Welcome, everybody. Thanks for joining us for our Global Healthcare Conference here at Leerink. My name is Roanna Ruiz. I'm one of the senior biotech analysts here at Leerink, and it's my pleasure to introduce the team from Lexicon. With me here today, I have Craig Granowitz, the CMO, and also Scott Coiante, the CFO. Welcome, and thanks for joining us. Thank you, Roanna. Thank you. Great. General plan for today, I'll start with some bigger picture questions and start to drill down across some of the different programs that you guys have. To kick it off, I'll ask about just help frame things for investors that are new or revisiting the story. Can you talk about current business, some of your top priorities this year and going into 2026? Sure. Roanna, first off, thank you to you and the bank for inviting us to the conference. We're really happy to be here and appreciate the opportunity. For those new to the Lexicon story, Lexicon was founded on the Genome5000 program, which utilized knockout mouse gene technology to study nearly 5,000 genes, which yielded more than 100 potential therapeutic targets. This work has informed us and our ability to develop innovative and targeted medicines in areas of high medical need. We've already brought several successful candidates through to late-stage development. In 2023, we launched sotagliflozin for heart failure. However, due to market headwinds and two established players in the industry, we made the very difficult decision to cease promotion on INPEFA and pivot and focus on our R&D pipeline. Craig will add some additional color about the past year and what's expected. Yeah, I think, Roanna, what we really try to do is focus. We have three key priorities right now for the company. The first, and most importantly, is to get our pilavapadin, which is LX9211, into phase III in diabetic neuropathic pain. We have three positive studies of that in phase II, two in DPNP, and one in post-herpetic neuralgia. The second is to continue to both differentiate and develop sotagliflozin, particularly in heart failure and in MACE, along with heart failure, which would be the first and only in the SGLT class in that regard, and also to complete our ongoing global phase III program in hypertrophic cardiomyopathy, both obstructive and non-obstructive. The third priority is to get our LX9851 asset, which is a non-incretin once-daily oral compound, into phase I development in obesity. That's a really interesting compound because it has activity both in obesity, reduction of liver fat, and then also reduction of vascular plaque as well. We think we have three really interesting assets in three very different therapy areas that are diversified across the range of development timelines as well. Great. Sounds good. Maybe I'll dig in on pilavapadin first, since you had some recent data. Could you just remind us about how you are thinking about the path forward for pilavapadin after the PROGRESS data? What are you hoping to learn with, I think you're going to do upcoming sub-analyses, and just go into the data and see more insights that you can gather. Yeah, it's a great question. We really tried to prepare the market for what the goals of the phase II program were for the PROGRESS study. We really had three goals. The first is, did we need that day one loading dose for efficacy? If we remove the day one loading dose, could we maintain efficacy and eliminate that dizziness? The third is to pick a final single dose to bring it to phase III to streamline both the cost and complexity of a phase III program. We believe we achieved all of those goals quite clearly. In that regard, I think the market perhaps was anticipating this was going to be a phase III pivotal trial, but we never tried to position it in that way. When we removed the loading dose, we still had significant separation within the first couple of weeks of the 10 mg dose arm from placebo, despite the fact that the placebo arm responded far better than we did in the RELIEF study, but we still had that significant separation. We continued to see improvement in pain score in the 10 mg dose throughout the eight-week dosing period. We expect that would continue in the pivotals, which would be roughly 12 weeks in duration. We did not see nearly as much dizziness. In fact, the completion rates were the same in the 10 mg dose as in the placebo. About 88% of patients completed the therapy. We also noted that in the 10 mg dose arm, we had really single-digit dizziness and dropout for dizziness. In that regard, we demonstrated the 10 mg works, the 20 mg did not perform as we hoped and did not separate from placebo. We did not need the loading dose to have the efficacy. When you remove that, you largely eliminated the dizziness. We feel that we have a phase III ready asset to move right into pivotals. Yep, got it. Just to answer the second part of your question on the additional analyses, I think what we want to do, like we did after with the RELIEF study, is there will be some additional sub-analyses, some of the secondary endpoints, the burning pain, the sleep interruption, the use of the rescue medication, some additional color on the tolerability, site performance, those kinds of things I think will be forthcoming. Clearly, we have the primary endpoint of the trial. We are looking, and I think we mentioned this at the earnings call, to have an end of phase II meeting with the FDA sometime in the second half of this year and really be prepared to move into phase III pivotals by the end of the year. Yep, got it. Yeah, talking about the end of phase II meeting, what are some of your goals going into that meeting with the FDA? What do you hope to achieve there, and what data do you think will shine through in terms of your discussion with them? The FDA has already told us when we had our meeting at the end of the RELIEF study that we could proceed into phase III if we so chose at that point in time. There is just a number of other operational issues we would like to understand with the FDA. In this category, there is always going to be the issue about likability. Is there a withdrawal effect from the drug? We did not see that. Is there going to be some sort of issue around when you remove the drug, would there be any sort of addiction potential? We do not believe that there is, but just to clarify exactly what FDA's concerns are in that. In CNS acting drugs, FDA generally asks about, is there going to be any next-day drowsiness or other effects? I think clarifying some of those points and then really finalizing the design with FDA, particularly the long-term extension and how much safety data do they want in addition to the pivotals, which are relatively short in duration. I think those are some of the things that we'd like to clarify. I think we have a very good handle on all the CMC issues and all the other issues related to manufacturing. We have a process we're comfortable with. We reviewed a lot of that data already with the agency as well. Makes sense. Thinking ahead to possible phase III trial design, I know it's not finalized yet, but how are you thinking about the different levers that you might use in that trial? Size, duration, endpoints. What are you thinking about there for pilavapadin? Yeah, so the two trials we powered were placebo-adjusted reduction of 0.6, again, from placebo, not from baseline. Many of the other programs that have been reported are really looking patient to baseline. There you get a significant reduction in pain score in all patients. We are really looking at roughly that same clinical benefit compared to placebo. I think we have a much better understanding now after running two positive trials on data variability, sample size, and duration. I think as we've publicly stated before, we are really looking at a single drug arm compared to placebo. We believe that the sample size would be in the range of 300-400 patients per group and look at two parallel studies. These are not really long studies and are not really large studies from the standpoint of cost and complexity. Certainly, having run a lot of studies in the cardiovascular area, these are far more easily achievable than CV outcome studies or heart failure trials. I hear you. Just to confirm, is your base case that you probably need two studies, or is there a chance you might only need one after talking to the FDA? Yeah, I think this is a great question that we'll certainly bring up with the FDA at the end of phase II meeting. I think our base assumption is we would run two trials. I think anyone who runs CNS trials knows that often you run three to get two because a lot of times in CNS drugs, there is some variability in the patient data, as we've demonstrated with the placebo effect here. Our base assumption is run two parallel phase III trials, probably one in the U.S. and then one U.S. global. Okay, got it. I got in this question from investors before, just how are you thinking about possible powering of the upcoming phase III or two phase IIIs, depending on what happens for pilavapadin? I think that's really the sample size that we're looking at is that range of 300-400. I think we've got a much better understanding of the variance of the data, which would feed directly into the sample size. We're looking at a placebo-adjusted reduction in that same range of 0.6. Overall reduction in the pain score, though, is probably going to be in the range of close to two when you look at the data. We were at 1.75 in this most recent trial of the 10 mg arm. Yep. And bigger picture, I know you've messaged pilavapadin may be a good candidate for a possible partnership down the road. Could you just level set for us how are you thinking about that going forward as you go forward to talk with the FDA, et cetera? Yeah, so I'll answer it from a medical and scientific standpoint. I think Scott certainly can add some additional color to that. We believe that having a partner on this would be very valuable for a couple of reasons. The first is that neuropathic pain is a very large area, and there are a number of indications where this drug has already demonstrated significant activity beyond DPNP, particularly post-herpetic neuralgia, chemotherapy-induced neuropathic pain. There is other interesting data that we have from the animal models about looking at spasticity pain states. Those that come to mind would be things like MS and spinal cord injury. We have demonstrated activity in both those in preclinical models. We think that there is a broad issue around scope. There is also the issue around geography. To really do a global program, we would probably want to run separate trials, particularly in Asia. First of all, there's going to be the requirement in Japan and China to run trials in those geographies, but also really having a partner that understands the regulatory and clinical environment in those countries specifically, where there are a lot of cultural and other differences regarding pain and pain management. Yep, got it. You mentioned post-herpetic neuralgia and MS spasticity. Could you just remind us, so what's some of the early data showing for pilavapadin, and what would you want to see to encourage you to move forward in these indications? I think this is an area where having the interaction with a partner could be very useful, as well as talking to the agency some more after we get the DPNP program running. The models we've looked at, and some of which has been presented and published, is that when you give pilavapadin in a number of these myelin models, whether it's a partial spinal ligation or an MS model, demyelination type model, that you see reduction in neuropathic pain or what is the model for neuropathic pain in these myelin models. We feel that there's a good basis for that, but you would really need to do a full development program in that, starting with pilot studies and trying to understand what are the right patients for that. These could be potentially really important drugs. Certainly, spinal cord injury is a major unmet need. MS, I mean, there are good therapies there right now, but not really to manage the pain associated with MS. Yep, got it. Zooming out a little bit in the neuroscience space, sometimes placebo effect is a thing in trial design. Curious, as you pursue some of these different indications, what are your strategies that you'd love to employ to just help control placebo effect, help run tight trials, et cetera? Based on having run now three trials in this area, I think site selection, patient identification, doing the right run-in, training the sites on the diagnostic tests for neuropathic pain are really, really important. I think those are some of my key takeaways. Having now run three of these trials is that that level of site selection, training of the sites and the patient, making sure that patients can actually fill out the diaries correctly, that they do it reproducibly, that they're actually taking the medication, that patient population selection is very important. It is also important that the sites really know their patients. I think we've seen much better performance where these sites have actually worked with these patients and know these patients as opposed to sort of advertising and bringing patients to the site. Yep, got it. Great. I'll switch gears to your commercial product, sotagliflozin, for heart failure and just thinking about where it stands in the market today versus standard of care. I did want to ask, how are you planning to continue to put out the differentiation sort of messaging of sotagliflozin versus other classes like SGLT2s, et cetera? How are you thinking about that? Yeah, we look at HCM as sort of a two-pronged strategy. The first is differentiation of the dual SGLT1 and SGLT2. And as a reminder, sotagliflozin is the only dual inhibitor that's been approved in the SGLT class. We've demonstrated that there is SGLT1 expression in the gut, on the myocardium, and along the endothelium and in platelets. Over the last couple of years, we've done quite a bit of work to demonstrate mechanistically that by inhibiting SGLT1 and SGLT2, you have incremental effects on reducing a number of inflammatory markers, proteins, and gene expression. We've also demonstrated that there is far less agglomeration of platelets, so much less thrombosis formation when you give animals sotagliflozin versus empagliflozin, which is a pure SGLT2 inhibitor. Some of that data was presented last year at ASH. There's a very interesting paper that was just published in Lancet Diabetes within the last month that demonstrated that out of all the pivotal trials that were conducted, only sotagliflozin shows a reduction in at-risk patients. These are at risk for heart failure and MACE patients in both stroke and MI. That has not been seen with any other SGLT2 inhibitor. I think continuing to develop the story, particularly on MACE, where these patients with heart failure remain at very high risk of MACE-related events, and also the data in HFpEF. There was some data presented last year in both HCM-related models and others that showed reduction in cardiac work in these slices that were cardiac slices from humans that were given sota. That gave us great confidence going forward in HCM. I think it's a positive study in HCM, both obstructive and non-obstructive. Also continue to develop the mechanistic story on reduction in stroke and MI and thrombosis and endothelial platelet interactions. The third is continuing our work in HFpEF specifically and demonstrating that you get continued good response in terms of reduction of heart failure events in those with normal or near normal ejection fraction. That composite together, we hope, will lead to significant differentiation and a resistance or reluctance to try to do any sort of substitution for an SGLT2 inhibitor upon approval of sotagliflozin in HCM. Makes sense. We did want to pivot to the HCM potential label expansion there for sotagliflozin. How are you thinking about sota fitting into the treatment paradigm for HCM? We've got the CMIs that have been recently approved, or at least one of them, and then standard of care, beta blockers, et cetera. Where does sota fit in that lineup? Yeah, it's a great question. I think one of the areas that is really exciting to a lot of the clinicians that are participating in the trial is that we're allowing the drug to be used on top of any background therapy. The entry criteria is symptomatic disease as measured by KCCQ score below 80. In that regard, the patients can be on a CMI, they can be on a beta blocker, they can be on a calcium channel blocker. It's similar to the approach we took when we did the heart failure program that we included both HFpEF and HFrEF in a single trial. Nobody else did that. We believe that there's a strong mechanistic basis for it. We also believe that it is a far more efficient way to run our clinical trials, both in terms of time, size, and cost. In that regard, allowing patients also with an ejection fraction much lower than the CMIs have, you're going to have far greater utility of this drug either on top of a CMI in obstructive. It's not really clear yet whether the CMIs are going to work in non-obstructive disease. I think there's a fair amount of discussion. Will they work as effectively in non-obstructive as obstructive? I think the future of HCM is there's going to be, I would imagine over time, again, this is speculation on my part, but there's going to be far more non-obstructive disease than obstructive disease once people start looking with genetic markers for non-obstructive HCM. Yep, got it. You're starting to talk about the different segments of HCM, like obstructive versus non-obstructive. In context of your phase III, how is enrollment going across those two different buckets? I think it's really interesting you're including both. What should we know about how those two populations tend to respond in HCM trials? Yeah, it's a great question. One of the rationales for doing the program the way we did is that the underlying genetic malformation or genetic issues in both HCM, both obstructive and non-obstructive, are kind of the same because in a significant percentage of patients, if you remove the obstruction, you still have heart failure or heart failure returns within five to ten years. If you look at the genetic underlying issues, they are not so dissimilar. We believe that the drug will have utility in both. What we're seeing right now, and I think we've publicly talked about this and it's posted on ClinicalT rials, is that we're looking at a single 500-patient study stratified, both obstructive and non-obstructive, 250 patients each. We're doing the trial in 20 countries. We've opened a large number of sites in the U.S. and certainly are shooting to have all 30 sites in the U.S. open in a short period of time. We're already opening sites in other countries, starting with the U.K. We have country approvals in most countries that we've targeted for this trial. We're really looking at broad representation across the globe. The feedback we get from most sites is that this trial is going to be relatively appealing because the entry criteria are open, very open compared to the others. The duration of treatment is short. It's only 26 weeks. You don't need to do all of the intensive echoes and other things that are associated with the HCM trials, the CMI trials, as well as there's a single endpoint, which is KCCQ, and New York Heart is the main secondary endpoint. You do not need a lot of the complicated physiologic testing that I think FDA is moving away from, but many other companies are still performing those type analyses. I think they need to because with sota, we have already demonstrated we reduce mortality and heart failure events where the CMIs really have only demonstrated symptomatic relief. That data will only come with time for that class of medication. Yep, interesting. Just to confirm, with your interactions with the FDA, does it sound like you probably only need one phase III? Oh, yes. That is what the feedback they've given us. Yep, got it. Let's assume the phase III works. What would the next steps be in terms of thinking about commercial prep, strategy, marketing, et cetera? Yeah, again, I think ideally Lexicon would focus in the U.S. on the cardiology community. In a sense, this one's even easier than heart failure because the number of centers that are treating HCM is much smaller. I think the opportunity could exist with a drug like sota that HCM treatment could move more into the community because it's far less complex to deal with. Our goal would be we would continue to be interested in focusing on the cardiology world in the U.S. Really, our partner Viatris already has rights to sota outside of the U.S. and Europe. Europe, I think, is a really interesting opportunity for HCM because I think it could have a really interesting fit in the reimbursement realm in Europe. Yep, got it. Yes, just to remind some investors that do not know about the Viatris sort of partnership there, can you just remind us about the terms and what motivated that collaboration there? Alternator Scott. Yeah, sure. We announced the partnership in the fourth quarter of last year. It came with a $25 million upfront payment to Lexicon and the ability for us to achieve up to another $200 million in milestones and royalties. The partnership has gotten off to a great start. In fact, Viatris has even indicated publicly that they are moving forward with their efforts to register in their key geographic areas. That effort is moving forward in 2025. Interesting. I also want to give you a chance to talk about your earlier stage assets. With the obesity program, could you talk about your longer-term vision for this program? Where could it fit in the treatment paradigm? Yeah, we've publicly talked about obesity is really a very broad area. This asset would be best served by having a partnership. Moving into phase I, I think, is really pretty straightforward. We're certainly prepared to do that. We're doing all the IND enabling studies this year. We're targeting potentially to be first in human before the end of the year. I think in obesity, we have what we believe will be a once-daily oral medication that is non-incretin based. In the animal models, we've demonstrated the drug works independently alone to cause weight loss. It works on top of maximum dose semaglutide. It even works if you withdraw the semaglutide and add LX9851, that you continue to maintain weight loss. I think there's a lot of areas of opportunity where the drug could work because also with the mechanism, the ACSL5 mechanism, we believe in the animal models demonstrate there's a significant reduction in liver fat and also reduction in coronary plaque in certain animal models, which fits with the mechanism, which is a critical step in the synthesis of triglycerides and the distribution of the enzyme along the border of the ileum and in the liver. phase I, I think, would be pretty straightforward. We want to demonstrate that the drug causes weight loss, that it's well tolerated, and that the mechanism is not dependent on the incretin system. I think those are really three critical domains in the phase I program. Yep. Is your thought that this would possibly be combined with future agents? Or how are you thinking about that? Yeah, I mean, I think the standard of care right now is to start with an incretin or an incretin-like mechanism. You get dramatic weight loss in a significant number of patients. I think the interesting thing or the important thing to note is that the duration of treatment with these agents is fairly short, 6-12 months for a majority of patients. For one reason or another, patients just do not stick with these therapies over the long run. I think there's going to be a need for a number of different mechanisms. I think that what people are thinking now, and again, there's plenty of people that know this area better than I do, is that using the incretins for rapid early weight loss is probably going to be hard to replace, but that there's going to be other class of medications that would probably be important for the long-term maintenance of that weight loss or other objectives that patients have along with just loss of mass. Interesting. I wanted to zoom out a little bit in the last few minutes. You have a bunch of things going on. You have running the phase III for HCM, potentially starting up a phase III, potentially with a partner for pilavapadin. Where do you stand on cash runway? How are you thinking about executing on all those fronts in terms of balance sheet, resources, things like that? Thanks for the question. As Craig alluded to, we do have those three key objectives, which we are funding at the moment. In terms of pilavapadin, we are doing a lot of behind-the-scenes work to keep the train moving, if you will, so that if a partner does come on board, that we're not losing any time. Time is really important to us here. We are doing some of the background work. The HCM trial is, again, fully funded and ongoing. Our budget assumes the development and the progression of LX9851 for the IND filing by the end of this year. We have guided last week that our operating expenses for 2025 will be in the range of $140 million-$150 million. All those activities are fully funded with a cash runway that certainly takes us into 2026. Understood. I know in the past you've done restructuring and things like that. Is that on the table when you're considering moving forward? How are you thinking about that? No, look, I think in my seat, there's always an ongoing evaluation of costs and where you can reduce costs, potentially eliminate costs. I think that's an ongoing effort that just doesn't stop as far as I'm concerned. We'll continue to take a look at those type of items and look to save wherever possible. Yep. In terms of thinking about the next year or two, what data catalysts or regulatory events should we be watching for? Where do you think investor eyes should be focused on the most? I think that what we're looking to do is to not to oversimplify it, but execute, execute, execute, right? We are focused on those three items that Craig alluded to. I think that investors should focus on that and measure us against those achieving our objectives in those three areas because it's important for us to continue to find ways to invest and ultimately help patients. That's what we look to do when we come to work each day. We should evaluate on the progress that we make on those three primary areas of focus. Okay, great. Last question before we close out. I was curious, what do you think investors currently underappreciate or might warrant more digging in in terms of your different programs? Where should they be doing more work? Your thoughts, Craig? I think really understanding the neuropathic pain opportunity and to have three positive studies in neuropathic pain compared to others. I think that's an area that still investors, I think, are trying to wrap their heads around. It's a new area. There hasn't been a novel agent approved in neuropathic pain since Lyrica in 2002. I think it's just an area that when you think about morbidity-associated days of life lost, neuropathic pain is in the top five worldwide. The scope and scale of this problem is really large. I think the investor community, and I give the investor community a lot of credit, they're coming up to speed quickly. I think there's a lot of still education that needs to be done regarding endpoints, trial design, patient types, even basic definitional issues of how do you define what neuropathic pain is that we look forward to really working with the investment community to bring forward. Yep, sounds good. With that, we're at time. Scott and Craig, thank you so much for joining us. Thank you. Thank you, Roanna.