Good morning, everyone. Welcome to our 37th Annual Healthcare Conference. It's day three. My name is Yasmeen Rahimi. I'm a Senior Biotech Analyst here at Piper Sandler, and a covering analyst at Tenax Therapeutics. Really excited to have you, Chris and Stuart, here with us, and it's been a pleasure working with you as I initiated coverage this year, and very, very excited, not only for this year coming to an end, for 2026. I think for many investors who may or may have not followed Tenax, the phase III LEVEL studies on track to read out in the back half of 2026. So really, really exciting. So lots to discuss. Maybe a good place to start is, how is recruitment progressing? I think you guys have said the goal is to get done with enrollment by 1H. That would put top line 2H. So just kind of give us some broad commentary. Sure, sure. And thanks, Yas, for having us and for the work that went into this. I feel bad for the FDA Commissioner because I know he's meeting here now, and everyone's here. So back in August of this year, we forecast that we would enroll 230 subjects in the first half of next year. And that was several months after we had announced that the target for the trial has increased from 150 to 230, just based on the funding that we received. So in our most recent guidance, we've repeated that. So we're getting awfully close to first half, but we're confident we'll achieve 230 in that period. Then remembering that LEVEL is a 12-week study, plan on a month for cleaning and then locking the database, and a month for statistical analysis so that we can give a robust report on the results of the study. We're still confident that that will be the second half of next year. It is a, as you said, it's a big year coming up. Maybe help us understand the study is definitely upsized from 150 to 230. What drove that decision to increase the sample size? And how does this further facilitate a higher POS of success? The increase from 150 to 230 was supported by really all the investors who came in in August of last year, and then RTW came in in March of this year, along with us. With the funding that we had, then everyone was enthusiastic about making 150 patient phase III a bit larger. The FDA had agreed to 150 and 12 weeks as the first trial. They've always said they wanted the second trial to be longer and that it would need to be larger. But to go from 150 to 230 has just de-risked it a little bit. The standard deviation that's built into the power calculation at 150 patients was 45 m. That's based on the phase II. We felt good about it. But we were able to increase that to 55 and maintain 90% power in that calculation at 230. Same treatment effect, so no change in that, which was important, so easy for the FDA, I think, to agree to more data in that study, and so I think that it was really a funding limitation way before that time that led us to go pretty small at 150. Team, the study also LEVEL 1 allows a sample size readjustment based on blinded six-minute walk test deviations. This is communicated as either above or below assumptions of 55 m. When is that expected to occur, and when and what will we learn from the team in regards to that interim outcome? That's a good question. So the BSSR is a powerful adaptive element that we built in from the very beginning. And when we increased the target from 150 to 230, we just maintained that element. It's a powerful de-risking tool. We don't have to spend the next six months and the last two years wondering whether we'll have the right standard deviation. So it allows, in a very planned way and in a highly formal and documented way, one look at the blinded data once around two-thirds of the subjects have been through treatment to see what is the standard deviation in a pooled analysis. T hen the way we've designed it, that mechanism essentially pushes you to a higher number if the standard deviation is above what you'd planned. So we've described that in the, well, the authors of the protocol paper have described that. That's really, I think, the place to look. We haven't given guidance on whether it's been done and at what time. So what we've continued to simply say, and this is just consistent with what we've done from the start of the planning of the study, is here is when we expect to enroll this number of patients. So it's still 230 first half. But if once you get to two-thirds of patients finishing 12 weeks in treatment, that's when it would trigger for the blinded analysis to occur. T hen they would look at it, either probably the outcomes or what? What are the two outcomes once that occurs? So by design, you're right. That number is 150 for us. Once that number has been randomized, you watch them for the full 12 weeks, and then you run the assessment, which takes a bit of time as well. A t that point, then you cannot make the trial smaller the way it's designed. You can't say, "Well, we needed 206 available." Turns out the standard deviation is lower. We only want you can only go lower, or you can stay the same. Higher. Yeah, sorry. You can only go higher, right, up to a cap, or you can stay the same. A gain, what we're telling everybody is that we expect to enroll 230 first half. Okay. Perfect. It's not as the number allows you to start thinking about it or whatever. It's built in a way that 90% power will be preserved. And that's one of the great things about this tool. And the FDA does encourage its use when the number of patients you have backing your assessment of what the standard deviation will be is very small. S o that's how we did it. But it does allow you to preserve 90% power by adding those number of subjects only if you need to. Team, what do you see currently on a blinded basis in terms of standard deviation of a six-minute walk test? I think you probably have said that the assumptions are to be within 55 m. So until the point of time when that data is given to the company by the statisticians, you should see nothing. Okay. Yes. Especially with this endpoint. You shouldn't be in a position to have a glance. That is something that would lead, I think, many reviewers to say, "Gosh, how well controlled and blinded was this study?" So we, until a point by design with this protocol, at which that analysis is given to us and we're told it's 52 m, 58 m, you have to increase. Nobody should be able to see that. Okay. And then team, for investors who are maybe newer to Tenax, help understand sort of the mechanism of levosimendan, how it presents and how it underlies the pathophysiology of disease in PH Group 2 patients with HFpEF. This is the point at which I've answered enough questions for Yas, so good point, Stuart. So yes. To make it as simple as I can so they understand, PH HFpEF. The PH is defined by the pulmonary artery pressure, and we're defining it as a mean PH pressure above 25. And the HFpEF is defined as an elevated wedge pressure. W e're choosing as the lowest one will allow us 18. And the distinction between Group 1 and Group 2 is just a wedge pressure. They both have elevated PH pressure. And the line is set at 15, so 16 calls you Group 2 and 15 calls you Group 1. And the fidelity of the catheter doesn't even allow you to be sure that it's accurate. But we've made sure that our definition is accurate. It's been established that the key is that wedge pressure. I n fact, the key is the wedge pressure increased during exercise. You can even have a normal wedge pressure or close to normal at rest. The problem is when you try to do something, the normal physiologic response of sympathetic activation puts too much blood from your systemic circulation into your heart. You're flooding it. And when you flood it, you can't breathe, you can't oxygenate. S o the target, whether you're blaming its stiffness of the left ventricle or not, that wedge pressure has to come down. And our phase II trial confirmed that. That as the wedge pressure came down, they were able to walk much farther. Okay. And then maybe help for investors new, how does levosimendan work? Levosimendan is an interesting drug. It has this inotropic property called calcium sensitization. What that simply means is that it allows the heart to contract more vigorously. But with preserved ejection fraction, it already contracts normally. So that property is not being expressed by the drug. What's being expressed is this potassium channel activator property. Potassium channels regulate all of the circulation in your body. There's several types. And the potassium ATP channel that this drug has regulates the venous side of your circulation that would be primarily your intestines, your legs, etc. And since those drugs constrict inappropriately, like squeezing a sponge and put too much blood in your heart, our drug restores the normal tone. B y restoring it towards normal, the pressures come down and the patient's exercise capacity goes up. Thank you. T hen team, for investors also new to levosimendan, now that we understand the mechanism, we understand the pathophysiology of the disease, what is the clinical data, right, to ensure a success in the LEVEL 1 study, which has a six-minute walk test? I think publicly you guys said like a 20 m difference is considered clinically meaningful. Because it's Group 2 Pulmonary Hypertension, the agency said we will accept a six-minute walk as a valid cardiovascular endpoint. There's a lot of data in Group 1 of what the typical six-minute walk change is. There is no data other than our phase II trial, which is the only successful trial to date. We chose 25 m as the treatment effect in LEVEL, and that's based on looking at the HELP data and looking at the disease at large. We hear statements that 20 or 10 or whatever number would be meaningful. I think I'm just going to have to say that we're going to have to wait and see what we have. I think there's no debate that 25 would be remarkable, and we're powered to do that. Thank you. T hen maybe one question that often comes up is that in the HELP study, the study initially had an IV dose, which then turned into an oral extension, which then currently the LEVEL study is doing an oral. So maybe help us bridge as there is you went from IV to oral and then oral is the dose selected. Sort of what work was done to understand the proper dose selection, which is critically important in a phase III study? There's a lot of published research on the use of oral levosimendan that we relied on to pick 3 mg when the company transitioned patients off of IV onto oral in HELP. They were put on one and then 2 and then 3 mg for two weeks each and stayed there. The patients who are on Named Patient INDs today are still, to our knowledge, being treated with 3 mg a day. It's been several years. There's still a dozen of those 18 who are out of the open-label extension and cared for by their docs under an IND. We went to three there and we're at three here and we'll be at three in LEVEL 2, right? I think that's important to know. We are at the very start of, well, we have announced that we're intending to start LEVEL 2 this year, right? It's important to know that we're going with 3 mg again, right? So what is that data that we relied on? There's a 25-patient phase II MAD study where 2, 4, 6, and 8 mg daily were tested in patients with severe congestive heart failure. The optimal dose was described in the results of that study as 3 to 4 mg. So that was important to us. We know that in the PERSIST trial where patients were treated, several hundred patients were treated with 1 and 2 mg, that they had a good reduction in BNP, they had a good reduction in wedge pressure. These were also heart failure patients. We've got them on three. Those patients were on one and two and they had a good reduction. In the REFALS study, which is a respiratory function study in patients with ALS, the target dose was 2, 1 was acceptable. So we're at a higher dose in all of those. So we also know that when patients in the HELP study were at trough, the PK data show that the concentration at that time is less than they will be at by design with 3. So I go through all that because there's a lot of reasons in terms of the dose to be confident that it's going to have an effect that's measurable in these patients, at least comparable to what we saw at trough on IV when they walked 29 m, had an improvement in other endpoints as well. So I feel good about it. Then obviously a lot of investors have at times gotten spooked by a six-minute walk test, even though it's a very robust study, mechanistic rationale, existing data, thoughtful dose selection. Help us understand what measures are in place in terms of execution of the study to really keep the placebo responses in control and maybe what were your assumptions for, and of course you're the first company to run a registrational study in this population. A few comments about it. The Six-Minute Walk Test has been time-proven in Group 1 to represent efficacy. When I'm confronted with it's highly variable, my response is it depends how you conduct the test. Yes, I walk to the store and back in five minutes every time I walk there. It's very reproducible. What you do is you make sure the tester understands we don't want a cheerleader and say, "Can you walk faster?" or "Why are you walking so fast? Take your time." We start with the tester, and then the tester shows the patient, and the patient shows the tester, "Am I doing it right?" And then we say, "Fine." The tester knows, and the patient knows. And the other thing we've done is eliminate things that could limit your walk other than your disease breathlessness, arthritis. I've had patients who said, "My walk was bad today. I'm sorry. My hip was killing me." I don't want that patient in the trial. So arthritis, neurologic disease, muscle wasting, things like that are out. I actually think it's going to be a very reproducible test. Okay. Very helpful. Team, we'd also love to talk about the LEVEL 2 study. So maybe before we go there again, I want to use this fireside as an opportunity for investors who are just more newer to connect the dots for them. When you met with the agency to get the alignment on the study, right, they recommended what two studies? What was maybe the communication with the agency that led to the recommendation to run LEVEL 2 before we start talking about it? So, going back to early discussions, the company was always given the choice of a single Phase III with 0.01 and then meet the safety database requirements or two trials, 0.05, and meet the same safety database requirements. So the same, I think, financial considerations, but also a desire to reduce risk as much as possible led to the concept of, "Let's do a small initial shorter-term study." It's twice the endpoint is 12 weeks at HELP. Remember, it was only 6, and we saw 29 m, right? So we're going with 12 weeks. We'll do a smaller study first. We'll raise money before that study's even over, and then we'll move into LEVEL 2 was the plan before we were able to become substantially better funded back in August of last year. So we went down the path of two trials early on, and we actually had the opportunity to say, "Gosh, should we just make LEVEL longer and just do it all in one?" It's just a bit risky too. You always have that idea in mind. Speaking of like the variability of the six-minute walk, which we think is less of a worry than some, you still wonder, "What if I'm just almost at that?" And you miss it on one trial. So you still have the same worry with both of these trials now, you could argue. But I think we're much more comfortable with two. And we'll still, when we combine the data from these trials, we're confident that the FDA will have the safety data that they need in order to feel really comfortable. We need to understand too, with PH, we talk about the six-minute walk. It's always been the endpoint. There's one approved PH drug that was six-minute walk plus clinical worsening. Everything else was six-minute walk. It is the established endpoint. We got to remember though that population is less than 100,000 Americans. This is 2.2-3.7 million, we estimate. The focus on safety will be greater in that scenario. So we will make sure with the two studies we have that they've got enough data to be comfortable. Okay, and maybe frame like sort of similarities and differences between LEVEL 2 versus LEVEL 1, right? What are the parameters that have cons and? So the big differences will be 26 weeks instead of 12 weeks for the primary efficacy endpoint. The geography will be very different. We'll probably have 15 countries. In LEVEL, we have the U.S. and Canada. And it'll be a larger trial. We haven't put out. I think the design paper will come out and answer a lot of questions. So we haven't said how large it's going to be. But as I mentioned, the FDA has always intended that it be a bit bigger than the first study. What about sort of the non-hemodynamic inclusion exclusion requirements between the studies? Like, how do you keep sort of the population the same? Yeah, identical. So the trials are identical with respect to everything other than what Chris mentioned, the measurement at 26 weeks. It's the same disease, the same inclusion exclusion criteria. The conduct of the trial is the same and identically the same for the first 12 weeks. So we can do a pooled analysis of the two trials and have even more with that. Okay. And what is the powering of LEVEL 2 since it's a larger study, but the patient study is identical? Same calculation. The same population? 25 m treatment effect, 55-meter standard deviation to get 90% power. If there would be a reason to readjust that based on the results of the LEVEL trial, we are absolutely able to do that without an issue. Given that LEVEL 1 is mostly US study and LEVEL 2 is going to be a global study, is there any differences in standard of care between a more US study, which is LEVEL 1, versus a global study? How do you encounter that in the design of LEVEL 2? So you're talking about kind of committing medications. Sure, there are differences, especially when we're going Asia, South America. So I think the United States uses more of the SGLT2 inhibitors and GLP-1s than the rest of the world. You're probably right behind us with SGLT2 inhibitors. I can't really speak for Argentina or I should say South America and Asia. I'm just not that familiar. We allow all appropriate concomitant medications in the trial. We are able to do responder analyses and see if the combination of drugs makes a difference than the drug alone. And we intend to do that with LEVEL. S o we'll have a lot more knowledge about it. But honestly, when this drug is approved, it's going to be approved to be used on the back of concomitant medications that the doctors are using. And we're very comfortable with that. No other drug, by the way, has the same mechanism of action. So it's not an issue of competing mechanisms. And maybe it's good to know, right? So the LEVEL 2, but there will be probably some how much is the site overlap going to be? We just want to make sure that you're not cannibalizing enrollment in LEVEL 1 for LEVEL 2. That's a great question. We won't do that, right? We will bring on an additional 20-25 centers in the U.S. for LEVEL 2 before any of the LEVEL sites are moving over, right? We're able to start LEVEL 2 in the U.S. as well with a new Group of sites. Not every LEVEL site will carry over, but many of them will. But the enrollment in LEVEL will be the priority for the program. The good news in terms of the timeline to just start the trial is that there are other sites. I will say this: when you mentioned standard of care and how will it vary, I think the standard of care will be very similar globally. But even on a population, even disregarding the fact that the U.S. has a huge population compared to other countries we're going to, there won't be anything like 50 or 75 centers. But between the two trials in the U.S., we're going to have probably 75 centers. There won't be anything like that number because there's so much more guidance of care toward excellent centers when it comes to the performance of the exercise right heart cath and the treatment of PH in many countries. In the U.K., as an example, you still have about 80 million people total is seven centers where you treat PH there. So the great news is they all do the exercise right heart cath. They all know this disease inside and out. In the U.S., you can find way more centers, but they aren't necessarily as focused on that. So I think the standard of care globally will be very similar, but the number of sites needed in other countries will be much lower. Then, team, one thing that will come up is that the Six-Minute Walk Test assessment in LEVEL 2 is at 26 weeks versus 12 weeks in LEVEL 1. So how do you think that impacts both the longer duration on the treatment arm as well as what the impact would be on the placebo on the Six-Minute Walk Test? In terms of drug effect, the PERSIST trial told us that the efficacy of levosimendan on lowering wedge pressure was steady all across the six months that it was measured. So we're not concerned at all that we'll lose some drug efficacy. What happens is when patients get better and feel better, they become more motivated to do more. So without giving you scientific data, it wouldn't surprise me that the longer study will have a larger treatment effect in the active group than we see at 12 weeks. As far as the placebo group goes, you could argue there's a training effect, which may boost theirs. And then you could argue, "Well, yes, but their disease is untreated. They'll be worse off." So that's a little hard to predict. Team, is there an OLE portion of LEVEL 1? What have you communicated in regards to the rollover of patients on LEVEL 1 to the OLE? So both of these protocols have a built-in open-label extension up to 104 weeks. So we will ensure that there's a bridging strategy in place for any patient in both trials who goes past that, a bridge from basically care and access and safety follow-up during that full two-year period until commercial availability of the drug. So there'll be a strategy that we'll give more detail on soon. But in the HELP study, again, thinking of the company a long time ago with a lot less funding, there were patients who came out of the OLE, and they had to go on to a Named Patient IND with it. That won't happen this time. Got it. Stuart, Chris, thank you so much for being part of our conference and very much looking forward to a very catalyst-rich year. So thank you for spending time. Let's give a big applause for you. Thank you for the invitation, Yas. Yeah, no, we covered it all. I really appreciate it.