All right. Good afternoon, everybody. Thanks so much for joining us for another Fireside Chat here at Guggenheim's Emerging Outlook Biotech Conference that we host annually. I'm Seamus Fernandez, one of the senior biopharm analysts here at Guggenheim. To my immediate left is Chris Giordano, Chief Executive Officer, and Doug Randall, to his left, Chief Business Officer. So Chris, Doug, thanks for coming. Yep. Great to have you. You know, we're obviously excited about the PH-HFpEF market and the opportunity and the Tenax story, but maybe you can just kinda level set the playing field with a brief overview of the Tenax story. Sure. Thank you, Seamus, and thanks for continuing so much interest in the company and introducing us to a lot of great investors. We are at the moment starting what we expect will be a two-year recruitment period into our second Phase III trial of levosimendan in heart failure patients with PH. It's gonna be a global study, and we initiated it in Q4 last year. We're also nearing the end of recruitment of, again, around two years in our first trial, which was a US-Canada study of ultimately 230 randomized subjects. We've guided that we'll complete enrollment in the first half of this year, with data in the second half. Other than being here, we are pretty much heads down, chugging along with all those enrollment activities, and obviously getting ready for a big catalyst later this year. Great. Minus, you know, maybe just the baseline of challenges for developing drugs and PH-HFpEF, in particular, and some of the differences that levosimendan and, and Tenax have to offer. Okay. So a lot of drugs that successfully lower PVR in Phase II studies in patients with PAH go on to demonstrate a translation of that effect to improved functional outcomes. So patients walk further in the six-minute walk assessment in phase III trials every time a PH drug gets approved. A lot of those drugs have been tried in Group II patients. Group II patients have a profound increase in their wedge pressure, their pulmonary capillary pressure, when they exercise. So that same endpoint of PVR lowering has been followed into Group II, and even when drugs have lowered PVR, they haven't necessarily created improvements in function. So I think that's been the challenge that a lot of drugs have faced. We are, you know, developing a drug that's a vasodilator, so it reduces the amount of preload that these patients have to cope with as part of their disease, and that is really a simple target that we're after. So we'll find out later this year if we're successful. You know, levo's been approved in other markets for over 20 years. Why hasn't it been studied here before from your perspective? So it hasn't been studied in Group II patients ever really, until the work that we started in around 2018. So levosimendan has a calcium sensitization property that increases the contractility of the myocardial cell. And that effect of the drug was leveraged in patients with reduced ejection fraction heart failure. So patients who suffer from heart failure symptoms but have less than 40% ejection fraction are the only patients who were studied until our company started looking at a different mechanism of the drug in a different set of patients. So there's a much better understanding now than there was 20 years ago about the difference between patients with preserved ejection fraction, whose heart needs something different, and those with HFrEF. So, we feel like the success that we are set up for is a result of really leveraging a different mechanism of action than levosimendan expresses in HFrEF patients. And what we've seen in our phase II trial is one example where patients had a 29-meter improvement in their six-minute walk and very clear reduction in their wedge pressure on levosimendan. They, you know, they experienced those profound changes without any change in cardiac output, so they are not apparently responding to the calcium sensitization property of the drug. They are demonstrably responding to the wedge pressure reduction that comes with vasodilatation. So it's just... It's a potassium ATP channel activator, first and foremost, in these patients. Okay, great. You know, maybe just as a step back, contextualize the market opportunity for levo in PH-HFpEF, and then, you know, maybe you can sort of separate out U.S. versus international opportunity, 'cause you did just start the global study, so. Perfect. Yeah, so I think it's safe to say that this is a multi-billion dollar commercial opportunity based on a few factors. One, the prevalence is extremely high. In the United States alone, we believe there's over 2 million patients who have this condition and probably a roughly similar amount in Europe. The other thing is that these patients have no approved therapy. So a high-prevalence population and no therapy means high need, and then on top of that, we match that with a real significant commercial runway that's provided to us by significant IP that we have for levosimendan when used to treat PH-HFpEF. The opportunity we think is probably the biggest in the US, followed closely by Europe, but it is without question a multi-billion dollar commercial opportunity. Okay. We've heard a range of numbers from 600,000 to, you know, 2 million. Yeah. Where do we stand in our understanding of that opportunity? And is there a subset of patients that you feel levosimendan are appropriate for, or is it more expansive than that? Yeah, some of the differences that you have in terms of how the market is defined is based on the phenotype that different companies are targeting. Unlike some companies that are more focused on enriching their trials for the Cpc-PH HFpEF population, which is a relatively small, narrow population, in our trial, we're basically recruiting for the entire cohort in both the Cpc-PH phenotype that they're recruiting, but also the Ipc-PH phenotype. Okay. So in looking at it in that broad market context, that's where we come up with the larger number of around 2 million patients who have this condition in the United States. Great. So let's talk a little bit more about the LEVEL study, your phase II study there. Maybe just, you know, Chris, you kind of covered the headlines for that, but what was really unique about that study? You know, you had benefits on six-minute walk distance. You know, maybe you can talk a little bit about other endpoints that were focused on, but also maybe help folks understand what was actually delivered in the LEVEL study as well. Okay. I'll, in terms of what's unique about the study and the major outcomes, let one of the protocol designers respond, and then I'll talk about endpoints that are really important in addition to six-minute walk. Yeah. I think one of the most important and most unique things about the LEVEL study was that the invasive hemodynamics were tested under exercise conditions. No other product developed for PH-HFpEF has ever tested the invasive hemodynamic effects of their product under exercise conditions. We saw significant reductions in wedge pressure, central venous pressure, mean pulmonary arterial pressure when the drug was tested. So I think that's probably one of the biggest differences hemodynamically. Another really important difference was that we actually showed a clinical benefit in that study. Yeah. A benefit in terms of six-minute walk, which has never been shown before in this patient population. Great. So every drug, I mentioned this earlier, approved for PAH to date, has been approved on the basis of the six-minute walk data. One of them had a small walk and argued that they should be approved on a combination of that with clinical worsening, and that approval came through. So clinical worsening events, I think, is one of the important events that prescribers will look at. We're doing a 12-week study. Our next trial will be 26 weeks. We'll have a bigger trial, a longer trial there. We'll have at least as good a chance of showing that there. But probably more important than that is the KCCQ. Yeah. You know, it's a questionnaire for patients about how they feel they're doing. The FDA does genuinely place this division in this disease, which is a symptomatic disease, and we have a symptom-addressing drug. It's a feeling-addressing as well as a function-addressing drug. They do really prize that data, so much so that one could go for an approval on the basis of an improvement in KCCQ. We're not gonna do that. We like the six-minute walk, but we think that that probably be something very important. We also think, you know, when it comes to what the six-minute walk defines, right? An improvement in one's tolerance to exercise. You know, what the KOLs in this field have convinced us is that... Stuart, I think, argues very persuasively about this, and of course, he worked with FDA for a long time. The six-minute walk is an expression of a patient's motivation level that results from improved wellness in their life. Yeah. It's a little bit philosophical, but basically, they are trying to show that they are on a drug that's making them feel better. And so when we look at the six-minute walk data, we think, obviously, very important primary endpoint. We want to be stat sig. We're set up now to be stat sig based on the review of standard deviation we've done. That, that's an expression by patients that they're doing better all day long. And so that, you know, we also know that when KOLs look back on that data and consider their own use of those drugs, it is a meaningful endpoint, as tricky as it is when collecting... The bigger the six-minute walk tends to associate with the drugs that they like to prescribe. Great. And can you talk about the portion of the study, the OLE, where patients basically were on IV levosimendan for at least 18 months and then transitioned to the oral formulation? Just wanted to, you know, maybe hear a little bit more on the feedback, advantages of shifting to the oral formulation. Yeah. I- I can talk to that. That, a couple of good metrics there. When we got to the point in the open-label extension that we gained rights to the oral and offered every patient still in the study the ability to transition from a 24-hour weekly infusion at home to oral, one of them said: "You're asking me to do too many visits coming up, I'm out." 18 said: "Of course, I'd love to do that." So it's rare that you get such good agreement to enter an unplanned intensive phase of study. Yeah. They had to come back every two weeks to uptitrate. So they took 1 milligram, then 2, then 3. All of a sudden, we threw a bunch more visits at patients who were only coming in twice a year. Yeah. 18 out of 19 said, "I'll go for it." We still have 9 of them on therapy today. I shouldn't say we still have 9. 9 of them are still on therapy today under named patient INDs that their institutions set up with the agency. Mm. These patients like the drug. Right. There are anecdotes, and some of them will come out when you talk to KOLs who've been high enrollers and seen the drug here in this patient population, but they're anecdotes. It, you know, the patients did agree to much more intensive study in order to get an easier formulation. Yep. We saw... You know, we collected data. It's open-label data, but we saw improvements across KCCQ, across BNP lowering of over 20%, and the six-minute walk test improved once they were on 3 milligrams. Just the confidence that you have in the transition from the IV formulation to the oral formulation in Phase III, can you just, you know, PK characteristics? Yeah. What data do you have to really support that? Yeah. So as Chris alluded to, the numbers all went in the right direction, but the other thing that was important is the PK did as well. So we know that we had higher OR-1896 blood levels, which is the active metabolite. And the other thing that I think sometimes gets overlooked, but is, we think, important, is that all of the patients in the open-label oral study were getting 3 doses, 1 mg each dose, 3 times a day, of oral levosimendan. And that was very different than the fact that in the HELP study, those patients at the end of the dosing cycle, when they were tested in the HELP study, had the benefit of no levosimendan. Yep. We have every reason to believe that the patients should do at least as well, if not better. Got it ... in the oral. Okay, great. So, you know, let's shift to the Phase III program. You know, obviously, there's a lot of characteristics here. You know, 85% of the HELP patients who underwent a 24-hour infusion of levosimendan had, you know, a decrease in wedge pressure. You know, how do you know that you're getting a similar percentage of responders in the Phase III trials? You know, obviously, you're not doing an open-label assessment of the infused drug, so. Yeah. So one of the things we looked closely at was the hemodynamic profile of the patients that were in the HELP study that responded. Yep. We used that same information to make sure that we were screening for and enrolling a similar population in the LEVEL study. Importantly, one of the things that was an observation from the HELP study was the fact that these patients that were responders all had elevated right atrial pressure. That was included as an additional entry criteria for the LEVEL study. Okay. We've really gone out of our way to try to screen for the phenotype patients that were responders in the HELP study. Okay. But it was a high percentage anyway, so- Yes ... that's a good, that's a good sign for the breadth of the opportunity. Exactly. Okay, great. You know, maybe we can just kinda talk about LEVEL a little bit more. You know, and the LEVEL-2 is enrolling, but maybe just describe the trial designs, the differences in the two trials that are critically important, you know, just as a starting point. So the criteria for inclusion is the same. In a sense, we should be enrolling the same patient with the same hemodynamic criteria being met, and likely on the same other drugs that may impact exercise tolerance or various pressures, SGLT2 inhibitors, in some patients, GLP-1s. They won't be terribly different around the world than they are in the U.S. So, enrolling similar patients, treating them for 26 weeks until the primary endpoint is collected versus 12, so I think that's gonna tell us a lot. And again, collected around the world, so probably less of a tethering of overweight and obesity to heart failure in other countries. Right, so we might see a lighter patient. I think we expect the Class II, III... The percentage of patients who are Class II and III New York heart failure, be the same. So pretty similar patient, 26 weeks, more than double the number, so we will collect an enormous amount of safety data. We wanna put the agency, agencies globally in a position to feel they've got a lot of safety data in these patients on this drug, to include in their assessment of, of efficacy and safety, so. Great. And then, you know, late last year, you announced the findings from your pre-specified, blinded sample size assessment. You know, maybe just help us understand that look at the data, and, you know, why it was taken, just the rationale behind the assessment and what you learned from it. Okay. So when we initiated LEVEL, we included at that time a blinded sample size reassessment. It's an adaptive tool that allows you to maintain 90% power if partway through the enrollment, you can see that the variability on that key endpoint is greater than you anticipated. And most people going into phase III don't have a problem anticipating how much variability they'll collect in their, in their primary endpoint, but we did. HELP was 44 patients, and but when we randomized, we excluded seven of those. So we only had kind of 17 and 18 patients at the time that we assessed by the time we assessed at six weeks. So we had a small sample size, so the agency was, they actually encouraged us to include that sample size reassessment. We knew that 150 patients was very small for a phase III. We were cash-strapped at the time we started that trial. We brought in a lot of investing in the middle of 2024, and we increased the size to 230 subjects. We didn't have to do the BSSR until late last year. That's when we had 12 weeks of data on the first 150 randomized, and what we confirmed is that we do not have a 55-meter standard deviation. We're therefore very well-powered to detect a 25-meter change at 12 weeks. So it was a good confirmation that we don't need more time to enroll the trial, we don't need more money to enroll the trial, and that with 230, we're very, very well powered. We're 90% powered to detect a change less than 25 meters. We're not getting into the specifics there, but we're in good shape. Great. And, you know, when we sort of, I guess, advance through the trials, you are executing the OLE as well. How does that operate, you know, the open-label assessment? Are there any dose changes? Are there any sort of operating characteristics in the OLE that can provide some learnings along the way to the ultimate sort of phase III outcome- Yeah Later this year? Yeah. I think it's so we know a lot about the safety of two and three milligrams in these patients from the open-label data. More than, around three-quarters of the data we have in terms of exposure months so far is open label, right? So it gets us a huge amount of uncontrolled data about what the patients experience when they're on the therapy. So we like that, and we know again that the agency is gonna want that. They're gonna want a lot of double-blind, placebo-controlled data, and they're gonna want a lot of data total. So when a patient is randomized at the start to levosimendan and they take two a day for a month, and then they uptitrate to III a day, we don't know what they are taking when they're popped into the OLE. When they subscribe, they start on two, right? Mm-hmm. Some of those patients will have been on three levos for a while. They'll come down to two when they go into the OLE, and they'll go back up to three. I see. Okay. So there is some ability, anecdotally, for physicians to... You know, they're doing a KCCQ questionnaire, et cetera. Right. And again, it's a drug that, by design, will affect symptoms. So there is some level of, you know, you hear, you hear how the patients are feeling as the sponsor, right? But again, you're at that point, you're collecting all open label data, so, of course, they feel better, right? Right. Um- Right. So, you know, I think for us, with the timeline now being more certain for us and for everyone interested in the company, and obviously with the capital overhang having been removed from the company in mid 2024, you know, what's remaining is: what's the difference between the groups, when it comes to six-minute walk? Yeah. Like, that's really what we are waiting for at this point, and based on what we know so far, we feel really good about that. We do, we do see how many patients opt to go into the OLE. It's still over 95%. How long do they stay in, and how many of them are in today? It's a very reassuring percentage. We see how many pills they consume, right? I always say pills, but my pharmacist friend reminds me they're capsules. The number of capsules consumed against the denominator expected is very high. With a QD formulation, I would be very high with this. I would be very happy with this amount of consumption. It's TID. Yeah. We feel like the patients don't mind taking the capsule. Mm-hmm. Got it. That's great to know. When we look at the, I guess, the sequence, a lot of times, we'll see in cardiovascular studies the hierarchy of outcomes, that kind of comes sequentially. Just between LEVEL-1 and LEVEL-2, is there any difference in those endpoints or the hierarchy of secondary endpoints? No. Okay. No. In terms of key secondaries, just to sort of drill down on that, let's assume we're positive on the six-minute walk test. Where do we then fall on kind of key secondaries? KCCQ- KCCQ- is the first. - is the first. Right. Okay. Then clinical worsening events. Okay, great. Okay, so we covered that in good detail. Yeah, you mentioned TID not really being a problem in the clinical study. And so definitely encouraging. You know, Chris, you have a long experience in, you know, clinical trials and drug development versus potentially seeing where that goes in the real world. Maybe just translate that experience for us, what you just mentioned about, you know, the drug utilization and intensity- Yeah ... of compliance that you're seeing in your study versus what perhaps we might see in the real world with TID. Yeah, so I'll say there's been three sort of stages of introspection during LEVEL. First off, based on that experience that I have, just saying: What exactly are we doing to make sure these folks are taking their capsules? It's TID, it's not BID. And, you know, anything under a certain threshold of compliance between any two visits, there's a flag, we know about it, and like, okay, so that's good. That'll keep us... And then we looked at that data as we went by. We then sort of raised money from a bunch of very, very smart people who told us that TID dosing is a big issue. Mm-hmm. And we put that up against our own experience, but I would say we had a little bit of humility, and we said, "Let's take another hard look," et cetera. And then we got to the point where we thought, gosh, the consumption seems to be really—there seem to be very few instances of non-consumption of 20% between visits. Mm-hmm. But let's really take a hard look at what exactly would change the prescribed dose for that patient for any given of time, amount of time. How long is it? What was the AE that changed it? Did they stay there? How long did they stay there, if they're on two, that sort of thing. And that's kind of been the most recent stage where we're seeing that basically by flagging people taking 8 out of 10 capsules, we're getting way higher than 80% compliance. Mm-hmm. How does that translate into the real world? In the real world, usually what happens is you'd be happy with 70% of TID, but you're not really doing anything. Your pharmacist and your doctor are reminding you. Maybe they're saying, "Do you have one of those things with the days on it?" Or, "Do a paper diary forever. Just have a little thing, check..." You get that. Yeah. We feel like it's naturally high. Okay. Based on what you're... 'Cause yeah, 70% with a TID for, you know, I took my statin today because at a certain point, Doug went and got me some water. Like, every day, something happens at my job that reminds me, "Your pills are in your pocket. You haven't taken your vitamin- Right or your statin yet. You need more than that for-- But that's a typical patient. That's very-- That's a typical TID patient who doesn't take their lunchtime dose. Right. Our patients are taking their lunchtime dose. Okay. I think we've heard the same thing in the market research we've conducted with physicians- Yeah Kind of played out in the open-label trial is that this is a debilitating disease. These patients have real symptoms, and so maybe that if it's helping these patients, maybe that's an encouragement to comply. Yeah. Um- Great. Well, we didn't have enough time to kind of cover some of the-- how you're thinking about partnerships, the sort of broader opportunity. I have to imagine the-- or potential partners are quite encouraged by the design of level two and the broader patient population, and being able to apply that, more broadly from a global perspective. But, yeah, I mean, I guess the last sort of question that I would ask is, you know, it sounds like the patent estate is well formulated. There could be opportunities to change the TID profile over time. And maybe lastly is, what do you see in terms of competitors in the space? We'll get the Cadence data at ACC shortly, but that looks like it's a pretty small population. Yeah ... with a very high-priced drug. Yes. Yeah, exactly, and I think the reality of the competitive profile that we have, I mean, we've got a product unlike any of the other drugs thus far. We've shown an improvement in six-minute walk. We've shown an improvement in exercise hemodynamics. We have an oral therapy versus a subcutaneously delivered therapy. Yeah. As you've already pointed out, we're going to be able to apply that to a much broader population than those trials that some of the competitors are currently enrolling. So when you put all that together, we think we've got a very strong competitive product profile. Great. Well, thank you guys for joining us. Really appreciate it. Great discussion. Look forward to, well, I guess, additional opportunities to see you guys in person, but also a great continued execution of your clinical trials. And one of the few companies, I think, in our coverage universe that actually has a definitive Phase III result this year, so a game-changer year for you guys. Thank you, Seamus. Absolutely. Thanks so much. Thank you, Seamus. Appreciate it.