Before I turn the call over to management, I'd like to remind you that management may make forward-looking statements relating to such matters as continued growth prospects for the company, uncertainties regarding market acceptance of products, the impact of competitive products and pricing, industry trends and product initiatives, including products in the development stage which may not achieve specific objectives or meet stringent regulatory requirements. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those contemplated in such forward-looking statements. These statements are based on currently available information and management's current assumptions, expectations and projections about future events. While management believes its assumptions, expectations and projections are reasonable in view of currently available information, you are cautioned not to place undue reliance on these forward-looking statements. The company's actual results may differ materially from those discussed during this webcast for a variety of reasons, including those described in the forward-looking statements and risk factors sections of the company's Form 10-K for the year 2021, which was filed March 11th, 2022, and its other filings with the SEC, which are available on the investor relations section of Jaguar Health's website. Except as required by law, Jaguar Health undertakes no obligation to update or revise any forward-looking statements contained in this presentation to reflect new information, future events, or otherwise. Today's conference is being recorded. At this time, it's my pleasure to turn the call over to Lisa Conte, Jaguar Health's Founder, President and Chief Executive Officer. Lisa, the floor is yours. Thank you, and thank you, everyone, for joining this morning. Happy New Year to everyone. As you just heard, my name is Lisa Conte and I am the founder, president, and CEO of Jaguar Health and our wholly owned subsidiary in the United States, Napo Pharmaceuticals. Sometimes we use Napo and Jaguar interchangeably. We scheduled today's call to provide updates regarding two company activities. First, to again put a focus on what we feel is a value transformative event for Jaguar Health. Our ongoing pivotal phase III trial with crofelemer for cancer therapy-related diarrhea, which is being conducted with the same dose and formulation of our commercialized Mytesi, being commercialized now for the specialty market of HIV-related diarrhea, and is a study that aims to extend this indication to the potential blockbuster needs in patients with cancer therapy-related diarrhea. This trial is expected to complete enrollment in the second quarter of 2023. Just around the corner, and we do feel, as I said, that this will be transformative for value and value recognition. We will shortly, very shortly play the highlights of a commentary from Dr. Lee Schwartzberg on the unmet medical need of cancer therapy-related diarrhea for a focused and paradigm shifting biological approach for the management of this problem. Dr. Schwartzberg is a leading breast cancer medical oncologist and hematologist who serves as the Chief of Medical Oncology and Hematology at the Renown Health William N. Pennington Cancer Institute, which is in Reno, Nevada. The commentary by Dr. Schwartzberg was recorded during the symposium on November 18th, 2022, titled Management of Cancer Therapy-Related Diarrhea. Is It Time for a Paradigm Shift? The symposium was attended by clinical investigators located within and outside the United States who are participating in our phase III trial, which is referred to as the OnTarget clinical trial of crofelemer. When I say cancer therapy-related diarrhea, let me shorten it. Let me say CTD. The ongoing trial for CTD. The symposium featured presentations by various oncology and infectious disease experts who discussed the impact of CTD, as well as the unmet medical need of managing CTD based on current guidelines. There's over a million cancer patients per year in the United States who enter treatment for targeted therapies in the United States, with treatment lasting for months to years in both the curative and metastatic situations. The chronic safety and efficacy of crofelemer provides an opportunity for a paradigm shift versus the stopping and the blocking band-aid approach with opioids, which includes Lomotil and loperamide. These are weak opioids that are utilized in an acute situation. These targeted therapies, of which there's about 70 now, which are used on a chronic basis, over 50% have been approved just in the last five years, work for the most part by a mechanism that induces the type of chloride ion secretion that crofelemer normalizes. Most of us have had someone close in our life touched by cancer, and I will relay a personal anecdote of a dear friend of mine going through breast cancer treatment right now with two targeted therapies, one of which is a high offender of diarrhea. When the diarrhea and all of her supportive care symptoms were well managed, both she and her healthcare team were completely focused, as they should be, on the treatment plan and the outcome of her cancer therapy. When her symptoms were not well managed, the focus on the patient and the healthcare team was all about symptom relief. What did she have to do to get through the next day? Quite honestly, at the cost of suboptimal cancer treatment going off, reducing, changing cancer treatment, which happens about 40% of the time when diarrhea is not well managed. The short video speaks for itself from the leading oncologist and visionary patient advocate. After this, I am so pleased to have with us for a live presentation and discussion, Dr. Wade Davis, he will be introduced by his longtime colleague, collaborator and friend, our own Chief of Ethnobotany, Sustainable Supply and IP, Dr. Steven King. I won't steal the tremendous thunder of Wade's introduction by Steve, though I will take the opportunity after this video plays to sincerely brag on Steve. Let's go to the video now. Peter. That was terrific. Okay. We'll have time for any questions about crofelemer or the video clip at the end of today's webcast. Now I'd like to move to our live event focused on our Entheogen Therapeutics Initiative and introduce first Dr. Steven King. Steve and I have worked together since the founding of Jaguar's predecessor company 33 years ago. Steve is a passionate scientist and botanist working in the field of medicinal ethnobotany. When I say field, I mean not only the specific scientific discipline of ethnobotany, I also mean living in the Amazon jungle for extended periods of time, and not for the purpose of earning creds, which it does. Because Steve and his esteemed colleagues, such as Dr. Davis, have this passion for the culture, spirit, and learnings that come from immersing themselves in indigenous lives and cultures, that's why they're there living in the Amazon. It's not a drop-in visit. These explorers are the real deal, and thanks to their study of and deep respect for indigenous ways, we have an opportunity to leverage thousands of years of knowledge about medicinal plants that have the potential to address unmet medical needs we're facing in today's westernized world, and thus full circle, bring value and recognition to the originators of this indigenous intellectual contribution to humanity. Steven King is the force that brought together our scientific strategy team of the small cadre of leading medicinal tropical plant scientists, which led not only to the successful identification and development of crofelemer, but also to a library of over 2,300 plants and 3,500 plant extracts, most from first-hand field expeditions and experience from scientific strategy team members that reside in the Jaguar library. This Jaguar effort is termed internally the Entheogen Therapeutics Initiative, and you may have seen earlier this week this effort is part of a joint venture with Filament Health, funded by the visionary Will Peterffy through his venture fund, One Small Planet. The joint venture is named Magdalena Biosciences. The joint venture is named after a river, Magdalena, that has great cultural significance to indigenous peoples. The Magdalena is the great arterial river of Colombia, flowing northward from its headwaters in the south of Colombia, more than 900 miles to the Caribbean Sea, and is the title of one of Wade's many books, a captivating story that follows the passages of life through the rich past, present, and future of the Magdalena River. I highly recommend it. Entheogen, by the way, refers to substances from plants that affect the central nervous system, consciousness, spiritual intervention. In this specific scientific pursuit at the joint venture, seeking new ways of treating and potentially curing mental health and mood disorders. Steve, I will now hand the conversation over to you. Well, thank you very much, Lisa, for that, those kind words. We are indeed delighted to introduce Dr. Wade Davis and other highly distinguished scientists that serve on the scientific strategy team for Jaguar's Entheogen Therapeutics Initiative. An initiative, as Lisa mentioned, devoted to discovering novel, naturally derived therapies from plants. We are absolutely thrilled to have my friend Dr. Davis on our webcast today to speak about the history and uses of psychoactive plants in traditional medicine throughout the New World, and the possible potential of discovering new therapeutic agents from such plants to treat unmet medical mental health needs. Dr. Davis is an ethnobotanist, anthropologist, best-selling author, photographer, filmmaker, and former National Geographic Explorer-in-Residence, whose work has taken him from the Amazon to Tibet, from Africa to Australia, and from Polynesia to the Arctic. Named by the National Geographic Society as one of the explorers for the millennium, he has been described as a rare combination of scientist, scholar, poet, and passionate defender of all life's diversity. Trained and mentored in part by the late Dr. Richard Evans Schultes, who's often called the father of ethnobotany, Dr. Davis is currently the professor of anthropology and the leadership chair in cultures and ecosystems at risk at the University of British Columbia. Mostly through the Harvard Botanical Museum, he spent over three years in the Amazon and Andes as a plant explorer, living among 15 indigenous groups in eight Latin American nations while making some 6,000 botanical collections. Author of 22 books, including One River, The Wayfinders, Into the Silence, winner of the 2012 Samuel Johnson Prize, the top nonfiction prize in the English language. He holds degrees in anthropology and biology and received his PhD in ethnobotany, all from Harvard. His many film credits include Light at the Edge of the World, a documentary series written and produced for the National Geographic Society. One of 20 honorary members of The Explorers Club, Dr. Davis is a recipient of 11 honorary degrees, as well as the 2009 medal from The Royal Canadian Geographical Society, the 2011 Explorers Medal, the 2012 David Fairchild Medal for Botanical Exploration, the 2015 Harvard Centennial Medal, the 2017 Roy Chapman Andrews Society Distinguished Explorer Award, the 2017 Sir Christopher Ondaatje Medal for Exploration, and the 2018 Mungo Park Medal from the Royal Scottish Geographical Society. In 2016, he was made a member of the Order of Canada, and in 2018, something of which I know he is extremely proud, he became an honorary citizen of the country of Colombia. It is my honor and great pleasure to introduce you to Dr. Wade Davis. I will now hand the discussion over to Wade. Wow. Thank you, Steve, for that fulsome introduction. Thank you, Lisa, for having me with you this morning. It's just a joy to be with you. I thought I'd begin just by addressing directly an issue that can be of some concern in this entire revitalization, this renaissance of exciting rediscovery of these powerful and potent plants. I mean, there is a sort of clash between the ongoing federal prohibition and municipalities and states who are actually moving very quickly toward legalization for clinical use of these substances. With all the investment that has gone into this space, if it was $100 million a year for several years, now it's $800 million in a single year. There's that obvious question, will there be some kind of backlash? I think the answer is absolutely no. I think people have come to see that the war on drugs has been an abject failure. After 50 years, $1 trillion having been spent, an annual budget of $60 billion or more. There are more people in more places using worse drugs than ever before. The fentanyl crisis is a poignant, is an obvious example. There, there's a kind of a sense that the war on drugs is being engaged by two entities that alone in the world want it to continue. The obviously the DEA that would face unemployment if the war on drugs ended, and of course, the cartels would see their profits drop. Everywhere that substances have been legalized, we've seen that consumption has gone down, which has drawn people's attention to the fact that the fuel that fires this sordid trade is money as much as drugs. So I think there's also a generational thing going on. I mean, it's not a coincidence, I suppose, that in Canada we've legalized cannabis under the leadership of a prime minister who in his youth was famously a pothead at Whistler, the ski mountain. You know, part of this is generally a generational thing, and I think we're moving in a very positive direction. Part of that is a recognition that when we prohibited the clinical experimentation and the research into these substances, 60 years ago, we lost 60 years of potential research. When we look back, more and more of us see that these substances played a kind of critical role in the social transformation of our society. You know, it's interesting, in my lifetime, our lifetimes, women have gone from the kitchen to the boardroom, people of color from the woodshed to the White House, gay men and women from the closet to the altar. When I was young, just getting people to stop throwing garbage out of a car window was an environmental victory. Nobody spoke of the biosphere or biodiversity. Now these terms are familiar to schoolchildren. Yet when we try to account for those astonishing social movements, those transformations, there's always sort of one ingredient in the recipe of that transformation that seems to get expunged from the record, and that is the fact that millions and millions of young men and women took these substances and had revelatory experiences. I can say quite honestly that I don't think that I would think the way I think or write the way I write or understand culture and nature as I do had I not experimented with these powerful substances. I think we can all remember, those of us of a certain age, how concerned our parents were, and they would warn us that if we took these hallucinogens, we'd never come back the same. Of course, our poor and suffering parents didn't understand that not coming back the same was the entire point of the exercise. This is not to suggest these substances are panaceas. They're powerful and potent, and sometimes not for the faint-hearted and not for every individual at every moment in time. At the same time, they can be catalysts in a very positive sense to open our eyes to new possibilities of healing, of illumination, of insight. Before I talk about where I think these substances can be particularly useful in clinical practice, step back to reflect on how extraordinary these substances are, how rare they are, and how they were, for the most part, the gifts of indigenous people who came to understand the natural world as true natural philosophers. If you think about it, on Earth, there are about 400,000 vascular plants, capturing the light of the sun. Of these, only a few thousand provide us with all the food we have and all of our medicines. Only 100, perhaps 120, have the capacity to transport the mind and spirit to these distant realms of ethereal wonder. They've often been called the hallucinogens or psychedelics. Both terms are misleading. As Lisa said, entheogens is the preferred term, meaning revealing the god within. Because that, in fact, is the subjective effect, the sensation of taking these plants in ritual context. Effects so unearthly, visions so startling, that they acquired a sacred place in indigenous cultures throughout the world, and in some cases, they were worshiped as gods incarnate. They have a deep, deep history. The Rig Veda, for example, makes reference to a magical intoxicant, soma, which may date back 4,000 years. We think it's the mushroom and Amanita muscaria. In the New World, the prototypic civilization of the Andes, Chavin, dated to 2,500 years before the Christian era. You see at the type site, iconographic representation of a werejaguar clinging to the stalk of a columnar cactus, which indisputably is Echinopsis pachanoi, the legendary cactus of the four winds, a mescaline-containing plant found throughout the northern Andes. The pharmacological activity of these entheogens arises from a relatively small number of chemical compounds, really in two major categories: the phenethylamines, mescaline, and MDMA, and the indole alkaloids, the tryptamines, LSD. These substances can be found in all parts of plants from the flowers to the roots, seeds to the bark, and they can be smoked or snuffed or swallowed fresh or dried, drunk in decoctions, infusions, absorbed directly through the skin, or even placed in wounds or administered as enemas. Curiously, in the global distribution of these powerful plants, there is a remarkable anomaly that, on the one hand, suggests the role the plants play in traditional societies. There's no precise number known. Some hallucinogens can simply be toxic plants that induce reactions. Generally, we feel that there are about 120 known hallucinogenic plants, and of these, fully 100 or more are native to the Americas, and the rest of the world has contributed fewer than 20. This isn't because the forests of Equatorial West Africa or Southeast Asia are depauperate or that people haven't explored those areas for biodynamic substances. It may be in part because people in Africa, for example, have discovered other avenues to the divine spirit possession, for example. It may also be, and this is what interests us at the scientific strategy team of our Entheogen Therapeutics Initiative, is that it may well be an artifact of the concentration of research in the hands of the acolytes of Richard Evans Schultes. Most of the work on hallucinogens in the twentieth century was done by either Schultes and a small cadre of scholars who gathered around him, Gordon Wasson, Weston La Barre, Johannes Wilbert, and others, Peter Furst, and all his students, Andrew Weil, Tim Plowman, myself, Mark Plotkin, et cetera. This may be simply an artifact of the concentration of scientific research. The one thing we do know from that research is that the shaman and the indigenous curanderos who have applied the genius that we all share as human beings to an understanding of a force upon which their lives depends is nothing short of genius. They don't simply assay the flora for plants of interest, of pharmacological potential, of utility. They manipulate those plants with a level of wizardry that is simply dazzling. The great example of that, of course, is ayahuasca, the vision vine, known as yagé in Colombia, the vine of the soul. The most sort of potent preparation of the shaman's repertoire. What makes ayahuasca so interesting is it's not a plant, but a preparation. It's made from a woody liana in the genus Banisteriopsis caapi in the family Malpighiaceae. That plant is full of beta-carbolines that have a mild psychoactive effect. To that plant, they add in the preparation the leaves of a nondescript shrub, Psychotria viridis, leaves which are packed with powerful tryptamines. Tryptamines are orally inactive. That's why you see, for example, the Yanomami in the upper reaches of the Orinoco using these snuffs through the nose because the tryptamines are not active if taken orally. They are denatured by an enzyme found in the human stomach, monoamine oxidase. To make those powerful tryptamines active, you have to denature the enzyme in the human stomach. As it turns out, the beta-carbolines, harmine and harmaline in the woody liana are MAO inhibitors of precise sort necessary to potentiate the tryptamines. The fascinating thing here is the genesis of this knowledge. How in a flora of 80,000, perhaps 100,000 species of vascular plants, did the indigenous people discover the means to combine these morphologically distinct denizens of the rainforest in this powerful synergistic effect, a way to create a kind of biochemical version of the whole being greater than the sum of the parts? The only scientific explanation is trial and error, which is quickly, statistically unveiled to be a meaningless euphemism. Famously, when Professor Schultes was with the Siona-Secoya in 1941, he identified 17 different varieties of the woody liana, all of which were recognized by the indigenous people consistently at great distances in the forest, but all of which were referable to his Harvard-trained taxonomic eye as being one species. When he asked them as to the nature of their classification, they looked at him as if he were a fool because surely any botanist would know that the answer was simple. You took each of the 17 varieties on the night of a full moon, and each variety sang to you in a different key. That was not gonna get you a PhD in plant systematics at Harvard or Princeton, but it was certainly, as Schultes wrote, more interesting than counting flower parts. It also spoke to a level of knowledge that left him simply prostrate as if before the gates of awe. He realized that his mission was not simply to identify, or collect these rare plants. It was to understand a different vision of life itself, and that brought him into the realm of the shaman, and that is our transition to the potential use of these substances in contemporary life. You know, the shaman's both priest and physician. At times, he acts like a nuclear engineer who must, you know, invoke some technique of ecstasy to enter the very heart of the reactor to reprogram the world. Above all, he is the guide. One of the things we learn from indigenous people, and the answer to the question as to why they have used these substances for thousands of years with no difficulties and no societal impacts in the negative, and why we remain tormented by drug problems that simply don't go away, we can look to the shaman. What we see is that they recognize that the use of these substances is a reasonable thing to do if done carefully. They recognize that the powerful effects of these substances can be overwhelming, and so they consistently mediate those effects by enveloping the patient in a protective cloak of ritual. At the same time, they use these plants in natural forms, which is generally pharmacologically safer. It's kind of an axiom of pharmacology that the purer the drug, the greater the potential for abuse. Above all, the experience is engaged for explicitly positive reasons. The individual is not taking a drug in a state of alienation, depression, or fury, but rather for purposeful reasons to contribute to his own well-being and the well-being of the community. Every time the people gather to take ayahuasca, it becomes like a collective prayer for their cultural and spiritual survival. This kind of role of the shaman, and again, when we think of the shaman, shamanic medicine is based on a very different sense of the nature of illness and well-being, whereby disease is not defined by the presence of pathogens, but rather a state of imbalance that must be addressed. Health is seen as something whole, healthy, hale, words that have the same Anglo-Saxon root, meaning oneness and completeness. The role of the shaman is to restore the equilibrium of the individual, and I think that's the key to understanding how these substances can be used. These substances have an absolutely ambivalent potential for good or evil. They create a template upon which powerful cultural forces go to work. The use of these substances allows for the almost immediate transformation of awareness. This is the essence of their power and authority. How can we begin to think of how we could employ these substances? There's been a lot of rhetoric, a lot of talk, some of it perhaps exaggerated, but there are certain key things that these substances can do, and again, not perhaps for those suffering truly serious psychiatric challenges from schizophrenia to manic depression. These are major afflictions that must be treated with enormous care. What most people suffer from are more neurotic afflictions, a kind of existential malaise, and here, these substances can be extraordinarily useful. There's no question whatsoever, for example, that MDMA can be extraordinarily effective in treating post-traumatic stress or for couples therapy, or for just allowing people a kind of instantaneous reset of their thinking and point of view. Secondly, these substances without doubt can help us deal with our greatest fear, the fear that we always pretend does not linger, and that is the fear of death itself. I'm convinced that for the terminally ill, the use of certain tryptamines, for example, psilocybin, can be extraordinarily helpful, not in eliminating the fear of death, but perhaps making it more acceptable, more understandable, and surely this could be an extraordinary gesture of compassion. I think also there's a third category that we also don't think about when we talk about the need for healing, and that is our relationship with the natural world itself. I think we all know that we simply must change the way, the fundamental way in which we inhabit this planet. I think from indigenous people who base their relationships with nature, not on extraction, but on reciprocity, there is in fact much to learn. One of the most powerful objective experiences that virtually anyone who ingests, for example, San Pedro cactus, comes away with. is an extraordinarily new appreciation of the miracle of life itself, the miracle of biological dynamics, the extraordinary miracle of photosynthesis itself that allows us to live on this planet. If we add that to the mix of the range of therapeutic healing that we all seek to make ourselves healthier, more content, more productive, and the society itself more sane, if you will, I think these substances can be extraordinarily valuable. Just to pivot for a few moments to kind of put this all in perspective, to emphasize, in a sense, how blind we have been to the potential of these sacred plants, let's just consider for a moment, coca and cocaine. Of course, coca is to cocaine what potatoes are to vodka. Cocaine extracted from the plant in 1859, a pure cocaine hydrochloride salt, a powerful drug of obvious abuse potential, in contrast to coca leaves used for at least 5,000, if not 8,000 years by all the pre-Columbian civilizations of the Andes. A plant that has shown no evidence of toxicity, let alone addiction, over all of those millennia. In fact, coca has been so misunderstood. Efforts to eradicate coca fields, in fact, began 50 years before there was a cocaine problem. What happened is physicians in Lima, who's concerned for the well-being of Andean indigenous people, looked up into the Andes, their concern was matched in its intensity only by their ignorance of indigenous life. They looked, they saw social pathologies, illiteracy, poor nutrition, poverty, etc., they had to find a cause. Because issues of economics and land distribution and inequity challenged too close to the foundations of their comfortable lives in Lima, they settled on coca as a source of all Andean ills. For 50 years, they called for its eradication without once pausing to do the obvious, a nutritional study that would have revealed just what coca contained. A plant that, after all, was used every day by millions of their own compatriots. When that study was first done in the 1970s by Tim Plowman, Andrew Weil, and Jim Duke of USDA and the Botanical Museum at Harvard, what we discovered horrified our backers of the U.S. government because it turned out coca, yes, it had a small amount of alkaloid, no greater concentration than the caffeine in the coffee bean. Everybody knows if you extracted caffeine and injected it, you'd have a drug abuse problem. That's not a rationale for prohibiting the use of tea or coffee. In addition to the small amount of alkaloid that was used as a benign stimulant absorbed gently through the mucous membrane of the mouth, coca was full of vitamins, full of nutrients. It had more calcium than any plant ever studied, which was ideal for a traditional Andean diet that lacked a dairy product. It even had enzymes which enhanced the body's ability to digest carbohydrates at high elevation, which made it perfect for the tuber-based diet of the Andes. In one simple scientific assay that could have been performed at any time during the sordid history of prohibition, these scientists revealed that coca had been used for all those years benignly as the sacred plant in the Andes, as the Incas called it, the divine leaf of immortality. Coca became blackened in its reputation simply because opium was the source of morphine. Opium was such a problem that therefore coca must be equivalent to opium, as coca was a source of cocaine. Rather, stretched logic, which was simply not true. There is an enormous movement now in Colombia, where the people across the political spectrum are sick and tired of their gift to the world being denied. These are people who are the victims of a real war, a war that would not have lasted a year had it not been for the sordid profits of the illicit trade. Here's a country that has seen 400,000 people die, seven million internally displaced, five million people forced to flee. Most Colombians have never seen or certainly used cocaine, yet they have been victims of a sordid trade, of which the driving factor, of course, has been consumption. In Colombia, there is a tremendous move to decouple coca from cocaine and present it to the world as the gift that it is, in fact. This is the low-hanging fruit, I believe, in this entire discussion of plants of South American origins in particular. You know, coca is difficult to describe. Its effects are so subtle. Throughout the 19th century, when coca was being heralded by physicians across the world, one of the consistent reports was the subtlety of its action, a stimulant that was not a stimulant. That's made it perfect for today's economy. It is not only better for the body than coffee or tea or any of the plant stimulants we use, it is a much more effective stimulant in terms of its action. Who would not want, for example, given that we all suffer from these mild kind of existential malaise as we get up in the morning and have to get to work, who wouldn't like to have a little bit of a step, a lift to our step? Who wouldn't like to be able to discover that they can focus at their task, looking at that laptop for eight hours at a time, with a little bit of a kind of a sense of well-being that lifts one over the inertia that keeps you from writing that first line of that memo? After eight hours of incredible productivity, you can simply go home and go for a walk, have your dinner, go to sleep, and start all over the next day. coca has the potential, literally, because of its attributes and the way it works and its efficacy, to displace coffee if given a chance to enter the global market. That would have tremendous benefits for Colombia in particular. It would give a legal market to the 150,000 families who depend on coca for their survival. It would give Colombia the tax revenue to pay for the cost of peace, having exhausted its treasury, paying for the cost of a war that was not of its making. It would give Colombia a chance to finally share with the world a product that the world will embrace with extraordinary delight and goodwill. A product that will do such good things for people because it is so beneficial, so much potential, and has literally zero negative consequences. This is just a way of beginning to think of how this whole space of these sacred plants can be with collaboration that Steven King has really been a pioneer in terms of intellectual property and equity and justice. Bringing the gifts to the table of the world. In doing so, contributing to our collective well-being. Wow. Wade, that is absolutely fantastic. We are delighted, grateful to have that overview. It's so succinct, sort of, so much there. It's astonishing. Lisa, should I be Get back to you now? Yeah. Again, thank you, Wade. I've listened to you speak dozens of times, and I learn something new every time, even in the field that I work in. I did want to say, you know, First of all, the number of times I have been asked How do the shamans, how is that information about how these plants could work and what they could do known? I think from now on, I'm just gonna send them to your talk because my answer, I'm saying to you, it comes out so much better when it comes out from you. Your point of the ritual tied with the utilization of the plants in both indigenous cultures and in their rituals and their utilization, it's really fascinating what's going on now to the boring old pharmaceutical industry. There are several well-funded companies, really well-funded, that are looking to bring some of these psychoactives and psychedelics into Western medicine, but they're doing so in a really breakthrough way, working with the FDA, working with the regulatory agencies. The language they use is set and setting, which is, I think, trying to get to plant and ritual. It's utilizing the plant paired with appropriate therapy, paired with appropriate expectations about what's happening. You know, there was a work that was done with I think it was with LSD, to tell you the truth, with alcoholics. When it was done in set and setting, remarkably successful and effective. When it was just given in the way that we traditionally, you know, apply a medicine in traditional Western medicine, didn't do anything. The point of me saying that is what we're doing at Magdalena Biosciences is our contribution of what we do best, the identification of plants that are likely to have particular medicinal activity. What we did with crofelemer, bring a product through the regulatory process, the complicated manufacturing rules and regulations at the FDA to get a drug approved, a natural drug, an organic drug, a drug that is sustainably harvested, but through botanical guidance, working with Filament that has the natural product chemistry, laboratory capabilities, funding from OSP, and then present it to some of these very well-financed companies for the next generation. Beyond psilocybin, MDMA, what are additional new mechanisms of action and new ways of curing and treating mental health disorders? This is really a fabulous setting and understanding of how we can have even greater honor of the indigenous way of treating maladies beyond just the chemistry that comes from the plant. Well, I think. Thank you so much for that, Wade. I was gonna say very quickly, Lisa, you're so right, and I think, you know, to emphasize that statistic that, you know, of the 120, most in the Americas. My gosh, if you add up all the ones discovered by Schultes and his cadre, that could account for that distortion, right? Just to stress, there are many more plants to be discovered. Yes. There sure are. Schultes, I'm not sure everybody here understands exactly who Schultes was, but one way to do that is it's One River, right? Is that your book about Schultes, One River? Yeah. Mm-hmm. Yeah. Yeah. it's such an incredible inspiration for the start of our whole pharmaceutical effort. 33 years ago, he was the first man, first scientist I went to go see at the Glass Flower Museum at Harvard. many, many ethnobotanists today are doing what they're doing because they made that same trek. In fact, I was in a car once, in a cab in New York, and there was this great New Yorker article that was written about Schultes, and I was talking to the cab driver, and he asked me what I did. I told him, he goes, "Oh, I know that company. It's Schultes Pharmaceuticals," which perhaps should have been the name, but certainly in spirit is named. Did you write that article in the New Yorker, Wade? No. I, you know, It was a great article though, Lisa. I remember it well. You know, it was the first piece to kind of put Schultes a little bit on the map, which it was so deserving. For those that listen to the webinar here, the way to think about Schultes, he was the greatest Amazonian plant explorer of the twentieth century. In Colombia, mountains and national protected areas have been named for him. He was a man, in a sense, who sparked the psychedelic era with his discovery of the magic mushrooms, so-called, in Mexico in 1938. He was one of a very small handful of scholars who, on their own, were curious about these substances in the 1930s and the 1940s. It was actually Gordon Wasson who heard about Schultes from Robert Graves, the poet, that led him to be dispatched by Schultes to go to Oaxaca in the 1950s, in 53, and he wrote up his adventures for Life magazine, and the editor picked a snappy title, Seeking the Magic Mushrooms. The name stuck. Timothy Leary back at Harvard had a subscription to Life magazine, and so the psychedelic gold rush was on. I wanna just quickly Lisa, one thing you said that is so interesting, this notion of set and setting, the traditional healer, the contemporary clinician. You know, it all became and started in a sense as one. Remember that Tim Leary and Richard Alpert were serious social psychologists, they had faced a certain kind of crisis because a study had been done showing that no matter what the psychiatric illness, no matter what the treatment, a third of patients got better, a third stayed the same, and a third got worse. They were kind of in this crisis of their profession when Leary heard about these mushrooms, and they represented to him the potential for a true breakthrough. Long before he became a kind of pop icon, perhaps to his detriment, he was a very serious and well-regarded scientist. He coined that term set and setting, and Andy Weil elaborated on it in his early book, The Natural Mind. What they were really doing was, having gone through the subjective experience of taking these mushrooms, they knew what it was like, and they recognized almost intuitively, what the shaman had been, in a sense, advocating or practicing for millennia, that you needed a guide, that these substances produced a kind of ambivalent potential for good or evil, that you know, you needed a protective cloak or ritual. That's what the concept of set, meaning the psychological state of mind you bring to the experience, and setting being the physical space in which you do substances, would be pivotal to the outcome of your experience. You know, I remember that story and thank you for bringing it up because there was so much work also not only at Harvard, but at Stanford. I mean, serious work that could have progressed these substances to help in all settings, all populations, particularly the cleansed Western medical setting we live in. Then it all stopped dead based on some of the political machinations that you mentioned. The terrible thing about it all is that we now know from the memoir of Ehrlichman, who was the domestic policy advisor for President Nixon, that in 1972 when they initiated the so-called war on drugs, the president really wasn't very interested in drugs. He simply wanted to cleave off from the majority of Americans who he'd identified as the silent majority, those who were causing troubles in the country, students, African Americans in inner cities, you know, hippies... Mm-hmm. Withdrawn. In that sense, the war on drugs began as a deception in a sense, and it never really recovered. I mean, you know, Barbara Tuchman, the great historian, described folly as when a nation fully in possession of the facts, nevertheless pursues policies against its self-interest. The war on drugs has been really one of the most misguided crusades in the history of public policy, second only perhaps to the original crusades, and we all know how they ended up, you know. I think there's this very strong sense that the priority needs to be destroying the illicit market in all drugs, and the only way to do that is a cleansing stroke of legalization. I think we'll find that with legalization, consumption across the board will probably drop. Again, as I said earlier, the fuel that keeps that illicit trade going is not the actual drug. Cocaine is not an interesting drug. It's the money that generates this mania. When the money's taken out of the equation, I suspect that the interest in the drugs themselves will decline as we've seen in every jurisdiction that has legalized drugs, including Canada, where the expected explosion of cannabis use never materialized, and the promise, the commercial promise has not been realized either. You know, you never meet anyone, I've never met anyone whose decision to use or not use illicit drugs has anything to do with their legal status. People discover the good and bad ways of using drugs, and one of the good ways of using drugs is abstinence. Again, people make these choices personally, not generally based on laws. I think legalization would achieve so many great things, particularly for countries like Colombia. Surprise, surprise, that money fuels illegal trade. Surprise, surprise. I wanted to ask you, Wade, this is actually related to one of the questions that came in here. How did this timing of Nixon and the war on drugs, how did that match with any legitimate government funding that was going into these types of substances at the time? Well, in the early days, it's, you know. I mean, obviously, you had research being done across the spectrum. We know, of course, of the famous CIA experiments with LSD that were going on early on. Remember that LSD was originally synthesized by Albert Hofmann. It's an indole alkaloid. The progenitor of it is the ergobasine, the alkaloids found in a fungus that parasitizes rye crops. This was known as St. Anthony's Fire. Periodically in Europe, entire communities would sort of go mad and people would have necrotic tissue on their noses, fingers would sort of drop off almost. This was because the actual fungal parasite had a very powerful vasoconstrictor, hence the gangrene extremities. In Basel, Sandoz Labs was working on that, the medical potential of that, particularly for hemorrhaging women after childbirth. Hofmann had been given the task of synthesizing the indole alkaloid, and in 1943, he famously went back to his one of the formula and synthesized the 25th of series of analogs, and he became very dizzy in his lab because he didn't have petroleum or any gasoline for his car. He was riding his bicycle back and forth to work, and he decided to go home and rest. Of course, famously, he went on the most remarkable bicycle ride in history because the compound had seeped through his skin. Then it turns out that he went home on what would be the first world's first acid trip, you know. By 1943, the power of LSD was known. When Hofmann then deliberately self-experimented with the substance, he was astonished to see that it was effective on the microdose level. People were beginning to experiment with these substances even in the early years of the 1950s. This was hand in hand with an effort underway led by people like Nathan Kline, who won two Lasker Awards. Nathan Kline was probably the most prominent psychopharmacologist that studied the action of drugs on the brain. He and his colleagues in the 1950s were challenging the orthodoxy of Freud by suggesting that some psychiatric conditions could have a chemical basis in the brain that could be treated pharmacologically. In a sense, he became the father of both psychopharmacology, but also Thorazine, Prozac, and all the drugs that are used to this day. There was this big movement to, enchanted by the wonder of pharmacology, if you will. This is the same time that Schultes was securing from the pharmaceutical industry, and Bob Rafals, who I know was working with shaman in the early days, large grants to assay natural products from around the world. There was this very big movement. I think that that crossed from psychiatry into therapy. I suspect there were any number of initiatives and programs that were gradually shut down once the door slammed on psychedelics. You know, again, the door slammed on these substances because, out of fear, because these substances are indeed, subversive in a certain sense. You know, you really do not come back the same as our parents feared. I mean, I would argue that you come, you can come back a better and a more complete human being having taken one of these substances in the proper context. Again, you know, it's not about the twiddling of thumbs, and I think there was, you know. That's why they became catalysts in the social transformations that I referred to in my short presentation. You know, they were part of the genie coming out of the bottle. A genie that liberated women to their own, to realize their potential. You know, swept away the shadow of the Lavender Scare from the souls of gay people, you know. You know, addressed issues of civil rights that had been dormant since the Civil War. All of this stuff was exploding, and there's absolutely no question that the wide scale use, you know, the wide use of these substances, was very much one of the ingredients in that recipe of true social transformation. You can't look at a flower the same under the influence of one of these psychedelics as you do in your ordinary life. It's almost as if you get the sensation that the ordinary realm in which we live is kind of some kind of crude facsimile, dull facsimile of a world that's waiting beyond our imaginings. You know, this is again why these substances took on a kind of sacred essence, if you will, because they really are. They do open, as Huxley says, the doors of perception. You know, they are the doorways to the gods as Schultes wrote. They do give you a visceral, subjective experience, not just sensation, of realms beyond the ordinary. Of course, it's no wonder that they attracted the natural philosophers among the indigenous people who are constantly experimenting with the plants that surrounded them in their lives. Fascinating. Fascinating. You know, when we did our collection, the 2,300 plants that I mentioned, and Steven King can attest to this, in the early days, any plant that we collected that also had some psychoactive or psychedelic effect, we deprioritized because there was just no pathway we could imagine as a young startup company to bring it into the regulatory process the way this company was formed as a prescription pharmaceutical company. Here we are 30 years later, going back and looking at that library and reprioritizing and high prioritizing those plants. You know, there's just, there's the bumper sticker view that the world has of psychedelic substances, and then there's just this rich history of so many different lives and so many different pathways that had to intertwine and collide for what happened in the past decades. I'm so grateful. I feel like a fireside chat here, except we're on a Zoomie. We're so grateful to have you because I could ask you about any of those pathways, and you know them all. Thankfully. You know. Maybe we'll do part two at some point in the future. Yeah. Just to give you credit, I mean, you know, what a tragedy, you know, with all the genius that you brought together at your company, the fact that you were not able to do this research for those reasons, and multiply that by orders of magnitude. How many other initiatives were severed in the earliest stages simply because of the legal status of these substances? We're all grateful, I think, to you, and we're grateful that we all the chance to participate in this kind of revitalization as a renaissance, which I think will do so many great things for the world. Amen. Yeah. Severed and in some cases denigrated, it's nice to see them back in the true story coming out. I'm going to go back to a little bit of, you know, boring company stuff here. While it is transformative, what we're all doing, hopefully doing, and us and many collaborators and partners with Magdalena Biosciences. Let's go back to Jaguar right now for those interested stakeholders. Let me give a quick recap of, you know, it's a terrible time in the industry right now in terms of valuations of small cap biotech. There's a big JPMorgan conference going on right now, and you can just see so much research is being decimated and having to be severed because of financing right now. In this horrible environment, Jaguar is fortunate in one way in that we have two, what we feel will be major transformative events in the next six to seven months. Pharmaceutical research is a long proposition. To be in that position is not because we planned it. Who knew what was going to be going on in the industry? It's because we got, as I said, we're a little fortunate with activities that we started many, many years ago that happened to be coming to conclusion right now. The first one, as I mentioned, is crofelemer. As I mentioned, being in the midst of a final clinical phase III trial. That's something that takes a pipeline opportunity for cancer therapy-related diarrhea, CTD, as I refer to it, and moves it to a revenue-generating product with success in that trial, with success being success in the trial and of course the regulatory approval to expand the indication. We expect that patient enrollment to complete, I said in the second quarter, like we said publicly in April of this year. That's what our team is committed to. What that will be is seeking, as I mentioned, expansion of the label of a product that's already approved. Mytesi is the brand name for HIV-related diarrhea. It's approved for chronic indication, the safety issue, and it's approved product. We have a full supply chain in place from the rainforest all the way through to a bottle in essentially any pharmacy we want to put it in in the United States. That's the two most common reasons why new drug applications fail, safety and manufacturing. What we're looking for here is what is the statistical satisfaction of the primary endpoint to the requirements of the regulatory agency, the FDA, and then you go through the steps to expand that label indication for a product that is already out there. As I said, patient enrollment can be completed in April. That would give you a primary endpoint readout in three months, and it takes a little bit longer than that to clean up the data. The second core transformative event in about the same timeframe is also with crofelemer, but not with the Mytesi formulation. It's Crofelemer in a different formulation for a rare disease business model. Wade, if you want to talk about something that's fueled by money, that's definitely the orphan drug marketplace and the rare disease business model, because these are patient populations less than 200,000, in some cases ultra rare, less than a couple of hundred. You can do trials with a much smaller number of patients, you can have financial incentives, and you can have greater access for communication with the FDA. There's definitely financial reasons that fuel it, but remarkably rewarding to bring solutions to these rare diseases and really powerful and important advocacy and patient groups to come up with these financial incentives for companies to do research and development into these rare diseases. It's even more progressive in Europe. In Europe, there is something called early patient access. When for a rare disease, an unmet medical need, an orphan indication, and a proof of concept data, not approved data, but proof of concept data, for example, an investigator-initiated trial, that can be utilized for early patient access through the EMA, which is the FDA of Europe, that's reimbursed to the manufacturer. This is a program that does not exist in the United States. We established a company, Napo Therapeutics, in Europe with professionals who have worked in this environment, in this situation before, and they are running proof of concept studies right now that will be published. There's three conferences. One already occurred in December of 2022, an international gastrointestinal conference in Dubai. There's two more in the first half of 2023. With the presentation of proof of concept data, the plan is to get these products to patients in need through early patient access, and that's revenue generating for Napo Therapeutics, and that's data that's available to Jaguar. Napo Therapeutics exists under an exclusive license from Jaguar that has all sorts of financial aspects associated with it, up-front fee, milestone payments, royalties. Again-Fortunate that in this next very short period of time, seven months or so, we're gonna have these two major, what we feel will be transformative for value to all stakeholders and value recognition in the company. I think now we're gonna go to questions 'cause there's a lot of questions that have come in. I'm not gonna be able to get to them all. Some of them are for you, Wade. Let's start. Some of them are for me. Okay. Oops. I hope I didn't just delete them. This is a question about crofelemer. Can this treatment help with Crohn's disease or ulcerative colitis, inflammatory bowel disease? What we call crofelemer is a pipeline within a product. Because of its mechanism of action of basically normalizing gut function, not an antibiotic, you don't have resistance, not addictive, not an opioid, doesn't have the risk of constipation or addictive aspects associated with it. It's very well suited to be used in chronically ill, complicated patients because it's locally acting in the gut. You don't have drug-drug interactions. You don't have first-pass effect. You don't have secondary metabolites causing problems later on. What's interesting about inflammatory bowel disease is the diarrhea is not put in the category as it is with, for example, HIV as supportive care. It's part of the disease. You're talking about actual disease management. It's definitely on our list. We can't do everything at the same time. We have prioritized cancer therapy-related diarrhea. We've prioritized the orphan drug opportunity for short bowel syndrome in a pediatric version of intestinal failure called congenital diarrheal disease. We are very interested in inflammatory bowel disease. Just as we just announced the partnership for Magdalena, we are constantly working on partnerships to progress crofelemer to all the different disease populations, all the different diseases and all the different populations around the world, and in some cases, through partnerships, as we have global unencumbered rights. Yes, that is to come, but there's no data to speak to at the moment. May we get an update on the orphan drug designation of crofelemer for CDD? Crofelemer has orphan drug designation in Europe for short bowel syndrome and CDD, which is remarkable, two designations in less than one year, orphan drug designations, which, as I said, puts it in a good position for early patient access, reimbursed early patient access with proof of concept published studies in Europe. In the United States, we got orphan designation for short bowel syndrome. CDD, what CDD stands for is congenital diarrheal disorders. Congenital, you know, a gene defect, there are many different gene defects that cause the situation where the symptom that you see is that they are born with often these chloride channels wide open, so essentially like cholera levels of diarrhea, dehydration every single day. If they're not diagnosed right away, they often die. Some patients we know, two, three, four years old, have never even left the hospital. One of those defects is called MVID, microvillus inclusion disease. Our CDD application has been specified to that situation because we have in vitro data and targeted patients for that particular indication. I would expect very shortly we'll hear on that particular orphan application. Is there any news on partnership? Well, we just gave you news a couple of days ago on Magdalena Biosciences, and which is about, Steve, what, like about 18 months since we started to put a major effort on the ETI program and seeking partnerships- That's correct. -to move it forward. Is that right? That's about right. Yeah. That's like overnight in pharmaceutical years, right? Of course, as I mentioned, crofelemer is constantly in discussions about how to progress that pipeline and do so in a way that is important for the patients, first of all, and important for the different access around the world. You know, doesn't sell our future for a quick buck. There's a lot of stakeholders to take care of, and it's not just a money thing. You need to have a partner that is prioritizing your program, is working collaboratively with us, so it gets developed as quickly as possible. One of the reasons why we did the exclusive license to Napo Therapeutics in Europe, Napo Therapeutics, a company that we established, was exactly for that reason. The close collaboration between professionals at Jaguar Health who've been together, 10 of us for over close to 20 years. Steve and a couple of others of us for over 30 years. We can move very quickly because of the institutional knowledge and literally physically knowing where all the studies are for filings and things like that. Okay. With cholera prevalent in the Mideast right now, is the company positioned to take some lead in getting Mytesi to the forefront of the current crisis there? Boy, I love that. Our pursuit of cholera is not with crofelemer, which is the active ingredient in Mytesi. It's with a second-generation antisecretory. Antisecretory is the first-in-class mechanism of action of crofelemer. And it comes from a plant, Croton lechleri. There's a second-generation antisecretory which we have studied quite a bit, and lechlemer, I think we call it. What's the number in-house, NP-300? Correct. NP-300. Okay, we'll call it NP-300. It doesn't have a product name yet. NP-300. We're pursuing that for cholera for this reason. I need to show that there is a financial incentive, there's a business model for us to, you know, pursue a particular indication. First, one of the things that we may pursue is cholera could technically be an orphan indication in the United States. Not obviously around the world, but in the United States. Secondly, there is a published poster, I think there's two published posters, of cholera showing a remarkable benefit in cholera patients. This was done at the same cholera hospital in Bangladesh. It's where you do this type of research. It showed significance in reducing the dehydration by about 30% in the first 16 hours, which is considered sort of the death zone of cholera dehydration. Patients don't die from the cholera infection, they die from the extreme dehydration that occurs initially. If you could decrease that by about 30%, that is considered life-saving. It offers these patients an opportunity to get themselves rehydrated or get themselves someplace where they can get rehydrated and have their own natural immune system take over and fight the cholera infection. The gain in the United States is that there is incentive for rare diseases, tropical disease, rare disease incentives, and cholera is on the list. That financial incentive comes from the FDA, but only for the first indication for which a drug is approved, and crofelemer is already approved. We needed to move to a product that works the same way, has the same first-class mechanism of action, where we have a lot of data, and that's NP-300. We have filed the IND. We have the okay, the pathway, the green light from the FDA to go forward with the first study there, which would be a phase I study. This is different than CTD, this is different than HIV. Clinical trials are about three days, so they're much quicker, much less expensive. Again, as I mentioned, because we're in this fortunate position with this terrible market condition to have these major transformative events that go from pipeline to potential revenues in this year, a phase I study wouldn't do that, wouldn't have that impact. We've just slowed down the funding of that a bit, and you can expect to see that program go forward, I'm sure, in 2024 with the financial incentive of this tropical disease priority review voucher. Just to give you some ballpark of what that means, on approval, you get this voucher that is transferable that accelerates FDA approval for anything that you apply the voucher to, and they sell for anywhere from a little less than $100 million to $350 million, depending on who needs it at the time that you're selling it. It's an important program to us, not a milestone program in 2023. Okay. I already answered that. Steve. So Steve, this is for you. Does a new company, I'm sure they're talking about Magdalena, does the mental health interest, prescription drug interest also include the well-known psychoactive psychedelic plant sources, Which are now finally acceptable in the U.S. for clinical development? I'm gonna give it to you, Steve. Sure. you know, as Wade was discussing, there's quite a number that are well-known and quite a number that are the focus of a great deal of investment and enthusiasm among the medical and investment community. We actually are not focusing on those. We are looking at the other ones that are not so well-known, that are not the focus of many companies simultaneously. we're not really delving into the sort of top 10, if you will. We're doing others. I think that's part of our great advantage and niche because we've been doing this sort of approach around the world for decades. Okay. Oh, this question is specifically for Wade. Go for it, Wade. This is a commercial question. How best to commercialize these very compelling examples in the U.S.? What are your thoughts on that? Well, I think that the U.S. may not be the place where these breakthroughs will occur. I think Canada may be a more open environment, and certainly some of the countries in Europe. There, you know, there does remain a very strong anti-drug lobby in the United States. I mean, the Drug Enforcement Administration has this annual budget that I don't know what it is now, but it's been over the years anywhere between $40 billion and $60 billion. Virtually every part of the federal bureaucracy gets a piece of that pie. So they're... none of those forces are very keen to see that budget end. I think, you know, and in terms of the polarization of the political world in the United States, I think it's a harder nut to crack. Let's put it that way. I think, you know, what we've seen is when, you know, politicians generally follow, they don't lead. When the public demands something, ultimately they get it. I think that's why we're seeing this transformation on the municipal level, on the state level. Eventually, it will get to a point where they'll just be, maybe some individual jurisdictions will hold out. I think the big question, I'm not a lawyer, but I've always wondered how this will grow in the United States. Will there be, for example, a case that will reach the Supreme Court questioning who in fact has jurisdiction over drug use within the state, the federal government or the state authority? I can't imagine that that is not gonna eventually make its way, some case is gonna make its way through the courts, and there'll be some important decision made. In the meantime, I think what we can do our best to do is to communicate the value that these plants have and do everything we can to decouple them from the sordid products of the illicit trade, you know, by emphasizing, as I've done even in this short talk, that coca is not cocaine. To judge coca by the alkaloid that can be extracted in it would be as misleading as to judge the luscious fruit of the peach from the toxic constituents found in the pit of every peach. This is one of the challenges with a plant such as coca. It's a kind of a catch-22. Until people can experience the subjective effects and benefits of this plant, both health-wise in terms of their daily lives, it's more and more difficult to establish the very constituency we need to make the change. I mean, I find it really fascinating, for example, Lisa, that marijuana remains Schedule I according to DEA, which defines it, therefore, as a drug that has no medical potential and is dangerous. All these hallucinogens are still categorized as Schedule I. Yet we see cannabis now legal in 40 nations, and we see these psychoactive substances at the forefront of this revolution in clinical treatment. Curiously, coca leaves are Schedule II, which means plants with potential danger but known medical applications. Technically, a doctor can prescribe coca leaves legally in the United States right now. The problem is there are no established protocols, and there's no source of supply. The only legal source of coca leaves in the United States is and still is Coca-Cola, which imports coca by the ton to extract the cocaine to sold on the legal pharmaceutical market and then to use the flavonoids and essential oils in the formula of the popular beverage. It's, of course, those constituents of the leaf itself that makes Coca-Cola the real thing. Fascinating. Thank you so much for taking that question. We've got one more here, we're gonna wrap it up because we've kept you all for about 90 minutes. This is about the CTD study. The question is about the patients who come into the study. Have they already completed or have not taken opioids before starting the study? I took this question because I have neglected to mention that this study is a prophylaxis study. If you look at the culture in cancer supportive care, chemotherapy-induced nausea and vomiting is a well-established market. There's already many generic products there, and those products are used prophylactically. It's about a $3 billion market this year. As I said, that includes the pricing of the generic marketplace. Those products are typically used for the first three days in cytotoxic chemotherapy. What we are talking about with crofelemer and the enrollment criteria in the clinical trial is targeted therapy. Targeted therapy is what Lee was talking about in the video. There are mechanisms, TKIs, epidermal growth factor, receptor antibodies. These are products that are novel. Half of them were approved in the last five years. I mentioned there's about 70 of them. They're used on a chronic basis to maintain a patient in a curative situation. Or, in some cases, they're used even in a metastatic situation for the remainder of the patient's life. We're talking about months and year. They all work through a mechanism that induces this chloride ion-mediated diarrhea, which is the mechanism that is normalized by crofelemer. I'm saying all that to give you some idea. We don't put out financial guidance and forecasts. How big can this market be when you're talking about a product that should be taken on a chronic basis compared to CINV, which is only used for the first three days, not in targeted therapy, cytotoxic chemotherapy, and it's a $3 billion market. Prophylaxis is very important from a financial perspective, and it's very important for the patient, 'cause as I said, once the patient's supportive care gets out of control, it's all about managing the supportive care, and it's not about managing their cancer. 40% of the time, they're going off their life-saving therapy in some way, and now you're affecting the outcome to the patient's cancer treatment, and you're affecting the cost to the healthcare system. Patients have to be brought in for rehydration. It's usually about three times as much to take care of the patients. The bottom line to the question that was asked is, are these patients on opioids? To start in the trial, you prophylaxis, you take crofelemer in the trial or a placebo as you start your cancer therapy. You are coming in, and in fact, you're required to come in without diarrhea and therefore you're not on any opioid or any treatment for the diarrhea because the diarrhea is gonna be in fact associated with your treatment. I think that that gets to the answer to the question. With that, I will wrap this up. Great thanks to everybody who participated. Great thanks to Wade and to Steve for all you do in your careers and sharing a bit of that with us. I hope we can do this again sometime. I've learned so much, and maybe we can actually do it in person sometime. Peter, I think we can wrap it up. Thank you as well. Thank you very much, Wade, from me as well. Okay. Thank you. That does conclude today's conference. We do thank you for your participation. Have an excellent day.