Good morning, everyone. Thank you for joining the 24th Annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next presenting company, Lexicon Pharmaceuticals. Joining us today from Lexicon is CEO Mike Exton, CFO Scott Coiante, and CMO Craig Granowitz. For those of you joining on the webcast, if you would like to ask a question, please do so at any time. You can ask a question using the chat box at the bottom of your screen. With that, we'll get started. I'll turn it over to Mike for the presentation, and we'll follow up with a bit of Q&A. Yeah, great. Thanks so much, Joey, and pleasure to be with all of you this morning. Really look forward to having a great discussion. So let me see if I can get this moving. Yeah, today I'll likely give some forward-looking statements and remind everyone to refer to our public filings if they want further information. At the end of last year, Lexicon went through a reorganization to really focus on our R&D portfolio, our innovative pipeline. And We're seeing great success for that already in Q1. As a result of that, we've really come to a situation where, as a company, we have a portfolio of diversified assets. We have great candidates, lead candidates in the broad cardiometabolic space. And each of those have significant partnership potential. We've seen evidence of that already, as you've probably seen recently. We signed a very significant deal for one of our preclinical assets in obesity with Novo Nordisk, which really gives it a great opportunity of clinical and commercial success. Each of these opportunities have multiple indications aligned with them. We are able to take advantage of those assets because we have an incredibly strong development expertise led by Craig and his team, which designed very pragmatic, very effective trials that really get to strong evidence generation and allow us to provide our partners and clinical experts with the information that they need to take these medicines forward. We can do that now as a restructured, lean organization where we have removed essentially most of the commercial organization promoting INPEFA. I will talk in a little while around how we are taking INPEFA forward. That allows us to really focus our efforts, focus our efforts as a development company, continuing to provide value and evidence generation of our lead candidates in a way that has a great cash preservation now and really with significant cash runway into 2026. So far this year, we've got a number of strong catalysts. I'll talk to you about some of the performance that we've seen already, both for LX9211, our asset for diabetic peripheral neuropathic pain, for sotagliflozin, where we continue to enrol in our hypertrophic cardiomyopathy trial, Sonata, and for LX9851, as we continue to execute the IND-enabling studies to enable Novo Nordisk to file the IND and move into the clinic. You know, Joey, what's important with our medicines in the portfolio is that they're all simple molecules. They're all small molecules. They're all oral medicines dosed once daily. Aside from the dosing benefits that that gives you, it also allows these medicines to have the potential of each one being a pipeline in a pill. We've already demonstrated that for Sotagliflozin, where we've got an approved label for heart failure in the U.S. and are now working with Viatris, our commercial partner, ex-U.S. and ex-Europe, to file in a number of countries this year. We continue to have studies underway that will generate more information supporting further label expansion for Sotagliflozin. Additionally, now the pivotal phase III trial for hypertrophic cardiomyopathy with that medicine is ongoing, and we expect to conclude in the not too distant future. You know, following from Sotagliflozin, importantly, we now have Pilavapadin, which read out the phase II-B study just recently in the Q1 of this year. We are planning the phase III pivotal trials to initiate in 2025 in diabetic peripheral neuropathic pain, which is the lead and largest indication for Pilavapadin. There are many other indications for this particular medicine as well. We have proof of concept data, phase II data in post-herpetic neuralgia. We have very compelling preclinical evidence in a range of spasticity indications, including MS and spinal cord injury. Finally, LX9851, as you see at the bottom of the screen, which I mentioned, we have recently executed a worldwide exclusive license to Novo Nordisk for that asset, where we are continuing the IND-enabling studies. Novo will then take that forward, not only in obesity, but there are a range of other associated cardiometabolic indications that are possible with this medicine. You see a portfolio of medicines that not only is diverse in the types of assets that we have, but within each particular medicine, a range of indications that allow for this pipeline in a pill approach with each of them. Now, as I turn to the most recent advancement that we've got in our portfolio, and there's been a lot of exciting stuff already in Q1, where in Q1, we completed the Progress phase II-B dose finding study. This study really set out to achieve a few things. Firstly, to show that the loading dose that was included in the original phase II study was associated with the tolerability issues that we saw in that study. As we saw as Progress read out, that indeed was the case because in the 10 milligram arm, the tolerability was placebo-like. It was incredibly clean, which is important in this disease state. Secondly, to find a single dose that we would take into phase III studies. We achieved that with the 10 milligram arm. The 10 milligram arm separated significantly from placebo, whether it be the 10 milligram straight in green or the 20 milligram dosed for a week, followed by a 10 milligram maintenance dose there in blue. This study did not hit its primary endpoint because it assumed as a part of the statistical analysis that all doses would separate from placebo. That was not the case for the 20 milligram straight arm, which we hypothesize, and we are collecting the information in the follow-up four-week safety follow-up right now, that this was associated with a higher dropout rate from the 20 milligram arm and a greater level of dizziness. Those then caused the lack of separation from placebo. You know, when we look at the time curves that we see with the 10 milligram pooled arms here shown in blue from placebo, we see a significant separation very early in the treatment paradigm. At week two, the 10 milligram arm already separates from placebo, showing a reduced pain response, reduced pain level in those patients taking the medicine. This continues to separate as we go through week eight. That gives us a lot of confidence in taking the 10 milligram arm, which now has been shown across multiple studies to separate significantly from placebo and now has a very clean tolerability profile, which is very important in this disease state. To take that through into the phase, to the end of phase II meeting with the FDA, and we're looking forward to doing that later this year to presenting to them the data package and our thoughts for what the pivotal trial should be, which, as we've said publicly a number of times now, is going to be a very simple phase III program. That's incredibly important in placebo-controlled trials that we expect the phase III studies to be a simple placebo versus 10 milligram design, which allows efficiency of getting the studies done, but importantly, should also mitigate some of the placebo response that we see in multiple drug arm studies, such as in Progress. Why is all this important for us in neuropathic pain and DPNP in particular? I mean, this is just a massive market, first of all. There are currently 9 million people in the U.S. alone with a diagnosis of DPNP. You know, T his is a market that is incredibly unsatisfied, incredibly dissatisfied. More than half of the patients have tried multiple treatments. In fact, they do not stay on current treatments for very long. They cycle through the gabapentinoids, duloxetine, and in many cases, opioids, because they just do not either get the pain relief that they are looking for, or they suffer from side effects, dizziness, nausea, and other tolerability issues that really make it untenable for a long-term treatment paradigm. So It' s a completely dissatisfied market that has seen no innovation for two decades. It is a patient population that is crying out for new options. This, combined with the fact that, as I mentioned, there is a pretty significant opioid use in this population, about 20% of all scripts written for DPNP are an oral opioid. We have a situation now where there are political tailwinds, such as the Alternatives to Pain Act or the No Pain Act, which will facilitate the pathway of new medicines, new non-opioid medicines in neuropathic pain through the managed care process and into the market. Really getting, as we have here with Pilavapadin, the potential to have the very first non-opioid oral medicine in neuropathic pain offers a significant commercial opportunity where there are likely very few, if not zero, competitors in this marketplace. Having a new option, being the first one and potentially only medicine in this space, offers Lexicon an immense opportunity, not only commercially, but also to bring significant relief to patients. Let me just pivot to talk about what we are doing with Sotagliflozin now. As I mentioned, towards the end of last year, we closed down essentially our commercial operations for INPEFA in heart failure due to the current competitive dynamics. We still have INPEFA on the market. We've got the tools in place to support the ongoing use and commercial availability of INPEFA in the market, albeit with a skeleton staff, so to speak. Importantly, our efforts with sota continue because we believe that when we see the results from Sonata, our phase III trial in hypertrophic cardiomyopathy, we have an incredible opportunity to take advantage of this medicine. In the meantime, as I mentioned, we continue the Sonata trial. We continue to support our partner, ex-US and ex-EU, Viatris, to do the regulatory filings that they need to do to launch this medicine in their countries. We expect a number of those filings to take place this year. Importantly, the evidence generation for sota and building the differentiation for the time that we launch in hypertrophic cardiomyopathy is ongoing. All of these trials, which are not actually funded by Lexicon, they're all funded by third-party partners, are really differentiating Lexicon, not only in the spaces that they operate, but also from the other SGLT inhibitors. Perhaps the best example of that is the recent publication in The Lancet, where it was demonstrated for the first time that Sotagliflozin and only Sotagliflozin reduced MACE, MI, and stroke, significantly reduced MACE, MI, and stroke. This is an effect that is not seen with other SGLT2 inhibitors. This differentiation will be incredibly important, not only for sota in HCM, but also in heart failure as we march towards a potential launch in hypertrophic cardiomyopathy. Let me just speak about HCM a little bit here, Joey, because you know there's a lot of interest in HCM at the moment, and rightfully so. Like in neuropathic pain, it's an area where there are very few treatment options at the moment. You know, as you see in the gray there, patients, these are the approved agents at the moment. Currently, people start out on a beta blocker or a calcium channel blocker, and oftentimes the effectiveness of those medicines is not particularly great. There is currently one cardiac myosin inhibitor, mavacamten or Camzyos, on the market. There promises to be more as some companies bring other CMIs to the market. That's attracted a lot of attention, and rightfully so, because it's giving a new option in what is a large market. This is a market with over a million patients currently. About 70% of those have obstructive HCM, for which the CMIs seem to be very effective. It's unclear yet or unknown whether they'll be effective in non-obstructive HCM. The cardiac myosin inhibitors are being used. Now, they are being used, but there's a number of limitations that come alongside the use of a CMI. As you know, they have pretty significant Camzyos, and we'll see what happens with aficamten. They have pretty significant REMS attached to them that involve significant logistics for any treating site. Rightfully so, because the CMIs do have pretty significant drug-drug interactions that need to be accommodated. As you can imagine, these patients do take a number of concomitant medications. In fact, also about a fifth of these patients actually turn into systolic heart failure with EF drops below 55%. That results in a number of tests, a lot of echoes that need to take place. All of these elements together, with the pricing approach that these medicines have taken, means that it's a very specialized utilization. In fact, Bristol-Myers Squibb reported in the end of 2024 that they had 10,000 patients on Camzyos currently. I mean, that's less than 1% of the total population. The utilization of CMIs, in my opinion, will continue to be pretty restricted to academic centers who have the staff, who have the capability, and frankly, the patients to go through all of the testing and monitoring requirements that's involved in the CMI. That really leaves the blue opportunity for other medicines. At the moment, Sotagliflozin is the only other medicine being investigated in hypertrophic cardiomyopathy. Really, we see Sotagliflozin as living alongside the CMIs and the beta blocker and CCBs, not necessarily as a competitor, but really occupying a very different space. It's a class that is very well known. It has limited side effects. We expect Sonata to read out positively, so it'll have great impact on the quality of life and symptomology of these patients. Importantly, we believe as Sonata is set up, looking across both non-obstructive and obstructive HCM, that this potentially could be the first medicine with an indication for non-obstructive hypertrophic cardiomyopathy. Now, from a pricing perspective, it's important to note this will be a very different situation to what we experienced in heart failure. Whenever you become a first-in-indication medicine, unlike in heart failure where you have a number of SGLT inhibitors approved for that particular indication, the discussions with PBMs and other payers are very, very different. We expect that when and if Sonata ends out positive and we have an opportunity to launch this medicine, this has the potential to be a very, very significant medicine in Lexicon's portfolio. Finally, let me just touch on LX9851, which I mentioned is again an oral small molecule dosed once daily for obesity and related indications. Novo Nordisk was incredibly impressed by this asset as they themselves see the future of weight management moving into oral therapy as well as non-incretin therapies or combination therapies with GLP-1s and other incretins. We are really happy to do this deal with them. We think we have the perfect partner to take this medicine forward into the clinic and realize the potential of the asset. Just to show you what they saw, this is just one piece of data of the importance of this medicine. As you see, semaglutide shown there in the blue and green bars significantly reduced weight in high-fat diet mice. When you remove semaglutide in the blue bars shown there circled in red, treatment withdrawal, of course, you get a rebound back to baseline levels of weight. If you replace semaglutide with LX9851, you get a maintenance of the weight reduction, which was one of the elements alongside the synergistic weight loss that you see between semaglutide and LX9851. There are very compelling preclinical evidence that excited Novo to do this deal. I think that deal just recently announced shows our willingness and ability to make the most value of our medicines for patients, for other pharmaceutical strategic companies, and frankly, for all shareholders, because initially, when we did the Viatris deal at the end of last year, that was a significant opportunity for us to capitalize in geographies that we do not operate. Now, having a worldwide exclusive license with Novo enabling us to take forward medicine that really they have the absolute world expertise to continue to develop and commercialize provides us with a great financial position and a great pathway over the next decade to continue to maximize the opportunity in our portfolio. Nonetheless, we've got a lot of great things coming up this year, Joey, for Pilavapadin. We're going to have the full Progress data in the not too distant future. As I mentioned, we've got our end of phase II meeting coming up soon. We're going to present that all at an upcoming medical meeting. For 9851, we're going to complete the IND-enabling studies this year and enable Novo to complete the IND submission. For Sotagliflozin, Sonata is enrolling at full speed. We've got sites now in the EU and Latin America. We expect that all the phase III sites will be up and running by Q3, so Sonata will be firing on all cylinders. For heart failure in INPEFA, we continue to support Viatris, and we have a potential type C meeting to look at that MACE data and see if that's something that can be incorporated into the label. Finally, for Sotagliflozin, for Zynquista, we will have our end of review meeting in the not too distant future with the agency as well. Really a lot going on for us, Joey. Look forward to having a further discussion with you, with Craig and Scott here as well. Great. Thank you so much, Mike, for the presentation. To members of the audience, once again, if you'd like to ask a question, you can do so anonymously using the chat box at the bottom of your screen. We'll get started with a couple from me, Mike, and others. Heading into the LX9211 end of phase II meeting with FDA, what are some of the key questions or aspects of the phase II pain data that you'd like to discuss with FDA? Yeah, I think the first piece is obviously confirming our confidence in the 10 milligram dose, that we see that that is a dose that is both from an efficacy and tolerability perspective worth taking forward, as well as how we see the phase III design. I think what we feel very confident with now is that we've really refined the design in such a way that allows us to be confident that we can continue to design trials that will separate from placebo. It's just confirming a continuation of the trial design that we will continue to incorporate patients that have background standard of care as a part of the trial design. We think that's really important because it's pragmatic. It's how patients are treated in the real world. We are believers in enabling patients to continue on their single background pain med so that you do not wash them out and get this artificially high baseline pain score. That will be the key elements that we are going to take forward. Got it. I guess, could the phase II-B trial potentially serve as maybe one of the pivotal trials? What are your thoughts on that? Yeah, that is not our base case, Joey. We think that we will need to run two phase III trials, two confirmatory trials. If one of those comes out that it could require some supporting evidence from the phase II-B, it could potentially be supporting evidence, but we do not expect that the Progress trial will form one of the pivotals. Got it. Mike, you touched on it earlier in terms of what you are thinking about a potential phase III design. Anything else you can provide on design here in similarity to the phase II-B, thoughts on powering and effect size, types of patients enrolled, inclusion, exclusion criteria, background med, things like that? Yeah. Great question. We think that, as we've said publicly before, that this is likely to be a two-arm design, around 300 patients per arm, 300-350 patients per arm, which is interesting because it's not too dissimilar, in fact, in size to the PROGRESS study, albeit with just two arms. Significantly powered to see separation from placebo. We will likely power it for a separation as we've done in the previous phase II studies. Really, a lot of the other conditions should remain pretty consistent. Having said that, the execution of the trial, I think we will really dig into the data in some granularity to see, are there any other potential ways that we can continue to reduce that placebo response? It is an important but somewhat overlooked aspect of pain trials that the more active arms you have in the trial, Joey, and this is published in a lot of literature, the higher the likely placebo response. It makes sense, right? If you're a patient and you come into a trial and three of the four arms are active, and you know that, of course, because you sign the informed consent, then you're already thinking there's a high likelihood I'm going to be put on an active treatment. We did this very deliberately so that in the phase III pivotal trials, we end up with only two arms. That in itself has the effect of reducing the expectation, which, as we know, is a significant part of the placebo response in the phase II trial. So that really is going to be a very important aspect for us. It will be less so in the design, but in the execution. As you know, there were 80 new sites that we brought on for the progress trial that we will take a look at and ensure that they were really executing the trial to our expectations. But in overall, I think the design will be very similar to what we have seen in the previous phase II studies. Mike, could I add a couple of comments as well? Please. Yeah. Yeah, I think, Joey, one of the things that we really want to make sure that we reinforce, and this is something we've heard very strongly from the patient groups and the medical community, is patients and their providers assess the reduction in pain of patient to baseline. What Mike was really focusing on appropriately is our discussions with the regulatory authorities, which is going to be the placebo-adjusted reduction in pain score. There, as Mike mentioned, we're powering the study similarly to what we've already done and achieved twice, is really that reduction in pain score, which is similar to what pregabalin has experienced historically against placebo. When you look at the Progress study, the patient to baseline was 1.75 points in reduction in pain score. Importantly, some of the other elements that we're going to reinforce in the phase III in our discussions with FDA is the tolerability is that the completion rate of patients was identical to placebo. Eighty-eight percent of patients on the 10 milligram dose arm completed treatment, which was identical to one-tenth of 1% of what was achieved with placebo. We have a really well-tolerated drug with few to no drug-drug interactions in a group of patients that have significant drug-drug interactions. We also believe that we're going to have significant ability to enroll even a broader group of patients based on some of the additional supportive work that we're bringing to bear. We also think some of the secondary endpoints, such as burning pain, which we've showed briefly, sleep interference are going to be very important supportive points that could be very important in promotion. I think these are the kinds of things, particularly in light of a breakthrough designation that we have with the FDA that allows us to have quite a bit of dialogue with the agency that we hope that we can bring to bear as a very important novel option for patients with neuropathic pain. Got it. Thanks, Craig. Excuse me. That's very helpful. In terms of the asset itself, 9211, what are you thinking in terms of potential partners? Obviously, you'll want to have your end of phase II meeting, get the phase III trial program hammered out here. Do you plan to take it forward yourselves into phase III, or are you in active discussions with partners around the program? Yeah, we're in active discussion with quite a lot of companies at the moment to really take them through data beyond what we've shared topline to help them understand the context, the commercial opportunity. I think, as I mentioned in the presentation, this is an area where, as Craig was saying, we've got sort of two objectives. One from a regulatory objective, what do you need to demonstrate to regulators, but then what do patients and the market need, particularly in this area where you're a potential first to market in an area that hasn't had any innovation for two decades and has this real, if you like, political tailwind against oral opioids, helping partners understand that from a commercial opportunity. As we've said to these partners, we think that we have developed a really strong development expertise in this area. Running trials in neuropathic pain is complex for the reasons of placebo control. There are a number of factors that you need to be very careful with. We think that having a partner that can maximize the commercial opportunity of this particular medicine, because it's a multi-billion dollar opportunity, it's a multi-billion dollar market currently, and it's fully genericized, a partner that can take advantage of that, at the same time that we can work with to continue to develop the breadth of indications makes sense. We certainly intend on having a significant piece of this asset moving forward as well. Got it. I want to ask a couple of questions on HCM. The first one is on Sotagliflozin. You haven't specifically evaluated the drug in just HCM patients prior to the phase III trial, in your traditional phase II, phase II-B sense of the word. I guess, what gives you confidence that in the phase III trial success? Yeah, great. Craig? Great question, Joey. We've done a lot of analysis of the score dataset, which, as you recall, is about 11,500 patients. We looked specifically as a starting point at the group of patients with left ventricular hypertrophy and normal blood pressure. That group probably contains quite a significant percentage of patients with non-obstructive HCM. In that regard, we showed a 50% reduction in both heart failure events and a 50% reduction in stroke and MI events. Those numbers are even more impressive than the overall scored population overall that included all of the 11,500 patients. It was not a small sample. It was over 500 total patients. We've also looked mechanistically, and some of this data was presented by Dr. Sharlene Day at AHA. There are two major fundamental issues that seem to be at play in HCM hearts. The first is that there is an over dynamic use of energy in those hearts. The second is that there is diastolic dysfunction. We have demonstrated with Sotagliflozin an impact on both of those. In fact, some of the data that Charlene's team, Dr. Day's team, presented at AHA and is going to continue to present throughout the year is that if you take explants of human heart tissue from surgical excision of obstructive HCM patients and you put it in their model system, you show a reduction in overall cardiac work. We also know from a lot of other studies that use of Sotagliflozin is associated with an improvement in diastolic dysfunction. We already know overall the drug works to reduce heart failure events, reduce MACE events, has no impact on AFib. We've now demonstrated in HCM hearts a reduction in work. We know that the drug is associated with improvement in diastolic function. We are continuing to run additional mechanistic studies, but we have a very high degree of confidence that the drug is going to work in this subset of HCM. As we've shared with you, Joey, and your listeners on a number of occasions, we believe that the direct effects of SGLT1 inhibition on the heart and on the platelet and endothelium are associated with a continuous improvement of Sotagliflozin to reduce heart failure events across the entire range of ejection fraction, which is not something that you see with SGLT2 inhibitors, where you seem to have a reduction in benefit as ejection fraction approaches near normal ejection fraction. Again, all of these are indications, as well as the fact that the primary endpoint that we've negotiated with FDA, which is an improvement in KCCQ, is something that we feel quite confident that we can achieve in the trial and similar to the range on a placebo-adjusted basis that the CMIs are achieving in obstructive HCM. Sorry for such a long answer. No, very insightful. And thank you for the color. Very helpful. One last quick one. We're running up on time, but the thoughts on cash position and cash runway and what readouts does this get you through? Yeah, thanks, Joey. We ended 2024 with $238 million in cash. As Mike alluded to on the one slide, we're fully funded to achieve all those milestones and catalysts outlined on the one slide that he went through. We have cash runway comfortably into 2026. That excludes any potential results from partnering discussions that we've indicated are ongoing at this time. Great. Mike, Craig, and Scott, thank you so much for the presentation and the excellent discussion. Yeah, thanks for having us, Joey. Pleasure. Thanks, Joey. Thank you, Joey.