Welcome back, everyone. Next, we have Jaguar Health, Inc., trades on the NASDAQ under the symbol JAGX. It's a commercial-stage pharmaceutical company focused on developing novel, plant-based, sustainably derived prescription medicines for people and animals with gastrointestinal distress. Happy to welcome founder, CEO, president, and director, Lisa Conte. Welcome to the conference today, Lisa. We're looking forward to hearing your presentation. Thanks very much for the introduction. It's nice to be back. I'm going to do a quick summary of the company for those who are hearing this for the first time, really get onto the key messages for today and those who have been following the company for some time, that this is a moment and a year of transformation and convergence of catalysts for the company. In the pharmaceutical industry, you don't have news that moves every single day, sometimes it's years and years in development for meaningful clinical and regulatory milestones, this is the year of that happening, and a transformational financial non-dilutive way of supporting that. We'll jump right into it. Of course, we're a public company. We have forward-looking statements. A summary of who we are. Of course, we do all prescription drug discovery from plants that are used traditionally in tropical areas. That's our basic enabling technology, which did lead to the successful development and commercialization of our lead product, crofelemer, which is the active ingredient. The brand name is Mytesi, and that's approved for HIV-related diarrhea. We also have an FDA-approved product called Canalevia, which is crofelemer for chemotherapy-induced diarrhea in dogs. These products are plant-based, they're sustainably harvested, they're organic, they're fair trade, they are FDA-approved drugs. In particular, Mytesi is a human-approved product. It's the only oral drug approved by the FDA under botanical guidance. Under botanical guidance, there is no practical pathway to bring a generic to market. Even though we have IP and patents filed all over the place, about 160 or so are issued, we essentially have exclusivity to infinity and beyond, which is of great value when we talk about terminal value calculation. There's no patent cliff that is going to be faced by this product. It's a first-in-class anti-secretory agent, totally novel way of treating and potentially curing diseases with a really paradigm-shifting mechanism of action. In addition to all those lovely features of crofelemer, what's really wonderful about crofelemer is that it is a pipeline within a product. Because of this paradigm-shifting mechanism of action, which basically normalizes gut function, there are multiple disease states, multiple patient populations that can benefit, most of which we have powerful proof-of-concept Phase II data for. Of course, a huge body of safety because the product has been in so many clinical trials and has been on the market in people living with HIV/AIDS at this point now for, I believe, eight years. We can't do everything. What are we doing? Here's the transformative financial part. In January of this year, we closed a deal where we licensed Mytesi in the United States, the commercial rights to Mytesi, and by the way, to Canalevia-CA1, it's a conditional approval, for up to $38 million in non-dilutive funds. I'm going to go through these bullet points because these are important in setting up where the company is going this year and how it's financing the catalysts that are occurring this year on the regulatory and clinical side. In January, it was an upfront payment access fee to our commercial package of $18 million, $16 million which we received at close. $2 million is coming in very shortly based on some additional milestones we needed to hit on the contractual side. In addition to the $20 million milestone payments and future payments, several million of that on top of the $16 million has already been received. These dollars are being used for the sharp strategic focus that we have now in our pipeline on our rare disease pipeline, which I'm going to be talking about in a moment. We, Jaguar, continue to be the manufacturer of crofelemer. Again, it's a natural product. We have worked on the supply chain for a couple of decades at this point. There is a great economy of scale. The more we make, the cheaper it gets, and we manufacture it at a profit to Future Pak. We do have in our rare disease program, which I'm going to talk about, there's a great alignment of really groundbreaking clinical proof of concept that's going hand in hand with the financial transformation at the same time, and there's a convergence over the next, at this point, it's not even 18 months, over the next 12 months that lead to a new drug application. We're focusing development commercialization on our rare disease program. The commercialization on the license deal has gone to Future Pak. Why else did we do that? Last year, Future Pak acquired a company called Theratechnologies, which is completely uniquely focused commercially on the HIV population with prescription products that have abroad overlap with the targets for the indication that crofelemer has, that Mytesi has, and has about 5x the commercial resources that we were able to devote to Mytesi. It's putting Mytesi in better hands for broader access to the patient population and allowing us to focus on our rare disease program. To get into that, our rare disease program is based on intestinal failure. Two patient populations, one, a congenital diarrheal disease called MVID, pediatric microvillus inclusion disease, and then a larger, but still a rare orphan indication, Short Bowel Syndrome with intestinal failure. Both of these are under the umbrella of intestinal failure. Both of these indications are, of course, crofelemer, but they're not the Mytesi formulation. They are a highly concentrated liquid formulation, powder for liquid reconstitution, that is clinically relevant and, in fact, required for these types of intestinal failure patients. They would not be able to take a pill like Mytesi. It is a new product. It is a new NDA. It has a different business model, pricing reimbursement that is going to be associated with it, yet also gets to benefit from the safety and the CMC that is associated with the active ingredient, with crofelemer, which again, we will control and do control the manufacture of. What is intestinal failure? Let's talk about it first in MVID, which is an ultra-rare pediatric indication. Intestinal failure is when the patient is not able to absorb the nutrients of life, protein, carbs, minerals, carbohydrates, et cetera. They end up on TPN, total parental nutrition, parental support, IV parental support, often for 20 hours a day, seven days per week. A catastrophic healthcare situation, catastrophic quality-of-life situation. It affects the entire community, the family, the caregivers, the nutritionists, of course, the patient as well. Issues when you are on IV nutrition for that long are very serious comorbidities, toxicities of liver and kidney dysfunction, cognitive dysfunction, infections from the lines. Often it can cost $500,000-$800,000 a year to keep a patient on TPN and well over $1 million with the hospitalizations that inevitably occur from the hospitalizations. Pediatric patients, MVID is a congenital diarrheal disease, patients are diagnosed immediately when they are born, immediately go on TPN for the rest of their life. If they are not diagnosed, they often die of an undiagnosed weak baby syndrome. In any event, TPN for the rest of their life, short life. These children typically die in their early teens if they make it that long. What you would be looking for in treating these patients is adjunctive care to TPN. They are going to have to receive some type of parental support, parental nutrition. If you can reduce that amount of parental support by even 10%-15%, it is huge. From a quality-of-life perspective, it can mean that a child gets most of their TPN and their IV nutrition at night so that they would have an opportunity to go to school or have some sort of activity during the day.But then every time you decrease the parenteral nutrition, you decrease the comorbidities of the toxicities associated with it and can enhance their life and extend their life. That is the key endpoint, adjunctive therapy, what we are looking for with crofelemer to reduce the amount of time on parenteral support. We have a presentation coming up at ESPGHAN, which is the European Society of Paediatric Gastroenterology, this month in June of this year, following up on patients that we had in a presentation last year at NASPGHAN, which is the North American Society of Pediatric Gastroenterology, with proof of concept in patients that were treated under compassionate use or investigator-initiated trial or expanded access as a complementary activity to a blinded control study that we also have going on in MVID. The patients that were in the treatment-only expanded access, IIT, are where we have proof of concept data that can be disclosed at this point. Here is the endpoint that we achieved. This is the key thing to remember on the transformative convergent clinical and regulatory events. We were able to reduce parenteral support in both MVID and short bowel syndrome intestinal failure pediatric patients by up to 37% in the MVID patient. Absolutely unheard of, groundbreaking, remarkable, life-changing data. At this point, about 16% in the short bowel syndrome patient. In addition, there were all the other benefits, reduction of stool volume, reduction of diarrhea, increase of urine output, which means the patient is actually able to absorb some of their nutrients better. That's an indicator of that. We're collecting data on reduction of hospitalization, so cost of care, reduction of cost of the TPN. Again, if you are reducing TPN needs by 37%, are you reducing the $600,000, $700,000, $800,000 a year cost by the same bit by about a third. These patients then, because they were in expanded access IITs, at the end of three months, had the product taken away. They immediately relapsed and then again were put back on crofelemer. No safety issues, which we would not expect with this product. We've never seen a safety issue, and they will now be provided with crofelemer for the rest of their lives. One of these patients includes a patient who went into an expanded access program because she was diagnosed when she was born, and our placebo-controlled clinical trial has a requirement that the patient is one year old before they come into the trial. So this patient was just a newborn, so didn't meet the qualification, so went on expanded access. It's the first patient that we've had treated that young. A remarkable response. It's over 40% reduction of parenteral support at this point, and she's on a growth curve that is at the 40% level for her age. She's about 10 months old right now. Again, unheard of for an MVID patient. I have a new grandson. He's perfectly healthy. He's only on the 20% level of the growth curve. So with a very small number of patients, we're able to see that early intervention with these patients can have a huge difference on their life, and perhaps the extension of their life. This is an ultra-rare patient population. There's about 200 patients that are identified around the world, and because they die so quickly, incidence and prevalence are about the same. So we certainly hope to increase the prevalence as crofelemer becomes more available. Third-party market estimates are anywhere from $50 million-$1 billion on a global basis. We've had communications with regulatory agency, both the FDA and the EMA, and are looking to be able to file a new drug application with data that we have by the end of this year from our controlled study, enhanced by the IIT early patient access patients that we just talked about, a single-digit number of patients to file for this indication. The filing is expected to be mid-next year based on data that will continue to roll out this year in 2026. This is the same formulation for the SBS market. In fact, it has been in SBS pediatric patients as well. SBS expands beyond pediatric to adult patients as well. There is an approach that's out there for short bowel syndrome. There is a product approved called GATTEX. It's a GLP-2, not a GLP-1. GLP-2, so that's essentially a growth hormone. What that mechanism attempts to do is grow the gut a bit, so the patient has a bit more surface area. Short bowel syndrome is just what it says. Our gut is about 25 ft, 5 ft or less. There's not enough surface area to absorb the nutrients of life. If you can grow it a bit so the patient can reduce their parenteral support by about 10%-15%, that's how GATTEX got approved. That's the importance of reducing the amount of time that a patient is on parenteral support. Growth hormone has a lot of limitations. Can't be used in an abnormal hyperproliferative situation. You don't want to give a growth hormone to somebody who's growing cancer cells. That's about a third of the short bowel syndrome population, those who have had surgery because of cancer. You have congenital, you have accidents. Also, a growth hormone can't be used until about 12- 24 months after surgery for bowel adaptation. A lot of toxicity is associated with it. It's used in a single-digit number percentage of patients. Nevertheless, third-party market research puts that market at about $8 billion just for the knowledge of a GLP-2 mechanism of action. What we're looking to do is to become the standard of care in the intestinal failure marketplace, including, of course, short bowel syndrome, because we don't have the toxicity issues, we don't have the limitations on cancer and surgery. It's a different mechanism of action. We could also be used with GLP-2. At this point, proof of concept data is showing an even greater reduction in the need for parenteral support, which is the key endpoint. GATTEX is reimbursed at the rate of about $500,000 a year in the United States and a couple of hundred thousand dollars a year in Europe. There's also a precedent for the financial benefit that is accepted by reimbursement organizations and the incentives that are provided for rare diseases. We do have orphan drug designation in the U.S. and Europe for intestinal failure with MVID and with short bowel syndrome. The second message, transformative time for the non-dilutive funding for the company and the convergence of catalysts, I have to change this now over the next 12 months. We have our proof of concept data out there to be presented at ESICM in the next two weeks. We have our MVID patients that are in our double-blind placebo-controlled trial. At the end of that trial, if the patients benefited in the eyes of the investigator, the family, the patient, the whole supportive group, they would then go into a treatment-only extension phase, which is the data that we will utilize to file for our new drug application. The first patient has gone in. At this point, the indications are that every single patient wants to go into that treatment-only extension phase, which is a great surrogate for the benefit and the safety that was seen in the placebo-controlled phase. With that data in the third to fourth quarter this year, we will also file for breakthrough designation in the United States, which gives us the opportunity to have an expedited review, a review of more than four months rather than six to 12 months at the time we file our application next year. When we file the application for MVID, we will also be completing a separate study, a blinded study, phase II study that's ongoing right now with short bowel syndrome in adults. We look at the MVID approval of crofelemer in this novel formulation as the stepping stone to this patient population, which is a bigger unmet medical need in terms of number of patients and all the benefits to all stakeholders, the financial impact of the market as well. I just want to say at one point that that is the point at which we would seek to bring in a corporate partner, a commercial partner, similar to what we did and the success we had in bringing in non-dilutive dollars with the license to Future Pak of Mytesi. Outside of the U.S., these programs are all being done on a global basis. Look for a partner to bring in non-dilutive dollars, and we would expect to do the commercialization in the U.S. To give a feel for how big that can be, the market for intestinal failure is about 10x the size of the market for HIV Mytesi in the U.S., and that deal was close to a $40 million non-dilutive dollar deal. The other program that we do have going on that I hadn't mentioned, which is Canalevia, which has been out-licensed also commercially to Future Pak. We have just completed a confirmatory study that allows Canalevia to move from conditional approval, which limits the commercialization just to chemotherapy-focused veterinarians, to a full approval, which gives a broader opportunity for prescription and utilization of the product. Very exciting for the doggies and the dog family owners in the world. The last program that we are still focused on, a very sharp strategic focus on our intestinal failure program. What we did, we're able to mobilize a good portion of our plant library and our basic enabling technology in psychoactives and psychedelic plants, mostly psychoactive, in a joint venture that we have called Magdalena Biosciences. It was funded by an outside venture capitalist. We own about 40% of Magdalena Biosciences. There is no financial cost to us, and we were able to mobilize and bring value to about 20% of our plant library that we collected over a 30-year period of time, which has benefits in the CNS area. We have three botanical products there that would move into the approval program under botanical guidance like crofelemer and the protection and the IP protection there, all in the CNS area. Those are out seeking additional second round of venture funding right now. Again, costs us nothing. We have a lot of news. Year of transformation, year of convergence of catalysts. We have a team that's been together, many of us, about 10 of us, over 20 years at this point. A couple of us have been together over 30 years, and we are committed to bring this indication home in the rare disease pipeline. It's very interesting application of ancient knowledge to modern genetically defined diseases. I'll stop at this point. I'll leave our investment highlights up there and see if there's any questions at this point. Perfect. Thank you, Lisa. Really fascinating. Let's jump into some questions. Talk a little bit about how does research into plants, like you mentioned, that have been used for centuries by traditional healers support Jaguar's drug development efforts. The thing, I just love this about this particular program in congenital diseases and genetically defined diseases. Whoever even heard of MVID? Obviously, hundreds of years ago, no one did. No one knows about it in the rainforest. It wasn't even defined, I think, more than 15 years ago. The thing about doing ethnobotanical research is you go into the field and you observe symptoms. You work with healers to understand, and shamans and healers, how to manage these symptoms. It's a lovely professional exchange from our physicians, our botanists working with shamans who have both the medical knowledge and the botanical knowledge. Because we're managing symptoms, we are not constrained by known mechanisms of action. We're not doing high-throughput screening across a particular enzyme or a known approach to treating a disease. That's how we discovered crofelemer, a totally new breakthrough mechanism of action that is really paradigm-shifting in everything that it does in the gut, therefore has the potential to have application to new diseases that are being defined. That's exactly what happened with the match-up of the mechanism of action of crofelemer, the anti-secretory mechanism of action to the intestinal failure definition of a congenital diarrheal disease like MVID. What led Jaguar to focus primarily on orphan and rare diseases? It was very interesting how that came about. crofelemer was primarily looking at GI disorders, anything associated with diarrhea or IBS, IBD. I happened to be in the Mid East. I was talking to a fund actually in Saudi Arabia, and I said, "Oh, what are the types of things that you look at, indications you looked at?" And they said, "Anything that has a congenital aspect to it that might treat or diagnose or prevent because of the consanguineous marriages, marrying within that particular culture." At that same time, an investigator who was working on our cancer program at UCSF had a patient who had a congenital diarrheal disease and approached us about that totally from an anti-diarrheal approach. Those two events happening at the same time, us understanding the mechanism of crofelemer, is what was the spark to look at these intestinal failure disorders and then learn about the fact that they are rare diseases. There's some companies, many companies, that are only focused on a rare disease orphan business strategy. That's not us, but there is this component of our business which is now focused on orphan and rare diseases, and just so appreciative of the incentives and the opportunity in those types of programs. For us also, reduction of burn rate. We're talking about clinical trials of 10-20 patients, not clinical trials of 300-1,000 patients. Really appreciative of the impact we can have on the patient population and the conservation of resources of the company. Why powder for oral solution version of crofelemer rather than a tablet formulation? Mytesi is a tablet. It's enteric-coated and patients, HIV patients, cancer patients, they swallow it's protected in the stomach, goes into the gut, released, and does its thing. crofelemer is not systemically absorbed, so it normalizes gut function in the gut and then out it goes. Very appropriate in complicated patients where you don't want to interfere with the other life-saving drugs that they have. You don't have no first pass effect. You have no toxic metabolites hanging around thereafter, no drug interaction. Lovely, wonderful, all those benefits would be available and relevant for an IF patient population. But when a patient has intestinal failure, and particularly Short Bowel Syndrome, a pill goes right through, lands in the toilet bowl. It's like a sieve. Massive, massive diarrhea and water loss in these patients. So by having a powder formulation, we have the opportunity for it to stay for the period of time necessary to normalize and regulate the particular channels. They're called chloride ion mediated channels that are primarily in the small intestine, in the large intestine as well, and have a benefit in the patient. There's a very interesting situation where there was a Short Bowel Syndrome patient who was prescribed Mytesi off-label. Of course, we had nothing to do with that. The patient was successful, you thought, "Well, how did that happen? How did that product even get absorbed?" What the patient and the physician did, again, hands off by us, we had nothing to do with this. They pounded up the pill, which we would never recommend, pounded up the pill and essentially made their own home version of powder for liquid formulation for that particular indication. That is a published study. That patient is doing very well for years now on crofelemer. Wonderful. I guess you could maybe end with this, depending on how much more time we have. How large could the oncology market opportunity become if approved? The oncology or intestinal failure? Let's hit both. Let's do intestinal failure first. Intestinal failure, again, it's a rare disease business model. There's no doubt that the incentive for these very small populations for the manufacturers who develop the product is there's greater flexibility in pricing associated with the cost of taking care of these patients, mortality and morbidity. Mortality, hopefully, we are extending life and extending life does cost money. Even morbidity, if you're able to reduce the cost of $1 million plus to take care of the patient because of parental support and hospitalizations, that's huge. This market for rare disease and ultra-rare disease is blockbuster, over $1 billion. Even more important, blockbuster on the impact on their life, their medical conditions, their quality of life, the patient support groups. On the cancer side, we do have a first pivotal trial completed in cancer. It's going to require another pivotal trial, and that's an expensive program because of the number of patients that would be required. That would only be done with a partner supporting that. That is a huge growing market because the cancer diarrhea is very much associated now with these targeted therapies. There's about 60 or 70 targeted therapies approved. They all cause diarrhea by the mechanism that we normalize, and 40% of these patients go off their chronic life-saving therapy specifically because of the impact of diarrhea. That's blockbuster as well, it's interesting. It's considered supportive care, whereas our orphan program is disease progression modification, supportive care is still a little bit of an ugly stepchild when it comes to partnering interests. Again, our sharp strategic focus, clinically, regulatory, and partnering right now is on our rare disease program and our disease progression modification of that. Wonderful. It's always a joy speaking with you, and it's great to hear all of this important work you're doing, and I'm sure our viewers are really interested as well. Lisa, thank you so much for your time and dedication on such an important project, and we would love to see you again real soon. Thank you. Love to talk about it, and there'll be progress on a regular basis. Thank you. Wonderful. Thank you, Lisa. All right, everyone. We'll be right back.