Morning, everyone. Welcome to our second day of our Piper Sandler Healthcare Conference. My name is Yaz Rahimi. I'm a senior biotech analyst here at Piper Sandler. Super thrilled to have the team from Lexicon. Lots to cover, and as you know, I'm a covering analyst and a big supporter of the company and been really privileged to see the story for many years. Team, we have lots to cover, but maybe a good place is to go in chronological order of sort of events. I think, obviously, lots of investors are wondering how your discussion with the agency is going in regards to Zynquista. So if you could just give us a quick update there, that would be great. Yeah, great. First of all, thanks for the invite and great to be here. So it's a great place to start because we've just literally heard back from the FDA. And it's pleasing news inasmuch as they've confirmed that Steno-1, which, as you know, is an ongoing investigator-initiated study of soda and T1D, has sufficient design and data collection methods for us to use that to collect DKA rates with soda. And so based on that, we see the potential, as the study is ongoing, that as they continue to collect the data and if that continues to align with how we've seen this data fall out so far in this open-label study, that we could submit and have a potential approval in 2026. That's quite a nice way for us to enter into 2026 working with Steno and with the FDA to use this investigator-initiated study to move forward with Zynquista. Have they communicated how many data points they need to see in this open-label study to be sufficient to give you then the green light to file on it? Yeah, they've given us a range where we expect to be. And in fact, we've modeled up where we are seeing the data track so far. And of course, as you mentioned, because this is an ongoing study, we don't know exactly when that is going to hit. So we need to follow that along. And with that, we would think that if it continues as we see now and as we expect, then we may be able to submit and have an approval in next year. Wow. What is the cadence going to be around the disclosures? Now Now that you've got this communication, how do you foresee sort of the next commentary to Wall Street? I think the next big event is really as we get closer to that exposure level, which would be sometime earlier in 2026 in the first half. As we get towards that exposure level and a potential submission of the NDA, I think that would really be the most appropriate time. Perfect. Help us understand what is the market opportunity. So let's say fast forward, you get the data, you file on it. And is that something you're interested to wanting to commercialize on your own? Yeah, great. Look, I think beyond the numbers, there's 1.7 million Americans with type 1 diabetes. And remember, this is for glycemic control in T1D, for which there has been no adjunct insulin in 120-odd years. So really, these folks have no other options to help control their blood sugar. And that's the reason why we've seen a huge outpouring of support from the patient community. And so it's a significant market. It's a market that is very underserved. And we think that if we take an approach to commercialize it ourselves, we have got a number of options, either to do a small field force, to do that in a hybrid way, working through patient associations is another possibility to commercialize. And keep in mind, there's already significant awareness among the prescribing community of Zynquista because of the history of the medicine. So at launch, we would have pretty significant unaided awareness. And so that would give us a great opportunity for launch. Okay. I also think, yes, the differentiation of the SGLT1 mechanism in this regard is going to be very important because there's considerable use already of both GLP-1s because many patients with type 1 diabetes develop obesity because of the overusage of insulin. Patients would rather be over-insulinized than under-insulinized. And also SGLT use. But the fact is that with soda, first of all, we have the largest data set. Second, we've continued to develop additional data as a number of ongoing trials. The third, though, is that SGLT1 effect in the gut is a real important difference because insulin doesn't have to work as hard. As you flatten that glucose uptake curve, the issue that really happens in type 1 is the undershoot and overshoot, particularly around meals. So I think we've really, as Mike has mentioned before, and I think I have with you, that we're really focused on areas where that SGLT1 effect is very important. That's why we focus not only on T1D, but also on HCM and the cardiac effects and also with the stroke and MI effects of SGLT1 inhibition. Yeah, and we'll get into HCM in a second. But one last question is, what would the, let's say, fast forward, you get the data in one inch, how soon would you be in a position to file the NDA from getting the data to repackaging it? And then what would that review process be like? Is it start the clock again, potentially? Yeah, so Craig can expand on the data. This is really unprecedented from the FDA. Keep in mind, this is not a trial that's been run by Lexicon with the standard kind of methodologies, et cetera. So they've taken the step really collaboratively to work with us to think around how do we get this IIS. And so we need to continue to really work with the Steno group to work through all the methods that they've used to collect the data, store the data, process the data, et cetera, and with the FDA. So it's kind of difficult to say right at the get-go what that process is going to be like until we actually get in and view the data, et cetera. But at the same time, the important step is that the FDA has recognized that it's a satisfactory study. We need to get into the details of the actual data collection, Craig. Yeah, I mean, the end of review letter, I think FDA summed it up very nicely. They said they recognize the importance of the unmet need. They recognize the importance of the patient community. They're willing to work collaboratively with us and use trial data in a nontraditional way. And I think to date, and again, things can change as we see with the agency on an ongoing basis. But their approach here has been very open to discussing with us because this was a study we never would have run a study on DKA for all the reasons we've talked about. It's not ethical. It's too large. It takes too long. It costs too much money. But being able to repurpose a trial that is, remember, the trial endpoint is looking at MACE. So it's a five-year trial in 2,000 patients. To be able to use a portion of the exposure data to calculate a rate of DKA, there's really no other way to do it because you need significant exposure of patients. The fact that it's an open-label study as well as you can look at the data on an ongoing basis. It really is a convergence of a number of favorable dynamics. So, I think yes, the real take-home for investors is that the study is appropriate. It's ongoing. We need to see how the data continues to progress. However, if it continues to progress the way we've seen it so far, then we feel good that we have a package that is able to be filed as an NDA next year with approval potentially next year. So that's kind of where we're at. So we're really pleased with that significant development with the FDA. Wonderful. Team, let's maybe focus now on HCM. Maybe before we go and talk about the SONATA-HCM study that is enrolling and guided to finish enrollment next year is, let's talk about quickly one of the questions that a lot of investors have is the preclinical data of sotagliflozin. And I think they understand over the last year, year and a half, the importance of having an SGLT1 and its role in the heart. But I think maybe help us put into perspective, what was the data presented, preclinical data at AHA? How does that data compare versus other CMI competitors that are in development? And then we'll talk about the clinical data. Yeah, thanks. Yeah, there are really three important studies that are presented at AHA or the HCM meeting that was right before. At the HCM meeting, data was presented from Boston University, Dr. Colucci's work. And they have a well-known animal model. And they showed in that animal model not only slowing of progression of HCM, but also reversal of the disease. And they've really mapped that to energetics and particularly to the mitochondria. It is also interesting that this week's JACC, they have a consensus statement from the ACC on mitochondrial diseases that are associated with cardiac disease. And many of those variants are HCM genetic problems. So I think that data fits very well with the mechanistic base of the SGLT, and particularly soda is acting on energetics and acting probably at the level of, or at least in part, at the mitochondria. The second important data set is the HFpEF data that was presented, which is a large clinical trial. It was nearly 100 patients, placebo-controlled trial in those with documented HFpEF. Now, unlike many other studies with HFpEF, where it's not really clear how much preserved ejection fraction there is, 40 with a cutoff of 40, that's pretty low. These were documented patients with HFpEF and very consistent with a HFpEF population, which tends to run a little on the heavier side, more female and older. And what was found in that study was significant benefit on cardiac structure, functionality of the patients. They had significant improvements in peak VO2 and particularly six-minute walk test, but also symptomatology with a large increase, a 15-point increase placebo-adjusted for KCCQ. And many people in the field believe that HFpEF is a good read-through, particularly to non-obstructive HCM. I think that was an important presentation. That was an oral. The third, which didn't get as much focus, we went back and we took all of the type 2 diabetes studies that were done with sotagliflozin. These were not high-risk patients for MACE. But when you look at that set, no other SGLT inhibitor in a low-risk group has ever shown a reduction in stroke and MI. And this meta-analysis that was presented at the meeting showed a reduction in stroke and MI consistent with those unique effects of sotagliflozin. I do think it's important to recognize as people study HCM more and more, the rates of AFib in HCM are very high, particularly in non-obstructive. AFib is one of the most important reasons why people develop stroke and MI. So I think to have the only SGLT agent that has not only unique effects on the myocardium above and beyond SGLT inhibition, but a reduction in stroke and MI, I think could be very appealing. Now, you're not going to see that in these clinical trials because you're not treating enough people for a long enough period of time. But clearly, those with HCM are at high risk long-term of stroke and MI. And I think there are follow-through effects of that of soda that I think could be very important over time. Okay. Yes, I think it's important to note that both the clinical data with the potential approval in type 1 diabetes, the potential approval in HCM, together with this mechanistic data, really shows that soda is a new class of agent. I think for a long time, soda has been thought of as an SGLT2 inhibitor or another SGLT2. But really, the weight of evidence that we continue to show through a lot of these investigator-initiated studies, as well as the clinical studies and potential approvals we're having, is that soda truly is a novel class of agent that will stand alone as its own asset. Okay. Perfect. Team, maybe quick housekeeping questions. SONATA-HCM is progressing. How is enrollment going? How much visibility do you get to confirm completion of enrollment in 2026? We look at enrollment every single day. I like it. We have one of our project managers out actually doing a two-week trip through all the sites in Europe, so we have a good understanding of the dynamics. We have a really active steering committee that's very involved. We feel confident in the enrollment status of the trial. It's a real good opportunity because there are no large active phase 3 other trials running right now, and there's a real unmet need for novel agents, and there's also a capacity in the field of the major centers to conduct these trials, so we are confident in the timelines we have, which is finishing enrollment in the first half of the year and having data no later than the first quarter of 2027. Team, help us understand, given that the CMIs, one is approved, one is going to get it, second one is going to get approved right around the corner this month. What is the protocol for allowing usage of CMIs in the study? What are you capping it as? Yeah. Yeah, it's a great question. Yes, patients are allowed on CMIs in the trial. There are patients on CMIs in the trial, both obstructive and non-obstructive, because some of the obstructive patients, when they went on a CMI, they became non-obstructive patients, but were still symptomatic. So we really have all of those variants in the trial. That's a criteria we're continuing to follow. Reimbursement and access differs by country. But I think, as you've seen with the Mavacamten, that they are getting reimbursement with other countries. So we are seeing usage. But that is not a precondition because the trial enrollment is symptomatic, regardless of what therapy they're on. So it's really just managing symptomatic disease. But is there a thought process? You want to be at 10 or 15, like a certain percentage, or just naturally let the study be whatever you end up with? That is. I mean, it's not going to be a large number of patients. It's not going to affect the statistics in any meaningful way. We thought about doing a stratification criteria for it, but there just weren't enough patients that it's going to be a meaningful number. Then, team, one of the questions we also, obviously, we have seen the only other registrational study in obstructive is the Odyssey study. A lot of additional results came out. Help us understand, are there learnings from the Odyssey study when it comes? Because there was definitely a question that was asked, is non-obstructive a tougher population to study therapies in, or is it maybe a function of that the CMIs don't work? So I don't know if after seeing the Odyssey data, you guys have maybe thought differently around the heterogeneity of non-obstructive patients. I think that non-obstructive is going to be a more heterogeneous disease by definition because obstructive is defined by an outflow tract obstruction, regardless of its underlying etiology. But I think that's the opportunity for a drug like soda, is that it is not mechanistic, not driven by anatomy. Yeah, so I think in that regard, and again, Mike should comment, but I think there is a huge unmet need for non-obstructive. My guess is, as people do more and more diagnostics, there's going to be a larger percentage of patients that are non-obstructive just because that is a narrow precondition of having an anatomic obstruction. I think the things that we've really learned have been operational details. How long do you need your screening window? How do you get your imaging for your echoes? Because those are really critical issues. Defining the KCCQ, and not surprisingly, that's the largest single reason why patients are not enrolled in the trial: their KCCQ score isn't low enough, so we've learned a lot of operational details from the investigators who have participated in other trials. Yeah, I think ACC was a really important meeting for HCM in general and for us specifically for not only the Odyssey trial, which demonstrated that Mavacamten wasn't effective in non-obstructive, and it shows that, yeah, you can't necessarily assume that just because in obstructive you get improvement, you're going to get that, and in non-obstructive, we'll obviously wait and see how ACACIA reads out and see what that looks like, but clearly, for soda, that is a great opportunity across the board in HCM and specifically in non-obstructive, where we think that soda is not, well, we know it's not affecting the outflow tract, but it's really targeting the underlying basis of disease, and we have the read-through from the recent HFpEF study that gives us confidence that we'll get a positive outcome in Sonata. And more importantly, perhaps that the MAPLE-HCM study, which was run by Cyto, showed that beta blockers at best give no benefit, that at worst perhaps provide slight harm. And they've really been considered first-line treatment in HCM generally. And that really bodes well, I think, for soda because it naturally would fit into a first-line agent. It's safe. It's once-a-day oral. It's easy to use. There's no REMS. And it can be used in addition to CMIs if they're still symptomatic. So all of those really position it as kind of the perfect first-line agent, hopefully for a broad HCM use. What is the stratification protocol for the study? Both across some studies, it includes both population obstructive and non-obstructive. Yeah, the major stratification criteria really is the obstructive versus non-obstructive. So again, we want to make sure those groups are balanced. Okay, and another very important read, maybe before we go into SOTA-CROSS, what is the study power to show both in both studies? Yeah, I mean. Both populations. I don't know if we said specifically the exact number, but let's just say it is similar to what the powering of the other trials are. You're looking at about a four or five-point difference for the powering, but. In KCCQ, yeah. Yeah, in KCCQ. I do think, though, the results from the recent HFpEF data certainly are encouraging that we're getting a significant headroom above that. It is important that an unblinded trial that's run looking at KCCQ is not of much value because we know a lot about placebo effects, and there's a big placebo effect on KCCQ as well. When we think about the study in terms of SONATA-HCM, do you allow patients who are in SONATA-HCM, patients are going to be a population of obstructive and non-obstructive? Given the CMIs got approved, they saw KCCQ as, but the primary was pVO2. So I'm just trying to think about, do you need to show also a change in pVO2 to file, or is the KCCQ sufficient for the obstructive population? For both, for the FDA, this is the primary endpoint. I see. I think Japan, particularly, has been more focused on peak VO2. I think peak VO2, first of all, is very difficult to do that reproducibly. And second of all, it greatly limits the number of centers. I think, and that was really the discussion we had with the FDA, was that the only endpoint that is really meaningful to patients is symptom relief. And the other point being is that soda clearly already has outcomes data in heart failure. And so the CMIs, they need some sort of functional data alongside their KCCQ. But for soda, having already demonstrated outcomes was felt not necessary in this case. Team, thank you. Another big readout is going to be the phase I SOTA-CROSS-HCM that is in 26 symptomatic non-obstructive patients. It's going to read out mid to late. That'll be the first sort of POC study of sotagliflozin and SGLT1/2. Help us frame sort of it's an investigator study. What do you hope to gain in that study? I think lots of people are going to be asking you what's the bar for success. At what time point is that being measured? Yeah. It's a 26-week study in about 25 or 30 patients. It's being run at the University of Pennsylvania. It's an NIH-funded mechanistic trial. The power of any study in a crossover is that you're using the patient as their own control. And the endpoints are really the same endpoints, but there'll be more genetic testing done. There's going to be a lot of radiographic endpoints looked at, as well as KCCQ. So we sort of see them as complementary. And I think looking at all three studies together, the SOTA-P-HFpEF with the really dedicated non-diabetic HFpEF patient, which I think is greatly enriched for those very similar, if not overlapping, with HCM. The SOTA-CROSS-HCM, which is going to be, again, deep, detailed method, mechanistic study. And then SONATA-HCM, which has that primary endpoint of KCCQ, key secondary of New York heart. I think all of that will fit together really nicely, plus the mechanistic data we continue to do on looking at stroke and MI, both in platelets and in human plasma in patients treated with either soda or other antiplatelet agents or with EMPA. So I think all of that data together is a narrative we've been trying to create over the next 12-24 months of data flow. That soda study is a placebo-controlled study or open label? Which one is that? The SOTA-CROSS-HCM. Yeah, that's going to be a placebo-controlled crossover trial. Wow. Okay, so Wow. Okay, so 13 patients. No, 26. It's a crossover. Oh, okay. So they got. So you treat them with drug A, you wash them out, you put them on drug B, and you can compare them from drug A to drug B. And it's 26 patients that go through that algorithm. And the doses, I assume, in SOTA-CROSS are the same as SONATA-HCM? Yeah, 400. Okay. So it's a very big de-risking event for a lot of investors who are following the HCM space and maybe just wondering what is the clinical data to support Sonata. Obviously, a lot of mechanistic rationale, a lot of clear benefit. But I guess this data could be very, very important for reading out. And then, team, maybe last question is we didn't get to talk about LX9211, but 39 seconds. Obviously, you guys are going to be engaging with the agency. You're in active partnership discussions. So maybe give me a quick overview of where you are on both. Yeah. So we are going to meet with the FDA this year. Time's ticking away. So it's going to be in December. And we'll expect the minutes from that early next year. And once we have those minutes in hand, we'll continue to engage with the strategics that we've been discussing with. Okay. Wonderful. And just maybe I'd like one more question. Cash and cash runway for the company? Yeah, we're deep into 2026. Clearly, we're focused on potentially a deal with LX9211 as bringing in non-dilutive capital, and yeah, we'll continue to update as we go forward. Perfect. Well, team, a big year ahead. So let's give a big applause to the team. Thanks so much, yeah. Wonderful to have you.