Jaguar Health, Inc. (JAGX) Earnings Call Transcript & Summary

Good afternoon. My name is Lisa Conte. I am the founder and CEO of Jaguar Health and our wholly owned subsidiary, Napo Pharmaceuticals, a company committed to novel plant-based prescription drug development. I want to begin by thanking all of you for taking part in our very first Diarrhea Dialogues event. We've designed the educational event with the key goal of raising awareness among the investor community and global business development context regarding the need for supportive care for people related to chronic, lower gastrointestinal tract distress, specifically the debilitating diarrhea that often results from cancer and cancer therapy, also referred to as cancer therapy related diarrhea, or CTD. Research shows CTD occurs in up to 80% of cancer patients and is far from a trivial problem. The condition not only has an enormous impact on cancer patients comfort and sensitivity, over 50% of the time diarrhea triggers the need for drug holidays, dose reductions or treatment failure during cancer therapy, which can negatively accept a patient's cancer care. And let me underscore that, over 50% of the time a patient's life-saving cancer therapy regimen is interfered with the cost of diarrhea. Quite likely, we've all experienced an episode or more of diarrhea in our life. This is not your garden-variety Montezuma's revenge. What we're referring to today is often severe, chronic, may result in hospitalization for rehydration. And can -- has resulted in a septic shock and death in some patients as reported in clinical trials. CTD is a neglected health issue, an important health issue and one to which Napo is committed to bringing a novel treatment. By listening in on discussions with distinguished oncologists, cancer patient advocates and supportive care experts, you will hear firsthand the reality of existing cancer care regimens and the impact of diarrhea on a patient's comfort, quality of life, and treatment experiences. Another issue we aim to address as part of our larger Diarrhea Dialogues initiative is the stigma associated with diarrhea. Generally, unless you're in the Napo extended family, people don't want to talk about diarrhea. And many have trouble even saying or hearing the word. Today, we'll obviously hear a lot of dialogue on the topic. So settle in and get comfortable, diarrhea, diarrhea, diarrhea. 1 in 2 people will develop cancer in their lifetime in the United States, 1 in 2 women and 1 in 2 men will develop cancer. In 2020, there will be an estimated 1.8 million new cancer cases diagnosed in the United States. And while the overall rate of new cancers has been about the same over the last several years, more people are now surviving cancer, thanks to advances in treatments and new therapies. People are living longer. That was with the prevalence in the U.S. at up to 20 million people, and hence, the supportive care and the ability for cancer patients to prevent or treat the symptoms of cancer and the side effects and adverse events caused by the treatment of cancer is more important than ever. Despite this growing prevalence and potentially serious implications, cancer therapy related diarrhea receives a mere fraction of the attention given to, for example, chemotherapy-induced nausea and vomiting, another common side effect in patients undergoing cancer treatment. In a few minutes, we will be joined by distinguished oncologists, patient advocates and supportive care experts who will address diarrhea related issues in detail why they matter and what can be done. You will hear from our speakers about why discussions between health care providers and patients about CTD often fail to take place. Why CTD is now more prevalent than ever, given the limitations of opioid based diarrhea treatments in cancer patients is opioids. They will also discuss the significant impact of severe diarrhea and the extreme dehydration it can cause for cancer patients. And what needs to be done to elevate awareness about this critical yet often neglected side effect of cancer therapy. And let's be clear, CTD may, in fact, be an under-addressed issue because there is not currently an effective solution specifically tested in CTD patients. We are honored to be joined by 3 prominent oncologists and members of Napo's scientific advisory Board to discuss some of the side effects of cancer therapies in management of those symptoms. We've been so moved by their commitment to whole patient care. Dr. Lee Schwartzberg, Chief Medical Director of West Cancer Center and Chief Medical Officer for OneOncology; Dr. Eric Roeland, Assistant Professor of Medicine at Massachusetts General Hospital; and Dr. Andrew Davies, Clinical Director of the Department of Supportive and Palliative Care in St. Luke's Cancer Center and the President of MASCC. MASCC, an acronym is the Multinational Association of Supportive Care in Cancer, which is the largest professional organization dedicated to supportive care. I'm also so pleased to introduce you to legendary Iditarod Sled Race icon, DeeDee Jonrowe, one of the world's foremost female dog mushers, who will discuss her personal journey as a breast cancer survivor, her experience with cancer therapy related diarrhea and her experience caring for a patient with cancer. She'll also mention her beloved dogs about which there is no stigma in addressing poop. Also joining us is Kim Thiboldeaux, CEO of the National nonprofit organization Cancer Support Community, who will be speaking with a cancer survivor who also cared for her husband during his truly courageous battle with cancer. Finally, let me introduce Dr. Pravin Chaturvedi, Chair of the Napo Pharmaceutical Scientific Advisory Board and Acting Chief Scientific Officer, who will be in dialogue with our noted oncologists. I'll share a little background on Dr. Chaturvedi. During his impressive 25-year career, he has led the discovery and development activities for several new chemical entities, 7 approved drugs to his name. And of course, his favorite, the successful development of crofelemer, Mytesi, Napo's plant-based non-opioid FDA-approved anti-diarrheal indicated for the symptomatic relief of non-infectious diarrhea in adult patients with HIV AIDS on antiretroviral therapy. More on crofelemer later. During the latter part of our event, Pravin will share a brief update on crofelemer related pipeline development activities. Pravin and I will reveal the results of new data that uncovers the prevalence and burden of CTD, including the impact on a patient's lifestyle. We will close with a short Q&A section, during which we will address an assortment of questions that were submitted by those of you participating today. We will now start with our discussion with DeeDee Jonrowe. We are here with DeeDee Jonrowe. This is an American icon, a hero, a warrior, a female woman warrior. So I want to let the audience know with whom they are sharing this time. This is a woman of resilience and fortitude that most of us cannot comprehend, a woman who treasures relationships, in particular, her relationship with family and faith, a woman who loves and respects her animals, in particular, her trusted sled dogs and woman of dignity. So with those descriptors, let's give a more detailed background here. DeeDee, who lives in Alaska, that was born in Germany, is a dog musher. She lives with her husband, Mike. She has run in many races, though, in particular, she's run the grueling, Iditarod 36 times, 16 times coming in, in the top 10; 2 times coming in second place and the fastest time for a woman when she ran that time. So that's not her measure of success. She survived breast cancer. She's been a cancer caregiver for both her parents. She's survived injuries from a tragic accident and musher related injuries. She's had her home burn down. And through it all, she's continued to get up and compete. So what if we changed it to DDD, Diarrhea Dialogues and dignity, for cancer patients. What does that bring to mind for you?

I really appreciate the addition of the word dignity because that's usually one of the first things that you feel has been compromised before you actually realize that you don't feel as strong or you dehydrate. But the dignity issues that I might have felt on my own, but I particularly was protective of for my mom and dad. And people can't always control how their intestines are working. But they can't help but have a feeling that they've lost something that other people might find compromising not so eloquently stated. But dignity is particularly important to me, and it was very important to me when I was trying to preserve the dignity of my mom and dad.

So tell me, when you had your diagnosis and you had so many other things all colliding at the same time and dealing with your parents as well. And it had to affect your psyche. It had to affect your mood, your spirit, how did you get yourself up and going every day?

I can easily say that God used my love of dogs to make me get out of bed every day. And that was a gift, an absolute gift, a lifeline that was thrown to me because they didn't know what was going on inside of me, they were still expecting and relying on me to be able to provide their quality of life. And so that overshadowed any discomfort I had at the time until eventually, I wasn't able to respond to that for several weeks before, ended in the emergency room, and that was the end of any more chemo at that time, not the end of the side effects, but the end of any additional chemical intervention.

That's interesting. So the side effects continued beyond the chemo treatment.

Quite a while. And I can remember thinking if this as good as it gets, I'm not sure it was all worth it.

So the health care providers, the oncologists, they're helping you, your parents, deal with the cancer, survive the cancer, cure the cancer. Do you feel that they had an appropriate level of attention on supportive care and what it would take for you to holistically heal your whole body?

No. I don't think they're trained in that. They're trained in the medical issues that are to be addressed and praise God for that because the -- it's such a growing institution of knowledge. So what was right 10 years ago or 15 years ago has been improved upon or it comes -- I noticed the difference of treatments just from myself, which was in 2013 -- 2003 to my mother that was in 2010, and they had improved those treatments quite a bit, but there was still a lot similarities and side effects. And I can't remember asking why didn't you tell me an oncologist and she said, well, that's so minor compared to what it is we're trying to treat. But it's not minor when you're inside the body living with it. And so it gave me the opportunity in retrospect to be able to anticipate that with my mom and with my dad and do not have them be embarrassed to address it with me because I knew I'd already experienced it.

You had this preview, unfortunately, with yourself, then you dealt with your mom. Did anticipating or researching what supportive care might be necessary, where there might be diarrhea, where there might be other issues, did that affect treatment choices and treatment options for your mom?

It did -- and first should say I helped my mom through 2 years with breast cancer. Then in the year that she appeared to be in remission, my father was diagnosed with melanoma, should be really upset with herself because she couldn't control diarrhea. I had no idea that the treatment for cancer and the side effects that come with those treatments last years.

So you said you had a couple of bullet points written down. Do you think there's anything that you would like to get out that should be shared with this particular forum that I didn't ask you?

Well, one of the things is, when we talk about side effects, and we're talking about diarrhea, another aspect of diarrhea is dehydration. And there's many articles written about how compromised you are in dehydration, both in cold weather because we have the predisposition to have frostbite. And other issues like that with dehydration weakness, which, of course, is not helpful when you're trying to navigate in cold weather. And I -- and it's hard to make yourself drink when you feel lousy, you don't really want to drink. And even when you know you should, you don't really want to. So that was a point that I really want -- there are side effects more than just the discomfort of it all. The anemia that comes from just not being able to really absorb the nutrients that you're both I'm feeding my dogs and are or trying to take in myself, but like that can absorbable. And so there's more things like that, that are not really spoken about as often, but that have huge on your quality of life. When you don't really feel like doing anything, and you've got to constantly get up and address diarrhea, you just go, why should I bother? And when you can be a caregiver and talk to your loved one that they need to take in some electrolytes. They may -- you can begin to address it with them slowly and carefully to talk them into it because there comes a state in dehydration, in particular, where you personally ask that patient don't really want to address it.

Thank you, DeeDee Jonrowe for sharing your time with us, sharing your experience with us. It's been such a pleasure to speak with you. I could speak with you forever. And it's been really important and it's so meaningful to others in the community, in the cancer community and to speak so candidly and freely about supportive care, and in particular, about diarrhea, which is so difficult for so many people. And we really are -- found it so important that you were able to bring into the experience of your dogs as well, which are so important to you and so important to this community. So thank you very much.

Yes. Well, I thank you for being interested in the supportive care aspect. Because there's a huge void there and a huge need. And I'm glad that I'm in a position that I can actually share and perhaps make quality of life for somebody better.

That's a beautiful statement to finish with. And back to you now, Pravin.

So we have the pleasure now of speaking with Dr. Lee Schwartzberg, who is the Chief Medical Director of the West Cancer Center. And he's the Chief of Division of Hematology and Oncology at the University of Tennessee Health Sciences Center. Dr. Schwartzberg received his BA and MS Degrees from the State University of New York and is an MD from the New York Medical College. He finished -- he's completed his residency from the North Shore University Hospital and was the Chief President at Memorial Sloan Kettering Cancer Center as well as finished his fellowship at Memorial Cancer Center. He's board-certified in internal medicine, medical oncology and hematology, and he is a recipient of numerous awards and honors. Dr. Schwartzberg, thank you so much for participating in the Diarrhea Dialogues.

Thank you so much for having me, Pravin.

Thank you. Thank you. So we thought what we would do is really have you start with an overview. You've been doing this for so long and have such rich and varied experiences about diarrhea and bowel control issues and the problems and the complications and management and limitations that you've experienced over the years. We could start from there sort of as you will go from there.

Sure. In the 3 decades plus that I've been taking care of cancer patients, one of the things I focused on has been supportive care. And one of the areas where the problem has existed from the very beginning of my career and before that and has gotten worse over the last decade has been in the management of diarrhea. And that is likely related to the fact that we have many more drugs now that affect the gastrointestinal lining and Mucosa that causes diarrhea. Many of those drugs tend to be small molecule oral medicines, which is a large part of the development of new anticancer agents. And we're seeing remarkable progress in terms of taking care of patients with these drugs. But along with that progress comes the adverse events that are associated with those drugs and diarrhea is, in many cases, the #1 problem that patients experience with many of the most active drugs that we're using today. So that's a paradox because we have these wonderful agents, many of them oral, which means that they're taking usually continuously at home. And patients exhibit this toxicity, diarrhea at home not something that we can always predict exactly when it's going to happen, although for most drugs, we have a pretty good idea when the highest risk period is. And managing diarrhea becomes different than managing many of the other toxicities that are traditionally associated with cytotoxic chemotherapy. The reason for that is with a cytotoxic agent, it's usually given discontinuously every week or every 3 weeks more commonly and the predictability of the kinetics of adverse events is there. And you can have the patients come back to the office or we see the patients at a time when we expect adverse events. Diarrhea is very different, particularly when we're dealing with oral agents, which are given continuously. Particularly in the current era of, unfortunately, COVID-19 and trying to avoid patient visits whenever possible, it adds another dimension of identifying diarrhea from patients and having them self identify or having an active role from the practice in trying to find out about when the patient might have diarrhea and then the management of diarrhea. So we have this very prevalent problem that occurs in many cases, in the majority of patients with certain agents. In some agents, a very significant minority of patients have grade 3 diarrhea, which absolutely impacts the lifestyle. One could argue that grade 2 diarrhea or even grade 1 diarrhea impacts patients' lifestyle much more than certain grade 1 or grade 2 toxicities of other natures. So diarrhea is a pervasive problem. It's a problem that occurs in many patients, getting these agents, an increasing number of patients are getting diarrhea. It's hard to monitor, and that sets up a perfect storm of patients having this particular adverse event and getting into trouble potentially with it. So when it comes to managing diarrhea, we first have to identify the problem. And that can be done now through a variety of ways to communicate with patients. Perhaps, first and foremost, diarrhea has to be, first and foremost, it has to be education at the time the new drug is prescribed for patients about diarrhea. Because if you don't hear about it, you won't be able to treat it effectively, and that's when patients run into trouble. So there's really quite a bit of time that our staff has to spend usually -- our nurse educator, telling patients about the fact that they may experience or even likely will experience diarrhea. What to do in terms of a diet, so the so-called BRAT diet can be used for patients. That's a good start. It's certainly doesn't have a maximal impact on reducing diarrhea, but it does something. It's very important to educate the patients about -- for a particular drug when the highest incidence of diarrhea is. Interestingly, for many of these small molecule arising kinase inhibitors, it tends to occur early within the first week or 2 in its worst phase, but it can be unpredictable. And some drugs diarrhea doesn't occur until many weeks later. So patients are going along just fine and all of a sudden, they get into a problem. The really key issue here is communication with the practice. And that can be proactive from the practice. We have to use a lot of resources for our nurses to call, patients at particular times. They might call them the day after they start with a cytotoxic agent, but with an oral agent, it's really a week later or 2 weeks later. And figuring out the logistics of all that is complicated. It's costly. And frankly, it's inefficient for the practice. So educating the patients is important, but really both aspects with patients calling when they have a problem and also proactively calling patients to make sure they don't have a problem is important. Once we identify diarrhea, we -- to the present time, we have, I would say, what I would call limited tools to help it. Now there's no question we can use anti-motility agents effectively to shut off diarrhea. You get into this cycle where you have 5 or 10 episodes of bowel movements a day. That's not captured in the clinical trial adverse event reporting because there, it's strictly how many episodes are you having a day. And it doesn't really capture the quality of life impact that diarrhea has on patients, even when you use an anti-motility agent, and turn it off. And then we can go to the more opioid based or opioid analogs to use. And in those cases, we get even more reactions there. They tend to be stronger, but they cause more constipation and more cramping. And they may have other adverse side effects. It may cause dizziness. So they may cause a sense of unwell being for the patient. And so this cycle of moving back and forth from diarrhea, having to change your diet, actually being afraid to eat, which is what many patients tell me. As soon as they take something, even something that's bland, they have this urge to have a bowel movement. And so they actually are afraid to eat. So it's not uncommon for patients who have diarrhea from their chemotherapy drugs to lose weight, and they're simply losing weight here, not because necessarily of the cancer per se and not because they have nausea or vomiting, although both of those things can also occur with anti motility agents because, again, you stopped the GI tract which sends the signal particularly for nausea. So if you go into the situation, you have this rebound nausea effect. But it can also occur simply -- not because of anorexia, but loss of weight because patients are afraid to eat to -- and the consequences of eating. Because diarrhea can be chronic for some of these patients, it can lead to another unintended consequence, and that is adherence problems. So patients may simply stop taking their medicine or they may titrate their medicine to such a way that they themselves know that it will cause diarrhea or not. Patients are very smart, and they know how to take care of toxicities. And they might say, well, I'll take my medicine once-a-day instead of twice a day, or I'll take my medicine every other day because I found out that if I did that, my diarrhea is less. Not understanding that there may be a specific dose below which they won't get the effectiveness of the medicine. So they may be causing more harming good that way. And because patients on oral therapies cannot, under any circumstance, be monitored day-by-day by day, even using some of the nicest things that we're -- we use in our practice, these remote apps and things like that, which are becoming more prevalent. They simply -- it's no way to monitor patient every single day for their toxicities yet. And so really, a lot of things can happen as a consequence of any agent that causes diarrhea. The question of how much drug a patient has to get to get the effectiveness of it is surprisingly not well established. And for intravenous chemotherapy, there's a fair amount of data that suggests that giving dose intensity or at a level of 85% or greater gives you the effectiveness, and it drops off after that. If you're dropping more than 1 out of 6 days of therapy or 1/6 of the total amount of therapy that needs to be given for a drug that's given more than once a day, for example. There's the possibility of not getting what you'd expect out of it. First thing we tell patients is not to be embarrassed about talking about diarrhea. And this is a social stigma in the end of itself. I mean, people don't like to talk about. It's uncomfortable. And the other aspect of that, though, I want to bring up because it's really important and often forgotten is patients don't like to talk about any side effects if they think that it might impact what their doctor is going to do. Sometimes diarrhea has stigma, and it might be seen as shameful or it certainly impacts -- somebody's got an active lifestyle. And of course, with cancer patients, our goal is to get them back to as close to their normal life, as possible. Quality of life is every bit as important. If you query cancer patients on quantity of life. And if they're having to be around a bathroom, and can't go out and do the kinds of things they want to do, then there's a huge impact on their quality of life. Problem with diarrhea that's uncontrolled is quite substantial physiologically. We see many consequences. Number one, dehydration. If patients have large volume of diarrhea that's watery. They're actually losing a fair amount of their bodily fluids. It can be -- if they have nausea associated with the drug or nausea associated with some of the treatments that we've talked about already. They may be less inclined to take in more fluids and it becomes a vicious cycle. We also -- so dehydration is a critical aspect, and that drives patients to the emergency room or to hospitalization, or to unscheduled visits to the clinic for intravenous fluids, all of which have the consequence of costing the patient and the health care system more money. We also see these patients typically have hypokalemia and the low potassium level can lead to a whole host of other consequences, including muscle weakness and can lead to cardiac when it's severe to cardiac consequences. The dehydration causes acute kidney injury, and these patients can then have further consequences from that. Any downstream consequences of having uncontrolled diarrhea that can land a patient in the hospital and really can be very sick and can be life-threatening in and of itself because of these downstream effects of diarrhea. You set up a perfect storm that patients can have diarrhea that's really substantial to them that is life impacting, and no one knows about it until it's too late. And so it really is an ongoing problem. I would say that it's a growing problem because supportive care has become relegated to -- it may be a little harsh to say the backorders of the oncology world -- the problem is we don't have the best drugs currently to stop the diarrhea in an effective way. Yes, diarrhea is a growing problem because we have more drugs that are closing diarrhea today. But in a general rule, I think it's fair to say as we have more targeted therapies, we have more diarrhea. Even if you look to the future, it's hard to see how diarrhea will not be a problem in chronic therapy going forward. Chronic diarrhea is a very intractable problem for us, thankfully, a small but a real percentage of patients.

Well, thank you, Dr. Schwartzberg.

Thank you, Pravin. I'm so happy to be here. I'm Kim Thiboldeaux. I'm the CEO of the Cancer Support Community. We're a nonprofit organization, and we provide support and navigation and education to people with all cancers. At any stage of their illness, we provide these services for free. We have 50 affiliates around the country. We have a health line, we have a digital community and folks can reach us at cancersupportcommunity.org, where they can call our health line to speak to one of our counselors right now at (888) 793-9355. I'm so pleased to be here with [ Ellen Kerry ]. Ellen, I'm so happy to welcome you to our discussion today. We have a lot that we want to discuss with you today. But I just want to start, Ellen, by telling folks a little bit about you. Who you are? Where do you live? How do you like to spend your time?

Okay. Well, I live in -- I'm retired officially, but I do a lot of volunteer work. I live in [indiscernible], California, which is about 30 miles south of San Francisco. And I do a lot of work with our local history association. I'm a dose [indiscernible] local white house here on the coast. So I spend a lot of time doing stuff that's more like work, but not getting paid for it these days.

Well, as someone who runs a nonprofit organization. I have to thank you. We couldn't do the work that we do without our wonderful volunteers. So thanks, and kudos to you for so active in your community, Ellen. We all appreciate that. It's wonderful. Wonderful.

It's a labor of [indiscernible]. So

Wonderful. Wonderful. So Ellen, I want to talk to you about Bill and about your experience with Bill, but I want to go a little bit further back because I know some years ago, you, yourself, were diagnosed with cancer. So would you share with us a little bit Ellen when were you diagnosed? How was your cancer discovered? Take us back in time?

Sure. Well, let's see. In 1999, so that long ago. I discovered a lump in the shower, the class of doing yourself exam. So I went to my doctor who surprisingly enough advised watched full waving, which I didn't think sounded good at all. So I went and found a doctor who would biopsy it because my mammogram was normal. So everything looks copasetic. So I went to another doctor who said, well, let's just biopsy, it looks -- I'm sure it's fine. I think it's probably -- well low and behold, it was breast cancer. And it was Stage 1. Let's see, it was an infiltrating ductal carcinoma, HER2 negative. And so I had a lumpectomy and they also removed 10 lymph nodes, which were negative. And then I had radiation, but no chemo. So I came out relatively unscaled. And here I am, low, 21 years later, still kicking in.

I imagine at that time, you thought you had maybe had cancer in the rearview mirror, right? Had your follow-ups and very diligent about taking care, but then cancer came back into your life, not that many years ago. But tell us a little bit about Bill. Bring us forward, Ellen, to what led to his cancer, diagnosis? What be having symptoms, what's the screen? You tell us a little bit about that moment.

No, he felt fine. He felt absolutely fine. And ironically, he was to get some pre-op labs for cataract surgery. And there was something a little bit off in his creatinine in one of the kidney function tests, and so his doctor said, man, let's just do an ultrasound. I'm sure it was so they did an ultrasound and called and said, come back now, you need an MRI. So they found that his right kidney -- the raise in creatinine had nothing to do with the cancer as it turned out, but his right kidney was engulfed in cancer. The disease was progressing. And so they had to make -- take certain measures, and he went on to a drug called cabozantinib, the trade name of which I can't recall. So he was on that for a while.

So Ellen, I know that they'll have some different treatments. Talk to me a little bit about some of the side effects that he experienced from those treatment.

Okay. A lot of the side effects were kind of the common side effects, the stomach upsets, the diarrhea, the taking diarrhea medic -- things that he would swing from diarrhea to being constipated and back again. So it was very tiring and debilitating in that way. And also, he -- and I'm not going to be able to remember any of the names of the drug, but that, but they went to different types of drugs because I didn't note that early on that his -- being the rare bird that he was, it was a rare form of cancer, that 85% of the people get one kind and he had the other. So the drugs that were available and had been tested, and were known to be effective or the right ones for him. So he went through -- I forget how many different drugs but -- and different doses of them. And -- but he persevered and so -- but his time more on, it just started wearing them down. I mean, the disease itself, which had -- was not quick. I mean, it was not growing quickly, and they had -- when he was diagnosed, they said it had probably been there for some time because he was still growing cancer. And it's astonishing that he had no symptoms, and he was feeling just fine, but hadn't he not needed cataract surgery, it would have been -- we'd be having a different story here.

So what were some of the more intense or debilitating side effects that he experienced from treatment? What were some of the things that did start to kind of interfere with his life or his activity?

The big one was diarrhea. I mean it was so debilitating sometimes and uncontrollable that he ended up in the hospital dehydrated because you just, at some point, can't get enough liquid in to counteract what's coming out and needed hydrating in the hospital. And also it was humiliating. I mean really humiliating because it was uncontrollable often and he's a very outgoing personable person. And imagine, if you will, you're this person who loves to be out and about, and you have all of a sudden diarrhea running down, you're like you can't control it.

Right. It can really affect your dignity, it can affect -- it can lead to social isolation. It can lead to those kinds of things. Is that right in your experience?

Absolutely. Absolutely. And it was very difficult because we're not pretty outgoing people. To -- fortunately, we had each other. But it was pretty difficult to our big outing was to the doctor.

So some of the standard things that were -- the doctors were trying to manage the diarrhea just weren't working. They -- so they went down a different path?

They did. I mean, all the standard things, the standard diarrhea from kind of over-the-counter mild to the more stringent just were not working. They just weren't. And so Bill's oncologist -- excuse me had become upon an investigative medication that was a non-opioid drug and suggested that we give that a try, which he wrote a prescription for that, and we did. And it -- like a week after Bill start taking it took effect, and it was magic. I mean, that felt like magic because it was such a dramatic departure from being humiliated and debilitated to being more normal. And although by this time, this was about 2 years in. This was about 2017, I think almost exactly 2 years after the surgery. He had been losing weight and appetite, loss of appetite wasn't -- and here is the man who we and have a glass of wine. So the disease was progressing and things were taking their toll on his body as a whole. But the diarrhea abated. Although he did have to adjust it. I mean, he'd have to stop the -- he had had his oncologist said he had to reduce the dosage of his chemo because of the diarrhea was [indiscernible]. And so with this drug, he was able to start bumping the dosage up again to be more aggressive. So that was good.

And so by getting that diarrhea under control, did it allow Bill to go back to doing some of the things that he enjoyed. Tell me about that?

We -- by this time, 2 years and he wasn't doing dosing and those kinds of things, but we'd still go down to the light house and sit on the West Coast come and sit out on a beautiful deck at vision point like station, which is a deck that's overlooking them -- the rocks at this treacherous point in the Pacific Coast and just stood out there and talk to folks and socialize and be the ongoing person that he was. Over 2019, he went into the hospital with -- he was dehydrated again, although this time, it wasn't really so much from diarrhea. It was just kind of, I don't know. Anyway, he was back in the hospital and was in there for a while, and they kind of figured he would never get out and he did. I think it's hard for people to imagine what it's like if you're out in public and have diarrhea running down you're like all of a sudden that you can't do anything about. You don't want to think about it.

No, it's very upsetting, but it's a very real problem. Well, Ellen, it's such a pleasure to meet you and talk to you today. I thank you for sharing your story. I thank you for sharing Bill's story. He sounds like a wonderful guy. I wish I would have known him, but I'll come and sit at the lighthouse with you, and we can talk more about Bill some more good Bill stories, but it sounds like you got a terrific guy and a wonderful guy to have in your life. And I appreciate you sharing a little bit today, and I appreciate your continued advocacy for all people who are impacted by cancer. It's wonderful that you're out there, sharing your story and sharing your voice. And so we're incredibly grateful to be with you today.

And I'm grateful for what you do as well. And I mean it's mutual.

Thank you.

Hi Dr. Roeland today, we're going to talk to Dr. Eric Roeland, who is Assistant Professor of Medicine at Massachusetts Hospital, Harvard Medical School. He is dual Board certified and fellowship trained in both medical oncology and palliative care. His oncology practice focuses on patients with gastrointestinal cancers and is valuative care practice includes all cancer patients. Dr. Roeland has dedicated his career to improving quality of light for cancer patients by identifying, validating and expanding pharmacologic interventions to mitigate or minimize suffering in cancer patients. Dr. Roeland got his medical degree, MD from the University of Colorado Health Sciences Center and completed his residency at University of California San Diego Medical Center. He did his valuative care residency at the Institute of Valuative medicine at San Diego Hospice and his medical oncology fellowship at University of California, San Diego School of Medicine. Dr. Roeland, thank you. We can start with the overview of diarrhea and bowel control issues in cancer patients, such as causes complications, limitations of management, your experiences, that would be lovely to start with that. Thank you.

Yes. So diarrhea in cancer patients is actually one of the most overlooked symptoms that cancer patients experience. Causes of diarrhea in patients with cancer include infectious causes, of course, but also we have the complicating factors of the cancer itself, causing diarrhea and, of course, its treatment. Our typical approach is to treating diarrhea associated with cancer and its treatment, primarily focused on slowing the diarrhea down to avoid dehydration and kidney -- the impact on kidney functioning. I would say I spend approximately 50% of my clinic visits talking about bowel issues, given their impact on quality of life.

So you are one of those very rare oncologists Dr. Roeland, who actually talks about quality of life and diarrhea. Most oncologists almost never talk about that. So this is something that you have championed for a long time, and thank you for continuing to support us in this Diarrhea Dialogues. How do you think we increase the awareness of this, what you just described and this diarrhea constipation cycle that you have to constantly fight against?

Yes. I think that we need to educate patients and caregivers regarding the dynamic approach to treating this awful syndrome. So teaching them the ways to slow down their diarrhea, but at the same time, not become constipated. And also to be aware of which medications are most likely to cause either a symptom. And then really teaching patients and caregivers to advocate for help when they need it, because unfortunately given that diarrhea is a very personal topic for many patients. They will not actually share what's going on with their bowel habit.

Let's talk about that stigma this associated with and your patients and the FGI cancers.

I feel like our nursing colleagues are actually very good at engaging in this topic, and they actually receive the vast majority of the phone calls, which may be shielded from other oncologists. So I think that nurses, nurse practitioners and physician assistants are obviously very aware of this because they're on the front line receiving the phone calls. But to me, this is very much an issue around dignity. And we are trying to help patients either in the curative setting or in the non-curative setting to live life to its fullest. And unfortunately, when you have a leash to the toilet, you're not able to get outside and do the things that you want to do or even do those things without the fear of having an accident. And this can be very socially isolating and really prevent patients from doing the things that they really enjoy in life.

One of the things that's, shifting gears, clinically that you have talked about is both impact of diarrhea on cancer care and the burden of diarrhea on hospitalization costs and cost of total care. You're one of the few people who can speak to both ends of that. Can you elaborate on that a little bit?

Yes. So clearly, there is impact on the quality of life of patients and their caregivers. But also as a GI oncologist, I worry about any time I have to delay chemotherapy, reduce doses of chemotherapy. And so we call that treatment intensity. And unfortunately, diarrhea can really impact the treatment intensity of our ability to treat patients effectively. And moreover, when we look at potential causes of emergency department visits or hospitalizations, diarrhea is a common cause of admission in the setting of cancer and cancer directed therapy, which is potentially avoidable. So I think the impact on our health system at large because of this symptom is huge, and we talk about the cost of being in the hospital in the realm of $5,000 and up per night for patients. This expense then gets transferred across all of us, and we're all paying for it in one way or another.

Now in your cancer population's that you take care of, the incidence of diarrhea is particularly high. In the incidence of the use of diogenic drugs, it's extremely high. You would say almost 80%, would that be a fair number?

Yes. We're consenting for chemotherapy. This is one of the things that I highlight, not on and if this will happen to you, but when. And when we combined our typical chemotherapy agents with radiation, which we frequently have to give as well, for example, when you have a rectal cancer or potentially a pancreatic cancer or gastric cancer, or subdural cancer. These patients are getting combined modality therapy and therefore, have even higher risk of developing diarrhea. This is -- it's just shocking how common this is and how little attention it has received in terms of research and education.

How do you think we raise awareness amongst the treating oncologists about this issue?

Yes. So Pravin, I think my role is a supportive care guidelines codeshare for the American study clinical oncology. And our supportive care guidelines, surprisingly, are one of the most cited guidelines that exist out there, given the number of treatment algorithms that exist. And as you have pointed out, the management of diarrhea is not anywhere to be found in those guidelines. There's a couple of things that really drive that. And I think one of the biggest things is new or developing therapies. And so the management of diarrhea now has become increasingly more important for our newer therapies such as immunotherapy, which we know can cause a life-threatening colitis in a small percentage of patients, but it's potentially very serious. And I -- when we look at our other guidelines in terms of how they're being developed, there's a large amount of data regarding prior clinical trials in the same area. Sadly, chemotherapy-induced diarrhea has not been a major focus of supportive oncology.

You also have been very vocal about using the same mechanism for all forms of diarrhea, which is just basically use opioids, which cause opioid to induce constipation in addition to the drugs used for chemo and just not in vomiting. So that's another thing that you talk about, the mechanism of diarrhea and lack of physiological addressing of diarrhea.

Yes. So what you're describing, Pravin, is this one size fits all approach. This is not based off pathophysiology, and there's probably much better ways to approach this. And I think, again, a huge opportunity for research. Also, it's important to recognize that opioid use is very common within patients with cancer. And unfortunately, there's no way to predict how much constipation patients can experience with the opioids. Within the medical community, there's a thought that the more opioids equal more constipation, but that is actually not true. Patients can get constipated with very, very small amounts of opioids or not get constipated as much with larger doses.

One of the things that you have also spoken to me about in the past, is not only how to manage it with proper diet and electrolytes, but then you also talked about chronic diarrhea in patients that you actually completed treatment on that -- and those patients are sort of in no man's land. Would you like to talk about those 2 factors as well?

So as patients are going through treatment, we talk about the risk of diarrhea, and we have people asking and train to monitor them to the best that we can. When we do hear about it from patients and caregivers. But once patients are cured of their cancer, depending on the type of GI cancer they had and the treatment, they may experience chronic issues with diarrhea. So if we talk about diarrhea in the setting of cancer survivorship, sadly, patients will be cured over, but still have this symptom. Patients at higher risk of that, of course, are those who've had surgical resection of parts of their bowel or pancreatic cancer patients with a history of exocrine insufficiency of the pancreas. And then rectal cancer patients who undergo chemotherapy with radiation. And this issue is enormous in terms of moving forward with your life after cancer and greatly impacts your ability to work to socialize. It creates huge shifts in your diet. Patient of mine that really comes to mind is a young man who was a chef, a pastry chef. And unfortunately, that much time on his feet and not having available access to a restroom at a moment's notice, really impacted his ability to be at work and then has caused a big depression. So sadly -- so unfortunately, we were able to get him through his treatment, but the chronic side effects of diarrhea had immense impacts on his ability to live life to its fullest.

What percentage of your patients do you think actually due to the stigma and the social isolation indignity sort of get impacted with sort of mental depression and some of the other CNS psychological issues?

Yes. With this symptom of diarrhea, I think that because of its incredibly personal nature, and our reluctance to talk about it with even family, let alone friends or coworkers or a boss, this can cause a lot of isolation and lead to depression, which I see twofold. One, not being able to engage with the people that we love, but also for our inability to do the things that we want to do. And for many, that is to remain at work and actively contributing. And unfortunately, the symptom does not allow you the flexibility to travel or to be far away from a toilet, if this is going to happen at a moment's notice. And so we talk about other strategies, including having a change of pants and underwear. And even that for many folks, it's just like a deal breaker, they don't want to be in a situation where that's even a possibility.

Dr. Roeland, as always, a pleasure talking to you and getting your perspective on these very important topics in supportive care, in particular, bowel control issues and diarrhea in the patients, both from the cancer as well as from cancer chemotherapy, targeted therapy, radiation therapy and the chronic diarrhea in cancer survivors long-term and the mental health and all the other social isolation dignity issues that you've talked about. Thank you for that. And appreciate for your time today.

Okay, Pravin. Can you tell me what this survey is, who participated, why this was done, please?

Absolutely. So we did a cancer patient survey of patients with different types of tumors. That are receiving various targeted therapy agents without chemotherapy because we want to develop a protocol to study how the area was impacting them and how they were managing that area and what the prevalence of that was and how intense it was and the sensitivity of it. And there is very little literature out there on this topic because it's an unspoken issue and it's underreported in all of the clinical trials and their package inserts for most of the cancer drugs only grade 3 and higher diarrhea. So it was very hard for us to truly power a study and do a clinical trial. Where we would know what to expect at baseline in these patients. And just to put this into perspective, grade 1 diarrhea, according to the National Cancer Institute is 3 or more watery stools above baseline. Grade 2 is 4 to 6 watery stools above baseline on a daily basis. And grade 3 is 7 or more. And grade 4 is, of course, life-threatening and grade 5 is death. So when you just report over grade 3, that means these patients are having more than 7 watery stools over, but the percentage of patients experiencing that, that are on the package inserts were quite low, somewhere between 10% to 15% in terms of the incident. And so it's subordinated. Any of the patients that had anything less than 7 watery stools is above baseline. So we did all this to basically design our baseline program for the Phase III protocol because we wanted to make sure that we were aware of sort of full data from real patients and their experience.

I want to just reflect that on something that you just said. You said it's a small percentage of patients, maybe up to 15% of the patients that are dealing with grade 3 and above. I don't actually, that doesn't strike me as small. I mean, we're talking about 7 lose watery stools a day up potentially to hospitalization or death. And we do know that there are some patients in targeted therapy clinical trials who died who didn't make it through because of the severe diarrhea and the ultimate implications of that for their organ system and organ failure. So 15% is meaningful. What's in the survey is remarkable. Every single patient in the survey has experienced diarrhea as a side effect of their cancer treatment. 50% of them said they attempted something to deal with it. And this is on the background of literature research that says up to 80% of cancer patients experience some sort of diarrhea, but probably the most meaningful number that I see here is up to 45% of them have to have some sort of interruption or dose deescalation or failure of their life-saving cancer therapy because of diarrhea. So what I want to ask you as someone who has developed so many drugs in the cancer area or are so seeped into the holistic management of the patient. Do you think of diarrhea as a side effect of cancer therapy something to be managed, something to live with? But do you think of it as an adverse event that can actually interfere with the patient's cancer therapy?

Thank you, Lisa. That's a very good question. So I think I did not mean to minimize the incidence of the grade 3, I think you're very right that 80% of the patients are more experienced area. In general. But to your point about whether this is an adverse event of treatment or really something that one has to live with as a part of cancer therapy. I think the answer is the latter, that it is a side effect that is expected. And so when diarrhea happens, most of them will not report it, will not talk to their oncologist about it because it is considered to be par for the course. So I think it's an expected side effect, expected adverse event of cancer treatment. But it's an unspoken issue. When you say 45% of the patients have to reduce their dose that we found, it's literature reported. That is a nontrivial issue. At least some oncologists who will agree with me is that even 15% reduction of the doses is nontrivial. That has an impact on their cancer burden and has an impact on prognosis as well as resistance because what is the easier specify for resistance. Give us a therapeutic dose of the same drug. And so the survive and thriving and then you will have resistance, not just to that molecule. But as a class, you might get into it.

Yes. We've spoken with patients and also the experience that we have in the HIV community, that sometimes the patient community feels that there may be an indifference from the health care providers to their diarrhea to their comfort. But when you bring in the aspect of this is potentially reducing or causing failure of life-saving therapies, you don't think it's an indifference and that perhaps this is an issue of -- there's no solution so why ask? I mean, we've certainly seen that in the HIV area, if you don't think there's anything out there you can do, why are you going to spend time highlighting it? I don't know if you want to comment on that.

So we have sort of grandfathered in the use of opioids for managing the diarrhea. It is within the NCI guidelines for management. It is under the ASCO and ESMO guidelines for management, the use of opioids. We give it because it's easier to have reduction in gastric motility and lack of passage stools, and many of the cancer patients are getting opioids anyway for their pain control, these long acting. So they also tend to have a constipating effect from their long-acting opioids. And so there are effectiveness of taking all these measures, food changes, probiotics. Some of them took more of these bulking agents like Metamucil to basically cause reduction in stools and none of that really was satisfactory for them. So I think you're absolutely right. The lack of a physiological way of addressing this issue contributes to the problem. The worst-case is in the survey that we are talking about. 100% of the patients have at least 3 watery stools above baseline every day. Now by clinical measurements, that's only grade 1. But remember, that's an arbitrary scale that was made by us. Having more than 3 watery stools per day every day, and they take oral targeted therapy, which means they take that pill every day. It's not like a cycle chemotherapy that's given once every 3 weeks or once every 2 weeks so that the body gets a holiday. The targeted therapy is daily insult. And so -- and this was nontrivial. Then many patients had somewhere between up to 10 to 15 stools per day above baseline in our survey. And they were. Many of them had this area for more than 6 months. Some of them had it for up to 12 months. And they -- I found it remarkable in getting their feedback that they stayed on their therapy because all they wanted was about 30% to 50% reduction in the stools, they were that generous. That's how generous the patients are. They're willing to take enormous amount of, forgive me for saying it, poison into their gut to treat their cancer and live with this side effect or adverse effect, as you call it, whichever one you call it, it's quite remarkable. And so we took that information into our consideration to come back to the first question you asked me, which is how to design the protocol to really try to figure out what is a meaningful clinical benefit to these patients. And the patients did not ask for passage of 0 watery stools. Only 18% of them even said if we just get form stools, we'd be happy. The rest of them said just give us 30% to 50% relief. And we found that to be remarkable in our discussions with them in the survey that we did with them.

And I assume watery stools is associated also with urgency and the unpredictability. And of course, that's where this number comes from. 56% says it's impossible to do their daily activities that interferes with their daily activities, which is not only running to the toilet, it's not only the health issues of the dehydration, but when it's going to happen?

Absolutely. In fact, incontinence is a nontrivial part of it. So we measured urgency and rushing to the bathroom. We ask them that. And that's when we found out that, that's what they were doing. They pretty much -- some of them were just not going out anyway.

Terrific. Okay. Anything else you think we should address Pravin?

I come back to the first question, you asked me, which is there are dangerous consequences to unmitigated diarrhea. The management of that has been trivialized somewhat or neglected in many cases. The dangerous consequences are really the severe dehydration, septic shock you will have. And so unscheduled visits to the clinic, unscheduled visits to the emergency room from diarrhea are a nontrivial issue. I'm actually quite -- I learned a lot from this survey from the patients directly about the intensity, severity and how brave the patients are really, and hats off to them.

Okay. Thank you, Pravin. We all are grateful that you are committed to the overall management of patients with cancer therapies to supportive care, and in particular, here at Jaguar and Napo with supportive care.

Today, we are talking to Dr. Andrew Davies, who is the President of Multinational Association of Supportive Care in Cancer, also known MASCC. He's a Clinical Director of Development in Palliative Medicine at St. Luke's Cancer Center, Royal Surrey County Hospital. Dr. Andrew Davies graduated from St. George's Hospital Medical School, University of London in 1987 and completed his specialist training in palliative medicine in 1998. He currently serves as a Clinical Director of the Department of -- Clinical Director of Palliative Medicine at St. Luke's Cancer Center in Gilford, Dr. Davies sees cancer patients at all stages and patients with symptoms relating to both cancer as well as their cancer treatment. Thank you, Dr. Davies, for joining us this morning. Appreciate your time. And I thought we would start by just you talking about the overview of problems you've seen, specifically related to diarrhea and lower GI tract issues that result in lack of bowel control. If you can start with there, that would be great. Thank you.

Okay. I think the first thing to say is that diarrhea is one of the so-called orphan symptoms, probably doesn't get as much exposure as it should, particularly if you consider things like nausea and vomiting and other symptoms that are prevalent in this group of patients. But I think for the patients who have this symptom, it is actually as distressing as things like nausea and vomiting or pain. And terms of the burden, we see people who have relatively mild diarrhea that's an inconvenience, an embarrassment maybe right the way through to patients who have life-threatening diarrhea and indeed die as a sort of secondary consequence of their diarrhea. So we see the whole range. But for most patients, even if it's relatively mild, it does have a significant impact on their quality of life, on their activities of daily living. Restricts their ability to go out, restricts their ability to work, restricts our ability to socialize. So it is a big problem for the patients and their carers.

Thank you. So those are some of the complications, both social as well as physiologic and physical. What are the causes, Dr. Davies for lack of bowel control and GI issues in cancer patients?

We see a whole range of causes. So for some people, it's related to the underlying cancer. That's particularly patients who have gastrointestinal tumors, but it can occur in other types of malignancy. And then almost every treatment that our patients are exposed to potentially can cause diarrhea. So patients having surgery to the GI tract radiotherapy to their abdomen pelvis, conventional chemotherapy, immunotherapy, targeted treatments. There's a whole range of things that can cause diarrhea. And for some patients, they have a sort of combination of things. And we see it at all stages of the disease. We see it a presentation. We see it particularly during treatment, but also amongst the cancer survivors, patients who've completed their treatment and potentially have been cured of their cancer, still have ongoing problems with diarrhea.

So in your overview earlier on, you called diarrhea and lower GI tract, lack of bowel control as an orphan side effect of cancer patients. That, to me, means a neglected morbidity. Why is it that you feel that it is an orphan spectrum of what to expect in cancer patients?

I think if you look at, for instance, the literature and the research that's gone on within symptom control in oncology. There's very little published, particularly original research about diarrhea, causes, management. There's been very little research. I mean, if you compare it to chemotherapy-induced nausea and vomiting, chemotherapy is peripheral on neuropathy cancer pain. I mean, the percentage of articles, the percentage of funding is tiny. And the options for management are this -- in most cases, the same as what we will use in 20, 30, 40 years ago. So there's been very relatively little development in terms of our ability to manage these symptoms and actually we're seeing more of it and a different type of diarrhea and often a more severe type of diarrhea, but we're still using the same tools we used a long time ago.

Okay. Wow. So can you elaborate on the different types of diarrhea you're seeing now vis-à-vis the new agents because I think that's what you were alluding to that we are using technologies in management, which are 40 years old -- up to 40 years old. What is being done for that?

Yes. Well, I think in most cases, that the management of diarrhea at least initially is the same irrespective of what the cause is. So it's about rehydrating the patient correct if any electrolyte disturbances that there might be. I mean in some cases, there may be some specific treatment to reverse the underlying cause of the diarrhea. But for most patients, it will be certainly initially, they'd be started on some sort of an opioid.

You alluded to the fact that the current management guidelines, Europe, United Kingdom as well as United States and the rest of the world using mostly antimotility drugs such as opioids. What is your -- what are your thoughts about the guidelines that are currently in place? Are -- they need to be revised because you said they're up to 20 to 40 years old to manage the diarrhea?

Well, I think that there's two issues. There's one about the guidelines and there's one about practice. I think a practice is 20, 30, 40 years old. People when they're trained, they're told, if you have -- if the patient has diarrhea, you treat them with an opioid. I think there are guidelines out there about the management of diarrhea, which also recommend the use of opioids. I've mentioned a few other things. Those guidelines are somewhat limited. They endorse in reinforcing, I think what people believe is the management, how we manage diarrhea from a new treatment may be completely different to how we manage diarrhea from chemotherapy or somebody who had radiotherapy. And it is but they -- it's -- the guidelines tend to lump everybody together. It's diarrhea. So you manage it in exactly the same way. The same should be true of managing diarrhea. It's not a one size fits all, you need to have a better understanding of why the patients got diarrhea and try and reverse the underlying cause the diarrhea facts possible. But I think probably we need to have more targeted antidiarrheal treatments.

Thank you for that. We -- in the United States, the -- as you may have noticed, I don't know, if the same trend in Europe or U.K., we package insert now for new oncology agents, which have a higher incidence of area, particularly with their targeted mechanisms, they only report grade 3 and higher diarrheal episode occurring in more than 5% of the patients. That sort of minimizes and diminishes on the package insert, the impact because grade 2 diarrhea according to NCI criteria is more than 4 watery stools over baseline per day, which is quite debilitating, I would imagine. What are your thoughts on that sort of shift in some sort of minimizing this problem that's also contributing to the management issues, correct?

Yes, I think it is. The implication is that actually we shouldn't worry about patients who have lower grades of diarrhea. And obviously, the patients with the higher grades of diarrhea have potentially more serious consequences. But the impact on the patients with the lower grades is still significant. And those patients should be treated appropriately as well. And the other thing is that patients stop their treatment or oncologist amend their treatment because of even at the low grades of diarrhea potentially. So we need to find a way that patients can continue with their treatment. So they can get the best response from that treatment. If they're having the gaps between treatment cycles or they having reduced doses, that's going to impact on their outcomes.

You made an important point about dose interruptions and discontinuations. That is aside from the urgent unscheduled visits to the clinic and/or to the ER to the emergency room due to severe dehydration. When an oncologist lowers the dose so significantly, isn't that sort of a recipe for resistant cancer as well? Because now you're giving basically a targeted therapy that is actually not going to be at its optimal dose. And the outcomes could actually be worse in terms of cancer outcomes.

Yes. I think that this is an issue. And it doesn't just apply to diarrhea. It applies to lots of toxicities of treatment. There are some patients that we've looked after where the anticancer treatments had to stop because of, for instance, diarrhea -- severe diarrhea. And then there hasn't been an alternative treatment or -- so essentially, the diarrhea has resulted in the patient stopping potentially if not curative treatment, then certainly treatment that would stabilize their disease. And so their diseases progressed at a quicker rate. And so the diarrhea indirectly resulted in a shorter lifespan, not because of the complications of the diarrhea, but because their treatment has been amended, and therefore, their cancers progressed more quickly than it probably would otherwise.

One of the things that we noticed with the opioids is the diarrhea constipation cycle in addition to the dose interruption as well. Have you also experienced that in your practice with the patients?

So yes. And I mean, opioid in constipation is actually probably one of the biggest problems that I see in my practice. And usually the opioids have been taken to manage pain. But equally, we -- as you say, we see patients who have been put on opioids to control their diarrhea or indeed other symptoms that then become constipated. And then you need to put them on laxatives, and then they restart their treatment or whatever caused the diarrhea. And so you exacerbate the problem and patients go from having one set of symptoms, which are distressed into a completely different set of symptoms, which are just as stressing. You can have -- end up with a vicious circle where you have diarrhea and one set of symptoms and then you replace them with a different set of symptoms. One week you're giving them opioids to treat diarrhea, and then you're given them laxatives to overcome the constipation due to the opioid. So you can have a very unsatisfying situation where actually people's quality life is impaired, but by different sides of the same coin.

In terms of impact of diarrhea, on medical consequences. You've talked about one side about cancer care itself and the other side of it is the burden on hospitalization. Have you in your practice witnessed a lot of hospitalizations due to diarrhea alone that require intervention?

Yes. I think every ward run we do, we -- there's -- I mean, we have, I think, a 25 bedded oncology ward. That at any one time, there's at least 2, maybe more patients in there. The primary reason for admission is diarrhea, dehydration, secondary to diarrhea. And I mean I think the other thing is that in the outpatient, we are seeing many more cancer survivors who have chronic diarrhea as a result of their previous treatment. And people are surviving for longer and having more treatments and every few weeks and new treatment comes out. So we're seeing people that are on their third, fourth, fifth line of treatment, having a diarrhea. The have different with their first and second-line of treatment, but now they're on a different treatment. So there's a continuous almost conveyor belt of patients coming through. So it's not becoming less of a problem. If anything, it's becoming more of a problem. And this comes back to how you -- how big the problem is. If you actually go looking for it and you ask people, the problem is much bigger. I would say that we have seen in the last few years, an increase in patients needing to be admitted for rehydration. I think in terms of patients that we see in outpatients or the number of patients who are referred with diarrhea also seems to be increasing. So I think it's a bit like an iceberg. We see the really severe cases, but under the water, there's probably -- for every patient that we see in outpatient, there's probably another 10 patients that we don't see. For every patient that we admit to the unit, there's probably 20, 30 patients that we don't admit to the unit. It's -- we need to have a more holistic approach to oncology treatment. It's not just about what you give the patient. It's all the supportive care.

Well, Dr. Davies. We're coming up on the hour. So thank you for your time.

Now Pravin will provide a brief update on our pipeline.

Napo Pharmaceuticals pipeline leverages the power of plant-based medicines. Our lead product, Mytesi, is currently approved in the United States for the symptomatic relief of non-infectious diarrhea in adult HIV AIDS patients receiving antiretroviral therapy. It is the first and only drug approved by the United States FDA under its botanical guidance. In addition to our indication -- approved indication in HIV AIDS patients, we have just started a Phase III clinical study for the prophylaxis of diarrhea in adult patients with solid tumors receiving targeted therapy with a cycle chemotherapy. In addition to our indication in cancer therapy related diarrhea, reformer, the active ingredient of Mytesi has demonstrated clinical proof of safety PAUSE and activity in patients with diarrhea predominant ball syndrome. We are also currently evaluating the effects of crofelemer in patients with functional diarrhea and/or chronic idiopathic diarrhea. In addition to these adult indications, crofelemer is also being evaluated in a new pediatric formulation to be studied in pediatric patients with congenital diarrheal disorders. In addition to our initiatives with crofelemer, Napo's second lead product lechlemer is under development for the treatment of acute infectious area, such as that caused by cholera. Napo has a planned library or about 2,300 plants with medicinal properties, which we will continue to evaluate for securing new drugs. Thank you. We will now turn over to Lisa Conte to handle question and answers from the audience. Thank you very much.

Okay. Now I'll take a few minutes to answer some important questions for the benefit of our audience. And okay. Our first question is in. Does cancer therapy related diarrhea typically present with other side effects such as nausea and vomiting, or is it more of a stand-alone side effect? Okay. It's important. Yes. We know that with certain cancer therapy regimens, some patients, unfortunately, may experience diarrhea and nausea and vomiting. And while the nausea and vomiting are typically transient, it's usually a couple of days at the beginning of the chemo cycle, the diarrhea may be chronic and may be chronic in an adjuvant setting for a year or more. Okay. Another question coming in. Are you conducting, you being Jaguar, conducting market research on the burden of diarrhea in cancer? Yes, as a matter of fact, we've commissioned right now real-time a health economics and outcomes research study that will evaluate the health and financial burden of diarrhea in cancer patients, and we expect to have this very shortly in this quarter, and we plan to have those results published. And another question. What is the estimated market size for cancer therapy related diarrhea? Okay. That's a good question. It's always a good question when you have an indication for which there are no products that have been specifically tested or approved as is the case for CTD. So we're utilizing all the tools available to assess a latent market opportunity. The study just mentioned above, may provide us with some more specific information. But what I can tell you now for comparisons sake is that the global sales for approved drugs to treat nausea involved in chemotherapy-induced nausea and vomiting, CINV, are estimated to reach $2.7 billion by 2022 on a global basis. And as I mentioned above, the treatment for CINV is typically 3 days at the beginning of a chemo regimen. We are pursuing a chronic indication for Mytesi for CTD. Patients may be on targeted therapy causing diarrhea for a year or 2 in an adjuvant setting. And as we heard from some patients, the diarrhea may continue for years thereafter. And that's the questions that we have at the moment. Thank you all. Thanks to all of you once again for taking part in our very first Diarrhea Dialogues event. It was an honor and absolute pleasure to be able to host this event. We are so pleased that you were able to join us, and we hope you found the discussions by our speakers informative and engaging. We look forward to hosting additional Diarrhea Dialogue events in the future as we can continue to work to elevate awareness around the critical yet under addressed side effect of cancer therapy related diarrhea. Thank you all.