Good morning, everyone. Welcome to the Lexicon 2024 Investor Day. We appreciate all of those who came out to join us on a Monday morning. We hope we have a great program for you planned. To kick things off today, I'd like to introduce our CEO and director, Lonnel Coats. Good morning. Thank you to all of those who made it live with us here in the room and for those who are on the webcast. I'm Lonnel Coats, Chief Executive Officer here at Lexicon. Today, we will be making forward-looking statements, and some of those statements will contain risks. Our risks are identified in our SEC filings. Let me start by speaking to what makes me so excited to have been the CEO the last 10 years here at Lexicon. There we go. Three things. One is that one of the things I love about our company is that we're bold in our vision, we're fearless in our execution, and we have a tremendous commitment to our mission, which is to pioneer medicines that transform patient lives. We've been able to do that because we remain, as I said, bold. How bold was it for the company many years ago to take on a massive project that we called Genome5000, which was to systematically define the functions of 5,000 genes in mammalian physiology? And from that, we have a unique perspective and understanding of the potential therapeutic targets. From that, we created a scientific pipeline or scientific platform that essentially allowed us to use our knockout technology to take this company from its discovery roots all the way through to being a fully integrated pharmaceutical company. And I've had the privilege over the last 10 years to shepherd this company forward. So let's talk about that pipeline of scientific rigor. It has led to a pretty awesome set of targets as well as programs, starting with INPEFA or, the first and only dual SGLT1 and SGLT2 that received a broad label for heart failure nine months ago. We also believe very strongly in Zynquista. After many years of toil and debate and discussions with the FDA, we feel pretty confident we have a path forward for patients living with type 1 diabetes and chronic kidney disease, and we're well on the way of resubmitting. And let's talk about sotagliflozin, as Dave said on the video. We continue to find additional uses for sotagliflozin. Here, we believe very strongly hypertrophic cardiomyopathy is the next opportunity for which we are able to advance our mission forward and make it available to patients. We're now going fast forward into phase III. LX9211, 10 years ago when I arrived in this company, I had a few people that were urging me to pay attention to this asset. At the time, it was called something different, and it was in a discovery alliance with Bristol Myers Squibb. That target was called AAK1. That was, again, discovered by Lexicon. I'm glad I listened because here we are now in rarefied air, and the phase II study showed proof of concept where many have failed over and over in the last 20 years. So here we are now in late-stage development with LX9211, which is a non-opioid oral therapy for diabetic peripheral neuropathic pain. And lastly, my friends, today, here for the first time, we will announce another target that has come from the Lexicon platform of science, and that's in the area of obesity and chronic weight management. And I just want to say this: we didn't do this because it's the cool thing to do today, because it's the cool area to be in. This work has taken a long time to develop. What you're going to find is cool, is that we have a remarkable opportunity to be part of a remarkable market. With that, we're going to have an opportunity to dive deep into each of these areas so you, as investors who may be looking at this company, can understand why you should be paying attention. That long path from discovery all the way to being a fully integrated company happens only because investors have believed in this company and have made substantial investments in this company to allow us to carry forward the mission that we seek to do each day. So today, we'll start off with sotagliflozin. We're going to go over to MOA, and then we're going to introduce some new clinical information I think that would be very impressive for you to know. INPEFA will talk about the market overview and give you some launch updates. Then we're going to go to sotagliflozin, and we're going to make the case for hypertrophic cardiomyopathy, looking at the MOA, the clinical rationale, and give an overview and where do we think the treatment position is important should we be successful. Then we're going to talk about this Zynquista for type 1 diabetes, the MOA, the rationale for the resubmission, the regulatory history, the market overview, and unmet needs that still exist and the next steps that we're pursuing in terms of our resubmission. LX9211 for diabetic peripheral neuropathic pain will give you a history, market overview. I think we're also going to take a step back and give you some of the scientific rationale that got us here to late-stage development, that it just didn't happen. It took a lot of toil, a lot of work, a lot of effort, a lot of investing to get us to this point, to be in late-stage development. Then we're going to take a short break, and boy, we then got an awesome expert panel, no pressure on the panel, to talk about HCM, T1D, and diabetic peripheral neuropathic pain. That will be moderated by our Chief Medical Officer, Dr. Craig Granowitz. Then last but not least, we'll tell you a little bit about LX9851, the target and the molecule that we're now moving forward for obesity and chronic weight management. Then I'll come back to the stage, close with a few things I think are important for you to know to summarize why we think this is an investable company and you should be paying attention, and then management will open the floor for questions toward the end. Without any further ado, let me bring our Chief Medical Officer up, Dr. Craig Granowitz Well, good morning. And so pleased to be here. We've done so much over the last several years at this company, really grounded in that science, which is the Genome5000. And I think it's an important theme we're going to come back to again and again throughout the session today, is that we have defined all of our drugs based on targets that came from an animal phenotype. So as opposed to traditional drug development where you're starting with a pathway or an enzyme, we're actually starting with a phenotype. So in a sense, we know the answer before we start, and it's just a matter of then putting the pieces in place. So that's why we go into a lot of these indications with a tremendous amount of confidence, even very tough ones like neuropathic pain, because we know already the answer to the question that this gene is associated with this phenotype and in a systematic getting the right molecule that can deliver that phenotype in human beings. So I wanted to take a few minutes and first talk about the mechanism of action of sotagliflozin. The company's vision of this was not to develop another SGLT2 inhibitor. The world has enough SGLT2 inhibitors, and while they are great drugs, the world needs a dual inhibitor of SGLT1 and SGLT2, not perhaps for glycemic management and type 2 diabetes, but for the indications that we're looking at. We have taken a purposeful approach in each one of the areas that we're exploring based on the unique expression of where SGLT1 takes place and not SGLT2. So if you look on this slide, and we're really going to focus this morning's session, as Lonnel mentioned, on the endothelial cell and the issue around stroke and MI, and I'm going to share some data with you that was just presented at the American College of Cardiology meeting last week. We're going to focus on the myocardium itself and why we believe we are the best drug for heart failure, particularly patients with HFpEF, and why it flows right into the hypertrophic cardiomyopathy, and then also on the GI tract, and that limiting glucose uptake from the gut is another critical component of why sotagliflozin would be such a great adjunct to insulin, even better than an SGLT2 inhibitor in that use. Just as a reminder, SGLT2 is primarily restricted to one small part of the kidney, and it has a tremendous function of inhibiting reuptake of glucose from the urine. And that's, again, how these drugs work and have all the benefits they have. But there's also SGLT1 receptors in the kidney. So when you think about it, you have SGLT1 in the kidney, in the GI tract, in the heart, and in the endothelium, and that really ties very much to the life cycle management that we're pursuing with sotagliflozin. Now, if you look in a number of disease states, you see increased expression of SGLT1 and SGLT2, but you can see there is a broad range of particularly cardiac indications where SGLT1 expression is increased. And in fact, there are many that say when you use an SGLT2 inhibitor in the kidney, you're actually increasing SGLT1 expression also in the kidney. So by blocking both SGLT1 and 2, you're getting all the benefits you see with an SGLT2 inhibitor, but a lot of incremental benefits in SGLT1. I think there's another study that I wanted to share with you that I think is very important. This was a large data set of intensively qualified patients from the standpoint of genetic profiling and otherwise. And what you see is if you look at down mutations in the population of human beings in large studies called ARIC and others, and you look at mutations that are otherwise silent in those patients around SGLT1 expression, you can see that down regulation of SGLT1 is highly significantly correlated with a number of important disease states, including diabetes, heart failure, and death. If you look at that same population for down titration of SGLT2 expression, you see very weak correlations with some of those same disease states. So again, these are all indicators that SGLT1 is playing an important incremental role in human biology. Now, before moving on to some of the evidence from ACC, I wanted to share with you the strategy that we have really embarked upon, and I call it the short, middle, and long-term strategy to differentiate sotagliflozin from SGLT2 inhibitors. So the short-term strategy is what is the mechanistic differentiation, right? We have to establish these drugs work differently on physiology before we can establish them clinically and create a compelling story for clinicians and payers. The next is to explore ways to tie that to clinical differentiation. And I'm going to share with you some of the data from our own registration program in heart failure, but also in MI and stroke that show significant differences with sotagliflozin over SGLT2 inhibitors. And the third and the long-term value are some of the indications, particularly type 1 diabetes and hypertrophic cardiomyopathy. So the first stage is establish the difference. The second stage is drive value within our heart failure indication where we are to create differentiation and value creation. The third is to create novel indications and hopefully long-term durable value for the company well beyond the patent expertise of SGLT2 inhibitors that will continue to define and create value for Lexicon and sotagliflozin. So now I wanted to shift gears and move quickly through three important abstracts that we shared at ACC. I'm sharing these with you because we wanted to tell a story at ACC from mechanism to clinical validation. That story is the story of stroke, ischemic stroke, which is really one of the elements in cardiovascular disease that patients are most fearful of. Even more than in MI, people are afraid of having a stroke. That loss of autonomy associated with stroke is very troubling to most people. So I wanted to share with you three abstracts that pick apart the mechanism and then the clinical pull-through of that. And the first two are mechanistic studies. So the one on the left, which I'll go through first, is focused on the platelet and the use of sotagliflozin to inhibit platelet activation and degranulation associated with platelet stickiness and the formation of a plaque. There's a partnership in the formation of a plaque between the platelet and the endothelial cell. The endothelial cell is the landing pad that the platelet sticks to. And you really have to have both activated in order to form a plaque. And a ruptured plaque is, by definition, an ischemic stroke, right? It is blocking the blood flow. The third is to take some of our additional data from our completed heart failure program, the SCORED trial, to show the unique value of sotagliflozin and only sotagliflozin to reduce levels of ischemic stroke. Moving through this, the first is I wanted to focus on the platelet. Again, this was presented as a moderated poster at the ACC meeting in Atlanta a couple of weeks ago. What you can see on this slide is that there are a number of different stimuli that are associated with activating a platelet. Normally, platelets are not activated. You don't want sticky platelets. But when certain things happen, like collagen is exposed in a blood vessel or thrombin, which is part of the clotting cascade, is exposed, or ADP, which is an energy source that is available, which is another sign of cell damage, the platelet becomes activated. What I'm going to share with you in the experimental design was when you block the SGLT1 receptor with sotagliflozin, you limit the ability of that platelet to become activated. So you are limiting the ability of that activated platelet to be part of the clotting cascade. And what was done in the experimental design is there were two different experiments, but basically, you're taking human platelets and stimulating them outside of the body and looking at stickiness in a couple of different ways. And what you can see in each one of these different stimuli that I highlighted above, whether it's ADP or collagen or thrombin, the more soda you add to that system, the less you activate the platelet, whether it's degranulation or adherence. So the drug is working just as we expected to prevent that from happening. Going forward to the endothelial cell, again, what was done here is these are human endothelial cells. When you put them in an experimental system and you stimulate them with endothelin-2, you can see the control before the stimulation is in the gray bars. The green bars is after you stimulate them with the stimulus. And then if you add sotagliflozin, you're preventing or limiting that stimulation. Moving forward into the clinical outcomes is if you look at our 10,500-patient SCORE trial, you see a reduction in the left in all-cause stroke, whether it's fatal or non-fatal, in the middle ischemic stroke. Again, ischemic stroke is associated with a blood clot, or hemorrhagic stroke on the far right, which is far less common and is generally associated more with elevations in blood pressure. But you can see on the blue versus the gray, in all of those categories, sotagliflozin reduces human clinical stroke in these clinical trials. And I'll reflect back later and show you out of our own data compared to the data with the SGLT2 inhibitors, you do not see that finding with SGLT2 inhibitors. So what you see also is that differentiation in stroke happens early and continues to grow over time. And what you see is the placebo arm in gray and the sotagliflozin-treated patients. And again, these are patients with kidney disease and underlying risk of heart failure. And you can see that the patients treated with sotagliflozin separate early significantly, and that benefit grows over time, whether you look at all-cause or ischemic stroke with highly significant p-values, more than a 30% reduction in stroke. I hope that I've shared with you on the last few slides that there's a nice story that came out of ACC. When you inhibit the platelet, you inhibit the endothelium, and then you see the clinical correlate of that, which is a reduction in stroke, again, one of the most devastating outcomes in patients that have coronary disease who are at risk or have heart failure, but also have a risk of stroke, MI, and cardiovascular death. Now I'm going to entirely shift gears and move forward into our clinical data. I'm going to be tag-teaming this with my colleague Tom Garner, the Chief Commercial Officer. I'm going to cover first some of the clinical data, and then Tom will really talk about the market opportunity, as I've shared here. So I wanted to focus first, and Lonnel already mentioned, one of the things we're really proud of with the approval of INPEFA is a broad label across all left ventricular ejection fraction, the reduced ejection fraction, the preserved ejection fraction, and in patients with and without diabetes. And I think one of the things that we feel very comfortable with, and we're gratified to see the guidelines, is that regardless of the patient type, if you have heart failure or risk of heart failure, sotagliflozin is a great potential choice for patients to develop future heart failure events. So broad label. I'm going to share with you over the next several slides where and why we believe our data is particularly compelling in heart failure as well as stroke. Tom will really pull through on what the guidelines say that reinforce and provide tailwind for why we're so excited about INPEFA in heart failure. These were the two pivotal trials we did. This is a Kaplan-Meier event curve. The two trials are SOLOIST-WHF, which was in patients that had symptomatic heart failure events at the time of the inclusion in the clinical trial, and SCORED on the right side, which again is a group of patients that have underlying risks of heart failure but not an acute heart failure event, same combined endpoint of total cardiovascular death, hospitalization for heart failure, or an urgent heart failure visit. If you look at the group on the left, and this is a unique group, sotagliflozin and INPEFA is the only SGLT inhibitor that has studied this group of patients with an active heart failure event. What's very important, if you look at that, look at the scale on the y-axis. The event rates in these patients are extraordinarily high. Within one year in highly treated patients that are getting all the underlying medications, 50% of them are coming back to the hospital. Either a heart failure event or they have died of a heart failure death. And when you look at the benefit of INPEFA in this in blue, you see a very rapid separation occurs within three months. But look at the magnitude of the difference. Not only is it a 33% relative risk reduction, but it's a 28% absolute risk reduction. If you look up here, there are 76 events per 100 patient years in the placebo group. And again, all these patients in the placebo are on best medical therapy. They're all on beta-blockers. They're all on RAAS inhibition. They're all on MRAs. So these are getting best medical therapy, and you're still looking at 75, 76 events per 100 patient years. And with sota, that is down to 51. That is a number needed to treat of 4. I don't know of any other cardiovascular drug that has a number needed to treat of 4. And when I've seen data from the SGLT2 inhibitors, they're talking about NNTs of 15, 20, or 30, not an NNT of 4. And when you look at SCORED, you see, again, similar data, much lower risk group of patients, same outcome, but again, same great rapid early separation of the curves. The other important element, particularly for payers and patients as well as their providers, is about half of the patients in that SOLOIST population were started on treatment before they left the hospital or on the day they left the hospital. And what you see is a very rapid separation of the curve. And by 30 days, there is a 50% reduction in readmission to the hospital, 50% reduction that continues out to 90 days. And you're looking at highly significant p-values in this. And this is about 400 or so patients in this group. So again, a large group, rapid separation. We believe that is related to some of the SGLT1 expression in the myocardium itself, which again, you don't have SGLT2 channels on the myocardium. Now, while it's not a head-to-head study, the only other data that's out there in a similar hospitalized population with SGLT2 inhibitor is a study called EMPULSE. And EMPULSE was presented. It's been published. But if you look at the curves, these curves look pretty different. You do not see separation, same endpoint. This is hospitalization for heart failure, but you do not see that at 30 days, and you only begin to see separation at 90 days. Moving forward now to stroke and MI. While we are currently only indicated for heart failure events, these events of stroke and MI are also extremely important to clinicians. These were the data that came out of our SCORED clinical study, this large clinical trial. What you see, again, is very rapid separation. By 90 days, you see a separation in the rates of stroke and MI between the treated group with INPEFA or sotagliflozin and the gray in placebo. You see rapid, large separation, about a 23%-30% reduction. You see both in MI and in stroke. Go back to the stroke data I showed you before. This is that same set of data. But what I did in the ACC data is we looked further, refining that to both all stroke as well as ischemic stroke. So again, same large benefit there. Now again, while not a head-to-head study, and we were fortunate to have one of the authors of this paper here that was recently just published in the last month or two, but there was just a meta-analysis that was done on nearly 80,000 patients in all of the large randomized trials with SGLT2 inhibitors in heart failure. This analysis, which was just recently published, did not include sotagliflozin. And what you see in this, it's a little bit of a complicated slide. But whether you look at patients with diabetes at high risk for stroke and MI, if you look at their heart failure trials and here are all the studies, if you look at the CKD trials, what matters is down at the bottom, you see no benefit on stroke, zero. It is interesting if you look at the canagliflozin studies, and again, they're scattered through here, and you'll be able to see that in your packets with some of the slides, you see slight effects on stroke, but not significant. And it is interesting that of all of the SGLT2 inhibitors, canagliflozin is the only one that has a little bit of activity also on SGLT1. So again, while not head-to-head data, if you look at this and you look at this, I think the story tells itself. So with that, I'll turn it over to my colleague Tom. Thank you, Craig. Good morning, everyone, and thank you for joining us today. My name is Tom Garner. I'm the Chief Commercial Officer here at Lexicon. I'm going to take the next few minutes to just give you a sense, building upon what Craig has shared, as to the heart failure market opportunity that we believe that INPEFA can address. Starting with this slide, this gives you a sense as to the heart failure burden that exists in the United States today. If you look at 2019, starting on the chart on the left, you could see there's about 7 million patients who are suffering with heart failure in the United States. This number is expected to grow by nearly 70% by the end of the decade to about 8.5 million. This is a growing and very substantial patient population. Factored into that is then the impact that this is having on the health service as a whole. So going back to the beginning of the decade, the impact of heart failure costs was estimated to be about $44 billion. Again, by the end of the decade, this is expected to increase to nearly $70 billion. So this is a significant drain on resources, and we believe that INPEFA is very well positioned, given all of the data that Craig has just shared, to really address this need in addition to the currently available treatments. So in the middle, you could see that hospitalizations account for nearly 80% of that overall cost. And what's driving that cost is hospital readmissions in the first hospital admissions in the first place, but then the fact that when patients leave, they're often readmitted very, very quickly thereafter. As Craig has shared, some of the data that we have, specifically coming from the SOLOIST-WHF trial, shows that with INPEFA, we can really address this head-on with a very differentiated offering, given that we have a dual inhibitor. The SGLT class is really at its infancy in terms of uptake for the treatment of heart failure. The other SGLT2 treatments were given indications in the early part of this decade. Since then, we've seen the medical community really capitalize and catch up on the value that these products add. INPEFA is now one of three SGLT medications that are referenced in the ACC guidelines, which I'll come on to shortly. Obviously, we are the only dual inhibitor of SGLT1 and SGLT2, which, as Craig has mentioned, we believe offers significant value to HCPs, to patients, and to payers. But despite all of this energy and excitement around the class, as it stands today, only around 11% of patients are actually being started on an SGLT therapy for heart failure. Now, this is an area where I think the medical community is really pushing very hard. AHA, in particular, have a Get With the Guidelines program for heart failure. So we anticipate that this is just going to increase markedly over the coming period. Having said that, though, the market itself, the SGLT class, is growing very well. So it's growing at around 70% on an annualized basis at the moment, and we anticipate that that will carry on further into the near future. Craig mentioned the guidelines that exist for heart failure. I think it's important to note that the SGLT class now is recognized as one of the four pillars of guideline-directed medical therapy for the treatment of heart failure. So it's important, whether you're a hospitalized patient or a recently discharged patient or even a patient who is showing symptoms of worsening heart failure, that an SGLT medication should be considered, including INPEFA. We've been very excited recently with two important additions to the guidelines that came out in 2022. Last year, we saw the ACC consensus statement for HFpEF, which again recognized SGLT inhibitors as foundational for all patients who have HFpEF. Then just a few weeks ago, we were even more excited because we saw the updated consensus statement for HFrEF, which actually made mention of sotagliflozin as the newest agent that inhibits both SGLT1 and SGLT2. They also reclassified the SGLT2 class as the SGLT class, which we think is a nice hat tip to the fact that we are now approved and on the market. So this is a class that is recommended across all types of heart failure, is seen as foundational, and is obviously in a position where we anticipate it growing significantly over the next few years. Switching gears to what our customers have been telling us about INPEFA since we launched the product back in June. So there's four key things that we're hearing routinely. First is the product promise that exists for INPEFA. I think it resonates very strongly with cardiologists because they are looking for a treatment that helps keep their patients well and potentially out of hospital. I think that that's where the NNT of 4 and the fact that we reduce hospital readmissions by 50%, both at 30 and 90 days, is seen as very compelling, both for clinicians who are treating patients in the inpatient setting, but also those who are treating patients in the outpatient setting and preventing them coming back into the hospital. In terms of patient type, we've also been very encouraged that they see INPEFA being used across a broad spectrum of patients. I think building upon what we have shown in both this SOLOIST-WHF study for that hospitalized or recently hospitalized patient, but also thinking about the SCORED population, where you can prevent patients coming into the hospital, I think is seen as a significant value add. And on top of that, as I mentioned on the previous slides, GDMT remains a focus for us as an organization. Obviously, there is a significant amount of interest being put into GDMT as a whole, both within the clinical community and the professional community, but also through industry as well. We continue to work very hard to make sure that patients who are eligible for an SGLT, including INPEFA, have that option. To close, I just wanted to give a sense as to how we are doing in terms of access. I think we have mentioned previously that our current coverage is in the 40% range. We are working very hard with payers across the board to make sure that whether a patient is on a commercial plan or a Medicare Part D plan, that they have good, equitable access to this product. What you can see on the slide here on the left in the blue is those where we had covered or better coverage for INPEFA already. And you can see we are making some good progress. Medicare, in particular, remains a focus for us because we know that at least 60%+ of the patients that we are going to be targeting with heart failure sit within that Part D group. We do anticipate over the next few months, and we've been signaling this since last year, that we anticipate seeing far better access for INPEFA through the second half of this year, given the very encouraging discussions and dialogue we've been having with payers about the value that INPEFA can offer their plans and their patients. With that, I will hand off to Craig to talk about the next exciting opportunity for sotagliflozin, which is hypertrophic cardiomyopathy. Thank you, Tom. So I wanted to move forward now to our next innovation. And as we've talked about at the outset, it is differentiation, short-term value creation, and as Tom just mentioned, really segmentation in the market and creating that set of value. And now really moving into a couple of new indications, which I'll start with HCM and then turn it over to Jeff for type 1 diabetes. As a reminder, we're now going to focus right on the heart. We're going to go to the heart of the matter, so to speak, and really talk about hypertrophic cardiomyopathy and why we believe that this is a great opportunity for patients to improve care with sotagliflozin in this indication. And we're going to have more time to talk about that with our expert, Dr. Day, during the panel discussion. Now, when we looked at our data, this has been really a two-year journey. It's hard to believe we were talking about that, that we started these conversations two years ago with Dr. Day. And it really came out of the discussions when you look at the overall data and I apologize the slide's not showing so well here with the confidence intervals. But when you look at the hazard ratio, so this is outcome of a heart failure event by left ventricular ejection fraction. What you see here is either a line with a negative slope or a flat slope, which again, you don't see with any of the other agents in heart failure. They seem to work primarily in reduced ejection fraction to get the pump to pump a little bit harder, right? All those drugs are designed to get the heart to squeeze harder. But what you see in HFpEF is, in general, you see a heart that is not necessarily large and sort of unable to pump, but you have a pump that is too stiff. And the heart doesn't fill properly. So the mechanics and the mechanism is quite different between, in general, reduced ejection fraction and preserved ejection fraction. But the remarkable thing is that sotagliflozin seems to work similarly well across both. And that goes back to when we studied both HFrEF and HFpEF in our single registration program, people thought that was unusual because everybody else had studied HFrEF separately from HFpEF. And this is where the data is. So we started thinking about that. What could be different about INPEFA or sotagliflozin? And really, it goes back to, again, the physiology of the SGLT1 receptors on the myocardium. And then when we further looked at the data and this was, again, trying to model a group of patients that would have a normal left ventricular ejection fraction and looking at those with hypertrophy of the left ventricle, so a big, thick left ventricle, the primary reason for that is hypertension. So it's like any other muscle. As it's pushing against a harder load, in this case, high blood pressure, the heart, like most muscles, gets thick. The problem with the heart is, as the heart gets thick, it gets stiff and it's unable to fill. And remember, when the blood comes into the heart, it's at relatively low pressure. So when you actually get a thicker heart, that low pressure is not enough to actually fill the heart properly. When you look at this group of patients with left ventricular hypertrophy without hypertension, that's a pretty unusual group. In a sense, hypertrophic cardiomyopathy is a subset of patients with preserved ejection fraction and is a group of patients that have left ventricular hypertrophy without hypertension, right, because it's due to a genetic defect in actin and myosin. I don't know if you remember the slides I showed you several back, but in the overall population with sotagliflozin, you're looking at roughly a 35% reduction in stroke and MI as well as heart failure events. If you look at this group, they're at higher risk of disease progression than the overall group studied in our clinical trials. The benefit with sotagliflozin is actually even greater than the benefit that you see in the overall population. Just to put a point to that, if you look at these numbers and I apologize, the numbers are a little small here. But if you recall, I was showing you about a 33% reduction in heart failure events or stroke and MI, if you remember the overall group. Here, you're looking at a 60% reduction of heart failure events and cardiovascular death. And you're looking at a 50% reduction, roughly, in stroke and MI. So you have a group of patients that is, in a sense, enriched for a group that looks like hypertrophic cardiomyopathy. You have a group of patients that are at higher risk of disease progression than the overall HFpEF patient. And you're looking at a treatment benefit that is even greater with sotagliflozin than you see in the overall group. So we thought that was a pretty good basis to say maybe sotagliflozin could work in hypertrophic cardiomyopathy. And there's a lot of other physiology that would support, which again, Dr. Day might want to comment on later, that would support, again, the SGLT1 expression and why sotagliflozin would work on the myocardium itself, on the heart muscle itself, to do that. So just moving very quickly to design because I don't want to take Dr. Day's thunder. She's the expert here. But we went down to the FDA with a single clinical study with a symptomatic relief endpoint called KCCQ. KCCQ has been validated by the FDA as an endpoint for nonobstructive hypertrophic cardiomyopathy of other registrational trials. Our proposed indication is improve symptoms and physical limitations, which is what all these agents are designed to do. All of the CMIs and the other agents are to improve physical functioning, not to improve long-term outcomes. But as I showed you on the last slide, we already have long-term outcomes. And importantly, we include both obstructive and nonobstructive patients in the trial. So we have a single 500-patient study, 250 patients each with obstructive and nonobstructive. We have a KCCQ endpoint of patients that have symptomatic heart failure at the time of inclusion. And this is an endpoint that we know we achieve in the overall heart failure results. And importantly, we have a much broader group of patients included in this trial than the current CMIs because we're allowing patients to be on a CMI, to be on their beta blocker, to be on their CCB. We allow an ejection fraction down to 50%, not 60% with the CMIs because the major risk of CMI is that you trip the patients into heart failure. We're indicated to reduce heart failure. With that, I'm going to turn it over to Tom to go through the commercial aspects of HCM. Thank you, Craig. So I think anybody who's been following the HCM space recently would acknowledge that this has been a very hot area for scientific advancement with the recent approvals of the cardiac myosin inhibitors. Having said that and building upon what Craig has just said, though, we believe that there is a significant opportunity to improve patient care across the continuum of HCM as patients progress. So just to reorient everyone to the hallmarks of hypertrophic cardiomyopathy, this, as Craig mentioned, is a generally progressive disease caused by underlying obstruction within the heart, within the obstructive variant, and thickening of the heart within the nonobstructive variant. The symptoms that patients report are relatively common across both: shortness of breath, fatigue, dizziness, limitations on physical activity that get to a point where a patient just makes their life endlessly smaller to a point that they just don't leave the home. This is a disease that is relatively rare, but we believe over the next few years is going to grow as industry and as clinicians get more au fait with identifying patients with hypertrophic cardiomyopathy. And I'm sure Dr. Day will tell us about that later on today. In terms of the prevalence, it's roughly two-thirds obstructive and one-third have the nonobstructive phenotype. And we estimate there's around 1 million patients in the United States today that have the disease. In terms of diagnosis, this is an area where I think we can do significantly better. We do anticipate over the next decade, these numbers will improve significantly. Again, breaking that down, around 66,000 are symptomatic. The remainder are viewed to be asymptomatic. If you think about what happens to a patient who is living with hypertrophic cardiomyopathy, whether it be the obstructive or nonobstructive phenotype, most will go on to develop some kind of progressive heart failure over time. Some may also develop atrial fibrillation or AF. 11% may have a stroke. Unfortunately, around 6% may be impacted by sudden cardiac death. This is what we often hear about within the juvenile population of children or young adults playing sports. Unfortunately, the disease takes their life. Where do we believe sotagliflozin can play in the treatment of HCM? So the schematic that you can see here on the slide behind me shows a patient journey, a typical patient journey for a patient living with obstructive hypertrophic cardiomyopathy. And if you read left to right, this is essentially the patient continuum. As they start on the left, they maybe have limited symptoms. As they move further to the right, they have increased obstruction and their symptoms become increasingly marked. So today, most patients will be started on beta blockers and calcium channel blockers. And as a reminder, there is limited phase III randomized controlled data for beta blockers or calcium channel blockers. In fact, I think there's none, Dr. Day's telling me. So this is purely empirical. And then at the other end, we now have the advent of the cardiac myosin inhibitors, the first of which was approved a couple of years ago. We also, at the far end of things, have surgical intervention. So this could be alcoholic septal ablation therapy or potentially myectomy, which again is open heart surgery and has very significant complications associated with it if not done in a high-volume center. So where we believe sotagliflozin can play a really important role is between or on top of beta blocker, calcium channel blocker because those patients, they may well see some early benefit. But as the doses are increased, patients often complain of very significant side effects. And at the other end, the cardiac myosin inhibitors, although they have really improved patient outcomes for patients with more severe obstruction and gradients, we believe that there's an opportunity to play in between. And again, you could consider adding sotagliflozin into a CMI treatment as well. So in terms of the unmet needs that we believe that sotagliflozin would be able to address, for the patient, they're looking for improved quality of life. You know, it goes back to what Craig said a few minutes ago. Quality of life is the hallmark of what patients are looking for when they're taking a treatment for HCM. They want something that is safe. And I think that they also want something that doesn't have an impact on their everyday living, i.e., they don't have to go into the hospital for frequent echocardiograms or monitoring that may well be associated with the CMIs. And of course, they're looking for limited financial impact. So a very cost-effective medicine is what they're hoping for. For HCPs, again, they're looking to improve symptoms and disease burden on patients given the progressive nature of this disease, something that is safe and easy to use, and again, something that potentially reduces the burden on their services because a REMS-associated product can have some significant burden in terms of the impact that it has on an office. Finally, for payers, they're looking for something that alleviates budget impact and wherever possible, reduces their pharmacy or medical costs. We believe that with sotagliflozin, we have a unique opportunity to be the only indicated SGLT2 inhibitor for the treatment of this very different population to that suffering with heart failure. I mentioned a few slides ago that we believe that this is a market that's going to continue to grow significantly. So as I mentioned, we think there's around 220,000 patients today who are suffering with some type of HCM. We believe that by the time we get to 2033, there could be an excess of 500,000 patients identified with HCM. And how we're going to get there is through increased disease awareness. We believe that with the advent of new therapies and there are many new therapies being investigated in this space, some of which I think are going to be significantly more expensive than sotagliflozin, earlier diagnosis, advocacy is playing a really important role here. We know there's a very engaged patient community. But things like family screening and cascade testing, we think, will also play an important role in identifying more patients. And on top of that, with improved diagnostic accuracy, with the advent of AI to support echocardiograms and make sure that the patients are being identified more appropriately, that the numbers will swell significantly. So this is a large and growing segment. We believe it's a large and growing opportunity that we will potentially be able to tap into at the same time that some of the myosin inhibitors, if successful, would be launching in nonobstructive HCM as well. So to be able to tackle both the obstructive and the nonobstructive phenotype with one single study and gain both indications, we think, is a very compelling value proposition for shareholders. So to pull all of this together, building upon the evidence that Craig shared, we believe that sotagliflozin has the opportunity to address some of the unmet needs that still exist in this exciting and growing market. The timing of any SNDA would likely put us in the same kind of window as the myosin inhibitors for the nonobstructive variant. We believe the benefits that I laid out on the slide previous in terms of ease of use, cost-effectiveness, and the fact that we know that this drug is safe in an adjacent population, we believe, makes it a very, very compelling value proposition not only for Lexicon but for investors. With that, it's my pleasure to invite Jeff Wade, our President and Chief Financial Officer, up onto the stage to talk about type 1 diabetes. Jeff. Thank you. I'm very excited to talk to you today about something that, as a company, we have a real passion for, and that's really bringing benefits to people with type 1 diabetes. I'm going to talk about sotagliflozin and its development, some of the history behind it, the studies that we've done, the data that we've generated, the unmet needs in type 1 diabetes, and where we are in terms of getting an approval for sotagliflozin as Zynquista in type 1 diabetes and being in a position to bring that value to patients. As Craig talked about, sotagliflozin is an inhibitor of two targets that have important profiles, SGLT1 and SGLT2. We developed this with the intention of bringing the benefits of dual inhibition to patients. In type 1 diabetes, it's relevant that these two targets are both extremely important and effective in helping manage glucose. This is looking at glucose tolerance tests. This is how one of the first things that we identified about SGLT1 and SGLT2 is that they are particularly good in affecting the uptake and management of glucose. That's important in a population where managing postprandial glucose excursions is extremely important. Type 1 diabetes is a very different condition than type 2 diabetes. First of all, it's an autoimmune disease. As a result of its destruction of cells in the pancreas, it results in an absolute insulin deficiency. That means that people who have type 1 diabetes have to have intensive insulin therapy to survive. The other thing that's unique about it is that the glycemic unmet needs in type 1 diabetes go far beyond A1c, much more so than in type 2 diabetes. Insulin is a lifesaving drug. It is important for everyone who has type 1 diabetes to have insulin. That is the key to being able to save their lives and to be able to extend their lifespan. But achieving and maintaining glycemic control just with insulin is very difficult. Insulin has a relatively narrow therapeutic window. If you underdose, you can have hyperglycemia or high blood sugar. Also, if you don't have enough insulin, if you have type 1 diabetes, you have a risk of diabetic ketoacidosis. If you overdose or overshoot on an insulin dose, you can experience hypoglycemia. And this is actually one of the leading causes of death for people with type 1 diabetes. Also, overdosing with insulin can cause weight gain. And that's a challenge for people with type 1 diabetes just as it is for the general population. The management of the glycemic control during the course of a day is also important because that imprecision in the use of insulin causes glucose variability, which does have long-term consequences as well and causes distress for people with type 1 diabetes. Despite the fact that insulin is a lifesaving drug, most people are not able to achieve the goals that they have for type 1 diabetes. About 75%-80% of people don't achieve the ADA target of less than 7% in terms of A1c. That doesn't even tell the whole story because glucose variability, as I mentioned, is also a significant challenge. These two patients here have the same A1c. One of them has much lower glucose variability. Another one has much higher glucose variability on the top. So measuring A1c as an average, it doesn't tell you anything about glucose variability. Avoiding those highs and those lows during the course of the day are important because they're important in terms of evidence of long-term consequences but also in terms of avoiding the condition of extreme hyperglycemia and dangerous hypoglycemia. There are a significant number of needs that remain in people with type 1 diabetes. So reaching an A1c goal is one of the things without having hyperglycemia or hypoglycemia. Reducing that glycemic variability and getting better time and range is an important goal and unmet need. Controlling the complications such as blood pressure and reducing heart disease over a longer period of time, preventing and controlling weight gain, and preventing the downstream conditions such as cardiovascular and kidney-related diseases, which people with type 1 diabetes have a greater risk of than the general population. So back to history here. We conducted the largest ever program for a phase III oral antihyperglycemic agent in type 1 diabetes. We had three pivotal studies that involved a total of 3,000 patients with type 1 diabetes. I'm going to walk through some of that data on the overall population and then talk about where we are in the regulatory discussion and the population for which we're resubmitting for approval. In the overall population, this was a study that was done on top of optimized insulin. Before people ever saw sotagliflozin or placebo, they were optimized on their insulin therapy. That improved their A1c. Then at that point, they were randomized to either sotagliflozin or placebo on top of that optimized insulin therapy, which was maintained throughout. And on top of that, we saw a significant and important reduction in A1c from baseline following that insulin optimization in both doses and in both of the two pivotal studies that were done in optimized insulin. As well, we saw an improvement in time in range. And we're missing a couple of these. But there's a very significant improvement in time in range for both doses. And this is the time that's not in the low glucose range, the hypoglycemic range, or in the high glucose range but is in the target glucose range. And it was quite significant for sotagliflozin. Oh, there we go. A significant amount of time that was improved there. We also saw, and this is important, this population had a very significant proportion who were either overweight or obese in this population, which is consistent with the type 1 population as a whole. We saw reductions in body weight that were maintained over a total of a year, so not only the 26-week endpoint but also at 52 weeks. That, importantly, was really confined to body fat. There was very little effect on lean body mass. In this patient population, we saw a very substantial reduction in body fat. Turning to glycemic control and the safety concerns that everyone with type 1 diabetes has, people with type 1 diabetes have two significant areas of safety that are inherent in their disease and in insulin therapy. One of them is severe hyperglycemia. The other one is diabetic ketoacidosis. One, low blood sugar; one, inadequate insulin, really being what ties into that. In these studies, we did see consistently a lower rate of hypoglycemia in the safety data and the rate of severe hypoglycemia in the sotagliflozin-treated patients. We saw an elevated risk of diabetic ketoacidosis. I'm going to kind of tie into how this ties into the regulatory pathway. The rate of diabetic ketoacidosis in the general population is between 5%-8% on an annual basis. This was lower than the rate in the general population. We had a very low rate in the placebo arm. We did have an incremental increase in diabetic ketoacidosis risk in the patients who were treated with sotagliflozin. I want to talk a little bit about diabetic ketoacidosis and its management next. Diabetic ketoacidosis is a known risk in type 1 diabetes. It's an inherent risk within the disease. It occurs with absolute insulin deficiency that's misdoses or relative insulin deficiencies that can happen as a result of stress or illness. It results generally in an increase in glucose level, a metabolic shift to fat burning, and an increase of ketones or ketosis and potentially can progress to diabetic ketoacidosis. SGLT2 inhibition, and this has been demonstrated with sotagliflozin but also in other studies with SGLT2 inhibitors, does increase the risk of diabetic ketoacidosis in people with type 1 diabetes. It's important to note that diabetic ketoacidosis, with or without SGLT2 inhibition, is caused by that same mechanism, absolute or relative insulin deficiency. It's also important to note that a lot of people, although the standard of care is really to test ketones, which is the direct measure that will help you understand if there's a risk developing of diabetic ketoacidosis, many people, if you have an absolute or relative insulin deficiency, your blood sugar is likely to go very high. So people have gotten used to using that as a proxy for that risk. But when you use an SGLT2 inhibitor, you're reducing glucose levels independent of insulin. So it's not as reliable of a proxy of insufficient insulin. And that high blood sugar is not as reliable of indicator of that risk of diabetic ketoacidosis. So there has been developed a strategy to manage and mitigate this risk when using SGLT2 inhibitors. And this is a consensus strategy that's been published. It's called the STICH protocol. It's really keyed into using the standard of care assessment to identify the risk of ketosis, to counter that by adding insulin, and to be able to recheck and manage this risk in the presence of an SGLT2 inhibitor or an SGLT2 inhibitor like sotagliflozin. So this is a risk that exists and for which there are agreed methods to manage that risk. So we applied for approval of sotagliflozin in type 1 diabetes. And in 2019, we received a complete response letter. And it was really based on that risk of diabetic ketoacidosis. In the complete response letter, the FDA asked us to do one of two things: to either identify a patient population in which the benefit was greater or to show that we could reduce the risk of diabetic ketoacidosis. And what we have been able to do here is to do the former of those, to identify a patient population in which the benefits are greater. And since the time that we applied for the original or submitted the original application, we've generated a tremendous amount of additional data around sotagliflozin. But also, there's been additional data generated outside of us about the progression of chronic kidney disease and type 1 diabetes. And so the data that we've generated about sotagliflozin in a different patient population in the SCORED study, for example, has shown that we've demonstrated benefits on heart failure, as Craig mentioned, on MI and stroke. We've also demonstrated some data relative to reduction and progression of chronic kidney disease, which I'll share in just a moment. But we've also seen in the literature data published about the progression of chronic kidney disease in people with type 1 diabetes and the importance of better glycemic control in that population. And we'll share some of that as well. There remains a very substantial unmet need for better treatment options for people with this population. Following feedback and a couple of rounds of interaction with the FDA, we have aligned with them around a resubmission that we are making with a proposed indication of Zynquista being indicated as an adjunct insulin therapy to improve glycemic control in a population with type 1 diabetes and chronic kidney disease. So it's important that we be able to support that indication in that population and outline some of the benefits here. So better glucose control is particularly important in this population. Improving A1c in this population is associated with a reduced risk of chronic kidney disease progression. People with T1D who have CKD have been shown to have similar glycemic control in our data with sotagliflozin compared to the entire cohort. So we've demonstrated that we can improve the blood glucose levels in this patient population just as we were in the overall patient population. We've generated some evidence that's correlative of reducing the risk of chronic kidney disease progression in people with type 2 diabetes. All of these elements are important for this resubmission. This is talking about some relatively recent data. These data were published in the literature just at the beginning of this year. This is tied into better glycemic control is particularly important for people who have type 1 diabetes and have chronic kidney disease. Better glycemic control is associated with slower progression of chronic kidney disease. Worse glycemic control is associated with more rapid progression of chronic kidney disease. This is looking at long-term studies following people with type 1 diabetes over time. We have the data from the SCORED study, as I mentioned, that shows evidence of reduction and progression of chronic kidney disease. Again, these are type 2 diabetes patients with chronic kidney disease but quite compelling results in terms of reducing that progression. So this has added support for the proposition that we have a greater benefit in this patient population. And then the important part was we had to be able to demonstrate that we could have glycemic control endpoints, that we could satisfy those in this subset of the patient population. So we have two advantages here. One is that we had the largest ever program for type 1 diabetes. So we had a lot of patients who had type 1 diabetes and chronic kidney disease. The second is that we have a mechanistic advantage because unlike SGLT2, which reduces glycemic efficacy as kidney function declines, the SGLT1 mechanism has effects independent of kidney function on glucose management. So as we looked at this and looked at the data, we identified that the data in this patient population is basically the same on glycemic control efficacy as in the overall patient population. So we can satisfy the requirement of demonstrating better glycemic control in the subgroup of people who have type 1 diabetes and chronic kidney disease. And it's important also to look at safety. So you see the same general pattern of safety that we saw. There's an elevated risk of diabetic ketoacidosis in this patient population, for which the benefit of glycemic control is more important. But we also see the same pattern that we saw in the overall population of having a lower number of events of severe hypoglycemia. So turning to the population and to the opportunity here, there are 1.7 million adults in the U.S. who have type 1 diabetes. About 20%-25% of those people with type 1 diabetes have chronic kidney disease. Most people who have type 1 diabetes are at risk of, and many will progress to chronic kidney disease over time. But about 20%-25% at any given time have it. They also have other comorbidities that are important for us to consider in the context of our overall data. Many of them have high blood pressure. A substantial number of people with type 1 diabetes are overweight or obese. There is a very significant need for options to improve glycemic control in people with type 1 diabetes and especially those with chronic kidney disease. So primary glycemic control in type 1 diabetes is all about insulin. There are multiple daily injections as one of the prevalent uses but also using insulin pumps. As we looked at in the overall population, that doesn't achieve the goal for about 75%-80% of these people. Really, there's nothing available as a practical matter as an adjunct to insulin therapy. Sotagliflozin has the opportunity to really be the first meaningful adjunct to insulin therapy. Then as we think about how this fits, it would be something that could be used on top of insulin as an adjunct to insulin, which is still the lifesaving drug here, but also that can be used to help manage and reduce the risk of complications and can be used in combination with other treatments to address those complications. This is a significant white space opportunity. We're excited about that opportunity. Again, this indication that we're focused on is to improve glycemic control in this population with all of the benefits attendant to that improved glycemic control. Turning to who treats type 1 diabetes, it's primarily endocrinologists. Even when people with type 1 diabetes have complications, that glycemic control tends to remain under the supervision of an endocrinologist. They are the key quarterbacks of type 1 diabetes care. They're excited about the opportunity that we're talking about here, about the opportunity to have an on-label adjunct treatment to improve glycemic control in this population. They understand that it's important to have better glycemic control, and having an adjunct can have that benefit. There are people who are using off-label SGLT2 inhibitors that usually can find academic centers. There's reluctance to use them by many physicians because there is no labeled therapy. There is a very much strong preference among endocrinologists for an on-label therapy for adjunct to insulin. We believe that sotagliflozin will fit a very important need for this healthcare provider's desires for new therapies. It's also something that is a commercial opportunity that's very efficient and effective for us to pursue as type 1 diabetes is really primarily treated by a subset of endocrinologists, with about two-thirds being managed by about 1,000 endocrinologists in the U.S. and over 90% of the population being managed by fewer than 3,000 endocrinologists. I should also mention that there are a number of other studies that are being conducted by others that are using sotagliflozin as a treatment option in type 1 diabetes and evaluating that and the benefits of that. I'm going to bring attention to just a few of them. There's a study being conducted in patients who have heart failure and type 1 diabetes called SOFAST. There's another study that's being conducted that's looking at patients with type 1 diabetes and the risk of cardiovascular disease and to be able to reduce that risk of cardiovascular disease called Steno-1. And then another study that I wanted to highlight here is a study called Sugar and Salt, which is being funded by JDRF and an agency of the Canadian government that's evaluating sotagliflozin as a treatment for chronic kidney disease in type 1 diabetes patients. So I've talked about the benefits of glycemic control. This study is actually looking at the progression of chronic kidney disease itself in this specific patient population. And you'll get to talk to people who are involved in that study when we have the panel. We have also some additional supportive studies looking at the mechanism of action in this population. This is where we are. We've had a dialogue with the FDA. We have an alignment around a path towards a resubmission of our new drug application. We're expecting to resubmit that around the middle of this year. We believe that the nature of this resubmission will be a six-month review. We're anticipating a launch in the first quarter of 2025. We're preparing for that launch right now, doing pre-launch planning and activities. Most of the investment that we'll make in terms of a field force will be around the end of this year as we get into the beginning of next year. We believe that these broad unmet needs across better glucose management in combination with insulin will support a broad adoption within this patient population. I can say that people in advocacy organizations for type 1 diabetes have always been extremely enthusiastic about the ability to bring forward sotagliflozin as a treatment option for type 1 diabetes. And the patients that were in our clinical studies very much valued the benefit that they received from sotagliflozin in those clinical studies, which is part of the reason why we've been so dedicated in pursuing this. And we do also have the benefit of additional studies that will be generating data over the course of multiple years to come around sotagliflozin in this population. So we're excited about that opportunity. And this is one of the real significant opportunities, a new commercial opportunity that has come forth over a lot of work that's been done by many people over a number of years. But we are now at the point of making that transition and getting it back in front of the FDA and potentially bringing it to market in the relatively near term. So with that, I'm going to turn it over to talk to one of our other emerging programs, diabetic peripheral neuropathic pain. Thank you, Jeff. I think that was a great segue as well into the consequences of diabetes. I want to talk now about another major disabling and devastating consequence of long-term diabetes, which is chronic pain and neuropathic pain. Again, I think it's very similar to what Jeff talked about in terms of renal consequences and the importance of glycemic control, in Jeff's case that he was talking about in type 1 diabetes. This is in patients both with type 1 and type 2 diabetes. I'm going to talk a bit about the mechanism. Then I'm really going to turn it over to Tom to talk about the market opportunity in neuropathic pain with a focus on diabetic peripheral neuropathy. What I hope to share with you over the next several slides is that we believe that LX9211 has utility above and beyond diabetic peripheral neuropathic pain but in a wide range of peripheral neuropathic pain states in addition to diabetes. What I will lay out is the unmet medical need. Really, Tom will talk more about that. I really want to speak most of my time about the proof of concept that's been achieved and where we are in the late-stage clinical trial. During the panel, we'll have the opportunity to have the principal investigator of that study, the PROGRESS study, available for our discussion. Then I'll really turn it over to Tom to talk about the significant market opportunity. I think this is another one of those areas where the Genome5000 is absolutely critical. There are so many drugs that have failed in neuropathy, neuropathic pain, and particularly diabetic neuropathy. But remember, nearly all of the drugs that have been developed in this category were not developed as drugs for neuropathic pain. Even the Vertex drug was developed as a drug for acute pain. But all the drugs that are widely used, whether they're labeled or not, were not initially developed. And remember, the power of Genome5000 is we start with a phenotype. We start with a series of behaviors. So we know the answer before we start the journey. Knowing the answer, then it's a matter of, OK, we know the phenotype we're looking for. We know the gene we knocked out. Now we just got to find a great drug to knock out that target. And I think Alan will come back to that as well with our new target. So we're coming at this with a high degree of confidence before we even start that we know what we're looking for, particularly something as subjective as neuropathic pain. So I think grounding that increases our level of confidence that we're going in the right track. And this is about a 15-year journey that we've been on with this drug. So this is not something that we just sort of found overnight. And what you'll see on the left panel is if you look at the wild-type mouse and then the knockout mouse of AAK1, which is the target, what you see here is what most people have seen is that acute pain is quite different than neuropathic pain and that there are really very different biological drivers, which I think Dr. Busui can comment on during our panel discussion, that some of the biology is quite different. So a drug that might work in acute pain might not work in chronic pain and vice versa. Additionally, on the right panel, your right panel in the audience, is if you look across all of the 5,000 knockouts, AAK1, which is all the way in the left corner, was one of the most potent gene knockouts to mitigate a number of neuropathic pain states. So on the next slide, I want to share with you, if you look at the knockout mouse versus a normal mouse in a classic animal experimental model called a spinal nerve ligation model, you see the wild type in blue is if you inflict on those animals this spinal ligation, and then you look at their sensitivity to pain, there's a significant impact of that. If you then look at the knockout mouse, you see much less impact of the pain. So again, it is indicating as an example of what I showed you on the prior slide is that these animals are relatively resistant to the pain state, the knockout. And we looked at a number of different other knockouts along that pathway, including on the right, nearly all of the voltage-sensitive sodium channels. And we picked AAK1 above all of the other targets, including agents from other classes that are in clinical development today. Now, I want to shift from the knockouts to some specific experiments that were done with LX9211. And again, this goes to the point that I think Tom will also touch upon that the utility of LX9211 could be above and beyond just diabetic peripheral neuropathy. So the model on the left is an animal model and mouse model that replicates diabetes. You basically give a poison that knocks out the pancreas. What you see is that the normal mouse is in green at the top. So they have a certain resistance to pain. The animals that have been treated with this poison have significant resistance to pain. If you look in the middle, you can see that treating those animals with LX9211 restores them more to a normal phenotype. The model on the right is a different model of neuropathic pain. Again, this one models or is similar to modeling postherpetic neuralgia. Again, you see the same thing. At the top, you see without, with, and then the blue line below is if you actually treat them with this toxin. Then you can see that you're restoring your normal functioning of the animal to pain with the drug. So again, you see the gene knockout, a certain phenotype. The drug is actually restoring a more normal phenotype in those animals. This really led us through a whole series of experiments that ultimately resulted in a proof of concept study, which was a large proof of concept study. This was over 100 patients per arm. We had three arms in this trial. I think there are several important attributes of this study, which are quite different than a number of the other clinical trials that others have run in neuropathic pain. The first and importantly is we allowed patients to stay on their underlying pain medications. We allowed all the patients, if they were on a non-opioid, to stay on them. Most of these patients actually were on gabapentin, which if you look at gabapentin versus pregabalin, gabapentin seems to be a more effective agent in general managing neuropathic pain. The second is we used a placebo control. And the third is we carefully profiled these patients, including a 2-week blinded run-in period. So all these patients thought they were already on therapy. So their pain score is already coming down during the run-in period. But in a sense, the starting line is when the patients get the first dose of study drug or placebo. So their overall level of pain has actually dropped from the baseline. And so there's a couple of important differences from other trials that are running. The first is there's actually a placebo control. The second is there was a run-in, which actually allows us to qualify the nature of their pain but also, in a sense, has a running start because the patients have a significant placebo effect. And the third is we allowed patients to stay on their underlying DPNP medication. Remember, in the other trials, if you stop someone from being on their DPNP medication, their pain score actually shoots up. So they are starting at an artificially high level of pain. The other important attributes in this is that these were all adults. They had longstanding diabetes in general. And they had moderate to severe pain. We looked at the two different dosing arms. Since we had that long run-in period on placebo, we were concerned that if patients didn't see an immediate response to reduction in their pain, they might drop out. So we actually gave a loading dose on day one and day one only that was 10 times the maintenance dose but got all the patients to the minimum, what we thought was a minimum effective drug level on day one. That was great. The challenge is that there was a big overshoot. What we found when we did intensive PK afterward is that that Cmax was associated with the dizziness that we saw in the 110 arm, right, 100 on day one, then 10 thereafter, and particularly in the 200 arm on day one and then 20 milligrams thereafter. Nearly all of the dropouts were early. We really mapped that to the Cmax, which we believe was related to the loading dose, which we then addressed in the study that I'll spend a little time towards the end of this conversation about called PROGRESS, where we eliminated that high loading dose. If you look now, what patients view is, how am I feeling compared to my baseline? So when you look at that, there was a significant drop in the pain score in green in the low-dose arm and then over in the darker green on the right in the higher-dose arm compared to placebo. But the primary endpoint of this was on intent to treat, placebo-adjusted reduction in pain score at week 6. And what you see is a statistically significant reduction in particularly the low-dose arm. Again, this was intent to treat. So all of those early dropouts in the high-dose arm, in a sense, count against you because they're all in the efficacy analysis, even though for most of the time, they weren't on study drug. So this was not a completer's analysis. It was not a modified intent to treat. This was all patients who got a single study dose. So again, these are important differences, subtle differences, but important differences in being able to interpret and compare across trials. The other important aspect is the effectiveness of this agent was regardless of the baseline use of the DPNP medication or gender or duration of their diabetes or the significance where they had moderate or severe pain, so consistent response. The other aspect that we thought was encouraging is that the type of pain relief was the most common and troubling types of pain that patients get with this, which is a burning pain sensation and an inability to gain sleep. The most common and we'll hear more about that, the most common complaint of patients is, "I have burning pain that keeps me awake at night." And that burning pain is in my lower extremities or feet. And you can see that, again, significant placebo-adjusted benefit on both of those attributes of pain. So based on that and a lot of discussion with our experts and with input from the FDA, we are now currently running a large dose optimization study called PROGRESS. And there are a lot of similarities and a couple of important differences based on all that we learned from the proof of concept study. The first is that, again, the inclusion criteria and the trial design are very similar. We took patients with moderate diabetes, either type 1 or type 2, with moderate to significant pain score. And if you look at this, there are three treatment arms, again, of roughly 300 patients, again, placebo. So the total is about 400 patients. But we don't have that 10x loading dose. We have the 10 mg dose. We have a 20 mg dose. And then we have a dose that gets you to your target blood level about a week or two earlier with 20 milligrams a day for seven days and then 10 milligrams per day thereafter. Primary endpoint is at eight weeks. And as we'll hear more in the panel, this trial is actively open and enrolling patients. So I think in summary and again, Tom will really touch on a number of these points. But we feel that we have embarked on a clinical trial program that is capital efficient. We have reduced risk significantly and not impacted the timelines because by finalizing a dose, we believe we can go into phase III with one active arm and one placebo arm, which will greatly simplify and reduce the number of patients going into phase III while enhancing the overall efficacy benefit in that trial. With that, I'll turn it over to Tom to talk about the commercial opportunity in DPNP. Thank you, Craig. I'll just touch upon the market size as we see it today because, as Craig mentioned, this is a patient group that are looking for better treatments than they have today. Looking at the size of the market as it stands today, so we estimate in the U.S., there's about 20 million patients who are suffering with some type of neuropathic pain, of which about 5 million, so a quarter, actually have diabetic peripheral neuropathic pain. If we look over the next decade, we estimate that the compound annual growth for this market is going to be around 6% year-over-year. If we look outside of the U.S., it's estimated by the time we get to 2033 that this market as a whole will be worth close to $15 billion. This is a very significant market opportunity that we're talking about here. We're also delivering on the promise of the company of bringing new advances to treatments in areas of high unmet need. If you look at the patient journey that exists today, you can see there are three main stakeholder groups that are involved in the treatment and care of patients with diabetic peripheral neuropathic pain. It starts with the PCP. That's where the patient may be referred to initially. They would begin to look into the initial diagnosis of what is causing the symptoms that the patient is suffering with. If there is uncontrolled diabetes, then they'll be referred to a diabetologist or an endocrinologist. It's going to be wonderful to hear from Dr. Busui today, who will give you a sense as to what this actually looks like in the real world. They then may think about adding in additional treatments according to the pain that the patient may be feeling and may well consider interventional therapies where appropriate. About 30% of patients actually move on to the care of a pain specialist. There, they may well start taking on additional treatments such as low-dose opioids, given the fact that these patients have ongoing and enduring issues in terms of their pain. Where we believe LX9211 can play a role is across the entire spectrum of the management of these patients with DPNP. What we're showing behind me at the moment is DPNP. But I think as you think about neuropathic pain in general, it would look very similar to what we're showing here. Most patients would start on a gabapentinoid, so Pregabalin most likely. And we actually believe that LX9211, given the data that we're showing and given the study design that Craig has already mentioned, could play a role as a frontline treatment. Having said that, we know that around 50% of patients are never adequately controlled on the treatment that they start on. They have to move around through different lines of therapy. We believe that LX9211, either as a switch medication or as an add-in medication, given the study design that we're pursuing here, as either lone or on top of a background therapy, could also offer a real benefit to patients and to the clinical community who are looking for far better options in terms of improving outcomes for patients with DPNP. So you can see on here, we would potentially be looking at LX9211 in combination with an antidepressant in later lines for those patients who are progressing and looking for something additional or potentially, again, on top of a different gabapentinoid that they may have not been treated with already. So we're excited about this opportunity as we think, again, it's a great, we have a great opportunity as Lexicon to really bring new science and new scientific understanding to the clinical community in an area that is very high unmet need. And at the moment, there is limited investment in this space as a whole. Obviously, Vertex are also looking at this. But going back to what Craig has mentioned, we believe very, very strongly that now, with the evolved study design that we're taking for phase 2b, we should be able to move this, assuming that's positive, very quickly into phase III and be playing in this space both in terms of DPNP to begin with but then potentially more broadly across the neuropathic pain market. So with that, I will close this first section, looking forward to having the panel discussion. I think we'll be touching upon some of the additional information that we've shared this morning, whether it be around type 1 diabetes, hypertrophic cardiomyopathy, heart failure, or pain, as we've just spoken about today. So with that, I think we are taking a short 15-minute break. Then we will reconvene. Many thanks. Ask your neighbor next door. All of a sudden, I'm just sitting there. It has to do with wearing a mask. Is this the medical school syndrome that you get every disease that you're studying? No, this one. I promise I'm not making that up. I'm sorry. I'm sorry. So it's going to be here until tomorrow. And I think it's going to be in an update. OK. Welcome back to all. I'm really so thrilled to have our panelists with us today to help us further explore some of the topics we covered this morning. We know we covered a tremendous amount of content and did it relatively quickly. I hope we can give a little more context on areas. I'm going to draw a lot of the questions I have from investor questions that we've received over the last number of months and particularly the last several weeks. Hopefully, our panelists will be able to provide us with much better guidance and insight in what we, as the management team of the company, was able to present. I just wanted to thank, again, our panelists. I hope those that are in the room have had a chance to meet them all. Sitting directly to my left is Dr. Sharlene Day, who is the president and associate professor at the University of Pennsylvania and a cardiologist. I'm going to put this slide up. There we go. Charlene is the co-PI of our SONATA-HCM trial and can really speak with great authority as an expert in hypertrophic cardiomyopathy. The trial design has really been with us on this journey for the last couple of years. In the middle, we have an endocrinologist, Dr. Rodica Busui. Dr. Busui is currently a professor of medicine at the University of Michigan and has been really involved and a leader in the American Diabetes Association and with some of the most important trials that have been done in type 1 diabetes over really decades and is standing on the shoulders of giants in things like DCCT and EPIC. Really anchoring our panel is Dr. David Cherney. David is up at the University of Toronto and is our nephrologist here. Dave has really been a legend in publications across looking at renal disease and cardiovascular disease and metabolic disease and the overlap of those and is one of the co-PIs, the three PIs, of the sugar and salt study. Dr. Busui is also an investigator in the sugar and salt study. So we really have a great panel of folks here who are really experts in the field but know these programs and are really leaders on these clinical trials that we're doing. I hope we can bring some of those themes out in some of the questions that we have. I thought we would start first with the type 1 diabetes because I think it really overlaps between the areas of expertise of Rodica and Dave. Both of them have been involved in the Sugar and Salt study and some of the discussions that have taken place with the FDA regarding that trial as well. I hope that we can really focus on a couple of important themes. The first is talking a little bit more about type 1 diabetes. The second is the burden of the disease. The third is this subgroup of patients with CKD. Then really, I think Dr. Busui might be able to provide some perspective on the management of diabetic ketoacidosis as well. With that, Dave, I'm going to start with you. I think on this one, we're going to leave Dr. Day out of the conversation. She wanted to be in the middle of the conversation about type 1 diabetes just like Dr. Cherney wants to be in the middle of the discussion about diabetic peripheral neuropathy. But we said we got to hold you back. So anyway, I really wanted to start, Dave, and talk about why glycemia and glycemic management is important in type 1 diabetes. Sure. So thanks for the question. So patients with type 1 diabetes can have, of course, multiple risk factors for kidney and cardiovascular complications as well as many other complications, including neuropathy. And hyperglycemia is one of these key risk factors for developing subsequent complications. And so control of hyperglycemia is of the utmost importance. It's one of the tenets and foundational strategies for managing type 1 diabetes. And currently, when we see a patient in practice, there is essentially only one therapy for managing hyperglycemia, which is insulin. And in addition to that, beyond insulin, we have essentially no tools that have emerged over the last quarter of a century for managing kidney or cardiovascular disease. We just have ACE and ARBs. So managing hyperglycemia in this condition is critical. We need new therapies to target complications and to reduce risk, especially in the highest risk patients, which are patients with chronic kidney disease. Patients with chronic kidney disease often have other conditions, including heart failure or atherosclerotic cardiovascular disease. Patients with underlying CKD who have type 1 diabetes are at risk of further progression of kidney function decline and kidney loss. So managing a risk factor like hyperglycemia in this setting is absolutely critical. I think it's the point that was made earlier on that we have these older therapies for treating people with type 1 diabetes is critical to underscore. We have no alternate therapies in these patients. All we can do is sit and watch and wait for the development of complications, including kidney function loss, which is inexorable and progressive once it happens, especially in people with albuminuria. The identification of therapies that have a good benefit and safety profile compared to risk is absolutely critical. Thank you, Dave. Maybe you could just put a finer point on that, the difference between glycemic management and a glycemic endpoint and the value of that compared to the prevention of progression of kidney disease because that's the goal of the Sugar and Salt study, which is not a glycemia study but is a renal study. Absolutely. So the indication that's been discussed in type 1 diabetes would be one of treatment and reducing hyperglycemia in people with CKD, which is a risk factor for complications. And so this is a marker of a modifiable risk, which is hyperglycemia, that can be ameliorated with sotagliflozin, which we've seen from the data that was presented today. So that's the potential indication that's being looked at. Separately, are the use of SGLT inhibitors for reducing cardiorenal complications. And so that is the role and the goal of the sugar and salt trial and as well as the SOFAST trial to assess the effect of sotagliflozin as a medication that can be added on to standard of care as an adjunct to reduce the risk of kidney function loss. And our outcome in sugar and salt is kidney function decline. But of course, we'll also capture data around cardiovascular events, albuminuria, et cetera. That's a different strategy, which would be independent of glucose. So that's a totally different philosophy, different potential mechanisms, and also separate from the current strategy of an indication for people with type 1 diabetes who have CKD. And the important thing, I think, is that this is an area where there is a good risk-to-benefit ratio in the sense that these patients with type 1 diabetes and CKD are very high risk of developing complications. The risk of side effects like DKA we've seen is similar to what we see in the overall cohorts who have been studied with sotagliflozin. So the benefit is hopefully going to be higher. And the risk is the same or possibly even lower. So this is where that sweet spot is for benefit and risk. Got it. Great, Dave. I'm going to come back to that in a little bit. But Rodica, maybe you could give a bit of a historical perspective because it's interesting how new some of these insights or at least the confirmation of some of these insights are because even when we filed initially with sotagliflozin and Zynquista back in 2018, some of these late-stage complications of diabetes really were not as well founded. I mean, these publications have really come out over the last five years or so. Maybe you could just comment a bit on that. Yeah, absolutely. And first of all, good morning. And it's truly exciting to be here. And thank you for involving me. Yes, so people with type 1 diabetes for sure have actually a pretty high risk, maybe even higher than people with type 2 diabetes, to develop chronic kidney disease and actually heart failure. And the heart failure, actually, data has emerged very recently, particularly now that we have a capability to identify these people in pre-symptomatic stages. So that's actually putting an additional perspective on the potential of having an agent that can effectively help these patients. I'm a clinician. And I'm a scientist. And I treat these patients. But I also had had the opportunity to be part of the largest and most important trial that have enrolled more than 1,500 people with type 1 diabetes. And we have been following them for the last 40 years. As we speak, we still follow more than 90% of this original cohort. That's how we have demonstrated that in type 1 diabetes, glucose control, as assessed by this A1C, is the strongest risk factor for kidney and cardiovascular complication. However, A1C, as Craig said very nicely in his presentation, it's a mean. It's an average. Only very recently, we became aware that, in fact, a similar A1C may be actually found in people who have very different phenotypes. So this glucose variability, this excursion in glucose, have now also been demonstrated to be critical risk factors that can induce higher inflammatory burst, higher oxidative stress, which are a key component in developing both kidney and cardiovascular complications. Hence, besides insulin by itself that can cause both high blood sugar and low blood sugar, having an extra agent that can blunt these excursions can, in fact, have additional benefits. And that's actually very, very important. Now, of course, one can say that the risk of side effects of these agents is very important. And always, our goal is to make sure that our patient is safe. Patient safety is always at the very top. And I think that we have learned so much on mitigating potential risks. And also are very fortunate that we have the technology now that enables us to provide patients with type 1 diabetes with the education and with the tools to actually be able to monitor in real life what's happening with their disease and with these excursions and also with the risk for DKA. No, I think there are several important points, Rodica, that you mentioned during that. I think from the standpoint of the FDA, when we first filed Zynquista, all that was really known was retinopathy progression. And the difference between retinopathy progression and now all of the cardiovascular and renal benefits, that was really the key point of the discussion we had with the agency about finding a population where the risk of the disease progression about not effectively managing glucose was very high and would be great enough to outweigh the risk of diabetic ketoacidosis. And maybe, Dave, you could come in first and then, Rodica, on what is diabetic ketoacidosis? And how do you manage it? And I know that in the sugar and salt study, you also had some discussions with the FDA. What was their feeling around managing a diabetic ketoacidosis? Sure. So diabetic ketoacidosis is a potential complication that we've heard about already today of having type 1 diabetes and essentially involves a state of absolute or relative insulin deficiency, which can lead to overall hyperglycemia, high glucose levels, and also the generation of ketones, which are a metabolic byproduct when patients don't have enough insulin around. And that can make patients become quite sick, especially if they don't have the right tools to manage DKA safely and in a very proactive way. And this is why we have the STITCH protocol, which involves a variety of clinical strategies, including maintaining hydration, taking carbohydrates, keeping on with insulin administration, stopping the SGLT2 inhibitor, which may promote the generation of these ketone metabolic byproducts, and thereby get ahead of the condition before it gets too serious or too late and lands the patient up in the emergency room, for example. And so the STITCH protocol, which we use and have closely integrated in discussion with the entire sugar and salt team, especially including Rodica, has allowed us to have this strategy of balancing and mitigating risk while at the same time involving a population of patients who are being enrolled in the trial who, as we've heard, are at very high risk of complications. These are patients with significant impairment in kidney function, which is a tremendous risk factor for future risk of kidney failure as well as for cardiovascular disease, and patients who have significant levels of high albumin levels or protein levels in the urine, which is also a risk factor for kidney and cardiovascular disease. It's kind of like cholesterol for the heart. Albumin in the urine is like bad cholesterol for the kidneys and is a risk factor that accelerates the disease progression in the kidneys. We're involving very high-risk patients in SUGARNSALT. The discussion around inclusion of these very high-risk patients with kidney disease at the level of regulatory discussions has been very much focused on making sure we have this population of patients who are enriched to potentially have the benefits of this therapy while at the same time involving these very carefully planned out, rigorously controlled, and evaluated protocols called the STITCH protocol, which mitigates the progression of ketoacidosis if it happens. It rarely probably will happen. These cases will hopefully be very few. This is a strategy that we have in place to get ahead of it if it does happen. Maybe I'll hand over to Rodica to make any other additional comments. No, thank you, David. That was pretty comprehensive. What I'd like to add, perhaps, is that the reason that people may develop DKA even with relatively lower blood glucose level, which was, in fact, one of the issues that was first described with the use of SGLT2 inhibitor in general, not only in type 1 diabetes, it's this called euglycemic DKA. It's because the human body, the cells in the human body need insulin to take the glucose inside the cells and make energy. The brain, the heart need energy. When the insulin is not enough levels, then the body has to switch to other sources, including fatty acids, that generates these ketones and then creates this state of metabolic acidosis that can be indeed a very, very serious complication. Hence, the original FDA concerns is that since any SGLT2 as well as SGLT2 and SGLT1 inhibitor lower glucose levels, people may take less insulin. People with type 1 diabetes don't make insulin. Their pancreas doesn't make insulin. They will need a minimum amount of insulin to make sure that the energy is used correctly in the cells and not switch to these other sources like fat to generate energy. By creating this mitigation protocol, like David mentioned, the STITCH and STOP DKA that we have incorporated in our sugar and salt study, we can effectively actually prevent that to happen. In fact, David, you had the proof and correct because in Tandem 3 that was basically implemented during that trial and immediately resulted in a very substantial reduction in the rates of DKA, which was very similar with non-SGLT2 treated population. I think that that's a very important key component and actually highlights how the lesson that we learn by doing a trial and also putting the physiology in the picture and then combining the science with the actual observation that we do in clinical trial and the point of care. It's actually a generator of progress and making us able to do that type of trial that, first of all, will keep our participants safe and also will enable us to answer the main questions. Great. Thank you. Very comprehensive answers around, again, which is a new and complex topic. I wanted to now shift gears and talk a bit about hypertrophic cardiomyopathy. And Sharlene is our expert and really a world expert here. Tell me a little bit first about why, if INPEFA is approved in heart failure, why do we need to do this study? What's the value of what's the importance of getting an FDA label? Well, thank you so much first for inviting me to be here. That's a great question to start off with. As you and Tom have both highlighted this morning, and I'll reinforce, there is an enormous unmet need in patients with hypertrophic cardiomyopathy. HCM is really unique among the heart muscle diseases that lead to heart failure. I think it's important that we not extrapolate like we've been doing for years because we had no other choice to medications that we're currently using to treat patients with HCM but rather specifically test sotagliflozin in that population. Also, Tom mentioned guidelines earlier. There are also HCM-specific guidelines. These national and international guidelines are going to make recommendations based on the level of evidence. The highest level of evidence will come from rigorous randomized controlled trials like SONATA-HCM. And so if the trial is positive, the level of recommendation will be very high. And that will mean that that now defines quality of care for patients with HCM. So providers will prescribe the drug. And payers will pay for it. Thank you. Tell me a little bit more about the mechanism of how an SGLT inhibitor, and particularly sotagliflozin, might work in HCM? Well, we don't really know the mechanism, right? I think that it is a serendipitous discovery. So there's a lot of studies still going on to understand that at sort of the cellular level even to try and understand, is it affecting the heart directly? Is it an indirect effect coming from other organs? So as you highlighted earlier, SGLT1 is expressed in the heart. So I think there's a possibility that that could be a direct target of sotagliflozin that would be different than the other SGLT2 inhibitors and distinguish it in that way. There are some preclinical studies that we're doing that may provide some mechanistic insight. And we know that the SGLT gene, the expression of that gene is differentially regulated in hearts from patients with hypertrophic cardiomyopathy or heart failure. So I think it's possible that there is a unique mechanistic target there. When you say differentially regulated, it's upregulated in a sick heart? Is that, again, sort of. It's actually downregulated at the transcript level, which I think may be a compensatory mechanism based on what we know about sodium and glucose utilization and regulation in the heart. But we don't know for sure. Great. And how do you think sotagliflozin will perform in this population? And how do you see it being used in light of both the nonspecific inhibitors like the beta blockers and the CCBs and some of these very specific inhibitors like the CMIs? I'm very optimistic. I think that this drug could work in this population. Although HCM is unique, there are a lot of overlapping features with heart failure with preserved ejection fraction, for example. And you showed some of the subgroup analysis of the patients in SCORED who had LVH without hypertension. Some of those patients probably had HCM or something that was HCM-like. And that hazard ratio was very impressive. You had like a 60% relative risk reduction, which was even greater magnitude than was seen in the overall cohort. So I think those types of clinical data, I think, are very strong and argue that I think we have a good chance of seeing an effect. Just in terms of putting it in the landscape of therapies for HCM, there's no doubt that cardiac myosin inhibitors have been revolutionary in this disease. For someone like me who's been in the field now for almost 20 years, it was really gratifying to see something that was discovered at a basic level to translate to clinical practice. So we're very excited about them. However, I think you have to keep in mind that they're still only so far shown to be beneficial in a subgroup of patients that have symptomatic and severely symptomatic outflow tract obstruction such that they would otherwise be referred for a surgical or procedural intervention to reduce the thickness of their septum. So the other thing to keep in mind is that reducing the gradient does improve symptoms, doesn't cure the disease. You're still left with HCM and all that comes with that, so diastolic dysfunction and so forth. We just presented at ACC a couple of weeks ago data from a large international registry showing that 10% of patients who undergo successful septal reduction therapy with complete relief of their obstruction still develop heart failure. So some of those patients are still going to benefit from other medications targeted towards their heart failure that are beyond gradient reduction therapy. So for nonobstructive HCM, the phase II trial, the MAVRIC trial of 60 patients with mavacamten didn't meet its primary endpoint. Well, it was really a safety endpoint but didn't meet its efficacy endpoint of improved symptoms or exercise capacity. However, there was a signal based on the BNP level. And so that was the rationale for phase III clinical trials, which are ongoing, the Odyssey and testing mavacamten and aficamten being tested in Acacia. So those are over 400 patient trials. So I think we still don't know for sure. But you do have to keep in mind, again, the ejection fraction reduction and the long-term extension of MAVRIC, it's over 25%, which is much more than we see in the obstructive arm. So that's CMIs. I think beta blockers, briefly, they're actually zero data, Tom. Even though they are class one recommendations, it's all based on expert opinion. And I'll tell you, I don't really think they have pretty limited effectiveness. And patients don't feel good on them. And I will tell you, I'm not exaggerating. On my Friday clinic, I either dose reduced or withdrew beta blockers on half the patients that I saw. They feel badly. They're fatigued. They have mental fog. They're dizzy. They can't sleep. They're restless. They have nightmares. So I think in the HFpEF literature, there's now evidence that beta blockers may be detrimental. So I really think that sotagliflozin has the potential not just to be on top of beta blockers and calcium blockers but potentially to replace them and be far more effective. And again, sotagliflozin would be across the spectrum of patients with HCM and also different disease stages, which includes, in some patients, a drop in ejection fraction over time. So I think, Sharlene, great answer. I think there's a couple of things that I may want to just clarify a bit more. To take a half step back, not everyone is familiar with what is obstructive versus nonobstructive, where are they similar, where are they different. Yeah. So I think there's a common misconception that they're two different diseases. So first, just briefly to define, obstructive HCM means that there's resistance to outflow blood from the heart. So that results in the form of HCM where the proximal septum is affected. And that sticks out into the outflow tract and basically causes the. Just explain the. I'm sorry. Explain the. Dynamic obstruction. Outflow tract. Outflow tract of blood. Outflow tract is where all the blood is funneling to get out of the heart. So it's basically right below the aortic valve. And so it's a narrow space to begin with. And if you've got a hypertrophied septum and that causes the mitral valve to get sucked over or dragged over into the outflow tract, that narrows that space even more. So it's very dynamic. And it curves towards the end of systole. And so if the hypertrophy doesn't involve the basal septum, you don't get obstruction. But fundamentally, there's still the same disease, right? And so if you have a drug like sotagliflozin that's not targeting the gradient, there's potential for it to be broadly beneficial for patients regardless of whether there's obstruction or not. And so thank you for that because I think it's important for people to understand that these diseases, while separated, are more similar than different. Yeah. That's correct. I think the other question that comes up is, what are you actually treating with the beta blockers and the CCBs and the CMIs? What are you actually what are your goals of therapy? Well, I mean, I think, well, for patients that have symptomatic obstruction, the primary goal is gradient reduction therapy, which is a term I prefer to use now because I think for advanced gradient reduction therapy, we have CMIs and septal reduction therapy. Beta blockers and calcium blockers are the first line. There's a subset of patients that do fine with those. I think they have a modest amount of obstruction and, for whatever reason, aren't that symptomatic. They do OK with them if they can tolerate them. But I just don't think they're very effective in most patients. When you talk about effective because I think we're talking about a laboratory value, so what is the goal of clinical care? Our goal is always to improve patients' symptoms and how they feel, right? I mean, we get obsessed with a lot of numbers. We all cardiologists like numbers, wall thickness, gradients, ejection fractions. But the patients don't care about those numbers. And many times, they don't really even know what they mean. They just care about how they feel. And they care that they can go on vacation with their family and go on a hike, that they can go to the park and play with their kids, that they can go up the stairs without gasping at the top and having to stop, right? And that's what's really motivating the primary endpoint of this SONATA-HCM trial. Tell me then a little bit about the KCCQ score versus a six-minute walk test. What's important to patients? Then ultimately, now, what's of value to the FDA in terms of labeling? Yeah. I mean, I think what's of value to patients is clearly how they feel. And so that should be what's important to us. That's a KCCQ score? So that's how we're using the KCCQ. So the KCCQ is a standardized and validated questionnaire that basically captures the symptom burden of patients with heart failure. It is not customized to patients with hypertrophic cardiomyopathy. And there are many working on trying to make it a little bit more customized to that population because there are some differences in how patients with HCM feel. But it's been pretty well validated in. The FDA accepts it. The FDA accepts it. It has correlated well with other outcome measures in clinical trials of HCM. So I think that's really the best patient-reported outcome that we have. As far as some of the other functional tests, we did consider including some of those functional tests in the SONATA trial. Ultimately, I think we really decided to prioritize how patients feel. That was acceptable to the FDA as well. Yeah. Here's the trial design, Sharlene. Maybe you can talk about a few of the particulars of the trial design. Randomized double-blind placebo-controlled trial of sotagliflozin versus placebo. Patients will be randomized 1:1. The treatment period is 26 weeks long. Adult patients with HCM, both obstructive and nonobstructive, will be enrolled. We'll only exclude patients that have really severe symptomatic outflow tract obstruction for whom we're being considered for advanced gradient reduction therapy. KCCQ score less than 85, that's the clinical symptom score. What does that mean from a patient's standpoint? It means that they're at least modestly symptomatic, that they have limitations in their daily functions. Define that. What would be, just again, for some of the. Yeah. It's hard to sort of capture that exactly because it depends on how they answer different questions. But it basically means that they have at least a mild limitation to physical effort. And so maybe they can't go up a flight of stairs without getting out of breath. Or maybe they can walk a mile on flat ground. But if they try and rush, they get out of breath, things like that. They're carrying something, right? So something that's limiting their daily life, right? And that's really only something a patient can tell you, right? And then NYHA class two or three. So the New York Heart Association classification is determined by health care providers. So it's not something a patient tells you. But it's something the health care provider decides based on when they interview the patient. Again, NYHA one is asymptomatic, two is mildly, three is moderately to severe with exertion, and four would be symptomatic at rest. And then the ejection fraction at 50% or above was the other eligibility criteria for the trial. The primary endpoint is change in KCCQ, the clinical summary score. And the secondary endpoint is change in New York Heart Association class or the total symptom score for KCCQ. And then we have a number of exploratory endpoints. Tell me a little bit about the study, sort of the details, right? It's going to be starting soon. Yep. So starting soon, so hopefully end of second quarter, we have almost all of the 120-125 sites already confirmed. It'll be across 20 countries, as you can see, very broad eligibility criteria, largest randomized trial that will be conducted in HCM, including the ones that are ongoing for CMIs. And I think it's probably the first pharmacologic trial to enroll both obstructive and nonobstructive patients. So it's unique in that way. And it's a very low burden on patients. We're not doing MRIs and CPET. So I think it's going to be very easy to enroll. And I think patients will be very excited about doing the study. What's the provider feedback when you've talked to potential centers? Been very positive. Yeah. Centers are very much on board. We have competition for getting the last few sites. I think there's going to be very ready uptake of the clinical trial. Enrollment's going to go well. Terrific. So I wanted to now shift gears and sort of close this session really talking about the LX9211 clinical program, Rodica. I know you've been involved in this program for quite some time and really working with our outstanding clinical team in this regard. So tell a little bit about how you got involved in this program and your interest in it. Yeah. Thank you very much for the question. So diabetic neuropathy, it's another complication that I have been focused on during my career. And one of the reasons is that among these complications that people with diabetes develop, in case you may not be aware, it's, in fact, by far the most prevalent. So more than 50%, 60% of people with diabetes will develop neuropathy. And I think that to put things in perspective, as we speak, in the U.S. only, we have about 39 million people who have diagnosed diabetes. Around the world, we have almost 700 million. And neuropathy is very prevalent. It's also very complicated to study. We have data now from large cohorts with both type 1, like DCCT that I mentioned, and also type 2 diabetes here in the U.S. and around the world that neuropathy, it's not only impacting pain or sensation but, in fact, it's one of the strongest risk factors for mortality in people with diabetes, in fact, affects quality of life. Definitely, it's the leading cause of non-traumatic amputation. When a patient with diabetes is losing a limb, their mortality rates at five years are higher than most of the most aggressive cancer. Again, this is supported by the strongest type of data. I think that because it's difficult to study, because the peripheral nervous system has a complex anatomy, for the last 10, 15 years, there was a little bit of a, how can I say, disinterest by most of the pharmaceutical companies in developing viable drugs. And yet, our patients suffer from this complication and perhaps was the reason for which treating neuropathic pain by primary care physician led to this out-of-control use of opioids. And I like to say that besides the fact that opioids have horrible consequences, leaving aside the addiction, particularly in diabetes, the use of opioids increases mortality and cardiovascular disease risk by five to six times numbers. They also, if we actually look objectively at the data, have no effect whatsoever in treating diabetic neuropathic pain. All the opioid trials in diabetic peripheral neuropathic pain, in fact, have been negative because if you look at a trial in which 50% of the patient population enrolled is withdrawing after four weeks, this is a negative trial. So I'm just giving you some context here. In addition, I think that it's very important when we design clinical trials to make them relevant to the patient population that we see in clinic. Historically, again, many of the trials have been designed by cherry-picking patient inclusion and exclusion criteria. Therefore, it's not surprising that many of them either failed or were completely irrelevant at the point of care. Hence, I think that a breath of fresh air when Lexicon came and realized that in truly to make a difference, we need to enroll people as they are treated at the point of care. It's actually unethical to withdraw pain medication in these patients. Those were several of the reasons that made me so enthusiastic to see this interest and also participate in the trial design. I was also impressed by the fact that Lexicon was willing to listen to our voice. I wasn't involved from the beginning in the trial design. When I pointed some of this issue, Lexicon was very receptive to listen to this argument. That was also extremely encouraging. Some of these arguments are here. Thank you. Tell me a little bit about the importance of a placebo, particularly in this patient population. Maybe you could just give a little flavor of what is the primary endpoint of the study and how is it measured? Absolutely. So it has been demonstrated always that actually, placebo plays a huge effect in clinical trials in general but particularly in pain trial. And that has been demonstrated in every single agent that has been started. And therefore, having this run-in period in which everybody is treated with placebo enables us to start the actual active trial at a level of pain that is more realistic. And therefore, enables us to more clearly assess the actual effect of the molecule that is being evaluated. So that's one. Second, I'd like to say that by having the sorry, can you ask the second part of the question? Well, it was really just where would this drug fit in the armamentarium was the other part. OK. So yeah. And then I'd like also to mention that neuropathic pain has a very complex mechanism. It's not driven by one specific target. It's not driven by one specific molecule. Like, for instance, many of the Vertex trial, right, that it's evaluating this particular voltage-gated sodium channel. So it's extremely complex. And therefore, the expectation that the person may be treated with a single drug, it's also unrealistic in chronic neuropathic pain that we are talking about. And diabetes, it's a chronic disease, as I mentioned, and does involve so many people. Neuropathy involves so many people with diabetes. And thus, we need to be aware that a patient may require two or three agents. And the fact that the first phase 2a trial was able to achieve a clinically meaningful and significant endpoint reduction in addition to what patients were taking, it's very relevant. An additional point is that many of the existing agents that are FDA approved for neuropathic pain and in reality, we have two in the United States, this is pregabalin and duloxetine, do have an important spectrum of side effects that for diabetes can be detrimental, including fluid retention, weight gain, among others. So therefore, having agents that are targeting a mechanism that doesn't actually act through the same mechanism, it's very important. And the safety of the participant has been also a very important component that we were able to identify. Patient-reported outcome, it's extremely relevant as well. As Sharlene said, in hypertrophic cardiomyopathy, it's the same in diabetes. So yes, the pain reduction in score is an important patient-reported outcome. But we are also capturing the patient global impression of change, similar like with the Kansas City questionnaire, which is giving us an opportunity to understand the patient well-being. That's also something that both patients and FDA are strongly interested in. So just I know we're running short of time. What is success in the progress trial? What are you looking for out of the trial? So I'm looking to identify the same pain reduction with probably a similar, at least with a lower dose or even better safety profile, again, learning from the lesson. It's so important. And the fact that we understand now how to titrate this medication better, I'm confident that we will be able to mitigate some of the side effects that led to some of these participants withdrawing from the high dose arm, which also explains the results of efficacy on that particular dose. Just in closing, I know you've been so actively involved with the study sites. I mean, what are your impressions from what potential or actual study sites are telling you? You've been to the investigator meeting we had a few months ago. I know there's another one coming up the end of this week. I mean, what feedback are you getting? So it is a hunger among clinicians and investigators to have viable drugs for this disease and also to have an alternative to pain that can enable us to finally end this fight against the use of opioids because, unfortunately, this is still happening. Having effective medications will have a huge impact. I like to say that neuropathic pain in diabetes, it's a huge market. Again, just by putting the numbers in perspective, diabetic peripheral neuropathy, it's three times more prevalent than any other form of peripheral neuropathy. It's happening in people with diabetes. You heard the numbers. Dave, you might want to comment because I know you see a lot of these types of patients in your clinic. Yeah. So two comments. One is exactly this sort of hunger to have a new therapy that's not only safe but also effective for diabetic neuropathic pain is critical. But I think that's a theme that threads these different studies together, which is that the same kind of hunger and the same kind of proactive asking about, how can I send patients to you for these trials, is also in the type 1 diabetes and kidney disease area. And this is the first area where we have patients sent on a, I would say, weekly or every other weekly basis. We have patients sent around from the greater Toronto area who are referred to my clinic specifically because they've heard about sugar and salt and other studies in this field. So these are trials that have very significant buy-in from the diabetes community, endocrinologists, nephrologists, cardiologists, primary care even. They also have very significant buy-in from patients. So patient advocacy groups, Diabetes Action Canada, the SPORE Kidney Disease Network, and elsewhere, as well as some individual patients have very significant they're very vested in these trials. And they want to be involved. They want to be invested. And they want them to be successful. I think that's a great way to close, is that we're really meeting both an unmet medical need but really an unmet patient need, whether it's in sugar and salt, whether it is in the type 1 diabetes overall, whether it's in the HCM community. Really, I think the neuropathic pain community is so underserved. This has been a silent disease for so long that patients need a voice. I'm hoping that we're going to be able to put together a strong voice in support of that unmet need. These patients really are suffering in silence. With that, I think we'll draw this session to a close. Thank you. For another unmet need. Thanks, Craig. Oh, the clicker's here. Thank you. So I'm delighted to be able to talk to you today about the latest edition to the Lexicon portfolio. So the molecule is LX9851. And the target is ACSL5. Both the molecule and the target were identified and discovered by Lexicon and our Lexicon scientific team. So I think we're all aware of the huge medical need for weight management. But we believe there's real opportunities beyond the initial weight loss with a GLP-1 agonist, particularly a simple, small molecule that could be given orally for chronic weight management, an agent that reduces body fat but spares lean body mass, an agent that impacts the metabolic profile, reducing lipids, improving insulin sensitivity, and something that has potential additional related indications in metabolic syndrome and MASH. So our internal team identified a new target. I'm going to go into depth with the science of that, ACSL5. Then we had a very intense drug discovery program that identified a molecule that had all the requirements that we wanted to take it forward now into IND-enabling studies. This is the target. It's a bit of a mouthful, acyl-CoA synthetase 5. It's an enzyme that takes long-chain fatty acids and converts it to the CoA intermediate. And that intermediate, as I'll show you, is incorporated in many lipids. The homology between human and mouse is about 81%. In fact, we test our molecules on both the human and the mouse enzyme. And they have very similar activities. It's highly expressed in the jejunum, particularly in the enterocytes, and also in the liver. And as I mentioned, our strategy was to get a small molecule inhibitor. This is a diagram of the complex lipid biochemical cascade. In red, I'm pointing out where does ACSL5 lie. It lies at the very first step of the lipid cascade. That has two implications. First of all, it inhibits all of the lipid downstream lipids in the biochemical cascade. But I think just important, perhaps more importantly, in green, I show that when you inhibit ACSL5, the consequence of that is it redirects free fatty acids to the intestine. That activates something called the ileal brake mechanism, which leads to satiety and improvements in metabolic parameters without seeing steatorrhea or hepatic steatosis, which has been one of the challenges with other inhibitors further down in the lipid cascade. The knockout phenotype was really remarkable. We saw that the animals were lean and resistant to diet-induced obesity. We saw glucose tolerance with lower insulin levels. We saw decreased cholesterol and triglycerides. When we looked at more complicated animal models, we saw reduction in atherosclerotic plaque and also resistance to fat deposition in a model of NASH and actually even modestly reduced blood pressure. So it really counters all aspects of metabolic syndrome. Just as you've saw for all of our other targets, we looked at 5,000 genes. And this one really jumped out as one of the most exciting ones in the metabolism area. What we saw at the bottom of all the genes we looked at, it had the most profound effect on cholesterol and triglycerides. If it's on the left-hand side of the bell curve, it shows that it's really an exceptional target. We also saw reductions in body fat even with a normal diet and no change in lean body mass. So we thought this was really exciting. We really started to dig into the pharmacology of this target. The first thing we did is we looked at high-fat diet. What happens when you take these knockout mice and you treat them with high-fat diet? On the right-hand side, what we saw was an even bigger reduction in fat. It's about 25% in the knockout animals. In green, it's the knockout animals. There's 170 mice that we studied versus the wild type. You can see that suppression of fat in these animals. When we look at lean body mass, we didn't really see any difference. This is what really excited us as a potential agent for the treatment of weight management. So in the next few slides, I'm going to show the same kind of thing, which is on the left-hand side, you will see what we saw with the knockouts. And on the right-hand side is what we saw with our molecule. So this is looking at decreases in body weight and body fat. And on the left-hand side, the top line is the wild type animal. It's body weight. And then the green is the knockout. And you saw a nice reduction in body weight in the knockout animals. And that body weight is basically due to reduction in body fat. There's about 25%-30% reduction in body fat. So turning to our molecule, we spent a long time inventing this molecule. And we were pretty excited when we put it into the experiment and what's it going to do. In fact, we saw a beautiful reduction of body weight. When we looked at the adipose tissue, we saw that that's where the body weight was coming from, reductions of fat. The compound, in case I get a little confused, 9851 and this code name it 960345 is actually the same molecule. So where was this reduction in body weight coming from? We looked at food consumption. Again, with the knockouts on the left-hand side, you see that the knockout animals eat less. They have less food consumption. When we did the study with the compound, with just treating diet-induced obese animals with our compound, you can see you get a really nice reduction in blue compared to the control. That actually stays down throughout the entire 30-day experiment that we did. It's a highly significant result. This was quite amazing. I still find it amazing. So we gave mice a choice between a low-fat diet and a high-fat diet with two bowls in their cage. And we recorded where did they go to take their calories. So on the left-hand side here, you can see the very high-fat diet. And the right is a low-fat diet. And in black is the knockout. So you see that the knockout really isn't taking any of the high-fat diet to get its calories. But it's getting it all from the low-fat diet. And that's in marked contrast to the normal animals in green. Obviously, they go for the most calories they can get. So they go almost entirely for the high-fat diet and don't really touch the low-fat diet. So this is an amazing food preference that we saw, really astonishing. We were able to reproduce that with our small molecules in pretty much the similarly set up. You can see in gray here on the left-hand panel is the untreated animals. And when we treat them and so they're taking all their calories from high-fat diet and then very little from the low-fat diet on the right-hand side. And with our molecule, with a couple of different doses, we saw the same nice preference where they get all of their calories from the low-fat diet and avoid the high-fat diet. So I've showed you that we see reductions in weight. And we see reductions in food consumption. And when you look into the literature about the ileal brake mechanism, one of the aspects is really delayed gastric emptying. Again, knockout on the left, compound on the right. But it's a complicated slide. But let's just focus on the stomach. So what we did, we gave these animals a radiolabeled lipid. And we looked to see how that lipid makes its way through the stomach, the small intestine, et cetera. And if you look in the knockout on the left-hand side, look at the stomach panel, what you see is that the lipid stays in green. The lipid is staying in the stomach when these knockout mice compared to the wild type animals. And when you look at our inhibitor, again, at the stomach panel, you see exactly the same thing. So really, this represents delayed gastric emptying. The lipid is staying much longer in the stomach. We also looked at some of the well-known biomarkers. So we looked at GLP-1 and PYY. And we did this both in the knockouts. And we also did the same thing with our treated animals. We saw a nice increase in active GLP-1 and total GLP-1 and also PYY. We're doing a lot of studies as we speak looking at other biomarkers because the story is much more complex than just GLP-1 and PYY. So when we did an oral glucose tolerance test, so you give the mice a bolus of glucose. And then you look and see how high does the glucose level go? And how quickly do these animals clear glucose? And we saw a really nice effect both in the knockout. You can see the green line. You see a lower peak of glucose. And it's cleared more quickly. And we see a really nice effect with our molecule LX9851 as well in the same test. And if you look at what insulin levels are required to show this effect, we actually see lower insulin levels. So this is a really nice feature of improving glucose tolerance with less insulin. So we really wanted to look at another aspect of the metabolic profile, which is lipids. And so we used a really interesting model here. If you knock out the ApoE gene in mice, they have extraordinarily high cholesterol and triglycerides. It's really a model for some of the human diseases like that. And if you then take those animals and cross them with our ACSL5 knockout, you can ask the question, how does eliminating that target impact these extraordinarily high cholesterol levels? And we were very excited to see this data here. So if you just look at the left-hand panel here, we're looking at cholesterol levels. They're in the thousands for the sort of control animals that don't have the ACSL5 knockout. And then there's a dramatic reduction both in males and females between nearly 30% decrease in cholesterol up to nearly 50% in males. Similarly, when you look at triglycerides, you see about a 40% reduction in females and about a 56% decrease in males on triglyceride levels. If you then continue the experiment and take a look at how much aortic plaque is laid down and we see even more amazing results here. With females, we saw a nearly 60% reduction in aortic plaque and with males, over 70% decrease in aortic plaque. So this is another aspect above and beyond just the weight reduction that I showed you previously. If you take mice and you feed them on a very high-fat diet for 5 months, what happens is you get a lot of triglycerides deposited in the liver. And when we look at what does our knockout do compared to a normal wild type animal, again, in green, you can see this marked reduction of triglycerides in the liver both on a percentage basis and just a pure milligram basis compared to the wild type animals. So while Lexicon discovered the relationship between ACSL5 and weight management and metabolism, it's interesting to note that there's been some human genetic studies. So some GWAS studies have been looking to see what loci in the human genome are important. So I'll give you a point out to the top one here, which is an association between a SNP in the ACSL5 gene and its association with type 2 diabetes. It's actually the strongest association in the human genome with type 2 diabetes. There are other studies that have shown similar effects that we have seen in mice, which is lowering triglycerides. Interestingly, there have been some studies looking at how do patients respond to weight loss treatment? There's a nice correlation with ACSL5 SNPs for that as well. So as I said, we worked hard to get the ideal molecule. It's highly potent in the biochemical assays. It's selective against other biologically relevant ACSLs. There's a family of those enzymes. We saw good drug metabolism. But I think most importantly, we've spent a lot of time really looking at the safety profile of this molecule. In particular, we've just recently completed a full 28-day rat toxicology study with complete pathophysiological evaluation of all the tissues. We didn't see any adverse effects up to the very highest dose that we did in this study, 300 mg per kg. That's given us the confidence to select this molecule and start moving it forward into IND-enabling studies. These next few slides are really critical because I think it positions exactly where we think the value of this molecule can have in the treatment of chronic weight management. On the bottom, the x-axis is the number of days. It's a 30-day study with diet-induced obese mice. Then the y-axis is the body weight. The top two lines are the control, one for injectable, one for oral. You see in the light blue line, you see the really nice reduction in weight with our molecule LX9851. In black is the curve that you get from treating with semaglutide. As we all know, these are really fantastic agents for weight reduction. But the exciting thing that we found is that there's a good, strong additive effect of adding LX9851 and semaglutide together. You can see the green line with highly significant levels. There's a very nice demonstration of greater reduction of body weight. Not surprisingly, we also see that in food consumption. If you look at the green line here, the green line is actually semaglutide alone. When you add the 9851 to that experiment, in the black line, you see the biggest reduction of food consumption. Let me walk you through this experiment because this is also really critical to where we think we should position this molecule. What we did in the blue line, what you see is the treatment with semaglutide. We started the experiment as with the others. And for the first 14 days, the animals were given an injection of Semaglutide every day. And as expected, it drives the weight down nicely. And then we stopped the Semaglutide. And of course, what we saw is that the weight began to go back up to baseline, which is exactly what is seen in human clinical trials. The question here is, what happens when we stop Semaglutide? If we add LX9851, what do we see? And what we saw is that it really helps maintain weight loss after we've taken Semaglutide off. So we really feel this is a key area of positioning for our agent going into the future. So finally, I think hopefully, I've shown you that we have a really exciting opportunity here. We have an oral small molecule. We see an additive effect of our compound on top of a GLP-1 agonist. We've shown that it helps maintain weight after stopping Semaglutide. There's also, from all the other studies that we've done, a really broad potential on the metabolic profile above and beyond weight management, including metabolic syndrome and MASH or NASH. I think we all know from unmet medical need for patients and also the opportunity for this market is really quite enormous. It's projected to be of the order of $41 billion. Thank you. I'm going to hand back to Lonnel. All right. So we're coming to the home stretch. Let me first stop by asking all of us to give a round of applause to our panelists. They did a phenomenal job. Thank you so much. I know you're not going to believe this, but I learned a lot. I really did. So thank you so much for sharing your time with us. I thought I'd take a moment to give you some closing remarks and then open the floor for management engagement with all the folks in the room for Q&A. So let me speak to what's unique about all of these areas in which we have invested time and resources into over the years. None of it's possible without investors investing in the company and having fundamental belief in staying long with our company. We've moved this company into 10 years I've been here. We've moved it from its discovery roots into being a fully integrated pharmaceutical company, now participating in some of the largest markets we know across the globe. What's unique about all of these markets is our mission, which is to introduce real scientific value to patients to improve their life. What's unique about each of these markets are three things that investors should pay attention to. One is that these markets are all large. Two, these markets are all growing. And three, in each of these markets are opportunities, white space for our technology to exist, but most important, for us to fulfill our mission, which is to bring hope and promise to patients. With that being said, as investors, what do you have to look forward to? Let's start with INPEFA. I've said from the very start nine months ago with this, don't pay attention in the first six months or so of this launch because, quite frankly, it's not going to be so beautiful because it takes time to get access. It's a very competitive market. It's a very noisy market. And we're a very unique and very different compound. And it will take time for us to get leverage. So in the second half of this year, you should very much look forward to a real true-up. What's going to happen in the next two quarters, I think, will be very, very important for INPEFA. Secondly, so to go sotagliflozin. As you heard from our panelists, we firmly believe that this drug will work in HCM, hypertrophic cardiomyopathy. Therefore, we're full steam ahead into phase III that we should start to see value happening in the next quarter or so. Zynquista. Listen, I've been ebbing and flowing, dancing, and doing all the things I need to do in the time that we've been fighting this out with the FDA. But what I'm very proud of is that I think the FDA and Lexicon are on the same page of finding an opportunity to do what we committed ourselves to do for all of the community in T1D that we said we will not abandon you. And what you saw on the screen today is not just the work of resubmitting our NDA, but all the other work we're doing with sotagliflozin, whether it's the STENO-1 trial or the SUGARNSALT study, we are still committed to T1D. We said that seven-eight years ago, and we're still true to it today. We could have easily yielded and moved out of this. But our mission is to bring real value to patients and families. And we intend to do it in type 1 diabetes. So stay tuned for the steadfast work we're doing to resubmit for type 1 diabetes. LX9211 or AAK1 coming out of the pipeline of Lexicon is pretty awesome. This is an area of diabetic peripheral neuropathic pain that is littered with failure. It would have been easy to not invest here. 10 years ago, when I arrived here, this was an alliance with Bristol Myers Squibb. And they were doing a lot of other very important work, but they weren't focused here. And therefore, we took it out of that alliance, and we took it forward. Now we have an opportunity to be not just in late-stage development, but we're already proving ourselves to be right based on the work that we saw in our Genome5000 scientific pursuit. Everything we do is not by chance. It's by efforts and diligence and good scientific pursuit. Now you just heard from Alan Main. You all know what we know. LX9851 is not something that just happened because it's the best thing to do at this point in time. This is something we've been working on for a long time. It's been 10 years. Alan's tired of hearing me talk about when we're going to make progress. Well, today, he's announced the progress that we've made. I can only tell you, it's better than any of us had expected. So with that being said, we have a whole pipeline of opportunity for investors to look forward to and continue to have hope and promise in investing in this company as it has done historically. What do we owe you? I want to thank all those investors who came in and invested in us in the last round of our successful financial raise. But what we owe you, we owe you as a management team to stay very much focused and fearless in our execution around the plans that we put in front of you. We owe you the responsibility to allocate our capital in precise ways in which we can continue to advance our compounds from discovery to development and ultimately to the market. And when we get in market, we have to show you we can do some things there as well. And thirdly, we should not close the door to the opportunity to partner because that is the best way to be efficient, and that's the quickest way to get a return to our investors. These are the things we owe you, and these are the things we will stay committed to. I think that's the best opportunity for us to stop there and then ask my team to come back to the stage to take your questions. Thank you. All right, Ms. Lisa, I believe we have mics. We're going to take questions from the extraordinary people in the room. All right. Are we asking for name and company? Yes, please. Would you like to start? Oh, you good. You want to start? Yeah. Josh can go. Hi. Yigal Nochomovitz from Citigroup. Great set of presentations and speakers. Thank you very, very much. I had a bunch of questions. Just a few, maybe starting with HCM. I don't know if oh, Dr. Day is leaving, but I had a question. Okay. I wanted to specifically because you made the point about the beta blockers not being so effective. Just curious, with regard to the design of the study, are the patients going to be on the beta blockers or the calcium channel blockers, or is that optional? If that, you could discuss that briefly. Yeah. So again, they can stay on their underlying therapy, whether it's a CMI or a beta blocker or a CCB. They can't change the therapy, but if they're on a stable dose, they should and can stay on that dose. Okay. Great. Then for Dr. Busui, I was just curious, and also for the company, for the phase II data for DPNP, there was obviously a plateau in response on the dose. If you could expand a little bit on the decision to include both the 10 and the 20 in the phase 2b, given that you hit a dose plateau in the earlier trial. Thanks. Well, again, there's a question, Yigal, of when we went and did the detailed population PK of that, and you look at the blood levels, there is a dose response based on exposure in the bloodstream. And remember, this is where we spent the time in trying to answer the question. And I probably wasn't clear enough. But since we analyzed the data on intent to treat, those early failures, by and large, count against you. So when you look at actual exposure in the patients to blood levels, there was a dose response, which is why we put the 20 in. If you look on an intent to treat basis with a rigorous design, the way we ran the study, you did not see an incremental benefit. And that's why we added that arm into the experimental design of the progress trial. Okay. And then last one for me. You showed the very nice data for Intandem 1 and Intandem 2, Jeff, on the CKD benefits. In Intandem 3, did you see anything there as well when you looked at the CKD people, or was that not looked at? Generally, the data are consistent across our entire program as it relates to people who have type 1 diabetes and chronic kidney disease, on both efficacy and on safety. We were using those two because they were both on top of optimized insulin, but the data are consistent across the entire program. And y'all, that data was presented at ATTD in the last couple of months in that 312 subgroup, which is a different design. Got it. Thank you. Your colleague here. Thank you. Joseph Stringer, Needham & Company. Thank you for the presentation. First question is for maybe Dr. Day, but just around the sorry. Just curious, given the phase III trial design in HCM, how representative are those patients in terms of those that you see in your clinical practice? And then I have a follow-up for management as well. Go ahead. Just quickly answer. Yeah. I mean, I think the eligibility criteria are very broad. And I think we'll be able to generalize to many patients with HCM, much more so than other trials. And I think our screen failure rates will probably be very low for that reason. But I think it'll be very generalizable. And we also have a diversity plan across multiple countries. And so yeah. Got it. Thank you. Then as a follow-up to that, you're enrolling both non-obstructive and obstructive patients in the phase III trial, which is different than what has been previously done for competitors. I guess, what gives you the confidence that you have enough patients in terms of potential differential treatment effect on the KCCQ primary endpoint? Will they be stratified? Any details around the powering stats plan there? Yeah. So Joy, I can answer that question. So the study is powered on the overall population, just like our heart failure trials were powered based on the overall population. What the FDA will look for is a consistency in the response in the subgroups. The study is not powered independently for each of the two subgroups. It doesn't need to be. That is part of the statistical plan that was discussed with the FDA. So FDA, we said we're going to come in stratified. We're going to look for a significant difference between the overall group. And then obviously, some of the sub-analyses will be the response within each of the two subgroups. But each of those groups of 250 is not independently powered to show a statistically significant difference to placebo. What we do expect is that there won't be an interaction p-value in a sense that, "Gee, we're going to get this great response in one group and not the other," and it'll sort of drag it, in a sense, across the finish line. Great. Thank you very much. Over here, please. Hi. Andrew Tsai, Jefferies. Thanks for hosting this. So one more on HCM. At the end of the day, what do you think is positive data to you on KCCQ scores, especially with Mavacamten in the market today for obstructive? And secondly, just to confirm, you do have FDA buy-in to use this as a registrational endpoint, just to be clear. So the answer to the second point, yes. And again, it's very consistent with what has already been approved from other companies for the FDA as they've publicly talked about in the non-obstructive group. The other is that the endpoint that we've picked for KCCQ, I don't think we've disclosed what that magnitude is. I don't think now is the exact time to do that. But I think we have confidence that we can achieve that based on looking at our prior data because remember, we've got an 11,500-patient cohort that we've studied KCCQ in with our SCORED and SOLOIST programs, and that's a number that is both clinically significant and regulatorily satisfactory to the agency. If we achieve that, that would be compelling for labeling. Thanks. And maybe for the pain program, we've seen some NaV compounds get breakthrough designations. So the question is, have you filed for a breakthrough for your pain asset? And if not, when do you think you would consider? I think our expectation would be, after this study, we would have an opportunity to file for breakthrough status. That would be something that we would definitely consider doing. May I ask one more? Can I ask one more? Sure, Andrew. Thanks. And maybe going to the type 1 diabetes program, I guess it's for the doctors. We understand DKA is a safety thing, but the benefit-risk profile could be better in the subpopulation. So at the end of the day, at peak, what percentage of your patients would you prescribe sotagliflozin to if it were to be approved in this population? Maybe for the doctors. Oh, you're asking Dr. Busui. I think Dr. Busui perhaps can answer that. Dr. Busui, come in your way. What percentage of patients with type 1 diabetes I would prescribe sotagliflozin to? That's the question? Yes. Right. So I think that that's a great question. Maybe at least 50% of my patients I would prescribe. I'm telling you why. It's because I know that these patients not only have a certain degree of chronic kidney disease that may be even in an earlier stage, but we also are now in the possession of data demonstrating that people with type 1 diabetes have even a higher risk of developing heart failure than those with type 2 diabetes, which is actually quite new information that we were able to extract from very large registries with type 1 diabetes here in the U.S. and across the globe. In addition, we are in a position to identify these earlier stages of heart failure with easy-to-test at-the-point-of-care biomarkers that have been demonstrated to be extremely sensitive and specific to predict those who will develop those later stages that will require hospitalization. And our goal, it's actually to prevent these later stages. In fact, the American Diabetes Association, by comparison, has created different guidelines in which people who have even early stage A or B heart failure and have diabetes, in this patient population category, an SGLT inhibitor is an expected element of care without people actually having symptomatic heart failure because our goal, it's to prevent these people to go to the hospital and actually to die. So that's my answer. Thank you. Thank you, Doc. Well, congratulations on a great presentation today. This is Liam on for Yasmeen Rahimi at Piper Sandler. My first question is just, given that you're guiding about a 2025 IND filing for LX9851, I was wondering if you could provide maybe more detail on the timeline in 2025 and also any tidbits on the phase one trial design. I think that we'll probably lay out a little bit more information on that as we get closer to the time. But it'll take about a year or so to get the IND enabling studies done and get the IND filed. So it'd be around the middle to second half of the year next year for the IND filing. I guess looking at the preclinical data, you see a preference for the low-fat diet. Is there any mechanistic reasoning behind that preference? I mean, I would argue that the concept that Alan talked about with the ileal brake is probably a critical component of that in that it's a well-known mechanism. There's just never been a drug that has acted on that. So based on all the data and Alan's good education doing some additional looking into it, it's that getting those fatty acids further in the GI tract has an effect of satiety in some way in the brain that changes your food preference and amount of food eaten. So we believe that that ileal brake mechanism is probably involved in the food choices as well as the amount of food required before satiety. We also know, based on what Alan was showing, that it's not just an incretin-based mechanism. So there's probably a lot more going on there, as you would expect with all these neurohormonal signals regarding satiety and food choices. And then with GI tolerability being somewhat difficult to measure in mice, do you have any expectations on the translation from your mouse data to humans and how potentially you would expect the GI tolerability profile to be for your drug? Alan. Yeah. Well, one of the things our mechanism isn't doing, which is it's not pushing a lot of triglycerides into the GI. And that's what's been one of the big problems with other inhibitors of the lipid pathway. You're right. It's hard to judge from mice. But our expectation, people have done studies where they've actually infused fatty acids into the stomach of humans. And they don't see really any issues with diarrhea or anything like that. Thank you so much. Thank you. Any other questions? Oops. One more. I had one other question, Dr. Cherney left, but maybe the company can answer. Regarding the sugar and salt study with the STITCH protocol, how will that be handled from a DKA collection of events standpoint? If they successfully pass the STITCH protocol, is that not counted as DKA? Or how is that treated when running the numbers on the study? Thanks. Well, the whole point of STITCH is to prevent the DKA event. So it would not be a DKA event. Okay. Just trying to understand exactly how it works. Yeah. Yeah. Okay. Because again, a lot of what STITCH is driven by is symptoms. So again, you're going to look at the ketones. But since there's not a specific threshold where, say, "Gee, this is DKA," a lot of it is symptom-driven. So the whole point is to get ahead of it, educate the patients, know their behaviors, know how they normally feel about their body. A lot of STITCH is really defining your own baseline and being sensitive and aware of that change from baseline and then taking action so that you do not develop DKA. Okay. Well, I guess sort of following on that then, what's known in the literature about how effective STITCH is as a method? Is that well-established in terms of its success rate? Well, I think Dr. Busui commented on that already. And maybe he can comment again. But it was instituted in the actual In Tandem program and was deemed to be effective from an educational and mitigation standpoint of being effective. No. No. That's true. In fact, it was pioneered in tandem tree and demonstrated a very steep reduction in the number of DKA events. Now, I'd like to say that there is a difference between ketosis, like ketone bodies that are elevated about a certain level that can happen even in people who are engaging these high-fat diets or keto diets, right? But from having elevated ketones to actually getting DKA, it's a different step. And the STITCH protocol, it's doing exactly that. So there may be situations like a person may get a viral infection while they are enrolled in the SUGARNSALT. But with the STITCH protocol, since we are educating people that if they develop nausea, abdominal pain, immediately to test their ketones because we are providing them with ketone meters and we have clear thresholds of how high this ketone body should be and immediately starting high fluids, administering extra insulin, that has been very effective to prevent this transition from, let's say, transient ketosis episode into the actual DKA. And the success of such a protocol was demonstrated in inTandem3. And we have implemented all these steps in the SUGARNSALT. Any other questions? So before I turn it over to Lonnel to close, I wanted to thank everyone for joining us. I know all of you will ask. So we will have the presentation posted shortly on our website. And we will also have a reference materials slide with all the reference materials that were referenced throughout the presentation. Lonnel? The only thing I would add is stay tuned. We did not provide a lot of financials and things of that nature. We do have an earnings call coming up. So I would ask you to chime into that for further details. Okay. With that, thank you so much for attending.