Windtree Therapeutics, Inc. (WINT) Earnings Call Transcript & Summary

Good afternoon, everybody, and welcome to a session here with the team from Windtree Therapeutics as well as a specialist in the area of cardiology and more specifically heart failure and cardiogenic shock, which Windtree is focusing its development efforts on. From the company, we have Craig Fraser, who is the company's Chief Executive Officer. We also have Steve Simonson, who is Chief Medical Officer. We're also joined by Dr. Alexandre Mebazaa, who is based in Paris, where he is the Director of -- sorry, I just lost my window -- there we are. He is the Chairman of the Department of Anesthesiology and Critical Care at Hôpital Lariboisière and he's also a professor in anesthesiology and critical care medicine at the Paris Diderot School of Medicine. So thank you for joining us. Welcome, and this should be an interesting discussion as we talk about the drug candidate, istaroxime, which has a dual mechanism of action, is being developed by Windtree for a couple of indications. I've mentioned acute heart failure and cardiogenic shock -- early cardiogenic shock for which we recently saw a very compelling data. Maybe I'll turn the podium over to Craig who may walk us through some background on Windtree and development programs, and then we'll carry the conversation on from there.

Thanks, Leland. Really appreciate it. And welcome, everybody. We were looking forward to giving you an update. The company has a lot going on, and we're very excited about what we've seen recently with istaroxime, as Leland was mentioning, particularly in this area of cardiogenic shock. We think it has created a really nice opportunity for the company and is promising in terms of the ability to hopefully ultimately bring a drug to clinicians that can address what is a need in such a critical population. Today, I'm going to make some forward-looking statements. I just remind everybody, particularly as a public company, there's a lot of information and a lot in our filings and our 10-K and our 10-Q, and we do a pretty good job of keeping everybody updated with our news and information, but I refer you to all of our public filings for additional information. So as an introduction to Windtree, Windtree is a biotech company that is focused on late-stage development of a couple of assets. Today, we're going to talk primarily about acute cardiovasculars and what has become our lead asset and our priority focus istaroxime, but we're advancing in this acute CV market. And every company mentions high unmet needs, it's almost a cliche. But I really want to point out that the patients that we're addressing in the programs that we have, have such a profound unmet need that you see supportive regulatory pathways and designations. Our assets have fast tracked -- the programs have fast track designation and orphan drug designations, and this area of cardiogenic shock based on precedent and discussions with the FDA, we think, has an opportunity for either possibly achieving a breakthrough designation as we continue to build out our data set, something that's highly unique, particularly outside the world of oncology. And ista is this drug that we have now had in 3 separate Phase II global studies, big blinded studies of critical care patients that are in heart failure or now in early cardiogenic shock. And the product has been exceptionally consistent in its profile across a wide range of severities across multiple studies and across many, many measures and data points, not just 1 or 2, and we're excited about this profile that we're seeing in acute heart failure and shock because it's proving to be perhaps the only cardiac agent that can approve the cardiac function of a failing heart, certainly one that's not catecholamine based of a failing heart as well as have rapid and significant improvements in blood pressure. That's something that's desirable in many of heart failure patients. But that last characteristic is absolutely critical for the cardiogenic shock patient. And not only are we not having to make the trade-off or clinicians make the trade-off between cardiac function improvement and blood pressure, but we're doing so with what can potentially be a very differentiating safety profile when you look at parameters such as the renal profile that we'll be telling you about in avoiding some of the other use-limiting side effects of some of the other agents around arrhythmias and so forth. I mentioned that the recent positive Phase II study of istaroxime in early cardiogenic shock has created what we believe -- that those results have created what we believe to be a program that can be relatively fast and less expensive development and regulatory pathway certainly versus acute heart failure, which is this big area, but cardiogenic shock has a precedent. And in fact, it was coming out of discussions with the FDA and talk with our medical reviewer and being at meetings and talking with our scientific advisers that people were pointing us towards looking at cardiogenic shock. There is a precedent there where increasing -- significantly increasing systolic blood pressure or blood pressure can be a primary endpoint be pivotal in a study. Now that's highly unique in the world of acute cardiovascular and something that is a very attractive pivotal endpoint to go after. It can help create a program that has less scale, it's faster and quicker. At the same time, while we are focused on improving blood pressure, we are seeing other assessments and other measures that can build upon the evidence of other benefit around cardiac function and what we ultimately hope to achieve coming out of a Phase III program that we're planning by the end of next year. And given what we believe to be such an attractive opportunity to pursue right now in cardiogenic shock, this has become our priority. And this is what we set an organizational focus on. The other thing that I'll mention is this is -- all of this opportunity is being addressed internally by a highly experienced management team. I've been in this business now 32 years. I've been the CEO here for the last 6.5, combination of small start-ups and also running business units in some of the larger companies like J&J and Pfizer. And our whole team is that way, Dr. Steven Simonson, who's joining as a CMO, practicing clinician for many years at Duke followed by about 15 years or so at AstraZeneca, and other small company prior to being here for the last 8 years. And just really across the board, we have a team that delivers, I think evidence of that is the fact that we executed 2 global studies that were ICU or CCU-based studies in the middle of a global pandemic and got the studies done, which I think is remarkable. So istaroxime, looking at the agent, how unique it is, the first thing is, as a first-in-class therapy that has a dual mechanism. So it works in 2 different ways. The first mechanism of action increases the force of contraction through inhibition of the sodium, potassium ATPase channel and the sodium calcium exchanger. This increases the force of contraction with each and every heartbeat. And then in between heartbeats in the diastolic phase, istaroxime very uniquely, the second mechanism of action is SERCA2a activation which then enhances calcium reuptake, calcium up out of the tissue, which results in a greater relaxation of the heart in between heartbeats, which also helps to have more calcium available for the next force of contraction. And by working in both cycles of the heart, we are seeing not only very nice efficacy but we also seem to be avoiding many of the rate limiting side effects of some of the older agents and, in particular, seeing a really unique clinical profile around things such as blood pressure and heart rate and renal profile. So the rationale for studying cardiogenic shock actually came out of what we were seeing in acute heart failure, specifically after conducting 2 Phase II trials in heart failure, Phase IIa in 120 patients hospitalized with acute decompensated heart failure, where we studied 3 different doses infused for 6 hours versus placebo and a Phase IIb, which also involved another 120 hospitalized patients due to acute decompensated heart failure, here with 2 different doses taken forward, 0.5 micrograms per kilogram per minute and 1.0 micrograms per kilogram per minute, that was infused for 24 hours versus placebo. But these heart failure studies demonstrated, and both of them were very positive, but they demonstrated this unique profile of improving cardiac function, things such as what we call the filling pressures of the heart or wedge pressure in the heart. Stroke volume is the amount of blood coming out of the heart with each and every heartbeat. All of the cardiac function improvements, these very important ones anyway were significantly improved with both doses. And uniquely, this improvement did not come at the expense of blood pressure. Many agents of heart failure work by getting forward flow out of the heart by dropping what we call afterload, the pressure that the heart has to pump against. But in many ways, that can have the clinician chasing their tail a bit, if you will, because you're really trying to perfuse the body and particularly the kidneys. And what we saw was we were able to have cardiac function improvement and systolic blood pressure increasing in a dose responsive way. Also, the renal profile was maintained or improved at the higher doses, the filtration rate which is really important as you're trying to support the patient being decongested and getting rid of fluid over a couple of days. And uniquely, the heart rate was decreased which is such an important factor in determining myocardi oxygen demand and the efficiency of the heart and a nice safety profile and tolerability profile. But it was this profile, particularly around systolic blood pressure that led us to cardiogenic shock, this potential second indication. And just a word on shock. Shock is a severe presentation, a severe form of a failing heart, where the heart is failing so much that it shows up that blood pressure is essentially crashing up. Systolic blood pressure, on average, the top number is, for instance, 120, for those of us that are on this call. Here, the blood pressure, the systolic blood pressure is below 90, down to 80s, 70s, even down into the 60s, and it represents pretty significant hypoperfusion. And when it becomes severe enough, it's even beginning to affect vital organs of the body. And because of that, it's a treatment emergency. And when patients are in full shock, the mortality rate can be upwards of 30% or 40%, and the people are that sick. Now we've gone out and valued this market with Claims data and EpiData, and it's about a $1.25 billion total marketplace. And the thing about cardiogenic shock is there's really unmet need here in terms of having good satisfactory drugs that can be used earlier to reverse the condition because the agents that the physicians have to work with, many of these agents are not indicated for early or they get reserved because their efficacy often comes at a cost. You can get more -- you can get blood pressure up if you give somebody a catecholamine such as norepinephrine and kick up heart rate, but with that comes the cost of arrhythmias, increased myocardial oxygen demand, and there's a lot of these other things that can make for some challenges. And we went out and talked to clinicians, and our market research demonstrated a significant unmet need. In fact, we talked to 100 U.S.-based cardiologists who treat cardiogenic shock, 99 out of 100 cardiologists reported they have a high need for new drug innovation, and it's difficult to get 99 cardiologists out of 100 agreeing to much of anything, but there's a high unmet need there, and 84% of them when they saw profile of istaroxime said they'd be highly likely to use it. And in fact, it would be the first thing they would use if this profile shows up. So a therapy that can be used earlier is very attractive. With that, and going in the key question is, do we have the cardiac therapeutic power to treat these really much sicker patients? So Steve, do you want to cover down on the shock trial real quick and then before we get to questions?

Thanks, Craig. Yes, let me run through the SEISMiC trial quickly. This is the trial to ask and answer those questions that Craig just mentioned. In the SEISMiC trial, we enrolled 60 patients with early cardiogenic shock. They came in with systolic blood pressures between 75 and 90 millimeters of mercury, and their condition was due to acute heart failure. The study drug was infused for 24 hours. There was a 1:1 randomization to placebo or istaroxime. We looked at 2 istaroxime target doses in this study, 1.5 micrograms per kilogram per minute and 1.0 micrograms per kilogram per minute. The primary endpoint in this study was the systolic blood pressure profile over 6 hours comparing istaroxime to the placebo control group, and we had multiple secondary end points there, the profile over 24 hours. We did echocardiography. We looked at renal function and then other measures of safety and tolerability. The results of the SEISMiC study are here. The SEISMiC study was positive for the treatment of early cardiogenic shock patients. Systolic blood pressure significantly increased within the first 6 hours of initiating the infusion, and the result was highly statistically significant. And that increase was maintained throughout the 24-hour period of infusion, maintaining the statistical significance. The systolic blood pressure increases were rapid and occurred within the first hour and were sustained throughout the 96-hour post-infusion observation period. Key secondary endpoints of systolic and diastolic cardiac function and performance such as cardiac index, stroke volume index and left-sided heart geometry were improved. Renal function was maintained, and this is, as Craig was saying, a very unique characteristic for istaroxime in these patients. And SEISMiC provided very valuable information for optimizing our dose moving forward in the program. These data substantiate and advance the rationale for istaroxime as a treatment for acute heart failure as well as enables the program to progress in cardiogenic shock. With these positive seismic data in hand, let me tell you where we are going with the program and how we're going to progress the development to get us in the best position for planned regulatory authority discussions on a potential Phase III program in cardiogenic shock. We're going to be enrolling a small number of additional patients in 2 pathways of study. First, we will extend the SEISMiC study to incorporate longer dosing and a tapering dosing regimen. We're going to characterize the physiological and clinical responses. Additionally, we will get experience in sicker patient populations within cardiogenic shock, a group referred to as SCAI Stage C patients. This is a logical progression for our program. And once we have these 2 pieces of data, we believe we'll have a good package of data to take to regulatory authorities to align on the Phase III program. And with that, I will ask Professor Mebazaa, if you could comment on the need for pharmacologic treatment for these patients and how istaroxime might be able to fill that need.

Yes. Thank you, Steve, for your presentation, and thank you for the question. Right now, we are in this incredible position where when a patient is coming with cardiogenic shock, we have drugs on the shelf. We are going to take them and use them. And we know that we are going to harm more of the patient than really doing something that is going to help. All the catecholamines that we have on the shelves today going from norepinephrine, epinephrine dopamine. My research group and other shows that the harmful effect is much, much higher than the benefits. For years, we tested many other drugs. And in the best of my knowledge, all the positive inotropic agents that were tested, all had side effects, the first of them being hypotension that leads probably to decrease in coronary perfusion and kidney dysfunction. And here, for the first time, it seems incredible, but for the first time, we have a drug that is improving systolic blood pressure. And already, we are seeing something that is really exceptional. I mean it's like a dream come true because for years, when we're treating cardiogenic shock, we are giving a drug that is bringing arrhythmia, drugs that is decreasing blood pressure. And here suddenly, with a simple drug, we can see not only a quick improvement in systolic blood pressure but also something that lasts for hours. Now someone can say, yes, but other drugs like adrenaline or -- can transiently increase blood pressure, yes, but none of those drugs improve diastolic dysfunction. And diastolic dysfunction is this function that is aspirating the blood that comes from the lung and improving hemodynamics. Then, we have improvement in cardiac function, both the contraction systole, the relaxation, the aspiration diastole. You also mentioned renal function. In our patients with cardiogenic shock, renal function is almost always worsening. And here, it is maintained, which is also really amazing. And I would say on the top of everything, these positive results were seen with few patients, in fact, and which shows the power of the drug because usually in a Phase II -- everybody knows Phase II is more for safety, then we are more looking for a safety effect. And usually, the efficacy, you can hardly see it for patients. Then here, the positive thing is that all those benefits we saw with only a few patients, and this is really remarkable.

Thank you. And just as a reminder, if anybody would like to pose a question, feel free to do so through the chat function or you can always send me an e-mail at [email protected]. But thank you for walking us through and Dr. Mebazaa for your commentary. I think to help with this opportunity in perspective for the audience, I mean, patients who are either in the unit already or coming to the hospital, what's the breakdown? I mean, are these patients who are already in hospital with acute heart failure that's being managed and perhaps they're going to be on their way out with discharge? Or do you also see a number of patients who simply present to the emergency room because they have ECS sort of in the field? How should we think about that? Dr. Mebazaa?

Yes. In fact, there are 2 types of cardiogenic shock. The cardiogenic shock that like was really incredibly improved over years is the cardiogenic shock that is related to acute myocardial infarction. When the patient comes with a cardiogenic shock acute myocardial infarction, you open the coronary artery and then the shock disappears. But those are miracles, but those are only a few cases. Most of the many cases at least, even if you remove the clot, the heart stays sick and you need to improve this heart. This is one of the scenario. The other source of cardiogenic shock is the patients coming with a heart failure -- with a known heart failure since many, many years, and the heart is worsening and worsening, and you need to help this heart. I think in one of the first slide, Craig was showing and maybe for some people, they didn't realize that number. I think, Craig, you said 40% or 50% of cardiogenic shock die within the few -- first few hours or days in the hospital. This is what is incredible. The reason why, for years, we were using drugs that are harmful because you may say, come on, how can you, in 2022 use a drug that is known to be harmful? In fact, we are using drugs that are known to be harmful because there is 50% mortality. And today, we have nothing else. Then we are using drugs that are on our shelves because the nurses knows that when there is a cardiogenic shock, you are using those catecholamines or dopamine that are known to be harmful because you need to do something because the mortality is 50%. Then because mortality is 50%, we are allowed to give anything. And this is exactly what the company and this protocol is doing is changing our mind to say no. When you have a 50% mortality, you don't have the right to use a drug that is known to be unsafe. You need to explore another ways and istaroxime is a new way to try to reduce this mortality to go back to 40%, 30%, 20%, maybe 1 day, the mortality will be even close to 0%. And this drug is again the first drug that is showing so much benefit.

And I mean the SEISMiC data appear to speak for themselves in terms of showing efficacy and not carrying the liabilities of the currently used agents, milrinone and dobutamine and these other agents that are commonly used, and in fact were presented at the European Society of Cardiology Heart Failure meeting recently. Were you at the meeting? But maybe you could comment on kind of any enthusiasm or excitement you saw from other guests at the conference who saw these data and any reactions there?

Yes. In fact, it's funny because when you have a disease with 50% mortality, when you are like the public, you think that -- you are 100% sure that there are 1 million researchers around the world who are working around cardiogenic shock to try to find something, and it's not the case. Cardiogenic shock for years, we know that mortality is high. We know that since 30 years, believe it or not, I think Craig mentioned this earlier, mortality didn't change or hardly changed over the last 30 years. We have exactly the same mortality, and nobody is doing research. And the only research that is starting today is on devices. But you know that devices, it's really very late cases and indeed, they may have their way of treating those very, very severe patients with cardiogenic shock, it's thousands and thousands of patients coming in all the EDs in the world, and we need to start treating them immediately without having cardiac surgery and all those sophisticated department. And then everybody knew that we needed a drug that is in fact, similar to what we see with the istaroxime, a drug that is improving the contractility of the heart, relaxing the heart. I think Craig did mention one incredible benefit of this drug is that heart rate is unchanged. And heart rate, this is very important because all of you, when you're watching a game or something, your heart rate is increasing. And in fact, your heart -- as soon as the heart rate is increasing, your oxygen consumption of the myocardium is immediately increased. And here with this drug, you have an increase in blood pressure. You have an improvement in the contractility, what Craig named earlier, stroke volume, but with no change in heart rate. Again, in the best of my knowledge, I think it's the only drug I know, at least, that is improving hemodynamics without changing the heart rate. All of them increase the heart rate, which means that in those patients, it's increasing oxygen consumption. Then you see when the people in the European Society of Cardiology Heart Failure, when they saw those incredible things, no change in heart rate, improvement in blood pressure already, people are saying but what is this? And again, the big surprise is came with the Phase II. And usually, when you go in a room -- even if it is 6,000 or 7,000 people, when you go and you always see here, we are seeing a result of a Phase II, the only thing you are expecting is that the drug is safe and then you are waiting for the next communication. And here, well, a big surprise, already there is a benefit.

How should we think about the duration that we've seen so far? With the 24 hours of infusion and then the effect seem to persist for a few days, what would your expectation be in practice? Would this be a drug that would be used for longer than 24 hours, which you want to see data for longer periods of time before people are more comfortable? How should we think about that?

Yes. In fact, in many type of shock, but I would say cardiogenic shock was part of it, septic shock also, we know that the hemodynamic alteration lasts 2 to 3 days. And in fact, the therapy is like doing a bridge. It's a bridge to let the heart get going in a better direction and that the hemodynamics is improved, then we need a bridge of 2 to 3 days. And definitely, the first results are, again, amazing in a study that is more looking on safety and efficacy pop out immediately. We need now a longer duration to make sure that it's safe, probably is going to be efficient and benefits will last probably more than 96 hours, we hope. But definitely, we need safety data for a drug that is given for at least 2 days. I think with 2 days, we would be covering probably 80% of cardiogenic shock.

And in addition to the lack of change in the heart rate also, we note that there was improvement in diastolic function. Just maybe if you could, I mean, clearly in kind of the more chronic treatment of heart failure or maybe even acute decompensated heart failure, diastolic dysfunction is an area that is often in need of improvement that may be harder to achieve and is an unmet need. How should we think about the importance of the diastolic effects here in this much more hyperacute sort of context?

Yes. I don't know if everybody knows what is diastolic dysfunction. Then in fact, I'm giving a simple example. If you have a syringe and you are going to withdraw some liquid from a vial, what do you do? You first aspirate, you suck the medications and then you inject it. And sucking is diastole and then when you inject is systole. Then you understand that you need to have a very good action to aspirate the drug that is in the vial to make sure that your syringe is full before you inject it. And diastole, you see them, it is as important to even sometimes more important because you are filling the heart before injecting. And if the diastole is impaired, then you don't have so much blood in the heart. And even if the contraction is very good, your stroke volume is not so important. And the other function of this is -- diastole is when you are sucking this blood from the ventricle, you're in fact, taking this blood from the lungs and then you're reducing the pressure on the lung and then you are reducing the edema that is inside the lung. Here again, among many drugs that are either given to the patients today or tested, it's the first time we see the suction effect this diastole being improved. Now this may be related to the pharmacological effect that Craig was describing earlier. It may be also related to heart rate because, again, since heart rate did not change, oxygen consumption did not change. And we know that oxygen consumption, when it is increasing, it's affecting diastolic dysfunction. Then I think all this together shows -- and you're right, diastolic dysfunction is improved, which is again something that is unique.

And as we think about the further development here in this setting, obviously, in the SEISMiC data were a very compelling and initial look at the performance of the drug in certain patients. There's going to be some expansion to patients with different cardiac status, different SCAI Stage. What will be the most important things do you think that we'll learn from those additional patients who will be studied in the near future?

Yes. Again, maybe if someone -- some of the people in the teleconference are not aware what is the SCAI definition. Then the SCAI definition is probably something that was -- first, it was defined in the United States, and now it's taken over by the whole world. It's to try to -- in clinical trials, to try to include patients that are similar. And maybe one of the reasons why the few trials that we have done for years, maybe one of the reasons why they failed is because we put -- in the same basket we put different severity of cardiogenic shock, maybe some cases which were not so severe, which today we would name Stage A or B or cases which are extremely severe and maybe going to die within minutes regardless of what you are going to do, which is the E stage. Then this definition was -- came out a 3, 4 years ago, again, coming from the United States. And now it's accepted all around the world. And I think what is -- what was smart enough by Windtree is to say we are going to take slides. We are going to take homogenous population. We are going to start with Stage A and B to check whether the drug is safe, whether we are efficient. And this is successful. I mean this is already this first study, although, again, only 60 patients were successful. Now to try to expand and include more patients, in fact, because at the end of the day, we would be all happy to have this drug showing benefit to a larger category of patient, and then we need to extend to stage C. Then you see is what Craig was showing earlier. I think the company needs the next months to extend in 2 directions: one, a longer duration of treatment to fit with our daily practice and the second direction is to go to a more severe scenario, and this is stage C. Now probably it's going to be more difficult to go to Stage D or E. The trials in Stage E, I think will go more toward the device -- testing devices. Why? Because Stage E are patients who are going to die at the level of 80%, 90%, 100%. Then sometimes, when you have so high mortality, even if you separate the patients in 2 arms, it's difficult to see a difference. And again, those patients, I think, the FDA and many experts agree that probably the E will stay with the devices. Then for drugs like istaroxime, A, B and C is already -- if we can keep showing benefits, it's already incredible.

Leland, if I might add from a planning standpoint and the time that, that plays out, so when you think about the patients that are, A -- it's like an inverted pyramid, by the way, right? There's more As than Bs than Cs. And really, when you -- cardiogenic shock program is addressing -- and when we think about shock, it's really people that are in early cardiogenic shock through different extremes, B through E. And Bs and Cs represent nearly 85% of the population between B and E. And of course, we're really not looking at Ds and Es as Dr. Mebazaa just mentioned on the rationale and the reasoning with the devices and the rest. When you think about the population that's at risk, heart failure with low blood pressure headed south, that -- and you know from our forward-looking plans later, that's really our heart failure program, right? Our heart failure program where people really want this fitting in as a heart failure drug, first and foremost are acute decompensated heart failure people that show up with normal to low blood pressure because that's even in the heart failure where they're challenged. Those people have longer length of stays. They often are the ones that don't get fully dried out and get discharged in less than compensated state in and come back into the hospital in the next 30 days. So As are the heart failure, Bs and Cs are the focus of what we're doing. And extending the infusion, as Steve mentioned, with the tapering down, which is common vasoactive drugs and products in the CCU, given the physician control of that, and we're going through that. And then we think we'll be in a pretty good position. And uniquely, the one last point is characterizing this unique SERCA2a activation and that diastolic effects in ways that are more specific that you can gain, for instance, by having a pulmonary artery catheter inserted, you could get greater, more specific characterization of what's playing out the drug in the heart. And so while we're doing these next couple of steps, and they'll be pretty quick. When we think about something like the extension study, Leland, that's about a 6-month study. And in parallel, we'll be talking with the FDA. We plan on talking with the FDA this fall in a Type C meeting while we're building these next pieces of information to put on top of our SEISMiC data. And then we think we have a pretty good package, as Steve mentioned, towards for Phase III and enough information along with FDA feedback to design what that protocol should look like for Phase III.

Yes. And yes, and just to be clear for everyone, we're always hearing about open-label extensions. This has obviously done in an open label extension. This is an extension that is going to be to double blind randomized to the SEISMiC trial, which presumably saves the company time and this is not going to be like a new study, which you have to file and do all the steps usually would have to do for a new study. But rather you're kind of going off the existing trial schema and simply adding kind of a new part to it, if I'm not mistaken. And so we could have those data, Craig, would you say then by sometime in the early part of 2023?

Certainly the first half. So we begin the study here in the early mid-fall. You do -- you have some follow up, like a 30-day follow up on the back end of enrollment and then you get the data together and package it. So when -- and I would -- by the way, I should mention, we just posted an updated deck to our website. I refer people to that deck, and you can see the landscape and the timing. But we're looking at certainly in the first half of next year and then we should, at least in our plan, be in a good position to have the discussions towards the end of Phase II meeting and take it from there. Leland, you had mentioned -- you had asked a few moments ago about the reception at the European Society of Cardiology meeting, the clinical reception and Dr. Mebazaa and Steve was at a critical care research meeting, in fact, in Washington, D.C., really good reception by the scientific and the medical community. I'd be remiss if I didn't mention that. The other thing that I've seen is that the reception and the receptiveness of industry, people who do this type of work, other companies, right? And we have said publicly that we're pretty active on the business development front for possible partnerships, licensing and such. And this positive data and the nature of a program where the pivotal endpoint could be blood pressure, for instance. And when you think about time risk, cost return type of parameters that we think about in our industry, when you're doing valuations and thinking about business development, those types of things are very attractive, and it's had a very positive reception across those discussions. We just came back from -- in June from the BIO meeting, which many of us know is a big more or less business development meeting, and we're really pleased with the opportunities that this program has created for the company.

Yes, and that takes kind of me to the next portion of my questions, which have to do with -- as we think about this in the context of the industry and cardiology has always tended to be kind of the domain of big pharma which has historically developed kind of these big cardiac, cardiology, cardiovascular drugs in different kind of subcategories of that rubric and the like. And a lot of these drugs are now generic, and I believe all the drugs that are used in the critical care setting for people with early cardiogenic shock are effectively available as generics, which then attests to the fact that it's been a long time since there's been an innovation in this area. And is there -- and maybe Dr. Mebazaa, you could also comment, has there been any reason for kind of a long desert of lack of innovation? Has it been a lack of mechanisms that are novel and can be used to treat and address this condition? Has it been a lack of interest in the part of the companies? How should we -- just so that we understand kind of what's been the gap for several decades at this point from the drugs that we have and when they came about versus istaroxime, which is obviously a much newer agent, but not much in between those 2?

I mean I'm not expert in why people are investing in disease or not, but what I can tell you is usually companies hate when you have several trials that are neutral, even negative. And usually, then they say, okay, this area is too dangerous for us, guys, let's go somewhere else. And in the beginning, people thought probably because mortality is high, it may be easy to make a difference between 2 arms because when you have a number of events that is high, you think that -- but I guess the big mistake that was done for years and is that people thought in the beginning that cardiogenic shock, they were whole alike. And in fact, after all the neutral trials, as you said, they were a desert. But during the desert, I think many groups like mine, we were trying to understand what is cardiogenic shock. And then we build a very large biobank. You know that the biobank in cardiogenic shock are rather recent. We have 1 in Europe, and there is 1 in the U.S., that really -- it's very, very recent, biobanks, large database. We -- now we are joining database from Europe and the U.S. You know that AHA, I mean, the largest organization of the world AHA just starting. I think the first patient was included the last week or 2 weeks ago, just started the first like worldwide survey in cardiogenic shock in 2022 in June. And you say, come on, I mean it is incredible. This disease is known since many years. We know that mortality is 40% to 50%. Then really, all the research in cardiogenic shock is now -- starting now. The large organization, ESC, AHA are really putting money just now, then I think historic things comes really at the right moment to benefit from all this enthusiasm that is done by -- I mean, with all this large organization and national societies that are pushing cardiogenic shock.

And Dr. Mebazaa, how do you see -- I mean, obviously, we have a lot left to learn about ista in this setting. But based on what we do know about it and the performance so far and what the other options currently do and do not do or do in a bad way, where would you see istaroxime be used in early cardiogenic shock, would it be a first-line agent? Would it be used after kind of some of the older, more standard, more long-standing agents have been used, but maybe they haven't been as effective as desired or perhaps their impacts on renal function or heart rate? Where would you put this to kind of in that paradigm of the therapeutic approach?

If the results are confirmed, clearly, it's going to be a first-line therapy. Why? Because I think we will bring back all the data that my group and others showed on the harmful effect of dobutamine and epinephrine and dopamine, et cetera, et cetera. Then I think we will convince the world that instead of giving a drug with harmful effect, you should use as a first-line therapy, this drug. And this comes back to what Craig was saying earlier, the market is huge. The market is huge because today, when you have a patient with hypotension and you do the echo and you see that the heart's ejection fraction is low, people will immediately use a harmful effect -- drug with harmful effect and then patients will do arrhythmia and he or she will die. And then people would say, yes, but he was severe, and this is totally unfair. And tomorrow, for sure, those patients with hypotension, and there are many, many of them all around the world, with hypotension the heart is failing. Then we would immediately give istaroxime to have this patient improving. And then you can keep doing the exams to try to see why the heart was failing. Was it ischemia? Was it a chronic heart failure that is decompensating? And clearly, we should really stop using -- and I wrote many editors and articles stop using catecholamines. Catecholamines is killing the patients. There is excess mortality in any of the studies that we did and other did than first-line therapy for sure.

And even though the advantages seem to be clear for istaroxime, would you think there would need to be comparative studies of any type or that simply having this drug approved and available and its clinical profile would put it in kind of that full position for the majority of patients who need it?

Yes. I think there are maybe 2 answers. First is we need to perform clinical trials. And I can tell you, in many, many centers who are doing trials, today, they will not easily accept to do a trial wherein one of the arms, I mean their own patients, the patients they love and they treat would have catecholamines. I mean today, it's going to be rather difficult. And my other answer is that it's going to be maybe also unethical. I mean, if we see that this drug is the only drug that is increasing blood pressure, that is not harming the kidney, how would you accept, again to have half of your patients with a kidney that may be worsening. Don't forget that many of those patients may come with already a kidney failure, then you would be praying for days that the kidney will keep being in that situation and improve when the patient will be improving, but you would hate to see the kidney going worse and worse. Then again, everybody would accept if the blood pressure is higher, which is unique. If the heart rate is not changing, which is unique, if the echo is improving, which is unique to -- even the FDA will accept it immediately because, again, the FDA, they know. All the data that we were mentioning since many, many minutes now, they know them by heart. And the meeting you mentioned earlier in Washington, D.C. and the French Embassy, we had FDA. We had EMEA. We had really the top key opinion leader in cardiogenic shock. And many of them -- after I presented the data of SEISMiC, many of them came later to ask and many wrote e-mail later saying, how can you reanalyze the data like this? It's incredible. Can you check this? Can you see this? It's really amazing, even key opinion leader from the U.S. Then yes, there is a lot of enthusiasm and everybody would accept the data and the drug will be used immediately after it's clearly proven, but this effect is consistent.

And I think we may have already covered this, but are you aware of any other agents in development that would be competitive to ista being that there's been such a lack of innovation in this field. Presumably, there are no other compounds that are out there that seem to possess the properties that istaroxime does.

No. Other companies try to have a drug more in a chronic way, like oral drug or -- but in early administration, in an acute setting, I mean, cardiogenic shock is really you are in the ED or you're in the CCU and you are not aware and suddenly, phoo, the patient is arriving. And then you need to give an IV drug by definition. And the best of my knowledge is the only one tested today. But again, maybe I don't know, I didn't do the -- I go to meetings, I hear the late breaking trial, but maybe Craig and Steve knows other companies. But for -- and my knowledge is the only one in this setting.

Yes. Like Leland, what's even more amazing is that when we look at the really big area of acute decompensated heart failure, acute heart failure, something that's the size of -- can you hear me still?

Yes.

Okay. Sorry. I had a pop-up saying I was getting logged off. So acute decompensated heart future is something that's the #1 reason for hospitalizations in the U.S. and Europe, like 1.3 million, 1.4 million admissions annually. Despite that huge market, there's really nothing that we see in late-stage development for the acute decompensated heart failure patient, even in heart failure yet alone in something like shock moving down the spectrum of severity. There have been these diabetic drugs recently that in the outpatient setting or Entresto right at discharge have shown promise and some work being done upstream into getting that patient started on their therapy for discharge and capturing this so they get out on that therapy. But nothing for the acute patient in heart failure or cardiogenic shock in late-stage development that we can see, at least from our vantage point.

And then just a few minutes left. Just touch on the other program at Windtree, which is really in the acute heart failure setting. Obviously, that would require probably larger trials and more extensive development work versus early cardiogenic shock. How should we think about these opportunities now that ECS has kind of come sort of to the fore following the SEISMiC data kind of added on to the background in acute heart failure, which the company has been talking about for a longer time and you have had more data than previously. So how should we think about those 2 opportunities with the same compound as the company is in the midst of what could be multiple strategic discussions and trying to figure out sort of where to put the pieces on the board as we look over the next 1 to 2 years in terms of prioritization of these programs and what would be of greatest value to Windtree as it may look to do a deal with a large company?

That's a great question. So there's a couple of parts of it. So istaroxime, building on the base that we saw of acute heart failure, and acute heart failure is this really big market. And it's a market that while you could develop an agent and take it into the U.S. market and go from a development stage company straight into commercialization, I wouldn't think twice to do it, to be honest with you. And many of us here have done that before in companies with AMI drugs or reapprove -- back at Centocor, some of us came from that in '90s. The challenge with heart failure is the scale of the Phase III, right? And that tends to be bigger and can really benefit from a transaction type of a partnership with -- whatever form with another company that has revenues and all this figure and so forth. Acute heart failure -- cardiogenic shock presents a very unique opportunity because the scale, the speed, the cost right now are really within the capabilities of Windtree to run very quickly off of this data and to move to this next study, move towards Phase III and really from an option standpoint, to run it all the way through. But together, we have something that while very complementary to heart failure, cardiogenic shock certainly showing up to the hospital. I would love to have this be the lead indication that you show up to given such a need in the mortality setting backdrop. But we also have behind ista, oral therapies, next generations like ista, that are in preclinical development that create a really nice platform at the lead asset, having a couple of possible indications. The oral next-generation follow-ons, including for outpatient use, in preserved ejection fraction and so forth heart failure patients. And in general, I think these have created some optionality for the company over the next 12 months and a good bit of interest. We do look for business development to be a source of non-dilutive funding and partnership, particularly as you think about the bigger program. And I think here in the next several months, building on the data and regulatory actions while we're having these discussions should put us in a pretty good position to meet other objectives that we have for the company and partnership and support.

Terrific. And just as we wrap up, just to remind us, as we think of the catalysts, obviously, you're in discussions, so we could see something materialize. But in terms of the development program with the extension, we would be seeing the next set of data, it sounds like the first part of '23. And then we'll go from there in terms of what we may see from the standpoint of pivotal development. Would you need 1 or 2 trials for this kind of indication? How should we think about that?

We assume -- and again, we need to go talk to the FDA and the ultimate answer what Phase -- when anybody goes, "What's Phase III look like?" You have to go, "Well, I'll tell you at the end of Phase II meeting," in a definitive manner. But in general, when we look at the precedent and based on -- there's a couple of things. First of all, we already have a building safety database, right? We're at about 299 patients dosed with istaroxime across this heart failure shock front. So that's good. And we're building upon that. We'll be somewhere around 350 come spring of next year. And really, for Phase III, a couple of working assumptions as we go to have discussions with the FDA, of course, are that for Phase III, the scale and the costs and so forth are going to be more about what is an adequate safety database or an adequate safety look that you're not making mortality worse as an example. You have enough events and not what you need from an end to achieve systolic blood pressure increase because as Dr. Mebazaa and everybody mentioned, at 60 patients, we were hitting on statistical significance across a lot of different measures. So Leland, to answer your question, I think as we get to this, we are assuming 1 study of about a few hundred, but it will be a couple of hundred patients, maybe upwards around 300. Giapreza that was the precedent for distributive shock from the same division, they did their Phase III about 300 patients as well. So it's somewhere in that round, which is quite a bit different, not only in endpoint, but size as opposed to, say, heart failure for many of those cardiac indications that cause them to be big company stuff.

Excellent. Well, I think we're right up at the hour here. So with that, I just want to thank the team from Windtree, Craig and Steve and Dr. Mebazaa, thank you so much for joining us from Paris, and thank you all who dialed in and Zoomed in to listen to this discussion. Thanks, and I hope everyone has a perfect day.

Thank you.

Thank you.

A replay will be available as well for those who may want to send that to their clients or hear some of the comments again. Take care, everyone.

Thank you.