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

Hello, and welcome to Ladenburg Thalmann R&D Showcase. Our showcase is designed to highlight company products in the clinical or regulatory process. Today, we are excited to highlight Jaguar Health, and we'll turn it over to management in a moment. We would first like to bring your attention to our necessary disclosures. Further, we would like to reiterate this webinar is being recorded, and intended for the investment community. We'd also like to note the risks associated with owning shares of Jaguar Health. If you have any questions or concerns, please contact me, Destiny Hance at [email protected]. Without further ado, I will turn it over to Jeffrey Cohen, Managing Director, Equity Research. Jeff?

Thank you, Destiny, and thank you, everyone for joining us. Today, we're going to be speaking with both Lisa Conte, CEO of Jaguar Health; as well as Dr. Pravin Chaturvedi, who's the Chief Scientific Officer and discuss programs related to CTD cancer-related diarrhea and the programs going on at Jaguar Health. So without further do, I'm going to turn it over to you Lisa and to you Dr. Chaturvedi. Thank you for having us.

Oh, thank you. So pleased to be here. Welcome all. So as you hear my name is Lisa Conte, and I'm the Founder, President and CEO of Jaguar Health and our wholly-owned subsidiary in the United States Napo Pharmaceuticals. So I might use Jaguar and Napo interchangeably, and I am a Board member of our new subsidiary in Italy, Napo EU. And I'm so happy that Ladenburg has chosen this topic for today's webinar. Events like this raise are among the investor and business development community about the need for supportive care for people-related to debilitating diarrhea that often results from cancer therapy, which we refer to as CTD cancer therapy-related diarrhea. And as you'll hear, management of diarrhea also potentially impacts patient outcomes in cancer, allowing them to stay and manage the diarrhea, allowing them to stay on their life-saving cancer therapy without interruption. And cost of patient management, potentially keeping patients hydrated in a good nutritional state and out of the hospital with complications. So I am going to -- okay, why am I not doing this. How much further reversal Destiny. It's not moving my slide forward. Can you move my slide forward?

I can. Try clicking the shared.

I'm clicking the shared screen and for some reason, it's not happening. But if you just move it forward, if you don't mind, okay. So in addition to the Ladenburg required forward-looking statements. I have 2 quick required disclosures. First, I want to remind everyone that today's discussions will include forward-looking statements for me and mean others. And second, CTD is not an FDA-approved use for Jaguar's Crofelemer drug product and its under clinical development. Crofelemer is the subject of a pivotal Phase 3 trial for the proposed CTD indication, which was initiated in October of last year and for which enrollment is ongoing targeted to complete enrollment in late 2022. So Destiny, if you could go forward to the first picture side. I'll speak to what we do with -- at Jaguar Health. We do all our drug discovery from plants used traditionally in topical areas to leverage the knowledge of healers and chains to do more efficient drug discovery and development and that this lead to the approval of a first-in-class antisecretory agent Crofelemer, and is approved for the specialty indication of HIV related diarrhea. And we are a commercial organization for the specialty market of HIV related diarrhea. We are continuing -- and if Destiny you go to the next slide, we are continuing our plant-based drug development efforts in CTD. Research shows that CTD occurs in up to 80% of patients -- cancer patients and is far from a trivial problem. The condition not only has an enormous impact on the cancer patient's comfort and sense of dignity, but over 50% of the time, as I was alluding to earlier, the diarrhea triggers the need for cancer drug holiday, dose reduction or treatment failure during cancer therapy, which can negatively affect patient's cancer outcome. And let me underscore that more than 50% of the time patients life-saving cancer therapy regimen is interfered with because of diarrhea. Quite likely, we've all experienced an episode of diarrhea in our life. CTD is not [indiscernible] event. What we're referring to today is often severe chronic may result in hospitalization for rehydration and can enhance resulted in septic shop and even death in some patients as reported in clinical trials. It's a neglected health issue, an important health issue and one to which Jaguar is committed to bring a novel treatment. Unfortunately, over the years, we have learned there's a great deal of Sigma associated with diarrhea. Generally speaking, unless you're one of my children or you're in the Jaguar extended family, people do not want to talk about diarrhea. They have trouble even saying or hearing the words. So today, we're obviously going to hear a lot of dialogue on the topic. So let's just settle in and get comfortable with diarrhea, diarrhea, diarrhea, we're going to be saying it. So one of the 2 people will develop cancer in their lifetime. Which is very sad. And despite its growing prevalence and potentially serious implications, cancer therapy related diarrhea gets a near traction of the intention, for example, chemotherapy-induced nausea and vomiting. Another common side effect in patients undergoing cancer treatment. And perhaps this is because there is no pharmaceutical product that has been studied and accrued specifically in the diarrhea indication as we are now doing with Crofelemer. In a few moments, you will view interviews with 3 prominent oncologists who will address CTD in detail, why it matters and what can be done. You will hear from these speakers to [indiscernible] of members of next of Jaguar, Napo's scientific advisory board about why discussions between health care professionals and patients about CTD often fail to take place? And why CTD is now more prevalent than ever with some of the new targeted therapies that are in development and in use. They will also discuss the significant impact of severe diarrhea and the extreme dehydration it can cause has the cancer patients. And what needs to be done to elevate awareness about this critical -- it often neglected side effect of cancer therapy. I have been and we as a company have been really moved by the commitment of these 3 distinguished oncologists that you will hear from. One is Dr. Lee Schwartzberg, and he's affiliated with the Renowned Institute of Cancer in Nevada and is the Former Chief Medical Director of West Cancer Center; Dr. Eric Roeland is Assistant Professor of Oregon Health and Science University; and Dr. Andrew Davis is the Clinical Director of the Department of Supportive in Palliative Care at St. Luke's Cancer Centre and the President of MASCC, which is an UK-based Multinational Association of Supportive Care in Cancer, which is the largest professional organization dedicated to Supportive Care. And I'd also like to share little background on our very own Dr. Pravin Chaturvedi, he's Chair of our Advisory Board and acting Chief Scientific Officer, who conduct the interviews that we are about to do with these 3 oncologists. During his impressive 25 and growing plus year career with him, as what discovery and development activities for several new chemical entities, several approved drugs to his name. And of course, his favorite in line the successful development of Crofelemer for its current FDA-approved use in HIV AIDS patients. And following the oncologist interviews, Pravin will share a brief update on our development program for CTD, and I'll then provide an overview of Crofelemer-related pipeline development activities we refer to it as a pipeline in a product. We'll now listen to the interviews between Pravin and Dr. Schwartzberg, Dr. Roeland and Dr. Davis. Thanks very much.

So we have the pleasure now of speaking with Dr. Lee Schwartzberg. Dr. Schwartzberg received a VA in MS degrees from the State University of New York and he is MD from the New York Medical College. He finished his -- completed his residencies at the North Shore University Hospital and was the Chief President at Memorial Sloan Kettering Cancer Center as well as finished its fellowship at Memorial Cancer Center. He is 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 dialogue.

And 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 -- as we feel, we'll 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 number one 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 and them self-identified 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 a patient's 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 there 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 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. I 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 analog 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 and 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 [Audio Gap] particularly for nausea. So you go into the situation where you have this rebound anorexia 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 use in our practice, these remote apps and things like that, which are becoming more prevalent. They simply -- it's no way to monitor patients 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 at a level of 85% or greater gives you the effectiveness and it drops off after that. If you're dropping more than one out of 6 days of therapy or one-sixth 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 sigma 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 this sigma and it might be seen as shame for 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 is important. A few query cancer patients on quantity of life and if they're having to be around the 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. #1, 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 kind of 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. We 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 terms of therapy going forward. Chronic diarrhea is a very intractable problem for -- thankfully, a small but a real percentage of patients.

Thank you, Dr. Schwartzberg. Hi, Dr. Roeland today, we're going to talk to Dr. Eric Roeland. 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 its Palliative care practice includes all cancer patients. Dr. Roeland has dedicated his career to improving quality of life for cancer patients by identifying, validating and expanding pharmacologic interventions to mitigate or minimize suffering in cancer patients. Dr. Roeland Gates 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 Palliative Care residency of the Institute of Palliative 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 transit.

Yes. So diarrhea in cancer patients is actually one of the most overlooked symptoms that cancer patients experienced. 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, it's treatment. Our typical approaches to treating diarrhea associated with cancer and its treatment, primarily focused on slowing the diarrhea down to avoid dehydration and kidney impact on kidney functioning. And 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 a champion for a long time. And thank you. 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 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 habits.

Let's talk about that stigma that's associated with diarrhea in your patients and the RGI 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 a curative setting or in the noncurative 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.

Now one of the things that's shifting gears slightly 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 are 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 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 patient population that you take care of, the incidence of diarrhea is particularly high and the incidence of use of diarrhea and drugs, it's extremely high. You would say almost 80%, would that be a fair number for you?

Yes. I -- a little more 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 rectal cancer or potentially pancreatic cancer or gastric cancer, or subdue cancer, these patients are getting combined modality therapy and therefore, have even higher risk of developing diarrhea. This is 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 media, 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 the 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 support of 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 drug use for chemo induce not seen in vomiting. So that's another thing that you talked about, the mechanism of diarrhea and lack of physiological addressing of diarrhea?

So what you're describing, Pravin, is this one size fits all approach that 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 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've also talked about chronic diarrhea in patients that you actually complete a 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 trying 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, badly, patients will be cured of their connector, 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 in mind 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 it caused a big depression. So sadly, so fortunately, we were able to get him through his treatment, but the chronic side effects of diarrhea had immense impact in 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 -- it's 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 two-fold. 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 campus 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 your time today. Today, we are talking to Dr. Andrew Davies, who is the President of Multinational Association of Supportive Care in Cancer, also known as MASCC. He is the Clinical Director of Development in Palliative Medicine at St. Luke's Cancer Centre/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 the Clinical Director of the Department of Clinical -- 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. You can start with there. That would be great.

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 in terms of the burden, we see people who have relatively mild diarrhea that's an inconvenience and 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 their ability to socialize. So it is a big problem for the patients and their [career].

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 control and GI issues in cancer patients?

We see a whole range of courses. So for some people, it's related to their 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 abdominal 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 at a presentation. We see it particularly during treatment, but also amongst the cancer survivor 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, like a bowel control is 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, courses, management, there's been very little research. I mean if you compare it to chemotherapy-induced nausea and vomiting chemotherapy is peripheral neuropathy cancer pain. I mean the percentage of articles, percentage of funding is timing and the option for management are 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 diarrhea and often more severe type of diarrhea, but we're still using the same tools we used a long time ago.

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

Yes. Well, I think in most cases, the management of diarrhea and at least initially is the same irrespective to what the cause is. So it's about rehydrating the patient correction and the electrolyte disturbances that there might be. I mean in some cases, there may be sort of 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, in the United Kingdom as well as the United States and the rest of the world, are using mostly antimotility drugs, such as opioids. What is your -- what are your thoughts about the guidelines that are currently in place? Are they -- they need to be revised? Because you said they're up to 20 to 40 years old to manage the diarrhea.

Well, I think just -- there's 2 issues. One about the guidelines and one about practice. I think practice is 20, 30, 40 years old. People when they're trying to tell, if you have -- if the patient have 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. And I 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 some had radiotherapy, and it is. But they -- the guidelines tend to lump everybody together. It's diarrhea. So you manage it in exactly the same way. The thing should be true of managing diarrhea. It's not a one size fit or you need to have a better understanding of why the patients got diarrhea and try and reverse the underlying cause, the diarrhea that's 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, it's the same trend in Europe or U.K., the package insert now for new oncology agents, which have a higher incidence of diarrhea, particularly with the targeted mechanism, they only report grade 3 and higher diarrheal episodes occurring in more than 5% of the patients. That sort of minimizes and diminishes on the package insert the impact because related to diarrhea according to NCI criteria, it's more than so what we choose 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 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 and mandate treatment because of even the low grades of diarrhea potentially. So we need to find a way that patients can continue with their treatment, so they could get the best response from that treatment. If they're having the gaps between treatment cycles or they're having reduced doses, that's going to impact on their outcomes?

There is 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 -- and oncologists 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 this is an issue. And it doesn't justify to diarrhea, it justifies to lots of toxicity of treatment. There are some patients that we've looked after where the anticancer treatments have to stop because of, for instance, diarrhea to be a diarrhea. And then there have been an alternative treatment or -- so essentially, the diarrhea has resulted in the patient stopping potentially, if not curative treatment, then certainly treatments that would stabilize their disease. And so their disease progressed at a quicker rate. And so diarrheas indirectly resulted in a shorter lifespan, not because of the complications of the diarrhea, but because the treatment has been amended, and therefore, their cancers progressed more quickly than it probably would otherwise.

One of the things that we notice 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 into constipation is actually probably one of the biggest problems that I see in my practice. And usually, the opioid could be taken to manage pain. But equally, we -- as you say, we see patients who've been put on opioids to control their diarrhea or indeed other symptoms to then become constipated. And then you need to put them on laxatives, and then they restart their anticancer treatment or whatever course of diarrhea. And so you exacerbate the problem and patients go from having one set of symptoms, which are distressing to a completely different set of symptoms, which are just after stressing. So you can have -- end up with a vicious circle where you cut diarrhea and one set of symptoms, I mean you replace them with a different set of symptoms, when one week you're giving them opioids to treat diarrhea and then you've given them laxative to overcome the constipation with the opioid. So you can have a very unsatisfying situation where actually people quality advice has impaired, but by different sizes 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 hold we do, we -- I mean, we have, I think, a 25 bedded oncology award. Any one time, there's at least 2, maybe more patients in there. The primary reason for admission is diarrhea, dehydration is secondary to diarrhea. And I mean, I think the other thing is that in the outpatients, 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 in -- every few weeks a new treatment comes out. So we're seeing people that are on the third, fourth, fifth line of treatment having a diarrhea, they have diarrhea 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 if it 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 are 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 or 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 patients, it's all the supportive care.

Lisa?

So, Pravin, at this point, you want to talk about our ongoing Phase III programs in cancer therapy-related diarrhea -- remarkable to listen to those interviews, and how under recognized this problem is, and how serious it is for patient outcome as well as dignity? So can you talk about the program that we have going on with a drug that finally will be studied in the target patient population?

Thank you, Lisa, and good afternoon to everybody. So, as you heard in the interviews with those leading oncologists, there were certain themes that were emerging starting from the lack of awareness or recognition of problem of diarrhea to actually fully understanding the burden and impact of that, both on the patients' quality of life as well as the outcomes of cancer treatments. So, as Lisa mentioned in her opening remarks, that we have a drug, crofelemer, that is undergoing Phase III study for cancer therapy-related diarrhea. And we once again want to emphasize that it is still a subject of the Phase III investigation. It's not approved for the indication. But I wanted to make sure that I used a few minutes to sort of further refine the conundrum that we face and -- in patients who are going through cancer treatments, and both cancer itself and cancer treatment will result in diarrhea. And as Dr. Roeland and Dr. Schwartzberg reiterated that it is not a question of if, it's a question of when diarrhea will emerge. So, there is considerable confusion about the definition of diarrhea. So diarrhea is a clinical term that is not well understood by a layperson. So the clinical definition of diarrhea is passage for liquid stool. And even one liquid stool constitutes diarrhea. And so this here is a schematic of the gastrointestinal physiology of an adult human being. And you can see that from what we consume every day and from water we drink and all of the secretion into the intestine all the way through, on a daily basis, an adult individual will have somewhere between 8 to 10 liters of fluid in their gastrointestinal tract. This will be from all that we consume as well as 50 liters of blood constantly perfuses the intestine. Intestine is a very active organ, and they are our third line of defense after skin and lung for everything that we are exposed to. The body is very partial to reabsorbing all of the salt and electrolytes in water. So by the time, you look at a 24 hour period, and you look at the bowel movement, you see at the bottom here, that no more than 150 ml of the 8 to 10 liters is the amount of fluid lost in a formed bowel movement. The rest of it, the body preserves and keeps inside. So even another 100 ml of liquid going through will result in a liquid bowel movement, which is diarrhea. And so -- and constipation is the other way. If you reduce by 100 ml and you only pass 50 ml of liquid, constipation is passage of hard stool, which is very hard to pass and [indiscernible]. So the small intestine and sort of the large intestine play a very, very big role in both absorption and secretion of electrolytes in fluids and nutrients, and they are constantly facing impulse from various pathogens, for instance, from other challenges that we have from inflammation as well as the conditions that we might have chronically, such as inflammatory bowel disease or Crohn's disease, and all of these will produce watery stools and hence, diarrhea. So, if one looks at the definition of the National Cancer Institute, for the grades that Dr. Roeland and Dr. Schwartzberg were referring to, they mentioned that the patients that they see have either grade 3 or grade 4, grade 5 diarrhea, of course, death. So grade 2 diarrhea, as defined by the National Cancer Institute in the U.S., is increase of 4 to 6 watery stools over baseline, if a normal baseline bowel movement scheduled as 1 or 2 bowel movements a day, this is now gone to 6 to 8. And that is a considerable hardship for the patients, and this is not necessarily to force it. So if you look at the package inserts of all of these targeted therapies, immunotherapies, chemotherapy agents, they report only grade 3 and high. If you look at grade 3, that's an increase of 7 or more what we see above their normal baseline, normally requiring hospitalization, and there is a significant amount of renal failure in these patients as well. So it's quite life threatening. Grade 4 is, of course, extremely life threatening, and they have to be saved within hours. So this is where the patients, and the Dr. Davies was talking about that, the patients that they see in their ward, for every one patient they see, probably 10 or 20 more that they don't see. And so this is part of the physiology that has been a challenge for the physicians, especially oncologists to give appropriate care to their patients. So, when we look at the diarrhea incidents reported in clinical trials, which is a little bit higher always than on the [ pathogen ] side, and this is just a smattering of some of the things that are [ brought ] in the literature, we have much more broader list, but we worked very closely with the FDA, both the Division of Gastroenterology and the Division of Oncology Products to ensure that we actually outlined what we are talking about. And so you must take a targeted therapy agents such as the tyrosine kinase inhibitors, that are the first 3 drugs on this list here, and you can see the reported incidence of diarrhea and the critic on that. If you look at other targeted therapies such as anti-EGF or mTOR inhibitor or some of the CDK4/6 inhibitors, chemotherapy agents, these numbers are quite high. And while the packaging search for these agents is only reporting grade 3 or grade 4 diarrhea, when we looked at the publication, which is a few years old, or be it, it makes the point, if you look at all grade diarrhea incidents and you look at grade 3 and 4 diarrhea incidents, there is a substantial minimization of the reported incidence of patients when we just look in grade 3 and grade 4. And these patients are in dire straits and they need immediate intervention, and it is not specific related to just one drug. So somebody says, oh, that patient is getting capecitabine or 5-fluorouracil or taxol, that's when they got it. You see the targeted agents are right there. These are tyrosine kinase inhibitors in the top. And we have the FOLFOX  which is used for GI cancer. And we have Perjeta and Herceptin, which is used for breast cancer. Obviously, this is a combination that's used for metastatic HER2-positive breast cancer patients, which is pertuzumab as Perjeta, trastuzumab as Herceptin, Docetaxel as Taxotere, and Carboplatin, just given. And you can see 72% of those women have diarrhea, but on the label, it only say 12%. So this is a sort of data that we had when we took our study design, and we worked closely with both key opinion leaders as well as the agency and the division, and that's the subject of our CDD trial that's going on right now. The debate that we have to really address was some of the top points that Dr. Roeland was making and Dr. Davies was making, which is the mechanism of diarrhea if sometimes not fully understood, so you'll give an antimotility agents, such as an opioid or -- and for those of you who don't know loperamide, Imodium, it's also an opioid agonist. So it's Lomotil, Lomotil, as name suggests, is low motility, one of those agents is diphenoxylate, which is also an opioid, and the other agent in that is atropine, it's an anticholinergic drug, and so those are sort the palliated measures to slow down the gut motility. But really, the physiologic mechanism of that is described in schematic over here. If you see a healthy person's gut, and this would be a intestinal lumen on the top and this is the blood sign on the bottom, and you can see that there is movement of fluid and electrolyte back and forth into their intestinal mucosa, chloride is secreted from the valley over here, this valley is called crypt and from the crypt the chloride is pumped, which is CFTR, secretes chloride into the gut, and at the villi which is the apex is basically where the absorption of sodium occurs. So that's more dramatically shown here for the villi in an expanded view, which is apex here, and the crypt over here which is the valley, and you can see how chloride and sodium and water is constantly moving in and out. Just body is doing this constitutively CFTR, which is the cystic fibrosis transmembrane conductance regulator, CFTR channel, the same channel whose absence causes cystic fibrosis in case. It's a very, very important channel in our body. It's expressed in the gut, lung, pancreas and the kidneys. It maintains chloride, salt and water regulation. That's why cystic fibrosis gets do really well by the seashore, but they don't do so well in Arizona in the desert, because they need that salinity the air for their lungs to actually have some level of salt and water. So same applies to our gut. And so when you have diarrhea, there's increased secretion of chloride from this trip cell, and when that CFTR is hyperregulated, if you're watching my hands, this is a normal gating function. It's almost like you go to an aquarium and you see fish gill movement, it doesn't -- making very constant. That's how our CFTR channels are operating. But if you tap on the glass door of the aquarium, the fish gets sensitized and they start doing this, their gills start moving faster. This is exactly what happens with the crypt here and the CFTR channel. When it moves at that hyper frequency, more chloride gets secreted. Chloride is there in the lumen, sodium is already there coming in, sodium and chloride, they love each other. And for all of you know this from high school chemistry, sodium chloride is salt. And what to salt love more than anything? Water. So now you are driving the sodium chloride and salt is driving water, and that's how you get a liquid stool. And that causes dehydration. And that's when you get into renal failure and on the cardiovascular sequelae that Dr. Schwartzberg was talking about. So the advantage of crofelemer was, and if the Amazonian God designed it, it is not human designed, it comes from the rainforest, is that it regulates this very hypersecretory function of the CFTR channel to bring it back to a normal rhythm -- sorry, bright it back. And it corrects it, but it does not shut it down, because we can't shut down the CFTR channel. So, this is the physiological mechanism of crofelemer, which is unique. It's the first antidiarrheal drug that's been studied for chronic diarrhea, chronic diarrhea cause in HIV patients and long-term survivors. So in many ways, they're similar to the cancer survivors that Dr. Roeland and Dr. Schwartzberg were talking about. And so we are actually studying that in these patients who were receiving targeted therapy with or without standard chemotherapy agents. And we are doing it simultaneously with the agent because as Dr. Schwartzberg pointed out, with targeted therapy, they know it's going to happen, but they don't know when it's going to happen. The right way -- the timing could be 1 week, 2 weeks. So that's why we've started this as a prophylaxis trial. So our ongoing trial, on target trial, which is a Phase III study, that's ongoing right now, that Lisa alluded to, is recruiting patients that are on targeted therapy, and we are treating them under background of all their other medications. Crofelemer has this unique pharmacological profile. It has no significant food or drug interactions. It's taken twice a day with or without food. So it is really not a hardship for the patient to take. So that trial is ongoing, and that's sort of the background of what we are studying. And hope this webinar was useful for all of you, and I'll turn it over to you, Lisa.

Thanks, Pravin. And thanks, Destiny, I'll let you do this. And now we all know why a patient in The Velveteen Rabbit went to the seaside. So thank you for that as well. This is a really important day. I do want in to focus on cancer therapy-related diarrhea. We do refer to crofelemer as a pipeline in a product. So in addition to cancer therapy-related diarrhea, we have many follow-on indications: irritable bowel syndrome, for which we have published Phase II study; idiopathic functional diarrhea is a subject of an investigator study right now; inflammatory diarrhea; we do have orphan drug designation for crofelemer for short bowel syndrome and are also with intestinal failure and also working on a subset of intestinal failure in a pediatric congenital diarrheal disease. We can't do everything yet. We'll get to all the other indications so that we have 3 we are focused on in clinical development programs right now. And, Destiny, if you go to the next slide, please, the last one, we'll wrap this up. Cancer therapy-related diarrhea in the Phase III program that Pravin just spoke about and designed and worked with the FDA on. And this will conclude patient enrollment that's targeted for the end of 2022. The short bowel syndrome, the rare disease with intestinal failure as well as congenital diarrheal disease is a highly concentrated liquid formulation. So it's different formulation than the [ full ] formulation that we have, which is appropriate to go into feeding tubes and for pediatric populations, that is being pursued as the first indication under license to Napo EU, that is their intention. And that data as part of a license agreement gets shared with the parent organization, so we can use it to pursue the approval process in the United States. And then we have a second-generation anti-secretory that comes from the same plant as crofelemer that has the same mechanism of action. And that is in a program for color, where we also have publication, successful publications for the anti-secretory mechanism of action. Each one of those is paired with financing that is nondilutive. Either a royalty deal from the sales we currently have for the HIV indication or the license arrangement that we have with Napo EU, the European subsidiary, or the financial incentive of a priority review voucher program from the FDA. In the very near term, between now and the end of the next -- end of the year, and what do we think is the value drivers, first, we -- the confirmation of the funding, which is of Napo EU, which is coming from a merger with Dragon SPAC, this is all occurring in Italy. Napo EU is incorporated in Italy. Dragon SPAC is incorporated in Italy. It is -- the merger is literally going through the administrative functions in Italy right now, which were closed down because it always pretty much closes down in August. And when we said it publicly, we expect this to be consummated closed by the first or second week in October, administrative issues, not risk-based issues, and that then will trigger the license agreement, which has upfront payments and traditional license fees to the parent organization and also then the pursuit of their first target indications for bowel syndrome with intestinal failure. Part of the reason why it's the priority in Europe is because as an orphan indication, it would qualify for accelerated potential conditional approval, so faster ability to get into patients in need. We also announced, I think, just last week that we have acceptance from the Center of Veterinary Medicine of the FDA for the final technical piece of crofelemer for the dogs, Canalevia, which is where chemotherapy-induced diarrhea, which is under MUMS. MUMS is like an orphan drug designation for animals. And that is a process, the new animal drug application is a bit different than how human new drug application is filed. So we will be now with the acceptance of 4 technical pieces. We file the new animal drug application. And then it's a 2 months, for the most part, administrative process to launch the product. So we're targeting the launch of Canalevia, our first subscription product in the animal health area, in December of this year. And also in December, there was an investigator-initiated trial -- you could go back one slide, Destiny. There was an investigator-initiated trial that was done by Georgetown University with breast cancer patients on Herceptin with diarrhea. That study is over, and those results were submitted by the academic investigators to the very prestigious San Antonio Breast Cancer Conference. So that data, therefore, will be released at the conference in December. So December will be some important events associated with cancer. On the human side and the animal side, Canalevia, is developed in animals, but dogs, I must say, are very predictive model of the mechanism by which crofelemer works for the human situation as well. And just to say one of the things about dogs, we don't put out guidance at this point for any of our drugs. HIV is a specialty market opportunity. In dogs, as we're learning about this market, thanks to the pandemic, there's a -- Destiny go forward probably 2 slides, there's about 100 million dogs in the United States right now and -- if you flip through there, you'll get to the 3 points, about 25% are going to have a tumor at some point. In any given year, 350,000 up to 0.5 million will be dealing with cancer. So the dog owner is choosing to typically pay out of pocket, $5,000, $10,000, $15,000 to treat their dog. And just like humans, about 40-plus percent of the time, the dog will have to take a drug holiday or go on a SEF therapy dose of their life-saving therapy because of diarrhea. So how much would the parents -- the dog parents want to provide to make sure that the dog can stay, in fact, on the cancer therapy has some comfort. That's what it's all about. That's why you're treating all in the first place and also comfort to the whole family and the whole household, so dog doesn't lose control and you have a soiling at the carpet, at the bed, at the couch that's not comfortable for anybody. So this is a small part of our business, but we're very excited about it, and it sort of fills the gap and gives us some more revenue opportunity and benefit opportunity for patients as we're completing the cancer therapy-related diarrhea program. So, I will conclude my statements. With that, I'll turn it back to Ladenburg. Thank you very much for hosting this forum for something that I think we can all agree is really important and underrecognized.

And, Lisa, there is one question there.

Lisa and Pravin, thank you very much. I do have one question. Just need to not repeat. You talked about with the trial and the patient selection, are you taking patients that are both grade 2 and grade 3, or just 1 or the other?

We're taking everybody above grade 2, Jeff, in our trial. They have to be solid tumors and have to be receiving a targeted therapy. It's grade 2 and higher.

There was one question on the board about best foods to consume for folks to combat diarrhea in a general sense?

So Dr. Schwartzberg referred to something called the BRAT diet. So BRAT stands for bananas, rice, applesauce, and toast, that's what BRAT stands for. So when you have diarrhea, the main thing that physicians worry about is the cause of diarrhea. So there's an infectious cause, for instance, if there's an infection, they would need to do a stool culture and the BRAT won't work for that. But Lisa referred to something called Montezuma's Revenge, if you've had bad Mexican food, that one, you can actually combat with bananas, rice, applesauce and toast and some electrolytes. You can just buy electrolytes at the pharmacy and just replenish it.

Sometimes the T in BRAT is tea as well.

Yes, toast point, yes, I'm trying to get there, some nutrition.

We actually also have some questions coming via e-mail. So I'll just go through those quickly. One individual is asking about the formulation in CTD. Is that different from any of your other indications or any of your other potential studies or applications?

Pravin?

For CTD, we are using the same formulation that is approved for HIV. So it's preferred 125 milligrams delayed release tablets, the same that's approved for HIV. But for other indications, we will make different formulations. Those efforts are ongoing.

It's an obvious comment to that, therefore, the manufacturing the CMC section is already approved, since that's the product that we are in supply.

For CTD.

Yes.

Got it. And why does quality of life seem to fall so low on the list of priorities in these patients? I'm kind of surprised that, that's not at least top 5. Do you have any insight into that? Any opinion?

Yes, Pravin.

So, it's a loaded question, Destiny. And it's very well intentioned. I think what happens is when you have a terminal diagnosis, sort of mindset of the care provider -- the health care provider, is to really attack the problem. And sometimes they forget that there is a human being at the end of that problem. And so -- and because we are such an specialized care in the United States and oncologists only treat when you have cancer, and a gastroenterologist only comes into play when somebody is invited to consult on a gastrointestinal issue, so what happens is if you can visualize the cancer patients having an oncologist see their orchestra conductor, and unless he beckons to the drama to play the drums, there will be no drums playing. And so quality of life flows in the spectrum of the holistic treatment plan that Dr. Davies was referring to, we do have to -- do all of that. And that, unfortunately, is not something that is tractive so well in the United States. So it falls low on the total poll. The FDA is very aware of that. The patients' advocacy groups have done a really good job, especially breast cancer patients' advocacy groups. They get full marks on this. They've been barking about this for some time. So now the patients reported outcomes, as they call them, the PRO measures, are becoming a part of the evaluation. Unfortunately, because it's a subjective assessment, it's not an objective endpoint. The FDA, just so everybody knows on this call, approves a label and not a drug. So for the label, they need an objective endpoint. So quality of life becomes a soft endpoint. And so they can't approve it on the label, Destiny, that's why it falls low. Does that answer the question?

It definitely does. Thank you. And then going back to the commentary about the one of the KOLs made, do you think that improving the guidelines around, particularly diarrhea is going to actually cut application in practice? Or what you think it's going to take, what kind of efforts will it take to get that more integrated into the care that they give?

So, it's a very good question again. So we absolutely have that as one of our missions, and we are attacking it in with a 2-pronged strategy. So one is with the KOLs and with the Multinational Association for Supportive Cancer Care, in which Dr. Davies is a chair right now this year for that. We are trying to at least develop some guidelines. Those guidelines then need to be socialized, and we can't be privy to the socialization of that, because we are a sponsor. So it has to be done by academics, to the NCCN, which is the National Cancer Guideline -- which is the national cancer treatment guidelines. And so we are definitely interested in supporting that. So we're doing that. And then on the other side, from our commercial end, we're also going to have a disease awareness situation where we would have our medical science liaisons and some of these conferences to start to highlight the points that Dr. Davies, Dr. Roeland and Dr. Schwartzberg were making. So then the practitioner start to understand and have an awareness of how deep this problem is. Something that Dr. Davies said is actually staggering for every one patient he sees, he think there are 10 that are in the same boat, and there are 20, 30, who are not even telling. And so that's a substantially big problem. And so we want to build that disease awareness as well. So we're taking a 2-pronged strategy on this.

If I could just add a comment to that question, the previous one, Destiny, getting it into the guidelines and why is supportive care wise patient dignity quality of life not more elevated, if you look at it with chemotherapy-induced nausea and vomiting, it is fairly well recognized and elevated. And I think part of the issue with diarrhea is because you don't have agents that are specifically tested in cancer patients and specifically approved. So just the process of getting crofelemer developed will hopefully foster that attention and awareness and education.

No other questions on this end. Jeff, I'll let you wrap up.

Thank you, Destiny. And again, Lisa, thank you very much. And Pravin, thank you very much. That was exceptional. And please send our thank you to all 3 speakers, Dr. Schwartzberg, Dr. Roeland, and Dr. Davies, that was tremendously insightful. We look forward to hearing of your many future successes with regard to some of the clinical work and the [ spec ]. So with that, we'll call it a day. And thank you again, everyone, for joining us.

Thanks a lot.