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

Good morning, and welcome to the Windtree Pharmaceutical's KOL webinar on istaroxime for the treatment of acute heart failure and the upcoming data in early cardiogenic shock. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Windtree website following the conclusion of the event. I'd now like to turn the call over to Craig Fraser, President and Chief Executive Officer of Windtree. Please go ahead, Craig.

Thanks, Tara. Good morning, everybody. I was looking forward to joining you all this morning. Thanks for logging in. We have a number of topics to talk to you about this morning, and Windtree has a good bit of activity with some near-term milestones. So this is very timely for us to be connecting with you. Next slide, please. This morning, I'm going to be making some forward-looking comments. So if you could please refer to our public filings, you can find those on our web address at www.windtreetx.com, again, windtreetx.com, for all of our full disclosures concerning risks and the opportunities with our business. Next, so just as a point of introduction, this morning, we're going to be talking about heart failure, and specifically the area of acute heart failure, patients hospitalized due to their heart failure. And I will be introducing in a few moments Dr. John Teerlink, who will be leading the heart of this discussion, if you will. And he will also be discussing treatment goals, the challenges and what we see as the potential role of istaroxime or ista for short. We also then will be talking about our plans moving forward in the area of acute heart failure. And our CMO, Dr. Steve Simonson, will also be discussing another program that we have that's very active at the moment. In fact, we're within months of reading out data in the area of cardiogenic shock and our plans specifically for what we hope will be a registration program and that additional potential indication. And then I'll go ahead and close today down with some additional information on the company before we open up to questions. Next, so just as an additional point of introduction, Windtree is a company that has a small cap. We're traded on NASDAQ. We are focused on developing 4 what we call late-stage clinical programs. And these are assets and programs that have some Phase IIb data, and we're bridging in between Phase IIb towards Phase III. Specifically, our focus is on acute cardiovascular and acute critical care respiratory disease states. And the things that we're focused on are really important markets with these high unmet needs. And the fact of the matter is, a lot of companies say, well, we're focused on unmet needs, of course. But I want to draw out the facts that these areas and these type of patients really are patients that have a big need for innovation, and that's been recognized not just by us saying it, but by the regulators. Our programs have supportive regulatory pathways because of this need. Two of our programs have fast-track designation. One of our program has orphan drug designation. And the area of early cardiogenic shock, we believe, based on precedents, also has the potential to have a breakthrough designation. So again, we're focused on really important things. And by having done a series of moves with the company and some strategic transactions that have expanded our portfolio, coupling that with some successful rounds of financing, we put a lot into motion, and I'll show you the landscape in a second. But we have a lot playing out that set up a landscape of a number of milestones in the short to midterm and potential news flow. And one thing that's not talked about as much as it probably should be, particularly in start-up companies, is the people. We talk a lot about the science and a lot about the plans and so forth. But in my personal experience, having done this now for 31 years in a combination of some small start-ups like Windtree, and some of those have been highly successful and had good exits as well as being on the other side of the table and running some of the bigger businesses in some of the largest companies, I know, particularly though when you get to a small company and you bite off a lot and you're going to execute on a lot that it really comes down to the people. And I'm exceptionally proud of the highly experienced management team that we have at Windtree and what we've put together to be able to provide leadership and all of our scientific advisers that are helping guide the program. That's -- that is a critical dimension, and I think that we've addressed that very well. Next. So -- next slide, please. There we go. Our pipeline has a number of assets in it. Today, we're focused on talking about istaroxime and the 2 programs that we have active with ista. Ista has been under development in the area of acute heart feature. So critical care, patients hospitalized due to their heart failure. Ista has FDA fast-track designation. We brought ista in, read out positive Phase IIb, meeting with the scientific advisers and top leaders in the area of heart failure in the U.S. and Europe. Their outlook on ista just made us that much more excited, and we've had good engagements with the FDA where we picked up a fast-track designation and are aligned on what are the next steps and what would be needed for approval for ista. And we're preparing for the next big heart failure study that Steve is going to tell you about. And again, as I mentioned a moment ago, we're also developing ista in an area that's a bit more opportunistic. It's the area of early cardiogenic shock with these really critical patients. That's an active study that we plan to wrap up this quarter and read the data out shortly thereafter. Again, an area that we're very excited about that Steve is going to tell you about it. And behind ista, ista is a dual mechanism of action, and one of those mechanisms in the area of SERCA2a activation is a very novel and much sought after target in the world of heart failure. And our team has figured out how to get at SERCA2a activation, where others have been challenged to be able to achieve that. Ista is the first example of that. But we've taken those learnings and that understanding with -- and applied it to follow on albeit early preclinical assets that are -- we've also achieved oral bioavailability with in terms of pointing them in the direction for chronic heart failure. All in all, ista plus these follow-ons make for what we believe is a nice platform for strategic partnership and a good heart failure platform in the area of acute and possibly chronic care as well. There's another area of our business that we're not going to be talking about today, but we do have acute pulmonary care assets and programs centered around a synthetic KL4 surfactant that's been under development and a drug-device combination for treating little preterm babies that are born with underdeveloped lungs, lacking endogenous surfactant. And we came up with a very novel approach of being able to aerosolize the synthetic surfactant and treat these babies noninvasively for their respiratory distress syndrome. That program is being advanced by our partner in Asia, our licensing partner, and they're funding that. So it's nondilutive to the company and to our shareholders with our help and oversight. And given all of that history that we have in the area of acute pulmonary care and protecting lungs, including adults with ARDS with COVID-19, that was a call to action for us. And as such, we do have also a COVID-19 ARDS, people in respiratory failure due to their COVID-19 infections. And we are conducting a trial that's also going to wrap up this quarter in the area of COVID-19 around respiratory parameters of lung injury. So if we go to the next slide to summarize what the landscape looks like. You can see it's quite [ busy ] for us. For a small team, we're doing a lot. Early cardiogenic shock is executing. We plan on wrapping up that study this quarter, reading out the data in the first part of Q1. And if it's positive, and what we hope for, we'll go engage with the FDA. Again, Steve will talk about this a bit more. I also mentioned that we are ramping up our next big acute heart failure study that we plan on initiating in the first half of next year. That is the fundamental foundational program for the company and for this compound. So that's a big deal. And operationally, we're getting ready for that. I also mentioned we have the COVID-19 lung injury study that we're going to wrap up and read out. A lot happening on the other fronts with our programs, both in Asia as well as our preclinical assets. And then behind that, we have a lot of business development activities going on. We certainly have set objectives for ourselves to have transactional news here in the near term also. So if we can move on. Now I have the distinct pleasure to introduce Dr. John Teerlink, who I've known for a number of years because of his leadership in the area of heart failure has been invaluable to us and to our program and to a lot of people doing development in this area. But as a point of introduction, Dr. Teerlink is the Director of Heart Failure at San Francisco's VA. He's a Professor of Clinical Medicine at UCSF. And his background includes after graduating as an undergrad at Swarthmore, he went on to medical school at Harvard where he also did his residency as well as his cardiovascular fellowship. But he's also early in his career and continue through his career has executed a lot of basic science, both at Harvard as well as UCSF, but also in Switzerland as well. He has just an unbelievable amount of experience in leading clinical efforts at all stages and providing leadership and not just participation in all those trials. He has over 300 publications to his name. And he has been a former permanent member of the FDA Cardiovascular and Renal Drug Advisory Committee and is a frequent contributor to the efforts at the FDA. He is also the President-elect of the Heart Failure Society of America. So a true leader, not only in medicine, but in particular, in the world of heart failure. And as I said, he has been a fantastic adviser to the company and our thinking and plans for what we're doing with istaroxime. And with that, I will turn it over to Dr. Teerlink.

Thank you very much, Craig. And my mother will be sending you the check for that introduction. I appreciate it. Good morning. And for those of you who like me are on the West Coast, my apologies for the hour of the day in this talk. I'm really looking forward to discussing with you 3 main issues to give you kind of an overview of acute heart failure, and I realize having worked with lots of investors and analysts that you folks are really bright. But oftentimes, there's a wide range of experience. So for those of you who have a lot of background already in heart failure, I apologize this may be rudimentary. But for those of you who don't have the background, I hope it's helpful. So after that brief discussion about acute heart failure, I'd like to talk really briefly about the mechanism of action of istaroxime, which does provide a very special and unique approach to the treatment of acute heart failure as well as cardiogenic shock, and then discuss briefly the early clinical trials that have provided the foundation for this program. So starting with acute heart failure. Heart failure is overall is an entity that affects over 6 million people in the United States, 20 million people worldwide. These numbers are old and one of the efforts of the Heart Failure Society of America is going to actually be working towards getting more accurate numbers because we believe these numbers are very much representative at the bottom level of the range of this -- how much [indiscernible] our patients in the United States. Importantly, it's the #1 cause of hospitalization in the United States of patients over 65 years of age, which is all of us know the greatest growing portion of our population. Over 1.3 million admissions annually in the United States and even greater than that in the EU. So it's clearly, the hospitalizations are what are -- drive significant health care costs in -- across the world. And so any agent that might be able to influence hospitalization to hospitalization course would be really crucial to addressing this issue. In hospital, patient mortality is up around 7%, whereas a 30-day mortality can exceed 10%, particularly in the patients that we're going to be addressing with the use of istaroxime. As mentioned, it's already the most expensive of the Medicare diagnosis. And the U.S. hospitalization costs are over $18 billion annually, and some estimates have it actually at over $90 billion. There is not unfortunately, despite these horrible numbers, any really meaningful new pharmacologic advancements in acute heart failure for decades despite multiple attempts at doing so. One of the things that has been very important to help facilitate the development in this area is the FDA issuance of the new heart failure guidance, which I participate in, in July of 2019, which has given a lot of flexibility to developing appropriate approval -- regulatorily approvable end points and specifically saying, hey, actually, in this area, it's not important, you don't have to necessarily show mortality, which is important, because doing mortality trials requires thousands of patients, as many of you are aware. So what is heart failure? I've used this term already. And it's a little different than some of the other things that you may have worked with in this area. And as much -- it's a complex clinical syndrome and not a specific disease. And defined -- and this is a definition that Eugene Braunwald developed many, many years ago, actually, many decades ago, that heart failure is the inability of the heart to pump blood at a sufficient rate to meet the demands of the body for oxygen and cell nutrients at rest or during effort, or in order to do so, can only do so at cardiac filling pressures that are abnormally high. Functionally, that translates into some of the symptoms I'll be talking about later, but it can result from any structural or functional abnormality that impairs this ability of the ventricle to eject blood. And that is either -- which is the decrease of this pump function, it had been termed systolic heart failure and/or it can be -- needs to be done to fill with blood, which is called diastolic heart failure. Those terms are now a bit out of date. And so you'll hear more heart failure with reduced ejection fraction, heart failure with preserved ejection fraction. But those -- these 2 terms of systolic and diastolic heart failure get to the -- some of the functional and pathophysiologic approaches to heart failure. Importantly, istaroxime addresses both of those deficiencies in heart function. So one of the challenges in treating heart failure, and this is -- many heart failure physicians are essentially systems biologists because heart failure is a systemic disease. It clearly originates with the heart, but it involves multiple organ systems. And these -- the interactions result in a vicious cycle that leads to progressive derangements and worsening of symptoms and, ultimately, death. The initial triggering event is some degree of LV dysfunction, which causes in the setting of heart failure with reduced ejection fraction, a reduced cardiac output. This reduced cardiac output results in decreased blood pressure, decreased organ perfusion, specifically renal or kidney perfusion, that then results in stimulation of the renin angiotensin aldosterone system, which produces sodium and water retention, increases -- subsequently increases intracardiac filling pressure, which then leads to progressive LV dysfunction and this cycle continues. And one of the important factors is the initial decrease is due to this LV dysfunction. And so for over a century, there's been a lot of work on trying to find ways to specifically improve left ventricular function in this process. So what do the patients experience? Because ultimately, those -- that's the target of all of these therapies. We want to help our patients. And when these patients experience these episodes of acute decompensation and require hospitalization is often due to cardiogenic pulmonary edema. Their lungs literally filled with fluid, and they're trying to breathe underwater, which, depending on how you believe in evolution, is something that we haven't done for a very, very long time. These symptoms result in severe dyspnea and coughing. And then -- and clinically, they produce tachypnea or a rapid breathing pattern, rapid heart rate, hypertension or hypotension, depending on the patient's underlying physiologic condition, rales on exam, which sound like crinkling paper, and an increased jugular venous pressure, which you can see in the neck veins, and that's on that one image, you can see that gentleman's neck vein popping out there. So there are many clinical signs and symptoms of this decompensation. And these are related directly to the goals of therapy. So we want to specifically relieve pulmonary congestion and general edema, which we can do with IV diuretics. And IV diuretics have, by and large, been relatively successful in addressing that one portion of the heart failure presentation, but they're limited in their use, which I'll discuss a little bit later. The other goal is to improve cardiac function and with the goal of improving peripheral and organ perfusion and then to achieve a stable and fully compensated clinical state. Ultimately, though, we can't keep the patients in hospital forever, so you want to transition to oral outpatient medicines for the chronic management of heart failure, many of which have been shown to actually prolong life and reduce the risk of subsequent heart failure hospitalization. Unfortunately, most of these therapies decrease blood pressure and can exacerbate the hypotension that occurs during the acute heart failure hospitalization. And so agents that don't decrease this blood pressure would be essential in the treatment of acute heart failure. So all of these goals can be -- are addressed by the different therapeutic interventions, which, as I mentioned, are all to try to decongest the patient, which results in ensuring adequate oxygenation. Sometimes supplemental oxygen is required. We optimize the volume status by treating the volume overload, once again, predominantly with diuretics and then trying to initiate this and optimize the chronic heart failure therapy. Throughout all of this, many of these agents have interactions with adverse effects. And so we want to try to really minimize those adverse effects as we're adding additional therapies. The hospitalization period is also a time to assess the need for additional therapies such as cardiac revascularization, cardiac resynchronization therapies or assist devices. And then in the process of all of these interventions, we also want to do no harm. So we try to do venous thromboembolism prevention with administering a usually subcutaneous heparin. And then this is also the hospitalization is a teaching moment. It's a time to provide patient education and teach them about the precipitating factors and to initiate disease management programs, which have shown to have important impacts on patients' lives. Despite all of these efforts, and this is old data, but there's newer data, [ Maria Laura Cresoliero ] is a good friend -- and anyway, this shows in a European cohort, dramatic decreases in survival in patients who are both hospitalized and who are -- is outpatients. But note that even though they start at the same point, patients who were hospitalized for heart failure have a -- almost a two- to threefold increase in their subsequent mortality and heart failure hospitalizations, suggesting that when these patients are hospitalized, they are a very high-risk group for subsequent bad events. Now when patients are admitted the hospital, and this is from a colleague who unfortunately has passed Mihai Gheorghiade, what we saw is that the patients who are admitted with heart failure, there is a subgroup that have a dramatically decreased blood pressure. And these are some of the more challenging patients to treat who present with acute heart failure. And most of the agents that we have to treat acute heart failure currently -- actually, almost all the agents that we have to treat acute heart failure, further decrease blood pressure, meaning that in these patients, we have very, very limited options in terms of what we can do to actually help them. And in addition, what we've shown in this article from [ Privalax ] and multiple other studies that if you do interventions that further decrease blood pressure during that heart failure hospitalization, you can cause a new problem, which is the worsening of renal function, the worsening of kidney function, which makes it even harder to treat these patients. So interventions that don't lower blood pressure and don't adversely affect renal function are absolutely crucial. So where do the agents that improve cardiac function fit into all of our therapies? Well, this is a -- from the just-published European Society of Cardiology Heart Failure guidelines from 2021 led by Theresa McDonagh and a good friend, Marco Metra, who's been a long-term adviser to this program, they present that in patients who have evidence of hypoperfusion, inotropes are one of the first-line therapies that are to be considered. And why do they have only a Class IIb indication? Because as we'll get to, there are many side effects and adverse effects of these agents. So because of their side effect profile, they reserve for only, in general, patients and extremists, and it would be wonderful to be able to use these therapies in the broader range of patients for whom they're actually indicated without the fear of these adverse effects. And so as mentioned already, the low blood pressure and peripheral hypoperfusion can define this very high-risk group of patients with acute heart failure who have a low cardiac output. And these patients had a tremendous inpatient mortality that's at least twofold greater than those with normal or high systolic blood pressure. They also tend to be resistant to direct therapy, and agents that can improve this cardiac function would be very useful. And as I already mentioned, the use of these inotropes in this area are limited because these agents can cause heart rhythm disturbances, increased heart rate and myocardial oxygen demand, which can further exacerbate myocardial ischemia. They decrease blood pressure. They actually can increase troponin, causing damage to the heart and worsen renal function and have been shown to worsen mortality. And so despite the potential benefits of these agents that can improve cardiac performance, they have shown to actually have some prohibitory adverse effects. So istaroxime is being developed with the objective to improve this cardiac function without these unwanted side effects of these existing therapies. So let's talk very briefly about istaroxime and what it is and how it works. One of the ways is to inhibit the sodium-potassium pump, which then affects the sodium-calcium exchanger, resulting in increased contraction. So that's improving systolic function, the pumping function of the heart. And then another factor is it also stimulates SERCA2a activity, which enhances the ability of the cardiac myocyte to reuptake the calcium, allowing the heart to relax more rapidly and more fully. So that's addressing diastolic heart failure. So istaroxime allows an impact on both systolic and diastolic dysfunction, allowing it to address the 2 components of acute heart failure. So I'd like to talk very briefly about 2 important programs, and I'll focus on the second program. But the initial Phase IIa program was led actually by Mihai Gheorghiade and was called the HORIZON program. And in this study, it already showed that the pulmonary capillary wedge pressure was significantly improved. Now why is that? The pulmonary -- why is that important? The pulmonary capillary wedge pressure is a measure of left ventricular filling pressures and how much stress the heart is under. So that lower pulmonary capillary wedge pressures in the range of normal are important to reestablish. But most patients who present with heart failure have dramatically elevated pulmonary capillary wedge pressures. So this was an important demonstration of efficacy -- early efficacy of istaroxime. In addition, it showed that stroke volume and systolic blood pressures were significantly increased, which is also tremendously important given the adverse effects of prior agents that have been shown to improve cardiac function. And rather than increasing heart rate, which many -- most of these agents do, istaroxime was shown to actually lower the heart rate in this early HORIZON study. A subsequent Phase IIb study was done also in advanced acute decompensated heart failure patients who were required to have dyspnea and a need for intravenous furosemide. This was a dose-ranging study that included patients with both 0.5 and 1 microgram per kilogram per minute 24-hour infusions. So we've now gone from the HORIZON study 6-hour infusions to even more longer 24-hour infusions. And I'll talk more about the results of the study coming up in these subsequent slides. So one of the end points that was used in this study was the E to E prime ratio. So the E to E prime ratio is an echocardiographic assessment of this pulmonary capillary wedge pressure that is noninvasive. And so it's much more readily done and can be done in a serial fashion in multiple patients, which allows a great pragmatism to this study. This E/E prime is reflective of, as I said, the pulmonary capillary wedge pressure, which is reflective of those left ventricular filling pressures. And in this study, at the 0.5 microgram per kilogram per minute dose versus placebo on the left-hand panel -- the upper left-hand panel, you can see that the E/E prime decreased significantly, which suggests that the left ventricular filling pressures decreased significantly, improving an essential pathophysiologic factor in heart failure. In addition, the 1 microgram per kilogram per minute dose did -- had similar decreases in the E/E prime. And these decreases in E/E prime were associated with significant increases in stroke volume or the amount of blood that is pumped by the heart with each heartbeat. So this is showing a direct measure of improved cardiac function, which is quite dramatic. This 5-milliliter per beat per meter squared increase is a significant increase and very physiologically appropriate. Now what we've seen with other agents is that these -- they can drop the systolic blood pressure. But importantly, istaroxime at both the 0.5 and 1 doses increase systolic blood pressure during this increased stroke volume, which is a fantastic finding that can actually also result in improved global perfusion. And on the bottom set of slides, you see the glomerular filtration rate, GFR, which is a measure of renal function. And typically, and as you see in the dotted lines, which are represented by placebo, the GFR decreases over time in tendency in the heart failure patients. But with the istaroxime patients, there is no change in the GFR. And in the patients treated with one -- the dose level of 1 with the istaroxime, there is actually a significant improvement in the estimated glomerular filtration rate, which was statistically significant at the 24-hour time period. So this is important, showing not only absence of renal dysfunction, but also the possibility of improving renal function during this crucial treatment period of patients with acute decompensated heart failure. So istaroxime is hitting on all levels of the pathophysiology of heart failure, but one of the concerns that has risen in other areas is does it have adverse effects? So the increase in heart rate by other agents has been shown to be very detrimental. But what we can see from this study is that if anything, certainly in the 1 dose of the istaroxime, there is a significant decrease in heart rate during this infusion period. And this is important because it reduces the stress on the heart and reduces the myocardial oxygen demand, suggest actually providing cardioprotection. And this is reflected in the bottom set of slides that look at cardiac troponin T. Cardiac troponin T is a measure of myocardial damage. And as you can see, during these 24-hour infusions of this agent, there is no difference in troponin T during these infusions, unlike that can occur with dobutamine or milrinone, which can actually increase cardiac troponins during this time period, consistent with myocardial damage. In addition, the agents -- these agents that I talked about, such as dobutamine and milrinone, can cause significant adverse clinically significant arrhythmias. And importantly, in this trial, there was no increase in clinically significant arrhythmias or the specific arrhythmia ventricular tachycardia. So in the upper panel, the light green panels are the placebo, the darker tones in the istaroxime doses. And while because of just randomization, the istaroxime group had a lower baseline clinically significant arrhythmias, you can see that there was no change in those arrhythmias over time during the istaroxime infusion at either the 0.5 or the 1 microgram per kilogram per minute dosing. On the bottom set of panels, you see the more specific adverse event of ventricular tachycardias, which also are not at all increased with istaroxime. So what I hope I've given the background here is the importance of acute heart failure as a medical problem worldwide and the unmet need of an agent that can improve cardiac function in a safe manner and actually ultimately improve patient outcomes. Istaroxime in the 2 trials -- the 2 large trials that have been done so far has definitely kind of met that promise and now provides kind of the foundation for our further therapy -- further trials with this promising therapy. So I'd like to now turn it over to Steve Simonson, who will talk to you more about the advancing programs. Steve?

Thank you, Dr. Teerlink. I'm Steve Simonson, the Chief Medical Officer here at Windtree. And I'd like to build on that excellent review of heart failure and the istaroxime data that Dr. Teerlink just ran us through and tell you where we're going with the istaroxime program. So in our next study in acute heart failure, we would like to accomplish a couple of things. Number one, we would like to match the characteristics of istaroxime that Dr. Teerlink just described to you with patients who might best benefit from those specific characteristics. Specifically, those acute heart failure patients with normal to low blood pressure and/or diuretic resistance. As you heard, this is a group that needs better therapy, a group that is difficult to treat, a group that tends to have longer length of stay and more morbidity in the hospital and may be at risk for worse outcomes. The second thing we would like to do is extend the infusion time of istaroxime beyond 24 hours. As you saw in the IIa study, we began the program with 6-hour infusions. The IIb study infused istaroxime for 24 hours. And now we're completing a 14-day toxicology study to enable longer dosing while patient's in the hospital. And importantly, the third thing we'd like to do is obtain data on end point assessments that could be acceptable as primary end points for regulatory authorities in a Phase III study. The primary end point in this next study will be E to E prime as it was in the IIb study, but we will include as secondary end point assessments such as length of stay, days alive and out of the hospital over 30 days, dyspnea and symptoms and key safety assessments such as arrhythmia risk, troponins and renal function. We plan to do this in a global study of about 300 patients, and our start-up activities are well underway for this. And we are hoping to enroll this study in 12 to 18 months when it's kicked off. And this study will help finalize the Phase III protocol and put us in good Phase III ready position for development and -- further development and potential partnering. We've discussed this program with the FDA and our plan going forward, and we've got an agreed pathway. We've also been granted Fast Track designation. And we've been pointed in the direction of more severe patients toward those patients with early cardiogenic shock or cardiogenic shock if we are interested in being considered for a breakthrough designation. And cardiogenic shock is a severe presentation of heart failure that is characterized by very low blood pressure and hypoperfusion of critical organs. This condition requires urgent intervention to increase blood pressure typically to get it above 90 systolic and to assure adequate cardiac output to provide for the body's needs. The in-hospital mortality is high, and there is substantial morbidity with these patients. This could be a market with a value over $1.2 billion. As Dr. Teerlink mentioned, there is no satisfactory pharmacologic interventions in these severe heart failure patients. So there is a significant unmet medical need for a pharmacologic agent here to improve the patients but avoid the unwanted side effects of risk for arrhythmias and renal dysfunction. And with some of the inotropes, there can be paradoxical decreases in blood pressure and even increases in mortality rates in some trials in this population. They are using rescue medications when needed, but these come with some of those unwanted potential side effects that we review. So we've conducted market research with 100 practicing cardiologists who take care of cardiogenic shock patients. They substantiated the unmet medical need in this area, 99 out of 100 stating the need was high. 84% responded, they would be likely to extremely likely to use an unidentified drug with the profile of istaroxime for early cardiogenic shock patients. Furthermore, the majority responded they would position the drug ahead of currently available inotropes invasive pressures. The FDA has shared their thoughts on the use of blood pressure as an acceptable surrogate end point in shock. This precedent -- there is precedent for this in the case of GIAPREZA in distributive shock where a meaningful increase in blood pressure associated with an acceptable safety profile through 30 days was the basis for approval. So what we have done is looked at our blood pressure profile from the 2 studies that Dr. Teerlink reviewed with the 6-hour IIa study and the 24-hour IIb study and combined them on this graph. And you can see we have a clear dose-related increase in systolic blood pressure. At the 1.5 microgram per kilogram per minute dose, there was a mean increase in systolic blood pressure of 15 millimeters of mercury. If we can improve systolic blood pressure from 75 or 80 to 90 or 95 in a patient like this, we will have made a very favorable change in that patient's condition and reduced the risk for subsequent morbidity. So we have embarked on a pilot study in early cardiogenic shock to assess the ability of istaroxime to produce a meaningful increase in blood pressure in these very compromised patients. We're studying 60 patients with systolic blood pressures between 75 and 90 with acute heart failure from sites in Europe and the United States. 30 will receive standard of care plus istaroxime, 30 will receive standard of care plus placebo. The target dose in this study is 1 to 1.5 micrograms per kilogram per minute for 24 hours. The primary end point in this study is the systolic blood pressure profile over 6 hours. Other assessments will include systolic blood pressure at selected time points, systolic blood pressure over the 24-hour infusion period, echocardiographic assessments of heart function and things like clinically significant arrhythmias. We hope to complete enrollment by the end of the year. There's a 30-day follow-up period, and we'll lock the database. And as Craig has mentioned, we're targeting mid-Q1 for this data. A successful treatment in these patients would produce a rapid meaningful increase in blood pressure, getting blood pressure over 90 or an increase in blood pressure in the range of 10 millimeters of mercury. We would like to see that kind of improvement in cardiac function on echocardiography that we've described before and having an acceptable safety profile. If istaroxime can do this, it could provide the foundation upon which a breakthrough therapy designation could be based and potentially access to an accelerated regulatory pathway. So that's our next trial with istaroxime with data coming shortly. In our preclinical pipeline, we have 2 categories of compounds. First, there is the dual mechanism compounds that like istaroxime inhibit the sodium-potassium ATPase and activate SERCA2a. These compounds can be given orally or intravenously for acute use and chronic use. The second category of preclinical compounds we have are the pure SERCA2a activators. These compounds can also be given intravenously or orally and can potentially be developed in acute or heart failure with reduced ejection fraction as well as heart failure with preserved ejection fraction. Another area that needs more therapies. So this creates a portfolio of acute and chronic heart failure treatments that can be developed by us or partner-driven license. So to summarize, istaroxime and our portfolio of compounds have the potential to create significant value. Acute heart failure, as you've heard, is a big market with substantial unmet medical need. Istaroxime is in a unique position of not having a lot of developmental competition in Phase II or III right now. This compound with 2 mechanisms of action has been demonstrated to improve systolic and diastolic cardiac function in 2 studies. It produced this improvement without dropping blood pressure or worsening renal function, and the evolving safety profile is very favorable. We're moving the program into the population that may most benefit from ista. We're dosing longer, and we're getting information to advance planning for Phase III. There could -- there is potential for a development program that could be faster than acute heart failure with the early cardiogenic shock study with data coming very soon. And if there's success there, there could be opportunity for breakthrough designation. The preclinical compounds rounded out our multi-asset portfolio for acute and chronic heart failure and have some very exciting characteristics. And with that, I'll turn it over to Craig.

Thank you, Steve, and thank you, Dr. Teerlink. So just to close out, I want to talk about our position and outlook moving forward, but let me mention cash for a second. As of our last filing, we had $30 million of cash. This is cash that we have on hand, of course, funds the cardiogenic shock study, the COVID-19 lung injury study, all the study start-up activities that we have going on for the next big acute heart failure study. And myself and John Hamill, our CFO, feel good about the runway that's also associated with this. I think it's important to note that we're going to flip these data cards and put out news with cash under our feet. So in my experience, that's always important and better to have an appreciation for that data than being out of cash and instantly having to do a raise. So that gives us some flexibility. We also have, from a stock standpoint, 26.7 million shares outstanding of common stock, and on a fully diluted basis, about 46.6 million. So in summary, as a company, we believe we have a strong strategy for value generation that over time is focused on, first and foremost, deliver on the milestones. I think Windtree has given ourselves as a company a lot of opportunity with good assets, having both the regulatory engagements, good plans, working with some of the very best and brightest people across the globe, and we put a lot into motion. As you might guess here in the fourth quarter, we have a great team hunker down to bring these trials across the finish line and deliver these milestones here in the short term and midterm and get this next heart failure study up and running. So it's all about executional excellence for us. And like I said, I'm proud of the team and the job that they've done to put us in that position. We also have for value generation for us and our shareholders strategic transactions and licensing type of transactions as part of our plan to also bring value to the company, to programs and to our shareholders here in the short to midterm as well. And ultimately, as a company, we're developing a highly specialized company, acute care company and will look here in the future for opportunities that continue to round out our ability to generate value and have more shots on goal that are highly specialized critical care and rare disease. And I have a team here that is exceptionally experienced in all of those areas. Again, additional information can be found on our website at windtreetx.com. So with that, Monique and Tara, do we want to open up for some questions?

Yes. Thank you, Craig. At this time, we will be conducting a question-and-answer session. [Operator Instructions] Our first question comes from Leland Gershell from Oppenheimer.

First, a question for Dr. Teerlink. As we think about the patients who may be most appropriate for ista in the AHF setting, I know you kind of presented us with some different numbers and percentages around parts of the population that have different attributes. But based on the data that we've seen so far, could you give us a sense of what percentage or at least what kind of general fraction of patients you would see coming in for acute decompensated heart failure that you would think that ista would be most appropriate for? And then kind of a second part to that question is, do you think that there would be a patient whose profile would be sufficiently defined as to be an instant go-to for ista? Or would there be any contemplation of these existing agents in that patient before switching to ista?

As anticipated, excellent questions. You folks are always really smart, which is fun to interact with you all. I think that -- so one of the challenges here is that the easiest way to determine this patient population say, well, who are you using inotropes in now, right? But that's actually such a limited population because I personally do everything I can to avoid using those agents because of their adverse effect profile. So in some ways, I have to give you an unsatisfactory answer, which is that I don't know. But half of the patients who are admitted with acute heart failure, so half of those 1.4, 1.3, 1.5 or however many million in the United States alone, patients have reduced ejection fraction. So that is a -- that's the potential target for everybody because if it works as well as we think it does and has shown so far, it would have the possibility to improve function in everybody. Now we don't usually reach for these more advanced therapies right away, but that's once again because of the side effect profile. So my guess is that the ultimate target for the -- for istaroxime will be much greater than its initial use because as physicians get more comfortable with it, they'll expand. So the upper limit would be at least 50% of the patients who are admitted with acute heart failure. The lower limit is into the probably 15%, 20% range of those patients, which are the patients who are currently treated with inotropes or would be treated immediately with inotropes but were reluctant to do so. So it's going to be a range, and that's probably more from 25% to 50% of the patient -- heart failure population. But then also because of its diastolic properties, which I didn't emphasize as much, many of the patients that I excluded who have a preserved heart failure function, their predominant abnormality and presentation is an inability for the heart to relax properly. And this is the heart failure with preserved ejection fraction group, which I think you've probably heard about in other discussions in terms of heart failure. And that is a potential target for istaroxime as well. So that's that upper 50% that might actually emerge as well as a target. So I don't know. Did that kind of get to what you were asking?

Yes. And that's helpful. And we'll obviously probably need more data as well to fully understand the potential and think about how it could best be used. But I think given the nature of the population, that's a fair answer.

Absolutely.

And I also wanted to ask, can we tell -- and again, the data are still a bit limited. But from the HORIZON data, can we have an outlook on how long patients may be on ista? That may be hard to say because it may vary patient to patient. But could we also have an outlook on whether there'd be any advantages to the hospital itself in terms of reduction in the length of stay as an inpatient and things like that?

So one of the things -- there are 2 ways to get at that. One, what are the causes of when to stay in hospitalization? Well, there's the treatment of the initial decompensation, and that involves maintaining kind of the physiologic responses as well as decongesting. So there's -- because of that ability to improve stroke volume and perfusion, there is every suggestion that istaroxime will be able to actually facilitate that decongestion and the initial treatment of a low blood pressure setting. So that should help shorten length of stay. And when you give an agent that can facilitate -- maintain blood pressure, that facilitates the initiation of guideline-directed medical therapy. So that can also help shorten length of stay. And it avoids the adverse effects that come on with giving the other therapies such as the diuretics and things to provide some cardioprotective and renal protective effect. So it's preventing the adverse effects that can also prolong length of stay. So how that all sorts out? And measuring length of stay is an incredibly complicated factor in clinical trials, but it's certainly something that can be and will be measured, whether the study -- certainly the 300-patient study may not be large enough to give a definitive readout on that aspect of it, but it's certainly a very reasonable target and would be part of that value offer or value proposition, I guess, is the proper term. I'm just a doctor. So -- but for the hospitals to add this to their in-hospital formulary.

Our next question comes from Destiny Hance from Ladenburg.

I'm stepping in for Jeff this morning. Dr. Teerlink, it's great to meet you. And Craig and Steve, it's always nice to hear you tell the story. Perhaps, I'd just like to circle back to your comments around the lack of innovation to date in heart failure. Can you provide myself and the audience with a little additional detail on what has really stifled the innovation? And how do you anticipate the cardiologists in the market will think about or react to the entrance of istaroxime?

So once again, excellent question. I think one of the challenges has been that most of the therapies that have been developed for acute heart failure to date have all reduced blood pressure. And as has been shown in the one article that I showed, there are scores -- literally scores of articles that show that reducing blood pressure in the hospital -- in the acute heart failure setting can be quite detrimental. And so one of the challenges has been finding agents that actually help improve cardiac function, improve the physiologic state in heart failure without further lowering blood pressure. And so this is the kind of the target that istaroxime hits so uniquely and is kind of providing a real advance in this area. Did that get to your question? I'm trying to be brief.

Yes, it did. Steve, maybe one for you. As you kind of wrap up this cardiogenic shock study, are there any learnings from that, that could also help educate your heart failure trial as you move into that?

Definitely. As -- the more we study ista, the more we're going to learn about its impact in the heart failure population over a variety of severities. And certainly, we're gaining and substantiating that safety database that is important for any drug in these patients.

This concludes our verbal portion of the Q&A. I'd now like to turn the call over to Monique Kosse of LifeSci Advisors for any questions that may have come over the webcast. Go ahead, Monique.

Thank you, Tara. We do have a couple of questions. I'll read the first one here. What are the next steps after the Phase II data in shock?

Steve?

Once we get the data in hand and get a chance to look at that, assuming things turn out favorably as we're hoping, we want to get in front of regulatory agencies, talk to the FDA about the specifics of a development program directed toward that indication in that patient population and take things from there.

Excellent. Thank you, Steve. Another question here. Tell me about the competitive landscape in shock. And are there others developing in this indication?

As we look at this, there are a spectrum of therapies that cardiogenic shock patients can be treated with, with one extreme being pharmacologic and the other extreme being mechanical support with respect to pharmacologic support as a patient progresses through the severity. We're not aware of much pharmacologic development activity going on. There's been a lot of work in the device end, mechanical end. But I'll let John Teerlink comment on his view of the spectrum of development activity there.

Yes. No, Steve, I think you nailed it. There's very little in terms of the pharmacologic arena in terms of development along these lines. But the device therapies are advancing in multiple, multiple different ways. The challenge is, of course, in this setting, I, at least, am reluctant to use a device unless I absolutely am pushed to do so. So the kind of area that this -- where istaroxime might be really effective is preventing the need for those kind of more drastic interventions, which are associated with fantastic -- can really help our patients but also can be associated with some rather significant complications.

Monique, can I chime in? I wanted to make a couple of points with regard to early cardiogenic shock and essentially the opportunity and how we look at that for both as a potential therapy as well as what it means to the company. This area of early cardiogenic shock or cardiogenic shock when a patient has a systolic blood pressure, unlike you or I maybe at 120, but their systolic blood pressure we're talking about, as Steve mentioned, 75 to 90. And they're moving down essentially through that zone and deteriorating. There is an urgent need particularly if you have a therapy that has a cleaner profile, if you will, on the safety side and doesn't have the ability to perhaps drop blood pressure even further or pick up arrhythmias particularly in these really severe patients. But to be able to reverse that condition and -- rapidly and move blood pressure back up above 90, as you saw from the market research, obviously, would have a tremendous clinical value, at least reported from these clinical cardiologists. But from a bigger picture standpoint for the company, to have a potential second indication that is of the scale, again, systolic blood pressure as an end point, regardless of how the FDA ultimately would want to see that measured in Phase III, is an exceptionally attractive end point in the world of heart failure versus these bigger clinical outcomes and so forth. And it's something that you can much more easily power, design in the scale of that. So cardiogenic shock provides an opportunity to have a program that could be faster, cheaper, frankly, that's focused on a more severe type of patient with a higher mortality. And frankly, if that happen to be the first thing that gets to the market, that wouldn't be a bad way to show up at hospitals, right, in a highly specialized niche area to get people comfortable with that in a high mortality setting where you really fill a void there as you're developing the big heart failure. And frankly, that provides optionality to us because it is the type of program that Windtree, regardless of what we do with partnership across all these assets, can be of the scale that you can run right through. So we think it's very complementary in the area of cardiogenic shock with the foundational program of acute heart failure. And we're going to be doing -- the intention is to do both simultaneously.

Okay. Thank you, Craig. We did get another question in here. Can you please provide a time line as to when we can see the data in shock?

Steve?

Yes. As we mentioned, we're hoping to complete enrollment in this study before the end of the year. These patients have a 30-day follow-up, and we're pretty quick at getting a database locked and data ready to review. So we're looking at probably the middle of the first quarter for data to be ready for this trial.

Fantastic. All right. Thank you. And given the time here, I think we are out of questions. If there are any additional questions, please do feel free to contact me. I'm happy to answer those questions and follow up with the company. Craig, I will turn it over to you for closing remarks.

No. Once again, thank you, everybody. You're going to see us be pretty active on the IR and PR front as we're very active on the clinical front in advance of these impending milestones, data cards and so forth. And again, we're doing lots of business development. So appreciate everybody following us in these weeks to come as we prepare to get these milestones out. And we look forward to keeping everybody updated with all of our progress in development. I want to thank again Dr. Teerlink for joining us. He's a very busy guy with all of the leadership and all the things that he's doing in the clinic as well as across these areas of development and science. So thank you, Dr. Teerlink, and we look forward to keeping everybody up to date.