Ready to go? Okay, great. Good afternoon, everyone. I'm Colleen Garvey, hosting the Fireside on behalf of Guggenheim and Seamus Fernandez, and we're pleased to welcome Tenax Therapeutics to our second annual Healthcare innovation conference. Here with me today are Chris Giordano, Chief Executive Officer; Stuart Rich, Chief Medical Officer; and Doug Randall, Chief Business Officer. Chris, Stuart, Doug, it's great to have you here today, and we're excited to continue educating on PH-HFpEF and Tenax. Before diving in, can you give a brief overview of the Tenax story and how you got to where you are today, for those who aren't familiar? Sure. Okay, thanks, Colleen. So we're developing Levosimendan in phase three. We're partway through our first of two trials. We'll start the second trial this year. We're developing an oral formulation for daily use. We conducted a phase two trial starting in 2018 of the IV formulation in patients with PH-HFpEF. That's the first study that was ever done with Levosimendan in patients with HFpEF. The drug was approved as an IV formulation over 25 years ago. It's approved in 60 countries, but it had never been tried in those patients. That phase two trial was the first to ever show an improvement in six-minute walk distance in any HFpEF population. Very encouraging data and led us to start the phase three, which is ongoing. Great. Maybe just to start, what have been the challenges in developing drugs for PH-HFpEF specifically, and what is different about Tenax's approach? Stuart's been involved in so much development of drugs for PH in general. I'll let him comment on what's been unsuccessful in the past. For us, I would say the major de-risking strategy was to select patients for the phase three program based on what we saw in terms of a response in phase two. It's an enriched trial, and it's a trial where we're recruiting patients who we believe match the responder patient from the phase two. We have a venodilator, not an arterial dilator, and we're focused on lowering wedge pressure, not on changing PVR. Those are all pretty fundamental differences between us and the other drug trials in group two. Maybe you can focus on what's been a challenge in the past. Traditionally, HFpEF has been attributed to a loss of compliance of the left ventricle. All of the approaches try to find something to target the left ventricle directly with a drug to improve the compliance, and those have all failed. It is very hard, especially in humans, to even measure the compliance of the left ventricle. The approaches that appear to be more promising are ones that affect the mechanisms behind the stiffness of the left ventricle. Look at the SGLT2 inhibitors. They are supposed to have an anti-inflammatory effect. We know inflammation can lead to the stiffness of the left ventricle, so it is an indirect way to do it. Hypertension is another way that causes fibrosis and hypertrophy of the left ventricle. Treating the hypertension could then otherwise help the compliance. Our approach is the same way. We're looking at the volume overload problem of HFpEF, which has been known for a long time. Rather than trying to treat the left ventricle to be more compliant, we're treating the volume overload to get rid of the volume overload and restore the normal volume status of the patients. That has resulted in an improvement of the hemodynamics, translating to improvement of the patients. Great. You had mentioned that Levosimendan has been approved overseas for over 20 years, obviously not for HFpEF, but why was it never approved in the U.S., and why hasn't it been studied in PH-HFpEF before? That's a good question. We're starting the second trial now, and we anticipate maybe three-quarters of the patients in this trial will be recruited overseas. That means we're talking to investigators and potential sites around the world, many of whom use this drug all the time. They've used it for decades. We've been really encouraged to see how favorably the drug is viewed and to see how operators who are treating acute patients are able to predict its use and consider it a very safe and very predictable drug in the acute setting with the IV. The drug was successfully developed by Orion globally over decades, and I sort of don't second-guess them on that. I think they focused on a big market, and they were successful. I think maybe success bred more success, but also maybe they just narrowly focused on that HFpEF population. Because again, when we speak to investigators there, there's not a light bulb going off for them that this is a wedge pressure-lowering drug. They know that. They're familiar with the fact that the first thing it does is it lowers wedge pressure. That's what Stuart saw when he started to look at the data that we gave him all those years ago. I sort of don't fault them for focusing very much on that HFpEF patient and on that acute setting. I think we're doing what we're doing because the perspective is totally different. The perspective was, what drug can we find out there for group two? That is what brought Sanjeev and Dan and Stuart and others to our company and said, "You have this drug for these patients." It is a very different way of running a drug development program. Disease, high unmet need, nothing for it, and you seem to have a mechanism with this drug that would work for us. That is really where this started. That is sort of the way we look at it. It was a good thing for us that it was not ever really researched in PEF when it comes to our patent estate because we would not have that if there had been a lot of work done by others in these patients. It is considered counterintuitive. It might have even been considered by some to be contraindicated, but in these patients, we are seeing really good improvements. Could you just remind us of your history of acquiring the rights to levosimendan and then the terms of your licensing agreement with Orion? Yes. When we started HELP, and even when we finished the randomized part of that phase two trial, we had a North American license for the IV formulation of levosimendan. At this stage, after several adjustments to our license, we have a worldwide license to virtually any formulation. Of course, we've got the oral form we're developing now, but we also have the rights to any modified oral form. Different doses, different formulations, combination products. We announced some of those adjustments just a few months ago, or we filed the update in an 8-K. It is a very different situation in terms of the license today, partly because of the success we've had at the patent offices, Europe, Canada, the United States, but also, of course, the phase two data. Doug Randall's here as the Chief Business Officer and chief negotiator of that agreement. I can't think of anything you've missed, Chris. You've, I think, covered it pretty well. Okay. Okay, great. Maybe last question before diving into some of the data in the phase two, phase three program. Can you just contextualize the opportunity in PH-HFpEF, just where the market stands today and the opportunity for an oral agent? Yeah, I'd put it in kind of three dimensions. First of all, this is a huge market. If you think about the U.S. prevalence for PH-HFpEF, you're talking about a prevalence of about an estimated two million patients. Europe adds about another two million. Very large prevalence. Second dimension is there are no approved therapies. There aren't even any effective therapies proven to date. Some of the therapies that are used in this condition have actually shown to be harmful. Huge unmet need. You add to that that in those two very large commercial markets, we've got IP protection that provides us a commercial runway through 2040 and potentially beyond. If you put all those together and the fact that we're the only company developing an oral for PH-HFpEF, and we think all of those factors together make for a multi-million dollar potential opportunity. Great. Maybe moving on to the phase two HELP trial. That was designed as an academic study to truly understand the potential mechanism of levosimendan in PH-HFpEF. What was different about that trial versus some of the other trials in group two? Can you just walk through some of the essential findings of the trial? When we approached Tenax about looking into this drug, myself and my colleagues had never used it. It's not been in the United States for us to use. We read a lot of papers. We actually didn't have a sense as to what this drug did. We even debated amongst ourselves, calcium sensitization, vasodilatation, et cetera. We got great support from the Tenax team at the time to say, "Go ahead and put together a mechanistic study." The mechanistic study was that we want to take these patients, since it's an intravenous administration, and do baseline assessment, as cardiologists love to do in the heart failure world, of everything measurable that relates to heart failure. Rest, exercise, legs up, simultaneous echocardiography with the hemodynamics so we can measure everything we could think of, admit them to the hospital and give them an infusion of levosimendan for 24 hours, and then repeat it the next day and use them as their own control. When we did this, we saw the dramatic drops in wedge pressure and central venous pressure that we had never seen, at least as clinicians treating these patients before. When we looked into the mechanism of action, it was not inotropy. There was no change in contractility or cardiac output. It was not pulmonary artery vasodilatation; that pulmonary pressure barely nudged. It became obvious to us as a little small group who focused on this that this had to have to do with venous return. That's the only other thing that's been shown to have this type of benefit. Then Dr. Berkoff has a lab where he can take the hemodynamics and then investigate it. He came back and said, "It's absolutely the venous return where this is working." That's really unique for any company, not only here, even in pulmonary hypertension group one, of trying to understand exactly how the drugs work. You know, six-minute walk is the primary endpoint in that group two. No one's ever done an exercise cath study for those patients. That is somewhat, I would say, unique in terms of investigating to really understand it. I would say if your goal is to have an endpoint of walk or exercise, you really should know what happens when they exercise when you're measuring. Yeah. So speaking of six-minute walk, that is the primary endpoint for your phase three. In phase two, the 29 meters that was observed has been viewed very favorably by all the KOLs we've spoken to. Why is six-minute walk an important endpoint to consider? Yeah, what are the implications? There is a legacy in the agency to accept six-minute walk as an approvable endpoint in pulmonary hypertension of all types. There are these five groups, and they have done it already with group one and group four. They were not going to make an exception just because it is group two. The regulatory path for approval when you use exercise capacity rather than survival or outcomes is much more straightforward. We are a small biotech company. We were raising money to get through to this. It just seemed like an obvious trial designed to use six-minute walk and KCCQ so we can talk about symptoms and exercise capacity. When asked at times about would we ever consider an outcome study, I would say once we are on the market, we will consider a lot of studies to follow that as well. HELP also included the open label extension portion where patients who are on IV transitioned to the oral formulation. What were the limitations of the IV as a chronic treatment? Why don't you take that one, Doug? You were there at the time. I think the two that stand out are, one, convenience. These patients, 60, 70, 80-year-old patients taking a 24-hour, once-a-week infusion at home presents a real inconvenience problem. The other factor that is less than ideal is because they have an indwelling catheter. There's susceptibility to infection. One of the more remarkable aspects of that open label extension is that some of these patients stayed on that weekly 24-hour infusion for over two years, which we think is somewhat remarkable in itself. Fortunately, we were able to migrate or have all those patients move to the open label oral extension ultimately, which they greatly appreciated. Despite the downsides, they stayed on that for a long, long time. In that transition of patients from IV to oral happened in the second half of 2021. Nineteen patients at that time, they'd been in the open label, as you said, for some of them for over a year. Some of them were more recently out of the study. Eighteen of them transitioned. They agreed to continue with the study. They moved on to oral. It's four years later. I think we have 11 of them on oral now. I shouldn't say we have 11 of them. There are centers in that study who have named patient INDs for compassionate use. Eleven of those 18 are still on. Most of the patients who are not, they were at a couple of sites where the legal and admin functions simply don't let investigators do named patient INDs all the time. You can imagine some of the big academic centers, they'd have a named patient IND for every drug for every study. We are encouraged by that as well. Four years later, patients, some of whom had been recruited two and a half years earlier to do the IV. Small numbers, but presumably, we do not do a six-minute walk on them every two months either, but presumably,they are still happy with their experience. Do you see any risks from transitioning, starting the trial with phase three with an oral for IV, or what do you know about the different formulations that gives you confidence in the oral as the go-forward formulation? When we did the transition study, we did a dose escalation. There's a lot of legacy data of oral Levosimendan out there that was very instructive for us. There were two long-term trials, one in HFrEF and one in ALS for six months and a year. We had a very good sense of the dose, the AEs that are associated with as well. We know from the measurement of the levels of the 1896 active metabolite that we would have steady state levels on oral so that the patients would not have to go through pulse therapy where they had two good days at the beginning of the week and two bad days at the end of the week. Our hypothesis was that they should remain stable or potentially feel better, walk farther, and do better. When we looked at the efficacy measures from that oral transition, they felt better. KCCQ was positive. They walked further, seven meters more, and the BNP went down another 23%, which was pretty remarkable even when we looked at that. That gives us a lot of confidence that we can kind of write check. Great. You have the first phase 3 trial, Level, that's currently enrolling and the second phase 3 trial, Level 2, expected to start enrolling this year. Can you briefly describe the trial designs and the key differences between the two trials? Yes. Very similar studies. I would say level 2 will be different because the primary endpoint will be captured at 26 weeks instead of 12 weeks. The population will be far more geographically distributed. Again, I think we're going to be in 15 or 16 countries in level where in the U.S. and Canada. It'll be a larger trial. In all of our discussions with the FDA about the option to do two trials at a 0.05 versus one at a 0.01, they've accepted that the first trial would have a shorter endpoint, 12 weeks, and would be smaller than the longer trial. I think it'll be bigger. It'll be far more global, and the endpoint will give patients a bit more time. Other than that, in terms of the hemodynamic criteria, which are really essential to us in terms of making sure that we're recruiting patients we believe will respond to the drug, et cetera, very similar studies. Thinking about the primary endpoint, six-minute walk distance, what would constitute success to you and just being clinically meaningful in this space? For level two, does that change with the longer duration of treatment? What other endpoints aside from six-minute walk are of most interest? It's an unfair question because there's never been a drug that showed an improvement in six-minute walk in this population. The comparator typically is group 1 PAH, and 30 meters is considered the clinically meaningful delta in a much younger population with no more comorbidities. You move it up to 75 years with diabetes and kidney disease and all of the other things that go with, no one's anticipating a similar response to a favorable drug. We thought the 29 meters was pretty good. We've powered it for 25 meters for our phase 3 trials. We are confident in that selection of that endpoint. We've heard from other KOLs, some say as low as 10 meters would be considered very meaningful. I think, kind of, we have to wait and see. Of course, the patients, there's been new drugs on the market as since HELP has been run. Thinking about drugs like GLP-1s, SGLT2s, how might those impact? Are those patients allowed in the trial? How might those impact the results? A lot of the patients in the U.S. trial are on SGLT2 inhibitors because they've been approved since we started recruiting. We knew that would be the case. Very different to the situation in HELP when they weren't yet approved. GLP-1s are used by some of the patients because they're obese or they have diabetes or overweight. We expect to see roughly the same thing in level two. What we require is that during the randomized phase, patients are on a stable dose, and they're on a stable dose for 30 days before they randomize. They have to have been on the drug for 90 days before they randomize. The data that has come out on, for example, the improvement in six-minute walk in overweight patients and obese patients with HFpEF, that shows improvement. That data shows improvement pretty quickly. These patients will have had to have been through a period when theoretically, per that data, they will have improved in terms of their weight and also their six-minute walk. They still have to qualify with, for example, a wedge of 18 at rest or 25. They still have to meet the criteria that suggests they'll be a responder after having been on the drug for three months. We think that gives us, that kind of optimizes our ability to see what are the potential combinatorial effects of these drugs and make sure that patients in the trial and recruited into the trial are able to be on standard of care because I would want my patient to be on, not that I have patients, but I'd want my mom to be on empagliflozin. Level also does have an open label extension portion as well. Anything you can share on the progress of patients rolling over to that? Sure. Okay. The OLE, all patients who complete the 12-week trial are given the option to go in the OLE. As we stated, a very high percentage of patients agreed to do that. A very high percentage of patients remain in the OLE for periods now of over a year. There are anecdotes that we hear from the principal investigators of how well the patients seem to be doing and how well they accept the therapy, which gives us even more confidence. I do not want to go into all of those because you will think I am bragging and embellishing too much. All of the feedback we are getting, this indirect sense that you have when you are developing a drug of whether things are going well or things are not going well, we think things are going very well. Great. Okay. Thinking ahead to the competitive landscape and the commercial opportunity that you might launch into, how much of a barrier do you see three times a day dosing with an oral or any feedback you've been getting in the trials? For barrier to entry or barrier in terms of dosing, Doug? Yeah. Our market research with KOLs that treat a lot of these patients would indicate that it's not a barrier at all. I think some of this is a function of the fact that there are literally no other therapies available. Again, some of the therapies that have been tried in the past actually could be harmful. That's one element. The other element that we get from speaking with KOLs is that these patients, their quality of life is not good. This is not like blood pressure control or cholesterol where it's an asymptomatic disease. These patients are very symptomatic. If you're providing them something that actually improves their symptoms, we think that is also an incentive to be compliant. Finally, we have no evidence to suggest at all that there's a compliance issue in our current trial. Adherence looks pretty good. Looks very good. All of that taken together, we don't believe it'll be a barrier whatsoever. Now, there are some lifecycle management opportunities, we think. If we can reduce the regimen to once a day or twice a day, we think that's a possibility. That should add additional penetration into the market and also add additional consumption in terms of days of therapy. I'll say that with the additional funding we brought in this year, one of the things we were able to do is sort of think more about lifecycle management, think about both dosing changes to get to BID versus TID as an example, and definitely think about potential combination products that would be once daily. Another small molecule, et cetera. We're not doing anything, though, that will lengthen the time to NDA and MAA of 1 milligram TID. That's the strategy through both of the phase threes. Okay. Great. I see we're almost at time, but maybe last question. Could you remind us where we are now in terms of cash runway and how we should be thinking about the warrants outstanding and impact to new investors? Yes. Obviously, we need to file by the end of this week. I encourage folks to look for that. At the end of our last quarter reported, we had a little over $100 million in cash. If you're going to look at the 10Q later this week, also there's a KOL event on Thursday that I wanted to remind people about. That should be interesting. In terms of the warrants, it's future cash for more research for us. Okay. Great. Thanks so much.