Okay, let's get started with the next session. Andrew Tsai, Senior Biotech Analyst at Jefferies, thanks for joining us. It's my pleasure to have the Lexicon team joining me today. To my direct right is Mike Exton, CEO. To his right is Tom Garner, Chief Commercial Officer. And then to Tom's right is Craig Granowitz, CMO. Welcome, everyone. Thanks. Thanks, Andrew. Okay, so team, would you mind giving us a couple of minutes talking about the Lexicon story, what you're pursuing, your objectives, milestones over the next 12 months? Yeah, great. So this year, Lexicon has really driven forward a number of diverse programs that are coming toward their decision point. So on the one side, we've got a sodium-glucose cotransporter business, which across three different indications for heart failure, for type 1 diabetes, which we're coming to a decision point very soon with a PDUFA of December 20. And we also commenced the SONATA trial in hypertrophic cardiomyopathy, which is another area of significant unmet need. And we see a very good possibility for sodium-glucose cotransporter in that business. At the same time, we've also progressed the PROGRESS phase 2b study for diabetic peripheral neuropathic pain for LX9211, which we'll read out now in the first quarter of 2025. So we're very excited about that program. We think that has application across many forms of neuropathic pain and spasticity as well. So that has progressed very nicely. And then finally, we have LX9851, which is a novel oral medicine for weight management that is complementary to current existing GLP-1s and other intrinsic mechanisms. And we're continuing to drive the IND enabling studies for an IND submission in the mid of next year. So we've really got a diverse number of value creators for the company that are coming to exciting decision points very soon. Wonderful. And Mike, you joined the company earlier this year. And so my question is, what do you think you can bring to the table that we might not be appreciating? Certainly lots of drive and energy, and I think really what we've shown over the last three or four months is a decisiveness across those programs to look at where we see the best opportunities and making sure that we allocate resources in the most appropriate way where we see the opportunities opening up, and for some of those, we're also needing to deprioritize as we move forward and making sure that we create the most value for not only the patients that we're serving, but all stakeholders. Right. So let's spend some time on the type 1 diabetes program for sodium-glucose cotransporter. You did have an AdCom recently. What were some of the key takeaways? What went well? What could have went better in your view? So what went well was we were very much aligned on the population that was the target where the value benefit was best. That was the group characterized by GFR of 60-90. I think in that regard, we were very much aligned with the FDA on the value of that, both in terms of A1c reduction, percentage of patients that get an A1c target of seven, weight loss, reduction in blood pressure, as well as minimizing the risk of diabetic ketoacidosis. So I think in that regard, we were quite pleased. The other area, which I think was overwhelming, was the support from the patient community, the medical community. I think to have 23 speakers come to the open public forum, have 148 submissions to the public forum. And I think even as recently as yesterday, if you look at some of the major newspapers in the country, there were full-page ads taken from a group called Taking Control of Your Diabetes, TCOYD, that are talking about the need for the FDA to take action. So I think those are things that went really, really well. I think what were areas where it could have gone better is that it seemed that the agency, at least some within the agency and some on the committee who were returning members from the 2019 panel, had fixed and preconceived notions about risk-benefit. And despite the fact that I think we worked very productively with the review division to come to the 60-90 where risk-benefit was the best, they still had those fixed positions. Even though since 2019, the drug is now approved and has been on the market for more than 18 months with well over 1,500 patient- years of exposure and no case of diabetic ketoacidosis. There are international guidelines that have been established of managing diabetic ketoacidosis that the medical community feels that are appropriate. And these drugs have now been on the market 15 years. And we're really looking for an extension of the use of the molecule, again, with appropriate education that the FDA still seemingly has some of these fixed standing preconceived notions. Right. And despite the unfortunate mixed AdCom vote, I don't know how to characterize it else, the FDA did seem as it did sound as if the FDA just wanted to hear what the panelists were thinking. It wasn't as if the FDA had some I don't know. Is that your sense too, or? Again, we've had a long-standing discussion with the review division that goes back now almost a year. We've worked very productively and collaboratively with the review division. I think, as Mike said, we'll wait and see what transpires over the next month. I think the FDA is seemingly committed to a final decision by December 20. December 20. And can you give us a sense of the market opportunity for the 60-90 subgroup? Yeah, so I'll take that, Andrew. So I think we've publicly stated that going into the AdCom, that the patient population was around 400,000 patients if you take the originally filed application. Looking at the data that the FDA actually shared themselves at the AdCom, and we've done additional work, I mean, it's roughly 50% of the type 1 population that potentially falls into this mild to moderate category. So by our estimations, you're seeing potentially a 50% increase over and above that 400,000 to closer to 600,000 that would fall into the potentially labeled population, although we have to wait and see what happens on December 20, clearly. This could be the first SGLT approved for this indication, type 1 diabetes with CKD. Correct. Right. Andrew, I'd go one step further. There are no approved agents, no approved oral agents at all for glycemic management in type 1 diabetes. So I think that's one of the reasons why the medical and patient community is so active in this area. Zero. Right. And I don't know what day is it today? Okay, 30 days left, give or take. Have you entered final labeling discussions, or? It's not quite 30 days in the US yet. It's 3:00 a.m. We haven't heard anything. There's no guarantee that we will hear anything on the 20th. We continue to work with the FDA and await their feedback marching towards December 20. As you wait for the PDUFA decision, how have your plans been on the commercial side? Are you fully prepared? Do you continue to invest more, or are you kind of on pause? Yeah, so in terms of preparations, we've been preparing for the launch for the last six months. And we've been leveraging the existing commercial infrastructure that we had already built for the Inpefa launch. I think as you're well aware, Andrew, we did resize the sales team earlier on this year with the notion of focusing our efforts on a more concentrated customer base that exists for Zynquista versus Inpefa. It's about half of the 9,000 that we were looking at for Inpefa. So we have that infrastructure in place. The team have done great work in terms of preparing for the launch. So essentially, once we have the green light, the label, we'll be ready to go in Q1. In terms of your second question as to have we paused, I mean, obviously, we're in a position at the moment where we're in kind of a slight watch and wait mode. As soon as we're through that window, obviously, we will be ready to go. Are you guys hopeful, confident, nervous about the PDUFA? How would you? I think we are very much looking forward to the decision. I think we have put our best case forward. I think we have the incredible support of the patient and physician communities, and so we're very, very keenly awaiting the decision. Should it be approved, how do you foresee the launch cadence to be in first half or, sorry, 2025, especially in comparison to the heart failure launch for this drug? Yeah. So I would say in terms of launch preparedness and how we're thinking about the launch window, I mean, we would be anticipating a launch sometime in late Q1. In terms of some of the dynamics that we think are going to play out as you think about type 1 diabetes versus heart failure, I can tell you that the engagements that we've had with payers already point to the fact that this is going to look and feel very different to what we face with Inpefa. I mean, Inpefa in a category that's as highly managed as heart failure, as you would imagine, and some of the headwinds that were kind of overhangs as you thought about the Inflation Reduction Act, et cetera, they are not going to exist with this approval. We will be the first and only, as Craig has mentioned. I think just given the level of engagement of the type 1 community in their own care, this is going to be a substantially different looking launch to what we see with Inpefa. Great. And maybe one last question before we move on is during the AdCom, it sounded as if the panelists would like to have heard a plan on managing DKA. You've proposed Stitch before. Is that sufficient enough in your view, or do you think the FDA actually wants something more on top of that? Yeah, so I'll go back to really where the community started. And I think you've heard that loud and clear is that there are several international consensus documents that have been put forward in this regard to manage diabetic ketoacidosis. The quality of the diabetic ketoacidosis is no different whether you're on an SGLT inhibitor or not. I think it's also been made clear and the FDA has acknowledged that it essentially is not possible to run a clinical trial to look at a different intervention to lower rates of diabetic ketoacidosis further when you consider the rates of DKA are only about three per 100 patient- years. And how would you even run a trial? And do you need to run a trial when there is such a broad consensus across the medical communities around how to manage diabetic ketoacidosis? So as we clearly said at the AdCom, and we still believe, we've demonstrated overwhelming efficacy. We've demonstrated that there is an understanding of how to manage diabetic ketoacidosis. And there is no need or value to run another trial in this population. Right. Okay. So fingers crossed on the PDUFA. But in the meantime, we also have another asset, your AAK1 inhibitor with data, phase 2b placebo-controlled pain data in first quarter of 2025. So it could be a big deal for you guys. Maybe just high level, speak to the value proposition of an AAK1 for pain. So we see this as a hugely important program for the company. Clearly, it's an area of massive unmet need and relatively few players, a non-opioid oral medicine that can be used on top of standard of care. And this, if positive, would be the third positive efficacy trial that we've seen with this medicine and a medicine that could be applied across many different forms of neuropathic pain as well as forms of spasticity. So clearly, that opens up a significant program and opportunity for the company. And Craig, maybe you can talk about the program itself and where we're running with it. Well, as Mike mentioned, we've been really excited and gratified by the broad level of support for the program. The study enrolled a quarter early in terms of full enrollment for the trial. I think that speaks volumes to what the patient and medical community feels of this trial. It was 110 sites in the United States. And finishing a trial early is generally not what is seen as common. I think you can take with that what you will. But it's a program that we hear is pragmatic, easy to follow, is aligned with patient care, can be used on top of pre-existing therapy, which is very different than others that require withdrawal, and that the overall experience of the patients and the sites has been very positive. Again, we haven't seen unblinded data. But I think some of the concerns that were raised around dizziness, we're not seeing that profile in the blinded safety data. And we feel that that has clearly been addressed by the change in the dosing regimen. Great, and can you walk us through what you saw in the prior phase 2A data in terms of the placebo-adjusted change, how that compares to what Vertex has shown for their NAB? I know you just hinted at why there could be a difference, but maybe talk about the placebo-adjusted delta that you saw. So again, I'll focus on what the medical and regulatory community believe because it's very hard to, again, compare across trials and errors. So we've gone to the FDA. The FDA has reviewed what our plans are for running pivotal trials. They believe it's regulatorily meaningful, the endpoint and the magnitude. The medical community, we've had this data presented at no fewer than 15 medical meetings across neurology, diabetes, and endocrine, and that the trial enrolled the way that it did. So I think that speaks to is this clinically meaningful or not. We've talked around trial dynamics, the fact that patients had a run-in, patients were not forced to go off their underlying therapy. If you look at the overall reduction in pain score that is not placebo-adjusted, it's closer to 2, where, again, many of the other trials either don't have a placebo or don't have a run-in. So when you look at all of those criteria, again, it's very hard to compare across trials. But I think the data speak for itself regarding the excitement and participation in the program. Right. And in terms of the phase 2B, how did you power the study? Very similar to the pilot trial. And again, as a reminder, we also allowed patients to be on an underlying non-opioid DPNP medication. Again, quite different than others. What we saw in the pilot study was not a meaningful difference between the response, the DPNP, the pain score response, whether they were on or not on an underlying DPNP medication, which in nearly all cases was Gabapentin. I see. And remind us how many arms are in the study. And as long as you need, I mean, how many does one arm need to hit stat sig versus placebo to be considered a success, basically? Yeah, so it's a four-arm trial. It's well-powered to achieve the endpoint, again, similar endpoint that we had. The primary efficacy is drug versus placebo. There are three drug arms, three different regimens. One is 10 milligrams per day throughout, second is 20 milligrams per day throughout, and a third arm is 20 milligrams per day for the first seven days, then going to 10 milligrams. That gets you to what we consider the effective steady-state dose about a week or two earlier than doing 10 flat. And you. It's important to note for the powering that this trial will be over-enrolled, the original patient number that we powered it for because of the popularity of the trial, and so that will add a little bit of additional power for us as we go forward. Great. You mentioned earlier, Craig, that you're not seeing dizziness on a blinded basis. Why is that? So what we hypothesized, again, doing a real detailed look at the PK/PD after the phase 2A trials, both the DPNP trial and the PHN trial. So again, we have a large database of data to look at. If you look at blood levels, you see greater reduction in pain score the higher the drug level. That's why we kept the 20 milligram dose arm. And that seems to be related to the CMIN, the minimum concentration during the treatment. The dizziness seemed to be very much associated with a CMAX effect. When you gave that loading dose, you had a big upswing, big spike in exposure on day one. And so we believe that dizziness was very much attributed to CMAX and that efficacy was attributable to CMIN, not surprising. And that's what we really addressed in how we did the dosing in the PROGRESS trial was to achieve that CMIN without the overshoot in the area where we thought that dizziness would become more common. And I think we've demonstrated that, again, not knowing all the data, but it's still blinded, but that what we're seeing overall in the unblinded data, I'm sorry, in the blinded data. Right. By eliminating the loading dose, you should not see safety events. But just be clear, you do think you're reaching therapeutic effects quickly. Oh, yeah. I mean, again, look at how these drugs in general are dosed, right? These are chronic doses. In general, when patients go on gabapentin, they're not getting maximum dose, right? Normally, it's a three- to four-week period where they increase the dosing. And so we're really replicating that. And there's a very large placebo effect in all these trials. So it's not most patients feel relief from pain when they go on the trial. By reducing dizziness, potentially reducing discontinuations, do you think you could get stronger efficacy than what you saw in phase 2? That's certainly a thought. We're not powering the study for that, but that could be an upside. I see. And placebo is a key risk. What are some of the ways you've been trying to mitigate a high placebo response? Again, we have a pretty good idea what the placebo response is, right? We've already run two efficacy trials. So I think we've got a pretty good understanding of these populations and what the placebo effect is. We minimize that in the trial design. We have both a run-in period and another pre-treatment period. So we know the patients well. We know what their pain score is. We know that they have neuropathic pain. So we've really taken a lot of steps to understand and have a consistent response and consistent patient population. Got it. And should this study succeed, could it be considered as a pivotal study, or do you need two other pivotal studies? Our expectation is you're going to need two large power trials, but this could certainly be a supportive trial in that, and certainly, the safety data will be very important for the ICH guidelines of exposure. And speaking of that, do you have patients follow up to one year? I forget how much ICH would want, maybe 150? Yeah. So that would be one of the trials that if we have a positive signal, we would potentially do an open label extension right away, again trying to be very judicious with shareholder capital, not to rush ahead, also not knowing exactly what the final dose is of what the phase 3 program, because you need the exposure at that dose. Good point. And so this study will also allow you to pick a dose for the next phase 3 study. But maybe you would want to do two phase 3s just in case, one being a backup should this phase 2 succeed, kind of thing. The discussion we have with the agency, and remember, these are not large trials and are not long trials. So the cost of these trials is, again, they're always high. But it's not like what most people think. So really, what we would need is two large, well-controlled pivotal trials, plus this trial is a supportive study. Yeah. Yeah. Now, I think just wrapping up on 9211, cognizant of time, we've got a number of other programs to quickly talk about. But we see this as a clear partnering opportunity. You've seen evidence of our appetite for partnering with Viatris for sotagliflozin. And we expect that there will be a lot of interest in this particular actually, we know there's a lot of interest in this particular program. So that will be a very important readout for us in Q1 next year. Okay. Great. And maybe switching gears, like you said, other programs, you do have an HCM program underway. Data is second half 2026 or just 2026 broadly for that study? End of 2026. End of 2026. Maybe talk to us about why sotagliflozin could be differentiated for this indication. There was additional data that was presented. This was recently at AHA last week looking at HCM heart tissue and showing that there is a reduction in work, which is one of the major issues that you see is that you have overactive actin-myosin. We believe that the SGLT1 effects above and beyond the SGLT2 effects could be differentiating. There's a lot of other data since this is a diastolic dysfunction primarily that is common in both obstructive and non-obstructive. We're enrolling all patients, obstructive and non-obstructive, that have symptomatic disease that we believe that there's a common mechanism here that sotagliflozin can be effective in both of those populations in a single large pivotal trial. And keep in mind, Andrew, this is a mechanism of action that all cardiologists are familiar with, can be applied across all 20,000-odd pill-prescribing cardiologists in the U.S., and can be used on top of any therapy, whether it be basal therapies or CMI, and so really, the applicability of this asset across the population is very broad. The primary endpoint is KCCQ, which you do have FDA alignment on. Let's call it year-end 2026. What is positive data? I mean, do you need to see the same level of efficacy across non-obstructive and obstructive, or how does this all work out? The way the trial has been discussed for the agency, again, is quite common when you have two subpopulations where they are stratified is that it's the overall efficacy of the entire population. As long as the two groups are consistent, we would expect to get labeling that would include both obstructive and non-obstructive. Great. Do we have one? I actually can't see the timer. We've got 20 seconds. Okay. Obesity program, just last-minute comments about it, just timing-wise. Yeah. We're all on track for an IND mid of next year. This is an oral non-opioid, non-incretin mechanism, sorry, that can be used in conjunction with GLP-1s, shows additional weight loss, shows other impacts on triglycerides, on lipids. And we have a lot of interest in that particular program as well from various other companies that may be interested in obesity. Got it. Okay, well, thank you so much for the discussion. Thanks, everyone, for tuning in, and again, fingers crossed on all the upcoming milestones. Thanks so much, Andrew. Cheers. Thank you.