All right, thanks, everybody. We are kind of moving towards our—I believe this is our final fireside chat for the day here at Guggenheim's SMID Cap Conference. Got a couple of panels after this, but I'm Seamus Fernandez. I'm one of the Senior Biopharma Analysts here at Guggenheim Securities, and I'm really pleased to have the Tenax team here with me today. Tenax Therapeutics CEO, Chris Giordano, immediately to my left, and EVP Business Development and Business Operations, Doug Randall, to Chris's left. Chris, Doug, thanks for coming. Really appreciate it. Maybe just before we dive in, you can give Chris a—you can give a quick overview of the Tenax story and how we got here, you know, in terms of the HFpEF, sorry, PH-HFpEF opportunity. Love to, love to. Thank you. You guys do an incredible job covering every detail of the Group 2 space. One thing you did not know is that Doug Randall was promoted to Chief Business Officer. I thought I would throw that out there just to—one little edit. I should have made that. Fantastic. How did we get into Group 2 PH with levosimendan? An academic leader and a few colleagues came to us years ago and said, "You have a wedge-pressure lowering drug." The problem that patients in Group 2 PH have is not only that the drugs for Group 1 do not seem to work in them, they have nothing else. They have a problem with elevated wedge pressure at exercise. Please supply me with this product so that I can start using it in an investigator-initiated trial, whatever I need to do. Patients are desperately ill and neglected. We said, "Well, let's take a look at that and do some research, et cetera." We ended up with him designing the phase II study and looking very specifically at this group of patients and whether this drug would lower their wedge pressure, which is the defining impairment of Group 2 PH. We started there, and that trial gave us the evidence we needed to feel confident moving into phase III. We have a new formulation that's never been marketed anywhere in the world, the oral formulation. We're testing that in Group 2 phase III now. I mean, and you know, Chris, maybe you can talk a little bit about what differentiates, you know, the PH Group 2 opportunity, the PH-HFpEF population from just sort of standard HFpEF or heart failure. Sure, sure. Idiopathic pulmonary hypertension, right, used to be called Primary PH, is a disease of the arterioles. The drugs that have addressed the growth factors in the arterioles have been successful in treating PAH. They've been approved on that basis. Group 2 PH, these patients, 60%-70% of the patients globally with PH, who, as I mentioned, have no approved therapies, the target for these patients is left atrial pressure. As people get into PH, they learn all about the vasodilators and all about the orphan disease, idiopathic Group 1 PAH. The five groups are based on the underlying condition. That's what defines them as a group. It's what is the therapeutic target that we should have that leads to that grouping. One major difference between these phases, of course, one of these groups of patients has got 13 approved products. One of them has zero. The wedge pressure, which I mentioned, the pulmonary capillary wedge pressure is normal in Group 1 patients. It's elevated in these patients at rest, and it gets very elevated at exercise. That's a major difference, and that's why we're doing what we're doing. Great. Doug, maybe you can walk us through just kind of the challenge of developing drugs in the PH-HFpEF space and, you know, what you see are the differences for levosimendan. Yeah, I think historically, the drugs that have been developed for PH-HFpEF have been the drugs that were historically developed and approved for PAH, as Chris alluded to. Those drugs, as pulmonary vasodilators, are very effective in treating PAH but have not shown much utility and, in some cases, maybe even some safety signals in treating patients with PH-HFpEF. It really requires almost a kind of a rethinking of how to treat this disease. I think part of that rethinking that we bring with levosimendan is a focus on a drug that can actually reduce, as Chris alluded to, the pulmonary capillary wedge pressure and also the central venous pressure, which are really the primary hemodynamic defects that these patients have. We think, unlike some of the other drugs that have been developed historically and not been successful, we've got a whole new approach, and we think one that, at least thus far in phase II, has proven to be quite compelling. At this point, we're at, you know, zero drugs approved in the Group 2 patient population. Levosimendan's been around for a long time, 20 years. You know, just the, you know, talk a little bit about the request from FDA, why it was, you know, never approved in the U.S. And maybe you can talk, you know, talk a little bit about why it took so long to study it in PH-HFpEF. Yeah, so the history of levosimendan's approval is interesting because the FDA took really a different position than other countries around the world. It's been approved in over 60 countries around the world for acutely decompensated heart failure. Those countries where it was approved were willing to accept the data that was conducted in phase III that showed improvements in clinical worsening, improvements in hemodynamics, but didn't show any real significant improvements in mortality, which is what the FDA is now kind of requiring of acute heart failure drugs. They took a different point of view, and that was never pursued any further by Orion, the originator company, because it was deemed to be a trial that would require just too many patients and be costly. That's kind of the history around its development around the world in acutely decompensated heart failure. Now, with respect to PH-HFpEF, a rather unique situation in 2017 where we were approached by Dr. Stuart Rich with this observation that a drug that had never been approved or used in HFpEF, levosimendan, might actually have utility in this patient population. What Stuart brought to our attention was that this drug is a very potent reducer of pulmonary capillary wedge pressure, again, the primary defect in these patients, and convinced us that it was a population where it really needed to be studied. Because no one had ever thought about studying it in this patient population, it actually also led to a pathway that allowed us to get three granted patents thus far because it was a completely novel idea. Yeah. Hopefully more to come. Great. Just in terms of acquiring the rights to levosimendan, how did it end up in your hands and, you know, just the terms of the licensing agreement? Yeah, so going way back to the, you know, 2010, 2011 timeframe, myself and three other individuals founded a company around the license for levosimendan to develop it for high-risk cardiac surgery. As we were developing it for that indication, it was about the same time that Stuart had approached us with this alternative development path. That trial read out neutral on the top-line endpoint, provided some pretty compelling safety data and a favorable trend in mortality. We could have continued to pursue that path, but again, Stuart convinced us that this was a much more viable and certainly commercially viable path. We have been on that path since then. Okay. That trial was conducted with the IV form, just like the HELP trial that we conducted was. The license that we had at that time was for the IV form in North America. As we moved closer to getting the investment that we got last year, I think one of the things that helped us is that we, on the back of those patents and on the back of the ability to move into phase III, we renegotiated our license. We now have worldwide rights to oral and IV at all approved doses for the use of improving exercise in patients with PH-HFpEF. We also now have the worldwide rights that would support a much bigger opportunity for us. Great. That's helpful. In terms of that market opportunity, I think that, you know, Chris, or maybe either of you, if you want to sort of talk about the market opportunity for levo and PH-HFpEF specifically, you know, and maybe you can break down a little bit of the U.S. opportunity and does it differentiate at all from the international opportunity? Yeah, we're just in the midst of conducting some very interesting and important primary market research around the world. Include Europe, Japan, and the United States. I think one of the things that comes out of that research, again, it's still preliminary findings at this point, is that there's a huge unmet medical need and that there is significant interest by the physicians that we interviewed for a drug that would treat this condition because, as they stand today, there is no therapy that's proven effective. Again, as we alluded to, in some cases, there's actually some question about the safety of drugs that might have been applied historically to treat this condition. Very encouraging signals about physicians' willingness to adopt this drug once it's approved. Got it. Chris, talk a little bit about the phase II HELP study. You know, academic study, not, you know, without its challenges as an IV therapy with long-term treatment. Talk a little bit about those data and, you know, what you learned from the data, but also inferences that might be important related to those data. Okay. Let me connect these two things. One thing that we're also hearing from the market research that has been a positive surprise, the level of concern with the TID product is lower than we thought it would be. Very little hesitation in terms of market uptake. That's been a pleasant surprise. I'll say at the start of the HELP trial, from the history that I've heard, I wasn't there at the very beginning, the idea of giving a patient a drug that had never been given outside of the ICU or the emergency department, critical care floor, as a take-home IV infusion was a bit surprising to the people who are supplying that. You know, we supply on an as-needed basis for infants. We supply levosimendan in the U.S. and Canada right now. We know where it's going, and we know exactly who's going to use it now. Dr. Rich and colleagues want, they said, "Oh, well, this is fine." You know, these patients will take on a lot more than a once-weekly, 24-hour infusion. We said, "Really? Okay." That was the pathway. At that time, without the rights to the oral and with the oral being developed in ALS by Orion, we foresaw a commercial future for an IV product. The trial, I like to think of it, if people haven't looked at it yet and they're being introduced to the company, is a trial with three right heart caths. A patient comes in, they've got PH-HFpEF, they get a right heart cath, we confirm it. Then we give them a 24-hour infusion of IV levosimendan. Right after that, you know, a couple hours later, they come in, they have another right heart cath. This is all open label. We see, how did your wedge pressure change? What we saw there determined whether we would randomize them. If they had a robust response, they were randomized, and six weeks later, they got the third right heart cath. The difference between those first two, it's an open label period where patients came in with an average of a 25 mm of mercury wedge pressure at rest, and it went down about 5 mm. A good response. They then lift their legs, maybe they lift them and put them in pedals, and they start pedaling. It's three stages, legs down, legs up. Each stage at baseline and after 24 hours, of course, their wedge pressure goes up. In all three stages, it's also 4 or 5 mm of mercury lower. The investigators decided that a 4 mm change minimum was required for anyone to be randomized. That's the enrichment strategy. Open label, you see, do they have that robust change? Again, the patients came in with an elevated wedge, 25, right? Fifteen is considered not really that elevated in these patients. They drop by 4 or 5 at all three stages. We randomize them. They get five more infusions once a week. After their final infusion, about a week goes by, and they come in for that final cath and their walk. This is one thing we really want to emphasize with people looking at this study, that at the time, because we would have gone forward with an IV product, we needed trough data. The FDA wants to see what does this drug look like at trough. We collected the six-minute walk in that randomized period at trough several days after they'd received an infusion with a drug, the active metabolite of which has a 72-hour half-life. It was late. They walked 29 m better at that point than they did at the point of randomization. Their hemodynamics all came down in a way that impressed us sufficiently. Remember that the hemodynamic changes, however impressive they are, the approval would come with, in our case, in phase III, and in the case of every PH drug, with a six-minute walk difference that's meaningful and statistically significant. Importantly, one thing we didn't really talk about is that that is the regulatory pathway that you're pursuing. Yeah. Yes. Yeah, I think it's, yeah, this is a population of people with heart failure, right? 7.5 million, 8 million Americans in a few years. Half of them have HFpEF, roughly. And we think 50-70, some studies show as high as 80, but probably 60-70% of people with HFpEF have PH. That gives you the kind of the addressable market number. Great. The pathway is PH. We don't have to show mortality. We don't have to show survival. It's feelings and function. Yeah. Great. More symptomatology is the focus. So, Doug, you know. You can tell I'm talking. Just talked about six-minute walk distance a little bit. You know, can you just help us understand a little bit of, you know, in the work that you've done, apparently the, you know, greater than 25 m difference in the six-minute walk certainly resonates with thought leaders in our conversations. You know, just talk a little bit about, you know, not just the importance of the endpoint for the indications and regulatory pathway, but what is that sort of, what do you think is kind of the threshold that matters to thought leaders? It's very interesting. That was another component of our recent marketing research. One of the things that, again, stood out continuously, and on this point in particular, was the significant unmet need. These physicians have nothing to treat these patients. We had a number of physicians in the research, and these are cardiologists, pulmonologists seeing a lot of these patients saying, "Listen, any statistically significant improvement in six-minute walk, I would consider enough because I have nothing right now." Now, is there some minimum threshold that most physicians would want to see? We didn't really identify that in our research, but I would say, generally speaking, a directional improvement that's statistically significant, you know, on the order of maybe 10 m or more, I think is going to be plenty to get physicians to prescribe this drug because they have nothing. Great. And then, you know, the open label portion of the study, I mean, patients just seem to be willing to stay in this trial almost forever. You know, what were the drivers of that? And then, you know, maybe just transition us from that, the limitations of an IV formulation. I think we talked about it quite a bit already, but it's sort of obvious. But in terms of the formulation and the need to move to an oral chronic treatment, it's helpful to understand. One of the more remarkable aspects of the HELP study and the open label IV portion is that we had a number of patients that stayed on the IV, weekly IV, 24-hour infusion. They had to be attached to an IV infusion pump for 24 hours once a week for well over a year. These are patients in their 60s, 70s, 80s. We do not think they would be willing to do that unless they were seeing some sort of, you know, significant benefit. Now, obviously, there is some inherent risk, safety risk to having an indwelling catheter in. It was in our best interest once we got access to the oral formulation to try to transition those patients to the oral formulation. Of course, they were enthusiastic about doing that. When we evaluated the patients after the transition from IV to oral, we saw numerical improvements in six-minute walk from their baseline at the end of the IV open label. We saw improvements in BNP on the order of 20-25%. We saw improvements in most of the components of the KCCQ, all of which, again, indicated to us that the oral was likely providing as much benefit as the weekly IV. Great. Obviously, you've sort of transitioned that opportunity, the IV to the oral, you know, high conviction. You know, maybe talk a little bit about the phase III LEVEL study. You know, we've got the, you know, primary endpoint, you know, and just sort of what would be statistical success versus, you know, what is kind of clinically significant success. Are those, you know, sort of endpoints fundamentally aligned? You know, and we can just kind of move from there. The phase III trial we're conducting now is a 12-week treatment trial. The second trial of the two that we'll need will be 26 weeks, right? Both, I'll give the powering of the first trial, it's powered for a 25 m improvement. We had 29 in the phase II when patients were tested at trough. We'll now have patients who will go on to 2 mg for a month and then 3 mg for two months. They'll be on a lot more drug systemically. We think 25 is conservative. We have a 45 m standard deviation built in. The trial is powered well over 90%. We factored in 10% dropouts. At present, we don't feel there's any risk there. A lot of patients who have randomized have completed and entered the OLE. That's a very positive sign. We still believe we have a very well-tolerated drug after the experience that we have in the phase II is great, but these are new patients. They're only on it for 12 weeks. The fact that they'd like to continue is a good sign, we think. A 25 m improvement would be plenty, we believe, for regulatory approval and the trial set up well to show that. You know, Chris, I think another question that we get a lot is just the other drugs in category. You know, we're starting to see HFpEF drugs emerge. Presumably, there's going to be some overlap with the PH population, SGLT2s, GLP-1s. Can you just sort of talk about the, you know, are there risks to overlap with those drugs or, you know, are they just sort of separate and distinct? No, I think they're very relevant to what we're doing. I mean, SGLT2 inhibitors were not approved in these patients at the point in the open label extension of HELP when one of our patients who was on, and they weren't approved for HFpEF. One of our patients was on one, and she walked 100 m more. She was in the open label. I thought, wow, this is great. We have a patent on that basis. We couldn't find another one. This is three years ago, maybe. The people who are commercializing those products will be delighted to know that at this point in a trial, a few years later, at this group of cardiologists who treat HFpEF, as predicted by one of our SAB members, certainly 50% of the patients will be on SGLT2 inhibitors. They're approved in these patients. These patients are sick HFpEF patients. That's one way to think about the PH-HFpEF. They're advanced HFpEF patients. No need to stratify for that. GLP-1s, which are showing mixed things in the data that's coming out in terms of improvement, six-minute walk and certainly weight loss early, we are being careful with those. We're making sure that we don't have people coming on and off drug. We're making sure that anybody enrolled in our study who's on a GLP for the indications approved, of course, have been on it for 90 days and that they're on a stable dose. We've had a few instances where their doc would like to put them on one, and they'd also like to put them in the trial. We say, just wait. Wait for one of those two things. Right. That we don't have any, we minimize the confounding impact. Because some of the data from Packer's study that's coming out right now, for example, is showing these drugs drop the weight and they improve the walk. We'd like to, you got to get from 0.4 to 2 or 2.4 mg. It's a long titration up. A lot of people don't make it. We're seeing that too. They need to tolerate the drug and be stable on it before they come in and take that first walk. Got it. Okay. That's super helpful. GLP-1s will probably be at a lower threshold in the study, at least in the first study, and then you sort of see how things evolve in the second study. You know, in the second study, which will be an international trial, we expect there will be a little bit less, but I don't know that anybody who's thought that there wouldn't be much GLP-1 use has been right. Right. It'll matter for sure. We'll do the same thing. We'll be very cautious. Fair enough. You know, maybe just to wrap up, the commercial opportunity, how you see the size of the opportunity for a drug like this if successful in the upcoming two studies. Doug's got the numbers. I'll just say, remember that we'll have kind of, you know, we would anticipate we will have first to market with an oral. That is part of what's behind, I think, those prescribers saying that any meters would be enough because they're looking at a TPP for a well-tolerated product with a well-known safety profile that's an oral daily. That's great, especially if you're first to market. The market size. It's a very large market, as Chris already alluded to. We're talking about 50-60, 70% of the patients that have HFpEF have this condition. Yeah. I would also say that from our research, not only with physicians, but also with payers, there is very good receptivity to the fact that these patients do not have a therapy that can help improve their exercise tolerance. All the indications are that this drug, when approved, if approved, will have very good receptivity, not only, we think, from the physicians, but also from the payers. Yeah. An opportunity for both uptake and pricing power. Yes. To some degree. Yes. I would say just on that final point that we might have been a little conservative in our estimates of price. I'm going to look hard at that, but it's all very, very encouraging. Great. You guys have a lot going on. Look forward to seeing the other side of the data, the trials being recruited, and hearing about the second trial hopefully being initiated sooner rather than later. Thank you, sir. Appreciate it. Thank you. Thanks Thanks so much. Thank you, Seamus. Thanks, Seamus. Thanks. Thank you, Doug.