bowel transplant. And in a sense, what you do is you remove this small bowel and put a bowel from typically a deceased donor. This is a huge surgery, unfortunately. It's done in few transplant centers around the world. Unfortunately, the outcome of this surgery is not the best at all. The survival rate is probably around 50% at 5 years post transplant. And even the 50% or so who survive this, they will be on lots of medications. And these medications, unfortunately, are immunosuppressant, i.e., increase your risk of having infections, which is really double the negative effect on these patients. Even if you have a small bowel transplant, it does not guarantee you will be able to eat. And many of them, they would have tubes in their stomach to put the food in. So the quality of life post small bowel transplant is not at the best. Patients that we have on an annual basis, many of them, they will go on a long-term parenteral nutrition. Obviously, home TPN is a fairly expensive setup. Let me give you an idea about here in UAE, the cost. The cost of the bag of the smallest child per day is about AED 1,000, which is around like $300. $300 per day per bag for this patient. That I'm talking about like a 3-year-old child. So imagine if you have to spend the $300 every day just to do the home parenteral nutrition. This is just the bag. I'm not talking about the accessories. I'm not talking about the home nursing. I'm not talking about the child who needs to come to the hospital and so on and so forth. So I have to see them at least once a month. And we have to draw blood once a month to make sure we are not giving them too much or too little. They cannot really travel because where ever they need to go, it needs a whole lot of plan. They need to have a cooling system or a refrigerator with them all the time to carry the fluid because the fluid has to be kept at a very low degree to prevent degradation and contamination. You have to carry all the accessories, all the antiseptic material you have to carry it with you. And you cannot stay there for too long. I usually have to contact a center or a physician in the country, in the city, they will be there to be available in case this child needs medical attention. In other words, there's a lot of planning happening with this, and that center should be willing to take somebody and to have their insurance covering their care if they have to go to a different country and to be clear, different continent. In addition, it has to be in a major city. They cannot go and visit a small town. It has to be a big hospital with a tertiary care services and all this. So it becomes really a hazard for the family to arrange all these things if they decide to spend a family holiday and vacation.

So under your care overall right now, is it fair to say that you probably have more than 100 children that you're caring for of all ages, if you get 12 new patients every year, roughly?

Something probably like that. Unfortunately, we have lost some. Unfortunately, whether because of illnesses or they get the small bowel transplant and others. Their expense is prohibitive to many families.

How do you triage these patients when they come to you? What kind of patients?

In the majority of these patients, we would not know until they are born. So there's no planning ahead.

They go on TPN and there is nothing else available?

Until recently, there's no real medications available for these patients. When the children grow up a little bit, they really want to try to eat something over. They really appreciated if they can taste any kind of food there. I think not only for the physical but also more important for the mental and the social development of these people. Food is a great socialization activity for all of us as humans. And if they can give just the taste or even if it's a small amount, I think that will make a huge improvement in these patients. Another thing I think we have to admit, although scientific research and achievements have really advanced in the parenteral nutrition, but it's nothing like the enteral nutrition. I am sure there is something missing that we did not recognize it yet, and we cannot add it to the parenteral nutrition yet. For example, even in the best centers, in the best outcome of the patient, patients on parenteral nutrition, they end up being shorter than their peers. There's something we are not recognizing with something we're not giving them to allow them to grow taller. Also, there is other diseases shared with parenteral nutrition, for example, not limited to is bone disease. The patients on parenteral nutrition, their bones are not as healthy like us. In other words, they can get fractures easily from a simple trauma or if they fell down or trip over something. So it's not only just to change the foods from oral to parenteral. No, there is something we are missing there. Hopefully, when we allow these patients to eat a little bit more, and if they can absorb that food, we can overcome these things. And this will be -- we can learn this once we get a medication that allows them to eat orally.

Do you have patients on GLP-2 like teduglutide or biogenerics in addition to PN? Does it help? Or you think it just adds to the cost? What are your thoughts?

The success of GLP-2 is really limited in these patients. And we don't use it routinely in my center because of this fact. It does not really work in most of the patients. If it's going to work, it has to be somebody who is not that bad and you start very early and you have to keep them on the medication for the rest of their life, regardless. So in my center, we decided we're not going to use it because the outcome is really not as good as we would like it to be.

Do you think there's a difference in the adults? Do you think adults respond better? Or is it just because the adult usage is not lifelong?

I don't have experience in adults as I'm a pediatric gastroenterologist. However, I would assume that the pediatrics, they do better because their body is still growing and adapted. Our patients in MVID, actually, we do have patients at Sheikh Khalifa hospital in home TPN as well. As you know, MVID is a congenital disease, who are born without the brush border that allows the body to absorb the fluid, the electrolytes and the -- and nutrients. This disease is probably all over the world. However, maybe it's more common in the Middle East because of the genetic background and the [Foreign language].

It's good to know that there are some MVID patients that you're looking after as well. We're now speaking with Professor Antonella Diamanti, the Head of Artificial Nutrition unit at Bambino Gesu Pediatric Hospital in Rome, Italy.

We have patients on parenteral nutrition from all over Italy because that our hospital is the hospital in the -- that is in the center of Italy. So in -- we developed during time a series of interest, a series of particular fields that are very important to follow patients with rare diseases. So follow patients with the rare disease, but also with complex nutritional management. In patients -- in particular, parenteral nutrition in patients with the short bowel syndrome, it's very important to improve the intestinal function. It's very important to favor the oral in the enteral nutrition.

In your center, the pediatric rare disease patients that you have annually in a year, how many patients do you see?

We follow that all the 3 categories of the main categories of short bowel syndrome, 50% to 60% of patients with short bowel syndrome, 20% -- 50% of patients with motility disorders at 10 -- 14% of patients with intractable diarrhea due to mucosal defect, congenital mucosal defect.

And like congenital mucosal defect would be something like microvillus inclusion disease?

Microvillus inclusion disease and congenital tufting epithelium in the syndromic diarrhea. Syndromic diarrhea that are the 3 forms, the 3 types of intractable diarrhea now known. We have a great number of patients that need parenteral nutrition early in the first day of life, that could need the intervention in patients with immunological disorders, the first treatment is the bone marrow transplantation. We have patients who are in need of parenteral nutrition for many days in the early and who have a great loss from intestine. In the patients with intestinal failure in the past didn't arrive to...

Adulthood?

Yes, and they die before 12 -- at 18 years. We have patients about 80%, 85% of our patients are patients [ achieve them ].

We look at short bowel syndrome with intestinal failure, mostly from necrotizing enterocolitis. And then we have, obviously, the kids that have the congenital intractable syndromes like you talked about congenital tufting enteropathy or microvillus inclusion disease. So do you keep your patients receiving TPN in your center or you send them home?

In our center, in general, we send home at least -- on parenteral nutrition, at least 6 to 10 patients per year.

And they're getting parenteral nutrition how many hours, 24 hours a day or 20 hours a day plus or minus throughout or...

In general, patients are very, very small. So generally, in patients less than 6 months old, generally, we send these patients on 20 -- between 18 to 20 hours per day. An important aspect of our management is that many patients are also gastrostomy. In general, the gastrostomy is put to improve, yes, to improve the nutrition because we know that if we start early enteral nutrition, the prognosis of weaning from parenteral nutrition is better, in general. We prefer to suspend parenteral nutrition and to start oral nutrition and enteral nutrition.

That's good because it's so toxic parenteral nutrition, so you manage how many toxicities?

Yes, it's toxic, but another important aspect is that if the -- in the first months of life, the intestinal tract should be stimulated. As soon as possible, as much as possible if we stimulated early the intestinal tract, the weening of parenteral nutrition -- the dependence of -- on parenteral nutrition is more -- is less protracted, is less...

So the frequency of the parenteral nutrition, what do you consider to be the threshold, the time where you think this patient is starting to show signs of taking more enteral nutrition?

We start enteral nutrition as soon as possible in agreement with the surgeons. We start enteral nutrition at the minimal enteral feeding, the so-called the minimal enteral feeding that is 1, 2 milliliter per kilogram per hour. We start oral nutrition with solid food, in general, according to the true gestational age of these patients. We think that bolus feeding are -- have a big action of stimulation of gastrointestinal tract. Our feeling is that bolus in enteral nutrition stimulate -- better stimulate the enteral hormone environment, so are better tolerated. And better and improve the motility of this gastro tract.

But by providing time for solids to be there, we firmly believe that it gives the intestine a chance to absorb nutrients and electrolytes. And by slowing down because the liquid stools are passing much faster. We are very, very much in agreement with you that the intestinal function in these patients only improves when the intestine is given a chance to work. Enteral nutrition is very important. And it's quite nice to hear that you start them right away as soon as the surgeons give you permission.

I expect that the landscape of the intestinal failure of shorter bowels is very great. So when the question is when to use teduglutide in children. And we choice to use teduglutide in patients who have -- who show -- dependence on parenteral nutrition, the possibility that the teduglutide could have an impact of the growth of the intestine. And in patients with low dependence on parenteral nutrition, we thought that 2 years of treatment should be a time useful to acquire any an intestinal -- a complete intestinal autonomy. Also in -- when we suspend this treatment because we -- our fear is that we could use the teduglutide for a too long period. So to have also to have other drugs that could in -- be in some way to improve intestinal function could be very interesting for us. So it's important for the patients with the work on intestinal failure to have -- to develop, for me, drugs that, in some way, could improve the function. So it's important to know intestinal function -- to have the possibility to research, to evaluate if there are other pharmacological strategies. I think that we have to develop the nutrients, the nutritional strategy because I think that enteral nutrition is not very known in this field. Today, a mother ask me about the microbiome. I am not sure at the moment about the safety. Another problem of microbiome is the lactic acidosis.

I think by promoting enteral nutrition and letting the child develop your own microbiome is very important.

You have to consider that for the use of teduglutide due to the problem of cancer in all patients, we perform a colposcopy before starting. It's important to have a complete and careful follow-up of these patients. We have the major complications with this drug. We cannot treat patients who need of parenteral nutrition at 400% of calories because this treatment could have a long-term duration as per parenteral nutrition. And in infancy and in children, we are not sure about a long-term treatment of this drug. But for the micro, I talked only about short bowel syndrome. But true problem of intestinal failure is the microbial inclusion disease is intractable there. In this, for these patients, we don't have anything. We are the only parenteral nutrition, only parenteral nutrition, we don't have anything. I think that this is the congenital diarrhea are the most important categories because it's a true rare disease, orphan disease. So we don't have anything to treat to improve the life of these patients, except for the use of anti-secretory drug drugs. I am very, very attracted to have research in this field because this is my field for 50 years. The last 50 years of my life, I have -- are in this field, in the field of intestinal failure. So for me, it should be very important to have a research to participate to be bordered in the research in which we can resolve some problems, some small problem, but I think that these small problem are very important for many families. But during this year, ask me for potential treatments but my answer was always, I don't know. We don't have anything. So at the end, after 50 years of work, I would like very happy -- I would like happy to answer now we have a possibility for young child. So I ask you to work with us about this to can answer to these families. We have something for you.

We are now speaking with Dr. Christos Tzivinikos who's a consultant pediatric gastrologist and the Head of Pediatric Gastroenterology, Hepatology and Nutrition Department at Al Jalila Children's Hospital Specialty Hospital in Dubai in the United Arab Emirates.

Thank you very much. Your question asking me where the journey starts. It usually starts in the neonatal unit because the vast majority of the -- this kind of failure in kids starting from short bowel syndrome is because of the either congenital GI abnormalities, like Intestinal Atresia Biliary Atresia or necrotizing enterocolitis. The journey starts in the patient and the first contact with the parents is usually in the neonatal unit, talking about short bowel syndrome. Now the congenital enteropathy, if they are born in our neonatal units, they will come to us. But a lot of them, they come from other hospitals where they born these babies, they have profused diarrhea. We have a meeting every week particularly for the parenteral nutrition with all the GI team, the clinical pharmacies, the dieticians, speech language pathologists. And every day, we communicate with the clinical pharmacies to moderate the parenteral nutrition according to the clinical needs of the patient. The last 8 years, personally I haven't sent any patient for transplantation. In my practice, I haven't sent anybody for intestinal transplantation. This is a huge undertaking. So we try the best short-gap syndrome talking. I always ask the surgeons and my colleagues as well have adopted that. When they close the stomach, I'm talking about short gas syndrome, put the gastrostomy so easy. At the end of the day, this side has so many scars in the abdomen. I will avoid the nasogastric tube. Sometimes you'll have a histoma and mucous fistula, we try to recycle the ileostomy contents, especially when the colon is still intact, just to avoid all this huge dehydration and the losses which we have high iliostomy. In our practice, we have short gas syndrome patients coming from the neonatal unit. The majority of them recently have managed to go to get out of PN. At least in the last 3 years, quickly within 6 to 9 months, the clinical pharmacists for me are the most important for the parenteral nutrition. With our clinical pharmacists, I have to say doctors ourselves, even with the other gastroenterologists, we don't have particular training on the parenteral nutrition.

So you have 7 pediatric patients. Any of them reach adolescent yet or they're all under 10?

They are 7 -- all together now in the home PN. So have 4 but they're....

You've touched upon the parenteral nutrition associated liver disease as well as catheter-related sepsis. When you reduce the PN with -- over time, do you see a change in the bowel habits because you're feeding them orally or through gastrostomy that they're eating, they're able to absorb enterally and they're getting more nutrients? Is their diarrhea changing at that point in time when the PN needs going down and the enteral nutrition improving? Do you have some thoughts on that?

It's a combination of assessment. You see the stool output is reducing. If the -- sizes are not is easy to measure and we allocate this, we measure every day. The balance, what kind of stools are there. As I said, we use quite high doses of loperamide plus soluble fibers. Every patient is different. I cannot say I have like a rule of thumb, but the first thing we do is to do cyclic of PN, reducing the hours. This is fundamental for the intestinal failure illustrated. This is actually the most, I would say, litigation measurement for intestinal bowel disease, which is very difficult when there is a neonatal 2, 3, 4 kilos. They get hypoglycemias. That's why you have to put the feeds. You usually give fluids to start with, just fluid will be hydration and then we'll cut the fluid. And then gradually, we'll go 5 days a week.

Bowel adaptation, as you said, even if they reduce PN, they never come off of it. And there's a finite reduction you get, whereas you have been able to move them progressively better, except for the MVID, the microvillus inclusion disease. You cannot do much because they don't have a brush border membrane, they can't absorb anything. So this is something that I'd like you to elaborate. Maybe your outcomes are better there because you're also aware of the challenges with PN. And why you want to force more enteral feeding? I'd like you to elaborate on that.

Talking about short bowel syndrome. There's nothing more important from the standpoint of the patient by feeding the bowel. Imagine the daily life, the absorptions like a grass, you have to keep water it, in order to grow. There is a limit. I'm not talking about over feeding. We're talking about little amount constant. The studies have shown the mild continuous feed and bolus feeds during the day is tolerated because some of them have severe motility as well. And even some of them their status is now coming. They developed some sort of intestinal inflammation, but they were chasing the tail because especially in the first few months, the more fluid you give, even if you are a parenteral nutrition, the most efficient is coming from the short bowel even if zero, zero all intake. So we have to not to replace all the losses. Now the 12-year-old, 8-year-old they're eating stuff. They're not eating loads, but they manage to tolerate some food. I really push it. I know not many centers, they advocate the gastrostomy. They go with natural gastric tube. That's called oral aversion, the oral aversion takes years to be -- to overcome this.

So it's our hypothesis that if we can reduce the secretory diarrhea due to the fluoride secretion at the modulation. We think that it will be a paradigm shift in sort of management of MVID patients. Can you elaborate on that hypothesis, like how welcome is that hypothesis? It's a new paradigm for treatment...

Yes. We used loperamide because we didn't have anything else to use. In the past, they're using codeine but as you know, now has been banned -- less than 12-years of age. And even Somatostatin the past, another futile use was Racecadotril. But a very, very mild decrease or nothing, to be honest. I'll use it. I use it mainly not probably to convince myself that I'm giving something just to, for the time not to lose oral skills. But it's not without side effects.

You see or envision these kids developing neurologically, I mean their cognitive skills better if you reduce PN because they will be able to have more enteral and oral, not have oral aversion. For instance, do you think they will actually get better, go to school?

Looking actually on the cognitive skills, there is a paper from [ Greg Thomas ], his poster for [ Susan Hill ]. Actually, they do quite well. We have so many toddlers with iron deficiency, vitamine D deficiency. I do this blood test all the time. So actually, cognitive skills, I'm not worried so much. It's the growth I see on the microvillus inclusion disease, even if we manage PN, and a lot of them get standard grow away part of the disease. We don't understand this very well, despite that we give everything as per prescription.

In short bowel syndrome patients, the ideal goal would be to take them completely off PN. That would be ideal outcome. But of course, it depends on how much remnant bowel that is in the child or adult. And how is the functional capacity of that remnant bowel because this thing is not going to increase the length of it. It is going to just reduce the secretory processes.

Yes. I mean, I thought about this, but they're not giving it.

We're now speaking with Lindsey Russell from the Department of Gastroenterology, Hepatology and Nutrition at the Digestive Disease and Surgery Institute of the Cleveland Clinic United States.

Thank you so much for this opportunity. Born and raised in Calgary, Alberta. I did all my medical training into Edmonton in both undergrad and internal medicine. And I move to McMaster for GI then I did an extra year in Nutrition. That's unique in Canada, the way that we do these fellowships. So we do GI first and then we do go into nutrition. So you really create gastroenterologists with expertise in nutrition. I managed to get a Masters in Translational Medicine as well.

When you're taking care of patients, based on how patients are so ill and by the time they come to you, what is the status of these patients that you received?

I would kind of group them into 2 groups of people. So typically, I see patients sometimes right in the hospital setting. So they've had an acute surgery. A lot of the times, it's a blood clot in the mesenteric and then massive small bowel resections, quite a shock for them to be suddenly short gut on TPN. I also see a lot of patients with new cancer diagnoses that have been placed on TPN. The second group of patients, I would say, are some patients that have significant malnutrition, sometimes they're on TPN and that have not been optimized. So certainly different issues for different reasons in their journey on TPN, different challenges as well, depending on what stage I meet people and take over management.

What are your thoughts on how to improve patient outcomes? As long as you can reduce the TPN, I assume they'll do better them over time.

That's a great question. Initially, for nutritional support, we always want to try to avoid TPN and try to maximize other ways, whether that's oral nutritional support or through enteral nutrition, gastric tubes or jejunal small bowel feeding. And you kind of have to work in a step-wise manner and start with oral nutrition support and then enteral nutrition, and then you're on TPN. So in order to even consider it and have it covered, you have to do your due diligence and try other ways. Once you're on the TPN [Audio Gap] Three, actually, main outcomes that give you a challenge on TPN: One is infection risk. The other issue is metabolic derangements. These are even heightened so in patients who have a higher BMI metabolic changes with hyperglycemia, hepatic steatosis, intestinal failure-related liver disease can all be a very big challenge. And the third I would say is vascular access, not so much for infections, but it's -- your vessels aren't meant to have a tube in there for too long, so people can get a lot of stenosis or blood clots, and that could be very, very challenging to treat. In Canada, we had other lipid emulsions more readily available that can minimize the metabolic rates of changes. We do know the longer you're on TPN, the higher rate of getting steatosis in the liver and metabolic-related liver changes and cirrhosis in some cases. There's still a lot of challenges on TPN. Certainly, I do have some patients that have been on TPN for years, but certainly, that's not without challenges. Their quality of life has been significantly lower. One is you infuse at night, so it doesn't involve your daytime activities. But if you're getting IV fluids at night, you're urinating multiple times. I think just even if we do our best efforts, a lot of patients know that it's medically necessary, but a lot of them are desperate to get off TPN, and it's a challenge to get there sometimes.

Thank you, Dr. Russell. How many patients are under your care?

We have about at least 370 patients at any time on TPN. And then we also have a lot of rehab patients as well that are on IV fluids. So that number is probably closer to 450. I believe I'm managing 125 [ secret ] patients like gut rehab, and about 95 TPN at this time. I think the majority of the visits that I see are TPN patients or gut rehab, short bowel medical management patients.

When they go on TPN, obviously, that's considered intestinal failure. Talk about that uniqueness of how rare that is, even within Cleveland Clinic, to have someone with your background in care of these patients.

I noticed that more in the U.S. that people who are endocrinologists or nephrologists or ICU critical care physicians that are managing TPN and a lot more surgeons, whereas back home in Canada, we did have some primary care physicians managing kind of the cruise controls. There are some commercial products that you can have like very minimal amount of TPN. But the more intensive needs, they are usually done with gastroenterologists, who have nutrition. And that's with the way they set it up.

You talked about giving GLP-2 analogs to some of your patients. When is that decision made by you or your patients, how do you do that?

Dietitians that I work with have kind of operating manual that will have GATTEX within the -- or sorry, GLP-2 within them. I, typically, always try to entertain it. My goal is to try to wean PN as soon as possible. In general, the way I'd like to see it is that people are on IV support. And typically, they are being on it daily or have some sort of high load at baseline. Now there is some hard stops if patients have had a history of GI malignancy or severe pancreatitis, and that's not an option, thinking of my framework of weaning TPN to either EN, which is enteral nutrition, or oral intake.

GLP-2 is only available to those who have already had intestinal bowel adaptation. You kind of stopped with giving them a lot of TPN till they kind of stabilized.

Yes. And I think it's unique from a GI point of view, also assessing for other modes of nutritional support. We have some tools in our toolbox that we use. Certainly, GLP-2 is common between all institutes, but the way we use other adjuncts for antidiarrheals have been different between different institutions. Some people would use things like codeine to help try to slow it down. Other people would use loperamide or diphenoxylate atropine or Lomotil at different rates. There's no real guidelines like, this is the recipe and this is going to work for people. It's really unique to each person. So coming from my background of knowing like people are on TPN, we want to get them off, we have GLP-1 that sometimes works, other things as we try are octreotide, which is not the best for decreasing those secretory secretions. Some places in The States, they use tincture of opium either to slow it down. And they're still having symptoms, and you try dietary changes as best as you can, but you really can't get ahead of it. A lot of patients are hesitant to try any loperamide. But using a different option, then it gives patients some control back into trying it. So I think those are kind of the more personal and professional excitements that I have for it. I think understanding the pathophysiology of how it works makes sense. That is a contributing factor to a lot of the diarrhea that we see. I have some patients that have Crohn's disease, not really active but post resection, and they're having liters and liters of output a day. And it's -- you just can't keep up to it. I'm trying my best with the tool that I have.

So we've been sort of thinking about it along the lines that your thinking that how do you reduce toxic treatment of TPN. We never know exactly how much length of gut is remaining, right? Once you said earlier, somebody with a short bowel can still have -- be well managed and not require TPN and with the same length.

I think generally, I approach it to, is there colon there? Yes or no. I always try to approach it, and where in this small bowel, they have left terminal ileum, some micronutrients, proximal jejunum. But sometimes I've been surprised. I want to point out is that a lot of patients are interested in a more natural approach, going to complementary medicine, functional medicine, integrative medicine or more traditional practices from other cultures. Some people, we can't push the GLP-2 for symptoms. So we were doing it every day, and they have worsening cramping. So then we're every other day, and then you can kind of half benefit and then not really pushing it. So I think my goal, if it's aligned with the patients, is to slow down their output, minimize IV support and -- safely, and that's my priority. And whatever way we get going, it's very rare that one thing works. And even people on GLP-2 are still on other bowel stoppers for various reasons. So I think it's probably going to be in a combination of different things. And then what it comes down to is just the safety of combining these things and monitoring the patients. A lot of the time, I put NG tubes, I put G-tubes in myself or GJs. I think as the surgical field recognizes the importance of nutrition, and they also have priorities of bowel rest as well, so it's really a challenge -- not a challenge but an opportunity to work together with different opportunities. In general, I haven't had a surgeon really say no to put a tube in unless it's been an absolute nightmare of an abdomen and they don't want to open it up.

Most extreme patients are probably 7 days of TPN, 20-plus hours a day. Is that a fair assessment? Or is it less than that?

Yes. I think my most extreme would be 7 days of TPN and then also a lot of IV fluids on top of that.

And if you had a choice between reducing IV fluids versus TPN, which one are you leaning towards, personally?

I think it would depend on the patient. If I'm trying to reduce infection risk, my goal would be to reduce the TPN. If they're malnourished and abscessing, then I would try to reduce the IV fluids. And sometimes they change my mind.

What do you do about this metabolic acidosis that you referred to earlier with all these TPN patients? How do you manage that?

It's a challenge. If the patients have short gut but a colon intact, but a short amount of small bowel, they can get something called D-lactic acidosis. And it's actually quite scary to witness. Generally, it's a 911 call or urgently managed in the hospital setting. Other challenges for acid base that we use, we sometimes do our best we can with the TPN, but sometimes we're limited with the compatibility of certain added micronutrients or electrolytes. And in that case, we encourage patients to take some sodium bicarb by mouth. And hopefully, that they absorb some of that bicarb. Some patients do have superimposed chronic kidney disease as well.

So when you make your prescription for the TPN, you're sort of balancing lactic acid and sodium bicarb and everything. What parameters do you monitor for fluid overload?

I like to group things now. Those are patients, again, who have multiple lines, something called superior vena cava syndrome, where the veins are not draining. Sometimes if you -- even with patients are feeling okay and then they're recovering from an infection or somewhat that their fluid needs will change drastically. Generally, if I'm seeing someone, I assess how much they're taking in orally because we do have some oral rehydration solutions that can really affect how much intravascular volume they're getting from oral intake. That's the first thing I assess. And then I assess their urine output, pending that there is creatinine is normal. Urine output is probably the biggest drivers that I have. Other things looking at, blood work as well. Patients are actually tasked to monitor ins and outs. So we do really work together to adjust, but it's a challenge.

Are certain patients more likely to be weaned off and say, older patients, certain conditions?

I think it's very unique to the individual and kind of their outlook on life. The biggest challenge for the young patients for not eating, if there's strictly [ NPO ], is like being around their families and watching them eat and realize that food is culture. So that might be the biggest challenge for them. I think challenges for me is always liver disease and infections. I think for patients, it's hospitalizations, time away from family, the nuances of hooking up and hooking off, playing with the pump all night long, getting up to urinate all night long. I think those are probably the biggest frustrations. They're really inquiring about a holiday from TPN. And when we cut a day down, it's just like -- it's a major difference. TPN has come a long way, but it's still challenging for patients.

Any other thoughts you want to give us as we think about management of SBS, like that?

Yes. I guess I'm a little bit biased. I want to highlight that yes, before TPN, all these patients would have passed. There is no option for them. And TPN does give them an option, but I've had some patients describe it as like still chained. It's a very unique population that not a lot of expertise in the field have. I think as a provider, I do have a responsibility to try to assess for new things and make things better for the sake of my patients. So I think it's -- I'm a little bit biased in a way because I'm personally invested in this, because I see these patients every day. And it affects their lives. And I think if we even slow down their output, if we don't change the TPN, slowing that bowels from 24 time a day to 5 is a huge difference for quality of life.

We are now speaking with Dr. Fabrizio Pasanisi, who's the Director of the Interuniversity Center for Studies and Research on obesity and Professor of Internal Medicine at the University of Naples in Italy.

Starting to begin with my medical studies in Naples in Italy, and then I spent 3 years in the United Kingdom for my Doctorate in Clinical Pharmacology. When I came back in Naples, I used to study metabolic diseases and the regulation of liabilities and complication of diabetes for a number of years. And then I did my training in Internal Medicine in the faculty of medicine as my main interest during the last few years has been in the field of artificial nutrition. And we also have a center for artificial nutrition, which is a coordinating center for -- regional coordinating center for patients, who need and require artificial nutrition. I am responsible for the unit of internal medicine and clinical nutrition unit. We have a team of dietitians. So there are 5 dietitians, 3 doctors, the pharmacists, the technician in the pharmacy. And almost everything you can desire to support in the hospital. When I say clinical nutrition, I mean the artificial nutrition intravenously. The specialized prescription is done only for people who are severely unstable, particularly immediately after the major surgery that may occur for the reason I mentioned before, say, ischemia or the intestinal infection or more extensive surgery for abdominal -- for oncology because some of them are oncological patients.

You take care of so many patients. At your center annually, how many intestinal failure patients do you treat or see or take care of?

Each day, there are 40 or 50 consultations, which are checked daily by 3 doctors because 1 is actually under supervision of 20 patients per day. You see, in my country, the gastroenterologists are not particularly dedicated, they are not particularly keen on the aspect related to malnutrition.

Let's talk about your more severe patients, Dr. Pasanisi, the ones who require prolonged parenteral nutrition, the ones that may get more than 4 to 5 days per week.

We also monitor the clinical nutrition status for the patients when we have people with short bowel syndrome, these patients are seen periodically. They need the supply, parenteral supply, and they are seen periodical. And the period depends on their clinical condition. When they are dehydrated or very malnourished, they are seen more often. [Audio Gap] For example, the complication can be a catheter infection or a sepsis or a thrombosis. If the patients are uncomplicated, we do not need to have them in the ward. The most serious of course, are people with the stoma or stomias. This happens with stomia or without stomia. This may happen. With the stomia, the impairment, of course, is very, very difficult to handle, particularly if this happens late. But if the supplementation is started very soon in terms of fluids, in terms of nutrients, the deterioration, the clinical deterioration of the patient can be stopped. It's crucial that from the surgery from the theater, the consultation happens very soon.

You use the term very short and intermediate bowel. What do you define as very short, 100 centimeters, 60 centimeters?

Less than 1 meter.

Less than 1 meter is very short. And what do you define as intermediate? I understand you only take care of adults, SBS, intestinal failure patients, not pediatric patients. Is that correct?

We don't see directly pediatric patients. We have the Pediatric Unit, and they follow up all the patients up to 15, 16 years of age. After 15, 16 years and up to 18 years, there is a sort of gray zone between 15 and 18 years. These patients are seen jointly with one of my collaborators in [ GS ] meetings monthly or for 2 years before the patients from the pediatric unit goes to the adult unit. There are very, very particular situation that are patient with also cerebral impairment, very, very difficult in that stage. We have had people surviving in the -- with parenteral nutrition taken every day because we have some patients who have nutrition -- parenteral nutrition 7 days a week, but also 6 or 5 or 4 or 3 -- or 3. We do not handle people with less -- with requirement less than 3 actually because this is usually dedicated to the district more than to the hospital.

Do you see any challenges in transitioning them over? And assume that they are -- they have very short bowels, so they have to require parenteral nutrition for each one?

The major challenge from a clinical point of view is the interaction with the family and the patient. This is crucial. In terms of improving absorption -- malabsorption, I think that we have to consider that how the intestine develops continuously until addressed.

When you make that decision, is there a particular point where you decide you must augment your parenteral nutrition with GLP-2 or Revestive? Is there a...

Well, you can actually predict when to do that.

You said adolescents and the young adults, they tend to get better because their intestine adaptation is so much better. Senior and very senior geriatric patients...

So going on over months and then years, there are people who progressively will require less supplementation parenterally. These need, over time, may slow down and be reduced progressively.

And even when you add Revestive to your parenteral nutrition, these patients do not necessarily have as good an outcome as the ones that don't have?

The number, at the moment, would be about 20 or 30 patients who are very chronic and so longer term, as seen. About 20% of them have -- 20% or 30%, so 5, 6, 7 have also been treated with Revestive for a length of time. And they had the opportunity to reduce their treatment in terms of supply -- daily supply for that.

Out of the 20%, 30%, 5 or 6 are doing well. About 20% response rate. So let's talk about the complications, right? You referred to earlier complications of parenteral nutrition, catheter-related sepsis, parenteral nutrition-associated liver...

Thrombosis infection. So the two things are usually combined. So we take the thrombosis plus the sepsis. And when this happens, the patients are hospitalized. [Audio Gap]

Everybody in the world of short bowel syndrome focuses on malabsorption and malnutrition.

You see, as far as malnutrition is concerned, we usually do an evaluation of all the concentration of the vitamins, all the irons and evaluation of the body composition and evaluation of the bone with the MOC analysis with the analysis of the bone. Body composition, we also stake -- stand for that DXA, the DuraVICs ] energy and it's [ importantly ] to know muscles and to know adipose tissue and how is the condition of the bones. And we also assess strength as an evaluation of -- functional evaluation of the strength of the hand to see also and to monitor how this changes when we start treatment for correction of malnutrition because we have observed that an improvement of the hand grip is important for that. For example, the calf measure -- the abdominal measurement, this is for the evaluation of the ED, visceral fat. But also for muscles, we measure the forearm and we measure the calf for that. We can monitor improvements over the -- over time. As far as drugs are concerned and opioids and other things [Audio Gap]

And is being read out from a clinical end point focused on reduction of stool volume or a reduction of both the parenteral nutrition and stool volume?

The two things together. Stool, well, all the liquid all the fluids output as well as input. So get information on in and out in stools.

What about the composition of the parenteral nutrition? You have a hospital pharmacy that makes it optimized for each patient.

As you know, there are manufactured products with fixed formulas. But we have also personalized formulas based on the requirements for age, sex and weight of all the patients. So we consider the amount of glucose, amino acids and lipids, considering also the clinical condition of the patient. And we can also change the electrolytes for that in the supplement the potassium, for example, or even increase phosphorus when it is needed.

In your summary statement in today's care of your patients with short bowel syndrome, very short and intermediate, in addition to the parenteral nutrition and even the GLP-2s, you feel there is a big unmet need and there's a place for a new antidiarrheal to reduce stool volume and correct parenteral support further to improve the quality of these patients. Can you elaborate your thoughts?

Yes, we also have the possibility, as I said, to monitor the needs, the requirements in terms of measurement of the resting energy expenditure. This is particularly useful for very low-weight people. We can see the changes in resting energy expenditure and to supply the right amount of energy in order to avoid the refeeding syndrome, in order to prevent this edema, which appears because they are -- they may be erroneously overloaded with extra energy, we monitor with the indirect calorimetry, the improvement in terms of energy expenditure, resting energy expenditure. We have a DXA or we have the body composition at entry when it's possible. Or we recheck when the patient is discharged, the body composition twice a year with DXA actually, twice a year. For bone, once a year.

If we change the stool volume and they get indirect edema, with indirect calorimetry, you'll be able to know that the resting energy expenditure needs to be corrected.

We could do that, yes, yes, make sure with the indirect calorimetry. It's useful to monitor using the visual impedancemetry, so-called via BIA bio-impedencometry, to track the so-called phase angle, has it changed, the electricity in the body actually changes. And this is -- can be repeated frequently. It's useful in terms of prompt information, considering the changes of volumes intra, extracellular volume of all the liquids. It is certainly useful in terms of monitoring for fluids, not for diagnosis, but for the changes of electricity and changes of the body in the fluid -- motion of the fluids. So when we compare or integrate indirect calorimetry and bioimpedance in malnourished patients, we get some extra information that help us to avoid the edema and the refeeding edema, which can be -- which can happen because of excess [ reglementation ] for these patients.

We're now speaking with Ms. Carol Wolin, who's a public health dietitian at Legacy Community Health in Houston, Texas in the United States.

I've worked as a registered dietitian with short bowel syndrome, intestinal failure, HIV/AIDS patients. And a lot of these patients have malabsorptive syndromes, and it's debilitating metabolic acidosis, metabolic alkalosis, electrolyte disturbances. These morbidities can be fatal if they're not caught, if they're left untreated. We're having so many shortages of micronutrients amino acids and lipids with the total parenteral nutrition that we really need to figure out how to slow down patient losses. With the introduction of GLP-2 analog, it did help increased absorption so that patients required less TPN, but it also posed a host of issues because of the risks involved. When you take a hormone and you just make an analog and you change 1 amino acid in that analog, do we really know all of the ramifications of that? If you're on the GLP-2 analog and you have intestinal cancers, pancreatic, hepatic cancer, the GLP-2 analog has to be stopped dealing with extreme losses with secretory diarrhea. The patients with short bowel syndrome and intestinal failure are really a very a very heterogenous group. And there's no one medication. There's no one drug that fits all types of intestinal failure. We also need to consider a very special population that really is not a candidate for any of the GLP-2 analogs, and that is the infant population under 1 year old. If you have patients with MVID, microvillus inclusion disease, typically, that can be diagnosed within hours to the first few months of life.

So you take care of both adult and pediatric patients?

I see mostly adult patients. On occasion, I will see a PD patient -- pediatric patient, if they're intestinal failure, short bowel syndrome, and they want my expertise or advice or guidance.

When is it that you are called in to help? Are you called in at the time of immediately post surgery, when they've had resection or when they get on TPN?

When I was with the Department of Surgery, if we operated on the patients, I monitored them from surgery or pre-op even, going forward. In my public health position, I see patients postoperatively, who have, unfortunately, become malnourished and the doctors are looking for input and resources.

Cannot really start GLP-2s right away after surgery, right? So you pretty much manage those initial postsurgical patients only with TPN. Is that correct?

We managed the postsurgical patients with TPN only, and the GLP-2 analog could not be introduced until they were about 1 year out on TPN.

Do you have a sense of the range of the stool output that you see in these patients that need TPN?

The patients would complain about a large amount of secretory diarrhea. Basically, the way we monitor it was monitoring fluid and electrolytes and their hydration.

How often did you see those patients, Carol?

I would see them once a week. It was very labor-intensive before and after we would initiate therapy because it was systemically absorbed and we would have to monitor their electrolyte levels. On a medically complex patient, it really added to the caregiver burden of daily injection. And anytime you puncture the skin, it's always a risk involved.

Was it a particular disease or condition that caused it more than others, like [ Peyronie's ] or cancer, colitis or -- what do you think the causes were?

It was so varied. There was not one. I could tell you it was more dominant reason for our short bowel syndrome, there were just so many reasons.

Do you have a feel for how much bowl is -- what is the minimal length of bowel, short bowel, that is basically necessary to even survive?

Everybody adapts differently to short bowel. One patient may not be able to adapt without TPN with only 150 centimeters resected, and another patient may adapt beautifully.

And so coming back to the TPN reduction because of the toxicities, when is it that you feel the TPN reduction? Is your goal to have them completely weaned off TPN and go completely on enteral nutrition?

The goal is to reduce the volume of TPN. Some patients may never be candidate for enteral nutrition through a PEG tube or a J tube. So if you can reduce the TPN volume so that it can cycle, that's much better for the liver. Plus, it also gives the patient freedom. If they have 1 hour a day or 3 hours a day or a full day where they don't have to hook up to the TPN, they are happy.

Do you think the TPN causes more stool output because you're giving them all this parenteral nutrition that kind of causes more secretions?

That's a hard question to answer because it also depends what that patient is doing.

When you have bowel resection, it's a malabsorptive syndrome. So all you have to do is to correct the absorption. But gut is so finely tuned between absorption and secretion. So your goal there is to reduce stool output. What are your expectations over a 3-, 6-, 9-month period of what you expect to see in those patients, acutely as well as chronically?

What I see in those patients is a happier patient because their stool output has decreased, and they don't have that urgency so they don't have to worry about leaving the house. And they feel like they have their freedom back, and they can function, and they're feeling better.

And do you see them gain any weight? Do you see any risk of fluid overload?

I have not seen fluid overload. When I use the GLP-2 analogs, we carefully monitored their fluid status to increase it and decrease it as needed to prevent that. Each patient is unique.

And this rule-break, this rule of thumb of 20% reduction in PN that they set up arbitrarily, how relevant is that, in your opinion, in your practice?

Any reduction is better than no reduction. If you can reduce it, you have a happier patient. 20% they said is the huddle up for success. Even 10%, I think, is success. The less, the better. TPN is a phenomenal tool when you have to use it. But the less you use, the healthier the patient is. With short bowel syndrome, intestinal failure, you need a lot of tools in the toolbox because there's no one solution because of the varied causes in patient responses to different interventions. There were really no predictive cofactors because a lot of it depends on patient compliance with the treatment regimen and the support of their care providers. You can't depend on one person to be a primary care provider all the time. It's such a team approach, both in the medical clinic and in the home setting. A physician cannot manage an intestinal failure patient by themselves. They need the practitioners. They need the dieticians, they need the nurses. It takes a lot of a team, an integrated team, to provide effective care for a short bowel syndrome, intestinal failure situation.

Yes. Okay. Thank you, ladies and gentlemen, for listening to this webcast of intestinal failure in adults and pediatric patients. I hope that all of you now have a better understanding of the magnitude and the devastating and debilitating condition intestinal failure is from various etiologies and various causes. As you have heard, in pediatric intestinal failure, the causes could be many, including short bowel syndrome, including microvillus inclusion disease, tufting enteropathy and other congenital diarrheal disorders. While intestinal failure has always been classified as a malabsorptive syndrome, you've also heard from all the experts that diarrhea, debilitating chronic severe watery diarrhea, is a major unmet need in intestinal failure patients, both in pediatric and adults. In adult patients, we mostly heard about short bowel syndrome patients who require chronic home parenteral nutrition and the amount of watery diarrhea that they suffer from, which basically tethers them to a toilet. We thank you very much for your attention, and we look forward to seeing you another time. Goodbye.