Tenax Therapeutics, Inc. (TENX) Earnings Call Transcript & Summary

Good morning, and welcome to the Tenax Therapeutics level setting panel. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Tenax website following the conclusion of the event. I'd now like to turn the call over to Dr. Stuart Rich, Chief Medical Officer at Tenax Therapeutics. Please go ahead, Stuart.

Thank you, Tara, and thank you, everybody, for joining in. If you're not aware, we probably have the most eminent group of heart failure pulmonary hypertension specialists in the world at one time. And so it is really a thrill for Tenax and our colleagues here to present to you the development of levosimendan for heart failure -- for pulmonary hypertension and heart failure -- pulmonary -- preserved ejection fraction, I'm sorry. We're going to start with Chris giving you a few moments about the company and then start the program. Chris?

Thanks. Good morning, everyone. I'll just add to Stuart's comments and just say hello, and welcome. Thanks for being here. I'll give a few updates after the presentations from the experts on the line about the LEVEL trial, but ready to hand off to our first presenter.

Okay. the first presenter is Dr. Sanjiv Shah, who is the Stone Endowed Professor of Medicine, Director of Research for the Bluhm Cardiovascular Institute and Director of the Heart Failure Preserved Ejection Fraction program at Northwestern. And Sanjiv is going to talk about the epidemiology and unmet needs of pulmonary hypertension due to Heart Failure Preserved Ejection Fraction. Sanjiv?

Great. Thanks, Stuart. So I think just to level set what is pulmonary hypertension and what is HFpEF. I'm sure many in the crowd know these things, but I think just making sure we're on the same page. So first of all, pulmonary hypertension. Pulmonary means lungs, hypertension, high pressure. So anything that can cause high pressure in the lungs will cause pulmonary hypertension. And so there are several causes of pulmonary hypertension. We need to understand what the different causes are. And fortunately, we have a categorization system for pulmonary hypertension. There's Group 1 pulmonary arterial hypertension, so a primary problem with the blood vessels in the lungs. Group 2, and that's pulmonary hypertension due to left heart disease or heart failure, further broken down into heart failure with preserved or reduced ejection fraction. Group 3 pulmonary hypertension due to low oxygen levels, so chronic lung disease, sleep apnea, Group 4 due to pulmonary embolism and then there's a miscellaneous category. But outlined in pink here is what we're going to be focusing on today. And why is this important? Well, there are many, many effective FDA approve -- approved treatments, I should say, for Group 1 pulmonary arterial hypertension. And as I'll show you later, there's only about 5,000 to 10,000 of these patients in the United States, and yet these are blockbuster drugs. They're often on the top list of drugs in terms of revenue. And there are no FDA-approved treatments for HFpEF with pulmonary hypertension, and it's a huge unmet need. You'll see the numbers later. So what is heart failure with preserved ejection fraction? Well, it was previously called diastolic heart failure, and you can see that the squeezing function, the ejection fraction of the left ventricle is normal. And that's unlike heart failure with reduced ejection fraction or systolic heart failure where the left ventricle doesn't squeeze properly. Now HFpEF in general is not as well understood. There's increasing in prevalence. There's a few definitive treatments and high morbidity and mortality, whereas heart failure with reduced ejection fraction is well studied, decreasing in prevalence, and there's many proven treatments with overall decreasing morbidity and mortality. So what's the societal burden of HFpEF in general? Well, heart failure prevalence is increasing. This is not consistent across all studies, but I think most experts think there is still a global burden of increasing heart failure with the aging of the population and epidemics of obesity and diabetes. Furthermore, if we look at the Get With The Guidelines-Heart Failure, this is an observational study of over 110,000 patients hospitalized with heart failure in the U.S. And in the closed circles here, this is the data that was collected. And you can see here that blue is HFpEF, red is heart failure with reduced ejection fraction and black is heart failure with sort of this mildly reduced ejection fraction. And what you can see here, if we extrapolate these curves out to 2020 and beyond, HFpEF is increasing, HFrEF is decreasing. So this is the major form of heart failure today, heart failure with preserved ejection fraction, and we -- it's an area of major unmet need. Now HFpEF is also common and debilitating. You're probably aware of TAVR, which is minimally invasive treatment of aortic stenosis, huge revenue maker, huge market. That's only 3% of individuals over the age of 75, whereas HFpEF is 10%, and it's got higher morbidity and mortality. We did a trial several years ago called TOPCAT in HFpEF, spironolactone versus placebo. Their activity level of these HFpEF patients was similar to moderate to severe or worse emphysema and their health status was worse or about the same as dialysis patients. So this is really high morbidity syndrome as well. And the outcomes are poor. What we can see is, especially after hospitalization, the survival is only 30% to 35%, and it's sort of similar with HFpEF and HFrEF. And if I superimpose Stage IIIb lung cancer, so late-stage lung cancer has the same sort of poor outcomes here. And so we often say that heart failure is more malignant than most cancers. And we see here that most cancers don't have as high mortality. So what's the epidemiology and prognosis, specifically of pulmonary hypertension in the setting of heart failure with preserved ejection fraction? Well, it's -- the most common cause of pulmonary hypertension. So first of all, 80% of HFpEF patients have elevated pulmonary artery pressures on echocardiography or heart ultrasounds. And when we measure the pressure directly, it's about the same. Furthermore, it's the most common cause of pulmonary hypertension that you see in the community. So if you just take everyone with elevated pulmonary artery pressure estimated on an echocardiogram, the vast majority, about 67% to 70% are going to have the patients with left heart disease or heart failure and then half or more than half of those have HFpEF. It's associated with the high morbidity and mortality. So this is all patients with left heart disease. You can see no pulmonary hypertension has a better survival than either pre-capillary. So that's that pulmonary arterial hypertension or that's pulmonary hypertension due to left heart disease. And it's similar if it's HFpEF or HFrEF, you can see the survival is much worse here if you have pulmonary hypertension versus no pulmonary hypertension in the setting of left heart disease. And there's no approved therapies. So this is a key slide. Now you don't have to pay too much attention to the hemodynamic criteria of how we define these things. But this is what I was getting at earlier. If we take population estimates, about 5,000 patients in the U.S. have this Group 1 pulmonary arterial hypertension. So drugs like sildenafil, like Bosentan, macitentan, prostacyclins, all these drugs that are major, major revenue makers are really aimed for a very, very small group of patients. Here are the patients who have heart failure with preserved EF and either isolated post-capillary pulmonary hypertension or combined pre- and post-capillary pulmonary hypertension. So 2.2 million in this category, 225,000 in this category. And so the burden of this with 0 treatments is very high. Now when we're in the clinic and we're seeing these patients, they are vulnerable patients. It's very, very common, and they come to us in various different forms. So some patients with HFpEF just come in and they don't have any leg swelling. They don't have any hospitalizations for heart failure. But when they walk, they get extremely breathless. They can't do anything. They can barely get across the room and their pressures go way up in the left atrium, but they don't necessarily have pulmonary hypertension yet. Then some of the patients have over volume overload. So they have leg swelling, they're getting hospitalized for heart failure. And some patients come in with us and they see us and they have pulmonary hypertension and right ventricular failure. So the right ventricle pumps blood into the lungs and those pressures are high. And so that right ventricle fails. And time and time again, in patients with any kind of heart failure, if that right ventricle fails, they'll have a worse outcome. So what does that look like? Well, if we look at the risk profile, the risk profile is much higher in these patients with pulmonary hypertension and right ventricular failure. Their BNP levels are higher and their clinical course is worse. So they're getting hospitalized and they're dying more frequently. So this is really a high-risk group that again has no treatment options. So what are the current treatment options for HFpEF? Well, SGLT2 inhibitors, I'm sure you're well aware of, these are the first treatments that have been definitively proven to be effective in HFpEF. And yet in this trial DELIVER, very large trial with over 6,000 patients, what you can see is in these patients, they don't even necessarily have pulmonary hypertension. In fact, these are lower-risk patients. But the absolute risk reduction was only 3%, and they still had a very high rate of cardiovascular death or heart failure hospitalization despite an SGLT2 inhibitor. And the other thing is that the KCCQ, so that's the sort of quality of life questionnaire, symptom questionnaire, barely budged with these drugs and same with this EMPEROR, HFpEF with empagliflozin. This is with dapagliflozin. So SGLT2 inhibitors don't seem to be the answer, especially for the higher-risk patients. So we've asked ourselves, is this syndrome treatable? And many things have been tested. But I can tell you that having run a lot of these trials, none of the pulmonary vasodilators, none of them have even come close to working in this patient population. Atrial shunts don't work in this patient population, nitrites. And really, levosimendan is the only thing, as you'll hear about, that seems to have worked at least in a Phase II trial. And so this new area of treatment also you'll hear about later, increasing the unstressed blood volume, the ability of the patients to handle this type of physiology, I think levosimendan is the only thing that really seems to work. And so when we think about these types of HFpEF on presentation, what are the treatments? This exercise-induced elevated LA pressure, maybe SGLT2 inhibitors, semaglutide exercise in this middle group, we have a lot. We have all of these treatments now and variably effective. But in this large group of patients here, the highest risk patients, the ones that are getting hospitalized the most, the highest mortality, we basically have diuretics. We're not even sure SGLT2 inhibitors do a whole lot. So this is the major, major unmet need in the field today. So my take-home points are as follows: Number one, HFpEF is common and it's increasing in prevalence overall. PH HFpEF is also very common. It's associated with an incredibly poor prognosis, especially when right ventricular failure is present, and it often is present. Current HFpEF treatments do not address pulmonary hypertension with HFpEF and pulmonary vasodilators, of which there are now several classes just simply do not work in this patient population. And so levosimendan, as you'll see, is really poised to fill this major unmet need. Thank you.

Thank you, Sanjiv. That was a wonderful, wonderful review. This is the team of the specialists that support Sanjiv and pick out his clothes for him when he gives his lectures. Okay. We're going to move on to the next presentation who's going to advance the slide. Dan, do you have the control there? Great. So Dr. Dan Burkhoff began his career in cardiology and in heart failure at Columbia University in New York, where he established and ran the cardiovascular research laboratory. He currently serves as the Director of Heart Failure, Hemodynamics and Mechanical Circulatory Support for the CRL, and he is going to talk about the mechanism of action of levosimendan in PH-HFpEF.

Thanks very much, Stuart. And I'm going to be picking up on a lot of the themes that Sanjiv just talked about. So this -- to start right off, talks about one of the key observations that was made actually by Barry Borlaug, who you're going to hear from in just a minute about what is -- what's really happening in HFpEF. So in this graph here, you see pulmonary capillary wedge pressure, which is the pressure basically that's in the left atrium and in the veins of the lung. And in green here, this shows what happens in a normal person when they exercise. As they exercise, the pulmonary capillary wedge pressure doesn't really -- that's the pressure in the lung doesn't really increase very much. However, in patients who have HFpEF, what you could see is there is an extremely rapid and very profound increase in the pulmonary capillary wedge pressure, within 1 minute of the onset of exercise. So these patients are very, very intolerant to the exercise. And so while they may not be symptomatic at rest and they may not have edema, as Dr. Shah said, when they get up and do minimal exercise, the pressure in the veins in the lung go up, and this is really contributes to their -- and maybe underlies the main symptoms that they have, which is shortness of breath and exercise intolerance. So -- but it's not only that. This shows the wedge pressure, which I just talked about here on the Y-axis. And on the X-axis here is the central venous pressure. This is the pressure that is right before the right ventricle. And in red are normals and in blue are patients with HFpEF. And you see a lot of patients with HFpEF have normal, which in the green zone. But many patients have abnormal wedge pressure and central venous pressures even at rest. But during exercise, these pressures in both chambers, both in the -- on the left side and the right side, they go up very dramatically. So it's not only that the wedge pressure goes up, but the central venous pressure goes up as well. So what causes this? So there are potentially ventricular properties that can cause this or vascular or peripheral factors. In the ventricles, we've talked about that both the left and the right ventricles may have diastolic dysfunction. That means that the hearts are not able to expand and receive the blood that's coming back to the heart during exertion. It could be either an abnormality of passive properties or that the heart is not relaxing fast enough. Another possibility is that the contractility, the strength of the heart of the right or the left ventricles can be decreased. Even though it's normal at rest, it may not be adequate during exercise and especially in PH-HFpEF, where the right ventricle is chronically exposed to these elevated pressures, which cause in that right ventricle chamber dilation and dysfunction of the muscles. And in addition, there are pericardial restraints that limit the amount that the heart -- the right and the left ventricles can expand to receive the blood that is -- that's coming back to it during exercise. So these are possible ventricular properties that could contribute to these findings. But then on the vascular side and peripheral side, these patients, as we know that we're talking about specifically have elevated resistance in the lung. They also may have elevated resistance in the vessels, in the arteries of the periphery, like the peripheral arteries. There also is properties during exercise, the veins, especially of the splanchnic bed as we're going to talk about, constrict and they may be overconstricting and causing too much fluid to come back to the lungs. And also, these patients may have, as Dr. Shah said, they may have fluid overload in general. There are something wrong either with the kidneys or just the metabolism of salt and water that is leading them to have just too much fluid in their body. So these are all potential mechanisms that have been discussed and investigated. And probably most of these do contribute. And the question really is what is the major factor. So levosimendan is an interesting drug because it has multiple effects. It has effects on the myocardium. It can increase the contractility of the heart. And it also has properties where it can affect the vascular tone, meaning that it can decrease the resistance potentially in the vasculature of the lungs and of the periphery and also of the veins. And in fact, there was -- so the study that was performed the HELP study I will talk about in just a second in the Phase II was really built on the premise that maybe what's happening is the right ventricle is not strong enough in these patients due to the chronic overload. And if we give the heart muscle, if we enhance the strength of the heart muscle with levosimendan, then these patients would have a better exercise tolerance and be better able to handle the load, the increase in the volume load that's coming back to the heart during exercise. So that was really the premise that we went into with the HELP study. And I'm not going to go into the details of this because this is going to be talked about later, but this was done -- the HELP study of levosimendan was done in 2 phases. where first, there was a run-in phase where all patients got levosimendan for 24 hours. And then there were hemodynamics that I've shown you were measured during arrest and exercise. And those that responded to the drug, meaning that their wedge pressure, that pulmonary capillary wedge pressure was -- showed that it was decreased were then randomized to either placebo or 6 weeks of treatment and then that those hemodynamics were repeated at the end. And this was a double-blind, prospective double-blind randomized study. So this is the result of the 24-hour infusion. So here you see in blue is baseline, and this is central venous pressure. This is again the pressure right before the right ventricle and the wedge pressure. This is the pressure in the veins of the lung that really contribute to the symptoms. And you can see both the central venous pressure and the pulmonary capillary wedge pressure were significantly decreased with -- at rest with a volume challenge by just raising the legs and with exercise at 25 watts. So both CVP and wedge pressure were decreased. And this is a 24-hour phase. And then also at the 6-month -- a 6-week time point, you see here, this is now the wedge pressure in the control group. You could see a rest and legs up. There was no change in the placebo group. But in the treatment group, there was really a very significant reduction in resting wedge pressure and also the pressure during a volume challenge due to a raising of the legs. So what we tried to then do was using the detailed hemodynamics that we have, we tried to untangle what was the mechanism since levosimendan can affect many parts of the cardiovascular system. where did -- where was the effect isolated to? So key observations were, first of all, we saw no effect on heart rate, the systemic or pulmonary vascular resistance. We didn't really see an effect on cardiac output. And that really then coupled with echocardiography showed we really did not see any significant effect on RV or LV function systolic or and no effect on diastolic function. Therefore, we needed to dig deeper and consider another mechanism of action that explain the effects of levosimendan on these really big effects on CVP and wedge pressure. So this is just a little bit of a background about what happens when you exercise. And this is really talking about a redistribution of volume from the periphery from the splanchnic circulation, which I'll talk about in a little bit, to the central component where the heart lives, which are really where -- which is determining both the central venous pressure and the pulmonary capillary wedge pressure. So when a person starts to exercise, there's sympathetic activation. And there is -- that sympathetic activation mobilizes what's called -- what's referred to as the venous reservoir. So -- which I'll talk about. And this happens very, very fast within -- literally starts to be evident within 30 seconds of onset of action. And this venous reservoir largely resides within the splanchnic bed, again, I'll talk about that in a second. And that increases what's called the effective circulating volume or what we more commonly now refer to this as the stressed blood volume. And this then when the stress blood volume increases, this leads to congestion. And what is congestion? Congestion simply is both the elevation of both the central venous and the pulmonary capillary wedge pressures. So we asked the question, did levosimendan block this or blunt this mechanism of increasing stress blood volume. So the splanchnic circulation consists of all the organs basically that are in the -- that reside in the abdomen. And the bulk of the blood that gets mobilized is in the mesenteric veins in the spleen and in the liver. These are the 3 places where the venous capacitance is most affected by the activation of the sympathetic nervous system, which can -- when the veins in those organs squeeze, they shift blood from the abdomen back to the heart. And so if we go back to this diagram of all the different mechanisms that levosimendan has, you see here there is a significant action on the vascular smooth muscle, which causes vasodilation. And in this case, we can isolate this to the veins because we show that neither the pulmonary vascular resistance nor the systemic vascular resistance increase. So we're now -- that really caused us to focus on the venous compliance and -- or the venous constriction. And this just shows a little bit more detail of the mechanisms by which levosimendan can affect smooth muscle tone. And there are at least 3 mechanisms that have been attributed to levosimendan's vasoreaction effects. One of them is activation of the what's called the potassium ATP channel that leads to this relaxation of the smooth muscle that I'm going to focus on because this is a study that was done, I believe, in the early 2000s. And you can see here, this is a study done in pre-constricted isolated human veins. What the experimenters did, they took these isolated segments of vein and you can measure the tension in the wall of the vein and they expose the vein to levosimendan. These veins were preconstricted. They were given a drug that made them contract. And as you see, as the levosimendan concentration was increased, the veins contracted. And when a drug that was added, that blocks the potassium ATP channel, you could see that the actions of levosimendan were also blunted. So this isolates the actions of levosimendan, the main effect, the bulk of the action of levosimendan to this potassium ATP channel. So with this kind of background, we ask the question, is the stress blood volume decreased by levosimendan? And this is the result of the 24-hour exposure, open-label exposure in the patients in the HELP study. And here, we developed a way to estimate the stress blood volume. And you could see at baseline, the value here at rest is 3 liters, which is quite large. Normals have a stress blood volume that is on the order of around 1,500 to 2,000 milliliters. But these patients have a baseline, they have an elevated volume. And as they are exercising, you could see that this stress blood volume increases dramatically. And this, we believe, is what really underlies the simultaneous increase in central venous pressure and pulmonary capillary wedge pressure. 24 hours of exposure to levosimendan, what you see is that there's a marked reduction across the board here of the stressed blood volume. So levosimendan appears to be blunting the venoconstriction that is leading to the reduction in -- that's leading to the increase in CVP and wedge that I showed you before. And this is now at 6 weeks. In the placebo group, there was really no change in the stress blood volume at rest or legs up. But again, at -- in the treatment group, there was a significant reduction in stress blood volume, both at rest and during the legs up phase. So in summary, it's well established for PH-HFpEF that exercise hemodynamics are distinctly abnormal and these elevations in not only wedge pressure, but elevations of CVP play a major role in the symptoms and likely the prognosis of these patients. We've isolated among the factors that contribute to these elevations is an important role of venoconstriction and changes in stress blood volume that are due to venoconstriction in the splanchnic circulation. And this is now very well established. With regard to levosimendan, this has a unique combination of potassium ATP channel activation and also calcium sensitization that works also on the heart muscle. There's no other drug that shares these particular properties. It's been shown and known for decades that levosimendan does have a strong effect on the venous bed. And what we've shown now that this causes reductions in CVP and wedge and clinical studies have confirmed, other studies, it's well known that reducing these wedge pressure at rest and during exercise are associated with improved outcomes and better long-term outcomes in patients with HFpEF. And therefore, levosimendan appears to be a novel and promising therapy for these patients. Thank you.

Thank you, Dan. That was a great review of complicated physiology. So we appreciate that. Our next speaker is Dr. Barry Borlaug, who is Professor of Medicine and Director of Circulatory Failure Research and the Chair for Research in the Division of Circulatory Failure for the Department of Cardiovascular Medicine at the Mayo Clinic. Barry is going to talk about the clinical efficacy of oral levosimendan in PH-HFpEF. Barry?

Okay. Thanks. So I'll -- this will be a little bit duplicative with some of the comments from Sanjiv and Dan, but I think it's good to like really hammer home some of these points. I'm going to try to maybe state it in a somewhat different way to help everybody understand. As Sanjiv pointed out, heart failure is very common. And we define heart failure ultimately based on the hemodynamic abnormalities that Dan was just talking about. So it's a clinical syndrome wherein patients have symptoms, mostly breathlessness and fatigue that are ultimately related to cardiac abnormalities, an inability of the heart to do its job. So what is the heart supposed to do? Pump blood out to the body, that's job number one, and then do so at normal pressures. So the heart has to squeeze blood out and then in order to squeeze blood out, it then needs to fill with blood again. And that ability to fill requires filling at low pressures. The heart is very compliant during the relaxation phase or diastole. And in patients with HFpEF, that ability is impaired. So they have a higher pressure. They need a bigger head of pressure to fill up that ventricle and then that can back up on the lungs. So as Sanjiv pointed out earlier, most patients with HFpEF, 80% of them have pulmonary hypertension, which is just an elevation in that pressure in the lungs. The majority of those patients, it's high just because the downstream pressure in the left atrium is high. So you have to overcome that pressure to push blood through the lungs from the right ventricle. So symptoms in these patients are sometimes present at rest, but in the vast majority of patients, they're brought on by activity. And for the reasons that Dan mentioned, there are increases in blood coming back to the heart, mediated in part by venoconstriction, but also just due to the action of contraction of muscles, squeezing more blood back to the heart so that the heart can then squeeze more blood out to the body. In people with HFpEF, there is an overexuberant increase in those pressures, and that can increase the filtration of fluid into the lungs and it makes you feel short of breath, limits your ability to engage in activity. So people feel poorly because of this. And when it gets really bad, it makes them come into the hospital for frank fluid overload. So as Dan mentioned, we tested this in the HELP trial. In this study, we tested the hypothesis that compared to placebo, treatment with levosimendan, which at this time was IV given once weekly, will reduce the main -- the primary hemodynamic abnormality that's driving these symptoms, that elevation in what's called the pulmonary capillary wedge pressure, which is equivalent to the left atrial pressure. And because we know that it's so important not just at rest, but with stress, with leg elevation and with exercise, we looked at the exercise value as the primary endpoint as well as the effects at rest and with leg raise. And the primary endpoint was the wedge pressure during just 25 watts of exercise, but secondary analysis, we looked at all stages together. And then we also looked at the 6-minute walk distance as more of a patient-centric endpoint, and I'll talk a little bit more about that. And Dan already showed these data. This is what we saw. So this is the wedge pressure or the left atrial pressure at rest and with legs up and then during exercise, and you can see as it goes up as we've known for many years in patients with HFpEF at baseline. And after treatment for 6 weeks with placebo, as you would expect, there's no effect. Pressures are still going up. In the levosimendan group at baseline, their wedge pressure was just as high, and it went up again with leg elevation and during exercise. But following treatments with levosimendan, it was substantially reduced. I would also point out that the levosimendan was given once per week. And at the time of this assessment, they were basically at the trough level. So the levosimendan levels in their blood and the metabolite of levosimendan was at its lowest. So it would not be unreasonable to expect that there might have an even greater effect if we would have looked earlier on. Now our primary endpoint was the wedge pressure at exercise. You can see that, that wasn't reduced as much as the earlier levels. So this was not met. But when we looked in a mixed model incorporating all the states, we did see that levosimendan reduced wedge pressure, and this was statistically significant. So it supports the concept hypothesis that we were trying to test here. But does this equate to a clinical benefit and how do we tell? And there are many ways that we can do this. The way we did it here and the way that it's done in many clinical trials is to administer what's called the 6-minute walk test. And this has been around for many years. It's very simple. You ask the patient to walk back and forth down a hallway for 6 minutes, and you measure the distance that they cover during that time. And people that have cardiopulmonary disease, they're not able to walk as fast, so they don't cover as much ground. It seems very simple, but it's actually very robust to assess whether a treatment is making them feel better and do better. And these are data from many, many years ago in a heart failure study showing -- so normal in patients in this age group in the high 60s to low 70s, normal 6-minute walk distance would be about 500 to 600 meters. And in patients with heart failure, advanced heart failure, as your heart failure severity gets worse, you can walk less far. So more of the people are falling into this study, what they call Level 1, which was less than 300 meters. And you can see that the patients who covered less ground had a much higher mortality. They also had a greater likelihood of being hospitalized for heart failure, Level 1 here, again, that low level, that 300-meter level. when we've looked at patients with HFpEF, impairments in 6-minute walk distance were actually the most strongly correlated with what patients perceive as impairments in their heart failure symptoms, their quality of life. That's this QoL. So this was better than other metrics that we look at like peak oxygen consumption with cardiopulmonary exercise testing. A lot of people think that this is really the gold standard. That wasn't as associated as 6-minute walk distance. And this is daily activity. This is just putting an accelerometer like a Fitbit on people and measuring how much they move around. And you can see that, that's also related to quality of life, but it wasn't as strong, the p-values here as 6-minute walk distance. So this is a really robust simple indicator. And we also assessed this in the HELP trial. And you can see here that as compared to placebo, treatment with levosimendan, even again, though it was at the dose -- the trough level led to a significant improvement in 6-minute walk distance. This was actually the first trial ever in HFpEF to show that any medical treatment, any medical treatment could improve 6-minute walk distance. Also note that at baseline, these people fell into this Level 1 group. They had an average 6-minute walk distance at baseline of less than 300 meters. So these are patients with really severe heart failure, and they enjoyed a significant improvement, which mirrored the effects that we saw on the pulmonary capillary wedge pressure. So very exciting. So in HELP, levosimendan, again, this was IV, once weekly, well tolerated, low risk of significant adverse events as shown in this table. So it was well tolerated and effective. But that's IV, and IV drugs, many, many problems, of course. You have to have an IV access. There's a risk of infection and clots. So can we do this with oral levosimendan? So that's what we tested in the open-label extension study. After HELP, we had an open-label extension where people could get IV drug and just continue to receive this, which they were very grateful for. But then we initiated this open-label extension with oral drug. And what we did was we started people on oral levosimendan about a week after their last infusion, again, when the drug levels would have been coming back down to 0. And we started them at 1 milligram per day, 1 tablet per day, and then we increased this up to 3 or in some patients, 4 milligrams per day or we decreased it. And this was just based on clinical impressions. How are you feeling? Are you having any side effects or having your headache or anything like that, that might be limiting your ability to take more of it. And then we looked at safety and efficacy assessments at baseline and follow-up during the study. And this is what we saw. There were no severe adverse events that were attributable to the study drug. It was well tolerated. There were some patients that had higher heart rates at the final visit, but we looked at the heart rates at home in their diaries and those were not consistent. So these might have been outliers that were noted. 18 patients did this, 15 of them clinically were judged to respond best to the 3 times a day. A couple of patients went up to 4 times a day. And this is what we saw. Now when I look -- when I show you all these data, I want you to bear in mind that these are the effects of oral drug on top of the favorable effects that we already demonstrated with the IV drug. So just keep that in the back of your mind here. So in these 18 patients, on average, there was a 6-meter improvement in 6-minute walk. Again, this is in addition, in excess of the improvements that we already saw with IV. This isn't that impressive, but there was one 1 who had a big drop in exercise capacity. And she had some -- she was actually enrolled here at Mayo. She had some issues. She missed some doses and had an issue of a bronchitis, and stopped taking her diuretics for a couple of days. So there were some confounding factors. If we just remove her, just to kind of look at what we saw, then the effect was much more impressive that we had a 13-meter improvement in 6-minute walk distance, again, in excess of the significant improvement that we already saw. So that's very exciting. The drug was well tolerated and evidence of efficacy. We also looked at -- now we didn't do heart cats, another heart cat. That would be very invasive and expensive, but we can get surrogate measures for the wedge pressure and the blood marker that we look at that's a surrogate is called BNP or NT-proBNP. This is just a blood marker that's released in response to stretch of the heart. And when the pressure gets higher, the heart gets more stretched. So the BNP goes up. This is what we saw after treatment with oral levosimendan. Again, this is on top of people who were already treated with IV, and you can see that the majority of patients had a substantial reduction in BNP, indicating a decongestive effect. And then we ask them, how are you feeling? And Sanjiv showed this earlier that some of the treatments like namely the SGLT2 inhibitors that we use in patients with HFpEF that are Class I recommendations, guideline-directed medical therapy. In some of the trials, these lead to very low modest improvements in quality of life of like 1 or 2 points. Here, with addition of oral, again, on top of what we saw with IV, pretty substantial improvements in KCCQ scores, so consistent with a favorable effect. And I will just relay one patient that I remember just to kind of hammer home that was participating in the study, he felt really great. I mean it was a game changer for him. He used to be a hunter, but he was so incapacitated by his heart failure symptoms. He wasn't able to do this anymore. But engaging in the study, he felt so much better. He was able to go back out hunting. And even after he had got his buck, he was able to drag it through the field to bring it back to his truck, so he could take it home. And for him, that was a big game changer in terms of how he felt. This fella unfortunately had a rare side effect that you can happen with any medicine, a side effect called angioedema, where the throat swells, it's an idiosyncratic response to drugs. You can get this with any drug. This is very common with ACE inhibitors, which are frequently used for patients with heart failure. So it's rarely seen, but it can happen to anybody and idiosyncratic. So it happened in him, and this is potentially a life-threatening side effect. So obviously, we stopped it. This guy felt so much better with the drug. He wanted to go back on it, even though we told him that this might happen to you again and probably would he said, I don't care. I'll take that risk. I'd rather take the medicine and feel that much better. So to me, that was really -- that really said a lot about how much of a difference this made in his life. So to summarize, IV levosimendan in the HELP trial, it didn't reduce exercise wedge pressure, but overall, it did improve wedge pressure or left atrial pressure incorporating rest and leg elevation and exercise. It improved 6-minute walk distance. When we transition to oral drug, which we're testing in the newer in the LEVEL trial, we did see that it was safe and well tolerated. We did see symptomatic improvements subjectively. We saw a signal of evidence of higher exercise capacity by 6-minute walk distance, lower BNP levels and higher quality of life scores, even in excess of the benefits that we had seen with the IV drug. And we found that 3 milligrams per day appeared to be the preferred dose in most of the patients. So I think that's my last slide, and thank you for your attention. Look forward to question and answer later.

Thank you, Barry. That was a wonderful clinical review. Our last speaker now is Professor Javed Butler, who is the President of the Baylor Scott & White Research Institute and also the distinguished Professor of Medicine at the University of Mississippi, where he served as Chair of Cardiovascular Research and Chairman of the Department of Medicine. Javed is going to review the current landscape of levosimendan in the cardiovascular field of HFpEF and PH-HFpEF, and he puts up the right question, do we need another therapy? Javed?

Thanks, Stuart. Thank you very much. So I'll take the opportunity to take the next few minutes and sort of tie the first 3 presentations in a big picture view as to where we are and where we need to go and hopefully, where we will be heading with this program. So first, just to expand a little bit on what Dr. Shah mentioned earlier in terms of the epidemiology of heart failure overall. American Heart Association set a sort of a commission. This is now, I would say, about 6, 7 years ago. And they said, what is going to happen to major cardiovascular diseases in the United States over the next 2 decades. And a very thoughtful group of people, and they took in a lot of things into account, looking at aging of the population, looking at the risk factor burden in the population, the immigration pattern, the finances, sort of a whole bunch of things taken into consideration. And as you might expect, they published this advisory that most common cardiovascular diseases will increase in prevalence. But what was interesting is that the proportional increase predicted was highest for heart failure, was highest for heart failure for all of those folks. And then because of the aging of the population and the obesity epidemic and the diabetes and other associated risk factors, the prevalence of heart failure with preserved ejection fraction is surpassing that of heart failure with reduced ejection fraction. So the unfortunate news is not only the fact that there are millions of patients with this disease afflicted today, the projections are that those numbers, at least in the near to intermediate future are only going to get worse. Now I will touch upon the pulmonary hypertension aspect of HFpEF in a second. But even if you don't take the higher-risk patients of pulmonary hypertension, just look at the general patient population, one can say 2 things. One if the patients unfortunately don't die earlier in their disease for other things because they had cancer or they had something else, the natural history of the disease is such that many, most patients will develop pulmonary hypertension anyway. So whatever epidemiology that we are -- we have discussed today, it's sort of a cross-sectional window of where we are today. But if you look at longitudinally in the natural history of the disease, most of these patients will develop pulmonary hypertension over time to begin with. But if you take all comers, we are looking at an extraordinary high risk of mortality, and extraordinary high risk of readmission. And readmissions or hospitalizations is a really marker for not 1, not 2, but literally 4 things, right? So one, is that readmissions is a big marker for mortality. So reduction in hospitalization and making patients feel better has sort of that aspect to it. The second is that it's a big societal cost burden. The third aspect is that affects the quality of life of the patient. And the fourth that we usually tend to forget is that if our patients are not feeling well, it's actually a significant burden on the caregivers as well. So the societal burden perhaps is even larger. This has already been expanded upon that these patients are very symptomatic. There are multiple lines of data. Again, there's really no reason to compare diseases. Hopefully, we will all live healthy and we have no diseases. But nevertheless, if you compare diseases, patients who have heart failure with preserved ejection fraction have more morbidities than heart failure with reduced ejection fraction and the impact on quality of life functional capacity is actually even worse than heart failure with reduced ejection fraction. I really like this slide because it puts things into quantitative perspective. We always sort of say that heart failure has worse prognosis than many forms of cancer and 50%, 5-year mortality. But what exactly does that translate in terms of the years of life loss? So these are data, Medicare data. So these are folks who are 65 years and older. You have the life expectancy in U.S. population at a particular age and then heart failure with reduced ejection fraction. They used to call heart failure with borderline EF Now we call it heart failure with mildly reduced ejection fraction, same thing in HFpEF. And as you can see that multiple studies have shown that the prognosis is very poor for these patients, that the prognosis is the same for HFrEF and HFpEF. But just look at the quantity of life that is lost. So huge symptom issue, huge quality of life issue, but we are talking about in excess of 10, 12 years of life lost if you're in your 60s and even if you are an octogenarian, nonagenarian, you're talking about several years of life loss. So we are talking about pretty substantial morbidity and mortality burden. So if that is the case, what therapy do we have for patients with heart failure with preserved ejection fraction. And it turns out only one so far, only one so far, and that is the SGLT2 inhibitor. So this is the 2023 American College of Cardiology Expert Consensus Decision Pathway, a document that came out. Everything at the bottom, diuretic, MRA, ARNI, ARB, these are all with some clauses as a Class IIb recommendation sort of in the considered range. The only thing that has definitively been shown to improve outcomes in patients with heart failure with preserved ejection fraction are these drugs with SGLT2 inhibitors. So let's look at it what exactly is the benefit. We already talked about the mortality risk, the quality of life risk, the hospitalization risk. So the question is what is the benefit do you get with SGLT2 inhibitors. Now I was involved in a lot of SGLT2 inhibitor development programs and absolutely delighted now we have 2 positive trials, almost identical benefit, about 20% relative risk reduction in cardiovascular death heart failure hospitalization. But let's look at not necessarily the relative risk reduction, but the absolute benefit. It turns out that the absolute risk reduction for this combined endpoint is 1.8%, exactly the same in both trials, 1.8% in both trials. So again, we should look at glass half full. That's great. We have finally positive trials. But there is unfortunately a glass half MTA that you have this much of a bad prognosis and now you've got it here. But boy, there's a lot more work that we need to do. On top of that, if you look at the cardiovascular death itself, that was a combined cardiovascular death, heart failure hospitalization. If you look at cardiovascular death, there's a good trend of about 12% relative risk reduction. It actually did not reach statistical significance, as you can see in the red box. But again, a significant amount of work that we need to do. And then finally, these patients are really symptomatic. So we need to really do things where if we can meaningfully improve patient survival, that's great. But at least make the patient be able to live a meaningful life while they are alive. So this issue of quality of life and functional capacity is really, really important. So what is the benefit? So again, focusing on the red box, the KCCQ has been mentioned a couple of times in this -- by my colleagues, Kansas City Cardiomyopathy Questionnaire. So it has a score from 0 to 100, 100 is like perfect and 0 is like dead. So where do people fall sort of somewhere in the middle. So most of these patients with PH and HFpEF have pretty substantially reduced quality of life. Their scores are in the 60s or 50s or something like that. Now these are the results with the SGLT2 inhibitors to see what is the net average increase in KCCQ, and that was 2.4 points on average, right? So again, the same thing about quality of -- the issue of glass half full, half empty. 2.4 points is great. We'll take anything in heart failure. But basically, what you're saying is that you went up from 62 to 64.6, and you need to get to like 85, right? So there's a lot of work that we need to do. Now another issue is that there is a little bit of an irony and everything that I've showed you so far is in heart failure with preserved ejection fraction. This one slide, just to explicitly state, I'm borrowing from heart failure with reduced ejection fraction, but it makes actually a point. And that is that there is a little bit of an irony that, the sicker our patients, the higher the risk they are at, the more the therapy they need, and unfortunately, the least the therapy they get because of intolerance as well. So these patients don't tend to get -- be able to take a lot of those therapies. And that at the bottom of that ACC document, I showed you all the sort of the Class IIb therapies. Those are these therapies that are really not tolerated well in patients with heart failure, again, underscoring need for further therapy development. Nothing in biology is sort of really black and white. There's a big sort of a grade of risk. So you have sort of patients who are sort of stable with heart failure, and I say "stable", there's no such thing as stable heart failure. But nevertheless, they're not coming into the hospital. And they kind of sort of start getting more symptoms and then you need to increase their oral diuretics and then you need to add some IV diuretics and then they start getting hospitalized. And there's sort of this graded risk that we are seeing with these patients. And the patients with HFpEF and PH is clearly on the right side of this slide. So now focusing not on all heart failure with preserved ejection fraction and focusing on this PH group. Clearly, of all the pulmonary hypertension patients that Dr. Sanjiv Shah described, those with secondary to left heart disease group 2 is the most prevalent group of patients, so large, large number of patients that need some therapy from us. This is actually one of the earlier trials that really -- earlier studies that really highlighted to us what is the importance of this. This is by our colleague, Carolyn Lam, who was a fellow with Dr. Barry Borlaug's group at Mayo Clinic, showing that a large majority of patients with HFpEF have pulmonary hypertension. And that goes to my comment that a lot of these studies are cross-section. And if you look at it longitudinally, a lot more patients have this disease and Mayo Clinic being a referral center, not surprising at all that over 80% of these patients had evidence of pulmonary hypertension. And if you crudely look at and divide the patients by median pulmonary artery systolic pressure, which was 48, you can see that those patients with higher pressures have really sort of a drop off sort of a bad prognosis over time. This slide has already been shown, again, comparing those patients who do not have pulmonary hypertension, the high risk in PH with HFpEF, higher risk of mortality. Any criteria you use, the sicker the patient gets, the worse the prognosis, common sense. So I showed you some data with PA pressures. This is looking at pulmonary vascular resistance and greater than 3, substantially worsening risk within the group of patients with PH. And this is when you start developing RV dysfunction. So raised PF pressure, pulmonary vascular resistance, and now we are looking at RV function. And by the time we develop RV function, the prognosis pretty much falls off. And of course, if you have the combination of the 2 abnormalities together, those patients are at an extremely high risk. Now I mentioned by saying that nothing in biology is really dichotomous. These are all continuous risk factors, and you need to sort of decide where you want to go. The earlier you go in the disease state, the more you can prevent, but the longer the trial because the absolute risk is low. And therefore, you got to make the decision where you start. But from a pathophysiologic perspective, I mean, look at the graph on the left, these are pretty continuous relationship and the risk starts at a much lower point. So I showed you the Mayo data with the mean PA pressure of 48 and the risk, but look at the number of people and the risk of mortality between 30 and 40. So I just wanted to highlight that these are pretty continuous variables. And similarly, if you look at -- rather than mean PA pressure, if you look at PVRs, again, there is a pretty continuous relationship and the risk starts going up at a fairly early stage as well. So I will conclude by saying that patients with heart failure and preserved ejection fraction are a very high-risk group of patients to begin with. The prevalence is increasing, the epidemiology is worsening. And I say few therapies, if I were to include all the Class IIb may be considered therapies. But if you're talking about really the recommended therapies, we just got one, and that is the SGLT2 inhibitors, no specific therapies for HFpEF-PH group. And the definite positive, but the modest benefit with SGLT2 inhibitors, we sort of already discussed. And I won't sort of belabor on the levosimendan because Dr. Burkhoff and Borlaug already sort of mentioned, there is clearly a need for therapy in this space. And if you look at the mechanism of action of levosimendan, it gives it a pretty good chance of improving our patient symptoms, quality of life and clinical outcomes. So I'll stop here. And Stuart, I'll turn it back to you.

Thank you, Javed. As usual, a phenomenal overview of the landscape. I think at this point, we're going to go to question and answers. Chris, are you going to make a comment first?

Sure. Thanks, Dr. Butler, and thanks to the whole panel, Dr. Borlaug, Dr. Burkhoff, Dr. Shah, illuminating discussion and jampacked with information. So very grateful for that. I'll give a very simple update, a comparatively very simple update on where we are with the trial. So Tenax Therapeutics received the first of 2 patents covering the use of oral levosimendan in this disease back in July last year. Our IND was cleared by the FDA in -- I think we announced in early November that the IND cleared and that we've had very productive discussions with them about the Phase III program. So -- because we've been at work for several months, we've been -- we were able to initiate our first site just before the end of last year. The goal continues to be to open at least 50 sites in the U.S. and Canada for LEVEL. That should allow us to enroll a little over 150 subjects before the second half of 2025. So before the 1st of July next year, we intend to pull in 153 subjects from 50 centers or more. So that would make top line data from the randomized phase of the study available before the end of 2025. So we announced that we started enrollment in February. We're on track to complete within that time line based on the number of sites opening up, the speed of that opening and the screening activity that we're observing so far in the study since that first start of enrollment in February. So we expect to have more than half of our sites initiated by the end of May. Already 15 sites are initiated. There are another 4 initiations scheduled next week. So we're moving at a steady clip at this point in initiating the sites. I'd remind everyone, these are all centers with large PH-HFpEF populations. They're all large cardiovascular research centers, and the majority of them are extremely highly sought after academic centers, those tend to be centers that are very slow to open. And so the progress that we've made opening up some great centers and the screening activity that's starting quickly after we open them is really encouraging to us at Tenax and to the whole LEVEL team. So there's a sense that this trial is long overdue. These patients do not have a therapy. And so here we are in the early days of enrollment and moving along well. So lots of enthusiasm for the program. And plenty of time left here, Stuart. I know there are some questions that have come in. So plenty of time to kind of dig in and give some answers to these. John Fraunces, I think you're going to walk us through those.

Yes. Happy to do so, Chris. Thanks very much. The first question is from Jonathan Aschoff from ROTH MKM. What difference in 6-minute walk distance do you expect to show in the LEVEL study? And what is the statistical power of the trial to see that difference?

Thank you, John. I think I'm going to answer this one since I kind of put together the trial design. We had a 29-meter difference in the HELP trial. That was a Phase II trial with patients getting pulse therapy weekly IV. We used 25 as the treatment effect to design the Phase III trial, and we are powered at 90%. So I think we're really pretty safe there. I will tell you, if you look at all of the pulmonary hypertension trials that use 6-minute walk, the differences were typically somewhere between 25 and 35 meters. So we hit the sweet spot in the Phase II trial. And we think given the oral therapy, which will then be steady state that the treatment effect will probably be better.

The next question is from John Vandermosten from Zacks Research. It's more of a 2-part question. First, what makes PH-HFpEF so difficult to address and find a therapy to treat? And how difficult will it be for a general internist to identify a potential patient with PH-HFpEF?

I'm going to ask Sanjiv to answer that.

Yes. And I think we all on the call have a lot of experience doing these trials and taking care of these patients. It seems like if you relax the blood vessels in the lungs with pulmonary vasodilators, they should do better. And this has been tested time and time again. And even in one of the more recent trials called SERENADE, where we basically said, okay, well, maybe it's the side effects of these drugs. So we had an endothelin receptor antagonist that causes fluid retention in some patients. So we had a run-in phase where we enrolled patients, saw if they have fluid retention on the drug. And if they did, we took them out of the trial. Even then, we couldn't find a benefit. And I think it's because one is that the pulmonary hypertension is really heterogeneous. And we know from pathological studies, from autopsies that there are problems with the pulmonary arteries, the pulmonary veins. It's not clear that the drugs we have today really can answer this problem and really help these patients. And so I think that's one reason why it's been really difficult to treat. And the other is that we don't -- we haven't yet had a therapy that we've tested that can support the right ventricle like levosimendan can do and also increase the unstressed blood volumes. So using those potassium channels relax the blood vessels in the gut. And I think having a drug like this that can do both of those really answers an unmet need. A lot of those pulmonary vasodilators don't necessarily have primary effects on the right ventricle either. They lower the load on the right ventricle, but not improve the right ventricle itself. So for all of those reasons, I don't think we've had a successful therapy like levosimendan. Now in terms of a general internist diagnosing it, I think internists are getting better and better at diagnosing HFpEF. Barry has -- and his research lab has created a really helpful H2FPEF, a score that helps clinicians diagnose it and consider the diagnosis. But I would say that typically, if a patient has signs of symptoms of heart failure and the ejection fraction is preserved, it's pretty much routine on an echocardiography to report out the pulmonary artery systolic pressure. And while it's not perfect, and it's not as good as a right heart catheterization or invasive hemodynamics, you get a pretty good sense that the patient has HFpEF and the pulmonary pressures are elevated. And so I think that although it's not totally straightforward sometimes. I think most of the times, general internist can diagnose this and treat it. Now the other, I think, thing that we have to consider is that there's nothing to say that this drug wouldn't help patients with HFpEF in general. And I think that, obviously, these trials have to be done. But if they're successful, my mind is that there's a role for levosimendan in HFpEF overall, and we're starting with this population that's at highest risk, and that was studied in the HELP trial. But I think for those reasons, I think internist will be able to use this drug. It's an oral drug, and we expect it to be safe and well tolerated.

Next question from the audience is this. The venous circulation seems to be so fundamental to heart failure physiology. Why haven't investigators recognized this before?

So Dan, you and I have kind of talked about this for years. But what are your thoughts about this?

It's a really fundamental question. And I think the answer is very -- is actually pretty straightforward, and we reviewed this in a detailed view article that we published a few years ago with many of our colleagues here that are on the call that the venous system is extremely difficult to study. There are ways -- very simple ways to index vascular systemic arterial properties, pulmonary properties, heart properties. But when it comes to the venous system, we don't really have good methods. And if you go back to the '60s and -- 1960s and 1970s, when all this physiology was outlined, the methods are very, very invasive and not applicable to human studies. And even we don't have animal facilities that can even do these studies anymore. So it has really been a matter of lack of ability to measure things in the venous system, the compliance and the stress blood volume. And so one of the advances that we made over the last 5, 6 years was to kind of get ways of indirectly assessing the venous system through comprehensive hemodynamics like were measured in the HELP study, the right heart cath. And we've applied these methods in many, many studies, including those that are directly looking at the splanchnic bed, looking at what happens when you actually block or stimulate the nerve that supplies the splanchnic bed and you kind of indirectly by confirming that when you deal with that nerve, stimulate and block that we get the expected changes is kind of been validating further validation of our approaches. So I really think that is -- just very briefly, it's really a very difficult vascular system to study.

Okay. Next question from the audience is this. Based on the patients you have cared for that were transitioned from IV to oral levosimendan, did you have any sense of how the oral compared to the IV?

So Barry, you enrolled the most patients in the trial and have the most patients in the transition study on oral. So if I can ask, take off your science hat and just wear the clinician hat, what was your feeling? You saw people on weekly IV and then you saw them on daily oral. Do you think one was better than the other, one more tolerated better than the other?

Yes. I think oral was better. I think people felt a bit peppier and a little less short of breath on the oral as compared to the IV. I mean people definitely -- remember, the IV, it was given like on day 1 of the week and over a prolonged period of time, and that achieves the highest blood levels. And then it just kind of drains off throughout the next 7 days. And people could actually feel that. They could feel like, oh, I felt so good for that first day or 2 after the infusion, and then it kind of just started to get worse again. And I could -- so they kind of get into this sort of rhythm, whereas with the pills, they're getting it each day. So it's just more consistent. So it was more like kind of that first day or 2 after the IV dose but on a continuous basis. So I think that they -- that was a big plus for them. And then, of course, just being able to take a pill so much easier than having a line that's just in there all the time with like a cap on it in your arm and you got to deal with that like in the shower and everything, and they can get infected and all of that. So people really like not having that as well.

Okay. Next question. Assuming that the Phase III trials of levosimendan confirm both efficacy and safety, do you see a potential for levosimendan to become a first-line therapy?

So I'd like to ask that to Javed, who kind of gave this big overview, especially if we get from levosimendan, what we're hoping to regarding efficacy and safety, where do you see this fitting in the whole scheme?

I mean I think that of all the questions that are being asked, I got the easiest question. I mean this is sort of would be shoe in for a Class I indication, right? I mean we are really in a space where there are no therapies. And again, I don't want to sort of inadvertently sort of diss SGLT2 inhibitors. I mean it's a great advance for the first time we had a breakthrough. But boy, I mean, we really need more therapies. And if the therapy is positive, I think it will be a Class I recommendation for 2 purposes. One is just because we don't have many therapies in this space, but also you're identifying a specific phenotype and SGLT2 inhibitors have not been tested in that specific phenotype. So I think it would be a nonissue.

Next question is, what does the approval of Merck's sotatercept for PAH mean for the space? Does it do anything for PH-HFpEF? Does the new mechanism of action change the view on treating -- excuse me, PAH?

Sanjiv, if you're familiar with the clinical side of this. What's your thoughts?

Yes. Well, first of all, sotatercept is not approved for PH-HFpEF. It's never been studied in HFpEF, at least a completed study. There's a trial called CADENCE. I'm not involved with that trial. But from what I understand of the trial, it has been extremely difficult to enroll in that trial. Basically, if you're looking at sotatercept in a drug that really remodels the pulmonary vasculature, that's looking at a very small subset of PH-HFpEF. That's the kind of sort of HFpEF with pulmonary vascular disease superimposed on that. And I think that oftentimes, that is complicated by other factors like lung disease or autoimmune disease and stuff like that. So it's been very, very difficult to enroll. So I don't see sotatercept coming out anytime soon for PH-HFpEF. The other thing is that if you look at the main trial that was done in PAH, it was -- the drug looked very good, but the side effects were pretty remarkable, serious, serious side effects, nothing that we saw with levosimendan. So I think that there may be a role for sotatercept in the future with a small, small subset of these patients. But in terms of broad sort of availability and applicability, I think levosimendan is much more likely to succeed.

Next question. How difficult is it to formally diagnose patients with PH-HFpEF? And are there unique challenges with respect to properly distinguishing this condition from other related cardiovascular indications?

Barry, what do you think?

Well, historically, it's been difficult, and it's been underrecognized, and it continues to be underrecognized. But that's why we developed this scoring system that Sanjiv mentioned briefly. This is called the HFpEF score, H2FPEF, and it ranges from 0 to 9. It's just based on 4 clinical variables and 2 echo variables that are universally available, even the primary care doctors. And you can add it up, and if the score is 6, 7, 8, 9, the likelihood that you have HFpEF is 95%. So you can basically take that to the bank. If the score is 0, it's extremely unlikely. In 1, it's about a 20% chance. So it's pretty unlikely, but not excluded. And then if it's 2 to 5, it's intermediate. And it's written about extensively now in lots of sort of review articles and this is like taught in like the general internists and family medicine doctors that if it falls in that sort of intermediate range, that's the time to refer to a cardiologist. And cardiologists are pretty familiar with this now, and they know that, okay, these are people with kind of an intermediate likelihood and we need to do more testing, which the best is with cardiac catheterization, some places try to do it with stress echo, things like that. But now there's a nice sort of process to get people identified earlier on. And there's much more impetus to make the diagnosis now because we have proven treatments with the SGLT2 inhibitors. In the past, we didn't have unequivocally proven effective treatments for HFpEF. So a lot of people were kind of nihilistic about it, like it probably HFpEF, but who really cares. But now really, it's -- as a caregiver, it's on you to make the diagnosis and people know that. So we've made it a lot easier. So it used to be more of a barrier, but now it's much more straightforward.

Stuart, can I expand on this for one?

Yes, please.

Yes. So one thing I would also say is that I'm sort of pessimistic about it in the next 3 years, but I'm pretty optimistic about it, say, in the next 5 years or so, is that the world and the sort of how we give health care is also changing a little bit, right? So these issues about undiagnosed patient and untreated patient is really can be said for any chronic disease right now, chronic kidney disease, you name it, there's under treatment. And I think there is more and more focus of health system working with KOLs and whatnot for population-based management. And with all the technological advances in imaging and AI methods for just automatic reads of these things, we will be transitioning at a point where we may not have to wait for every primary care physician to diagnose HFpEF PH and that a lot of those things can be managed at a population level, identify appropriate patient with the health system leadership and not necessarily at an individual physician level.

Next question, are benefits of levosimendan expected to be similar for less severe heart failure patients?

Dan, what do you think?

So if the mechanism that we're pursuing here, which is one of several, as we know, I do think that this could be -- this is applicable to all heart failure. Any -- what we see in hemodynamics is true in heart failure reduced ejection fraction. And those are patients in whom the actions of levosimendan on the muscle, the right and left ventricular muscle would be additive, I think, and would be -- we'd be likely -- more likely to see those effects. And in the modern era of beta blockers of ICDs, et cetera, I think there's much more enthusiasm to readdress the use of inotropes in general in reduced ejection fraction patients. So the fundamental physiology that we're talking about with the venous system is not restricted to PH-HFpEF. I think it's applicable to all HFpEF, and I think it's also applicable to HFrEF.

Okay. That's all the questions we have now, Stuart. So I'll turn it back over to you and Chris, for any closing comments.

Thank you. Well, look, I'm not an investor. I'm still on academic, even though I'm working for an industry, but I love this session. It's just so nice to have such scholarly people make such a clear presentation. And I think I'm going to now leave Tenax and join my academics and say, we really feel this is a huge unmet need that we've just struggled with for so long. And you don't know until the trial is over how well it will work. But I think we're all very, very optimistic that we found something out. I'll point out, remember, this drug was approved 20 years ago. So there is an extensive safety profile. And in my experience, Barry, maybe would say the same thing, it's one of the friendliest drugs I've ever used in a heart failure patient, maybe a headache now and then, and that's just about it. So that's really supportive as well. And I thank everyone who's signed in for your interest. I remind you that on our website, not only will this be posted, but there's an education center that has a lot of material, if you want more background information. Chris, do you want to finish this?

I think that's a great wrap up, Stuart. Thanks so much again to the panel and to everyone who committed time to attending. So thank you. Thanks for all the questions.