Welcome back, everyone. Next, we have Windtree Therapeutics, Inc., trades on the NASDAQ under the symbol WINT. It is a biotech company focused on advancing early and late-stage innovative therapies for critical conditions and diseases. Please welcome Eric Curtis, COO and Senior Vice President, as well as Steve Simonson, Chief Medical Officer. Welcome, gentlemen, to the conference today. Thank you very much. Hello, everyone. Welcome to our cardiovascular discussion today with Windtree. I'm going to be making some forward-looking statements today. Windtree is focused on patients with a failing heart in their moments of crisis, and we have a lead drug candidate called Istaroxime, or Ista for short. It's a first-in-class dual mechanism agent, and the first mechanism is designed to be able to strengthen the contraction, or the beat, of the heart, and the second mechanism is called SERCA2a activation, which really just allows the heart muscle to relax in between heartbeats so that it can properly fill the ventricles with blood in awaiting the next contraction, and SERCA2a has been a highly sought-after target, and Istaroxime is the first late-stage drug candidate that is a SERCA2a. To our knowledge, we are the only company that has a SERCA2a activating agent in late-stage development. Istaroxime has completed four phase II positive studies, treated over 300 patients so far. What we've seen has been very encouraging because we've seen generally consistent positive results across a wide spectrum of severity, many endpoints. The patients have been enrolled in many regions of the world in our clinical trials. The next thing I want to do is be able to familiarize you with our profile of Istaroxime. It's a very important part of our story. To do that, I'm going to take you back to the year 2019. That's when we acquired Ista in a merger and acquisition of a private biotech. At that time, Istaroxime was reading out a positive phase IIb acute heart failure study. We took these data to the FDA to share with them, and during that meeting, we picked up a Fast Track designation. We also had an informal discussion with the FDA about Ista's profile, and one of the things our medical reviewer mentioned was, given the profile of Ista, have you considered cardiogenic shock as a lead indication? Because we'll approve an agent that significantly improves blood pressure as a pivotal endpoint in a study, and again, these are things that will be confirmed in upcoming meetings and end-of-phase II meetings and so on, but it got us very excited because the prospect of this type of an endpoint is very straightforward, and it's not often you get an opportunity with a very straightforward, particularly in cardiovascular medicines today, in today's world, and so we were very excited about that. And we also were hearing very positive things from our scientific advisors about cardiogenic shock and Ista's profile. And we were hearing from them that they just weren't seeing other drugs doing what Istaroxime could do. And specifically, Ista, for patients that have low blood pressure due to a failing heart, it can significantly increase blood pressure. It can increase cardiac output, which is the amount of blood coming out of the heart. And it does so without racing the heart or increasing what's called the heart rate. And that's very unique and something that Ista actually most of the time decreases heart rate, which is because it's making a more efficient pump. And so that's very unique and very exciting. The other things that Ista does that are very nice to see are decreasing what's called wedge pressure. Steve will describe more of this, the lowering of heart rate, as I mentioned, and no significant arrhythmias, increase in arrhythmias, because this is something that we've seen now in repeated studies, and it's very, very encouraging, and the last thing I'll mention is something important because renal function or kidney function is important in heart failure patients because oftentimes these patients get excess fluid that builds up in their lungs due to the failing heart, and that's got to be cleared by the kidneys in the process of urination, but if the kidneys are damaged by a drug, this makes the situation much more complicated, but with Istaroxime, what we've seen is improvements in renal function and maintenance of those renal function, so that's been very, very positive. Now, what we've done as a result of all this learning and discussions is we've put everything behind cardiogenic shock for Istaroxime as our lead indication, and we've done this because there's been big needs for drug innovation in this area. It's a $1.25 billion global market valuation in 2020. We did this with U.S. hospital claims data and Epi data. We believe that by 2039, this will be a much bigger market, as you can see, about $3 billion or so, and we mentioned that there could be a positive, attractive regulatory pathway for approval, which is very nice to see. I'll also mention that our portfolio includes two families of next-generation preclinical SERCA2a activators. These are different drugs, and I'm going to show you now just the total portfolio. There you see Istaroxime in the lead position with cardiogenic shock. And also, we're interested in acute heart failure for Ista. And the Circuit 2A activators are next. And these are earlier-stage drugs, but they present particular opportunities. And you see the opportunities that I have listed here. Opportunity three is with a Circuit 2A activator called the dual mechanism. It has the same mechanisms of action as Istaroxene. And it could be a fast follow-on to Ista. If Ista's approved and used in acute heart failure, these dual mechanisms could be launched later on and very quickly follow suit for Istaroxene with a lot of learnings about how we get to where we need to go based upon everything we've done with Ista. Opportunity four here is a pure Circuit 2A activator, a separate category of Circuit 2A activation that will be used for chronic heart failure with preserved ejection fraction. And this would be an oral dosing as well. I failed to mention that the dual mechanisms are intended to have oral dosing as well and used in the outpatient setting to chronically dose the patient. Now, when we create value, we're looking for the remaining part of this year in 2025, finishing up some of the things. Steve will mention this about the cardiogenic shock study, which is a positive one called the SEISMIC Extension study, extremely positive and something we're very excited to be able to show you. We're going to execute a new study, a small study, which we believe will be the final piece of what we need to do to be phase III ready in this category for cardiogenic shock. We also want to support our licensing partner because through a business development transaction, we have a licensing partner for the region of Greater China. This pharmaceutical company that's based there wants to start up a phase III acute heart failure study at their expense as per the agreement. We're looking forward to that. We have very close communications with them to be able to make sure we approve of the protocol and the things that will be going on with that study. We're looking forward to that as well. We'd also like to secure additional licenses for Ista through business development transactions. We're working at that. Now, let me tell you a little bit about cardiogenic shock since I've been mentioning it. Let's start with heart failure because simply defined, heart failure is the inability of the heart to adequately pump blood so the body can operate the way that it needs to. But cardiogenic shock is a severe presentation of heart failure, so much so that the low blood pressure is causing a lack of blood flow to vital organs of the body. And this is a very medically urgent situation that really requires that these patients are put into an ICU, intensive care unit, or some other facility to be able to really monitor them very closely and treat them with great urgency. This is characterized by very low blood pressure. So ordinary systolic blood pressure, that's the top number on your blood pressure reading if you go to the doctor and get your blood pressure taken. Normal is 120. These patients are below 90, sometimes 80, 70, or even 60. And that lack of blood flow is what causes the high mortality rate of 20%-30% in classic shock. And again, this is something that is very serious. And these patients are generally already hospitalized when they experience cardiogenic shock. And as I mentioned before, the market valuation is shown here. And the potential pathway for regulatory is also attractive. Now, we were hearing a lot of things from our scientific advisors and reading the literature and understanding this market and cardiogenic shock that there was a need for innovation because existing therapies, drugs that are used here, have unwanted side effects and can have poor outcomes. And so we want to be able to really understand this better. And so we did some market research. We spoke to 100 U.S.-based clinical cardiologists who treat cardiogenic shock as part of their job responsibilities. And we asked them how much drug innovation is needed for cardiogenic shock. 99 out of 100 of those cardiologists said drug innovation is highly needed. And that is a very impressive result. I don't think I've ever seen 99 out of 100 cardiologists agree on anything at all, so very impressive. We went on to ask them how likely would they be to use Ista to treat their cardiogenic shock patients, and 84% of the 100 said likely to extremely likely, and the majority of those also, those 100, said it'd be the first thing that they would use in treating these patients, and so when you think about the reasons why it's an attractive indication to be in the lead for cardiogenic shock and Istaroxene, innovation is simply highly desired for this category, and we think about what's here. There's undesirable side effects involved and poor outcomes with the existing treatments in drugs, and the market size is certainly an attractive aspect of things, and the regulatory pathway, as I've mentioned, is something else to be excited about. And so, Steve, would you like to please take it from here? Sure. Thanks, Eric. What we found in our phase II program with Istaroxime is a profile for this compound that has been repeated in every study. And it's a very unique profile. Istaroxime's effects are characterized by an improvement in cardiac function, both the systolic or the squeezing component, as well as the relaxation component. We decrease cardiac filling pressures, which are characteristically high when someone comes in with shock and acute heart failure. We do not increase the heart rate. Increasing heart rate increases myocardial oxygen requirements and energy requirements. So we're able to do this very efficiently with Istaroxene. We have dose-related increases in systolic blood pressure, which is critical in cardiogenic shock. And we preserve or improve renal function. And this is also very important in patients with heart failure who are volume overloaded. And we need to use the kidneys to get rid of that fluid in the urine. Many of the drugs used to treat these patients now, or nearly all of the drugs, cause heart rhythm abnormalities. And so far in our phase II program, over 300 patients, we have not seen an increase in cardiac rhythm disturbances. And as I mentioned, we get rid of the pulmonary congestion, the fluid overload that these patients have that is the hallmark of acute heart failure, cardiogenic shock. Let me just say a quick word about how Istaroxene works because it's a very fascinating molecule. Ista is a small molecule that's given by continuous IV infusion to patients who are in the hospital. The first mechanism of action is to inhibit something called the sodium-potassium ATPase. And this results in an increase in calcium inside the cell, which produces a stronger force of contraction. The second and very unique element of Istaroxene is that it activates Circuit 2A. And Circuit 2A is a pump inside the cell that acts to sequester that calcium after a contraction takes place and hold it until it's needed to be released for the next beat. This makes the muscle relaxation more efficient. It contributes to better filling of blood in the ventricle for the next heartbeat and, again, puts the heart in a much better configuration for better functioning. So we affect both sides of the cardiac cycle, systolic and diastolic. As Eric mentioned, when we took control of this compound, we wanted to see if this drug had the horsepower to improve patients with very severe heart failure and cardiogenic shock. We embarked on a study called the SEISMIC study. We enrolled 60 patients with early cardiogenic shock due to heart failure. Their systolic blood pressure is between 75 and 90. We administered study drug for 24 hours. We compared two doses of Istaroxene to placebo. The primary endpoint was the systolic blood pressure profile over the first six hours of the infusion. We had multiple secondary endpoints around cardiac function, renal function, and safety and tolerability. Here's the primary endpoint of that study. The green shaded portion represents the effect produced by Istaroxene. The dark cross-hatched area is the placebo group. You can see that Istaroxene produced a rapid, consistent increase in systolic blood pressure from the time the infusion started, both clinically and statistically very significant. We also assessed cardiac function with echocardiography. We improved the cardiac output index substantially. It was due to improving stroke volume. Stroke volume is the amount of blood that the heart pumps out with each heartbeat. As I mentioned, Istaroxene does not increase heart rate. So we're not increasing myocardial oxygen requirements. We're doing it by getting more blood pumped out with each heartbeat. We also improved the cardiac geometry, which is important for proper heart functioning. Left atrial area was reduced. Left ventricular end-systolic and end-diastolic volumes were reduced. This contributed to the improved cardiac performance as well. After completing SEISMIC A, where we infused drug for 24 hours, we went into SEISMIC B because we wanted to dose Istaroxene for up to 60 hours and look at lower doses of Istaroxene as well to find what is the lowest effective dose for this drug. So we looked at 30 patients with early cardiogenic shock due to heart failure, systolic blood pressures in the 70-100 range, infused two dose regimens of Istaroxene, 1.0 for six hours, 0.5 for 42 hours. And then we did 12 hours of 0.25. The second Istaroxene group got 0.5 for 48 hours and then placebo for the final 12 hours. And then we had a placebo control group with dose regimens matched to the first two Istaroxene groups. Again, the primary endpoint was the systolic blood pressure profile over six hours, comparing Istaroxene, part A and B, to placebo. We did that because we're only enrolling 30 subjects. And we weren't sure that a small study would have the power to demonstrate statistical significance versus placebo. But you'll see in the effect size that we got from Istaroxene was so large and so consistent that even with a 30-patient study in SEISMIC Part B, most of our endpoints were statistically significant. The next slide here shows the primary endpoint of the study. On the left is the primary analysis endpoints, combined SEISMIC A plus B. And we had a very consistent and significant effect. The p-value is 0.007. On the right, you see that even though there were only 30 patients in SEISMIC B, the result was very clinically relevant, a 15- to 20-mm increase in systolic blood pressure. And it too was statistically significant. These graphs show the systolic blood pressure profiles looking out to 48 and 60 hours of dosing with Istaroxene. And you can see that Ista produces a consistent increase over placebo that's clinically meaningful and statistically significant. Pulmonary capillary wedge pressure assesses the filling pressures of the heart or how much backup of pressure there is because of the failing heart. And what you can see here in blue is that Istaroxene rapidly decreased these filling pressures and improved cardiac function. And this effect persisted out through the 60 hours of close monitoring on this parameter. This slide shows the wedge pressure again on the left, which is the filling pressure. On the right side is cardiac output or the forward flow from the heart. And these two pictures are really textbook of what you would want to see in a patient with acute heart failure and early cardiogenic shock. Forward flow has been improved. Cardiac function is improving. And on the left, the filling pressures of the heart are decreasing, reflecting the congestion is improving. We're getting rid of that extra fluid that they have and improving organ perfusion. As I mentioned, we do this without increasing the heart rate. In fact, there's a dose-related decrease in heart rate with Istaroxene. Again, that is a very favorable characteristic because it decreases myocardial oxygen requirements. Mixed venous oxygen saturation reflects how well our organs are being perfused. This measures the amount of oxygen in the blood that gets back to the heart. You can see the Ista in the blue lines here had an improved organ perfusion within 12 hours of starting the infusion. The separation began at the first time point we assessed at six hours, a very important endpoint to assess how well we're getting blood to the tissues. This slide shows the impact of Istaroxene on renal function. On the right-hand side, you see the combined SEISMIC A and SEISMIC B profile where Istaroxene significantly improves renal function over the 96 hours that we measured this, and on the left is just the patients in SEISMIC B. And again, the effect was even stronger in SEISMIC B than we had seen in the combined data group. With respect to safety, we're looking at the serious adverse events reported in SEISMIC B here. Our overall adverse event profile was very consistent with what we've seen in the program. Serious adverse events were rare in this study, but even more uncommon was the pattern that we saw of fewer serious adverse events in the Istaroxene group compared to the placebo group. Most notably, we had a decrease in the incidence of cardiac failure, worsening heart failure. All of these patients are at risk for that. And again, the numbers are small, but Istaroxene reduced that serious adverse event. There's a very exciting composite endpoint that we're also assessing as our program progresses. And there's three components to this composite. The first is worsening heart failure reported as an adverse event. The second is heart failure readmissions within 30 days. And the third is death within 30 days. And you can see here that Istaroxene in the blue substantially reduces that risk. It hasn't reached statistical significance because the program only has 90 patients being assessed here to this point. But if this effect holds up as we go through SEISMIC C in phase three, this will be a very important endpoint for the program, not only for the patients who don't want to experience those components of the composite, but for healthcare systems, for payers, and for the providers as well. So this summarizes our development strategy for Istaroxene. We did the SEISMIC study as a proof of concept in these more severe cardiogenic shock heart failure patients. We then went to the SEISMIC Extension to further refine our dose regimen and substantiate the effect in this population. We're now doing SEISMIC C, which is a study in SCAI Stage C, even more severe cardiogenic shock patients. These patients are so sick that not only do they have low blood pressure, but they have evidence of hypoperfusion to the organs and organ dysfunction related to that. So these patients will be treated with currently approved rescue therapies with all of the disadvantages and side effects that Eric mentioned. And then we will add Istaroxene to it. This is a study that will have a preliminary readout around first, second quarter time period next year and then a final readout later in the year, and after we get these two pieces of information in hand, we'll be in a position for an end of phase two meeting and phase three readiness to kick off that program. All right. Thank you, Steve. And so, Anna, I think we are ready for some questions if there are any? All right. Fantastic. Yes, we do. Talk a little bit about the fact that there aren't really other drugs pursuing development in cardiogenic shock because the opportunity seems very bright. Why aren't they? That's a great question. I think this boils down to the profile of Istaroxime really. In order to pursue cardiogenic shock as an indication in the development program, you really have to have the drug characteristics that are right to be able to help these patients because they are very sick patients in a spot where there's urgent effect is needed. Istaroxime does the things that are crucial for a cardiogenic shock patient to achieve, to get stable, and to get on their way to being discharged eventually. So I think it's really first and foremost that the profile of Istaroxime just happens to be really, really great at handling what needs to be done in a cardiogenic shock patient. Steve, would you add anything to that? No, I think you hit the nail on the head, Eric. In the past, others have tried to develop drugs in this space, and it's been difficult because they haven't had the profile that Ista does. They either increase heart rate and the risk for cardiac arrhythmias, or they decrease renal function, or in fact, increase mortality. We have not seen any of those with Ista, so it is the profile of Ista that is really allowing us to move forward in this space, and the lack of this profile is why others haven't been able to step in. This is really one of the remaining frontiers in cardiology, severe acute heart failure and cardiogenic shock. Could Windtree commercialize the U.S. with Ista in cardiogenic shock and partner with pharma outside the U.S.? That's something that in our business development discussions, we're going to continue to explore. Certainly, we believe that there would be a great opportunity to partner with a pharmaceutical company. The question becomes, is that a partnership that includes the opportunity for Windtree to co-promote in the United States or to have rights for the United States as opposed to a global license, which would be another alternative? We are open to all of those scenarios. I think it's something that when you look at the dynamics of cardiogenic shock, it's a very concentrated, specialized group of physicians that treat this condition. You're talking about maybe 3,000-4,000 hospitals that would be in the United States that would be the targets. A set of physicians that work there would be the folks to get to. And I think that from a medical and from just a commercialization perspective, it's a very doable scenario to have Windtree involved in the commercialization. And we'll see how this all plays out because we are in active discussions about business development options in terms of licensing and other things like that, which we're very pleased to say that there's good interest in that because we think these patients really deserve innovation. And we want to get it to them. Last question, what do you think your phase three program for Ista in cardiogenic shock would look like? Steve? Yeah. I think what we're seeing from our phase two program is that the approvable endpoint for phase three in cardiogenic shock is increasing systolic blood pressure. And we can do that with a very small number of patients. The size of our phase three program will be determined not by what it takes to show that blood pressure increase because we can do that in small numbers, but what regulatory agencies want to see to complement our safety database. So we're thinking our phase three program will be very similar in design to the studies that I presented today. The scope of that would be less than 500 patients, 300-400 patients in our phase III program to deliver the primary endpoint of blood pressure, all of the secondary endpoints that I reviewed today, as well as some of the health economic outcomes around length of stay and that composite endpoint that is very attractive, reflecting multiple characteristics of clinical importance. And Anna, if I could just tack on to that. Steve answered it perfectly. But I think in terms of also when you look at the valuation of something like cardiogenic shock, because it has a smaller size program for phase III, we believe, and the time that it would take to do that would be shorter than normal you would see in cardiovascular studies, the time risk, cost, and return of something like cardiogenic shock is certainly something that looks very attractive from a valuation standpoint. Fantastic. Thank you, gentlemen, for your time and presentation today. Important work you're doing. We look forward to seeing you in the new year. Thank you, Anna. Thanks, everyone. All right. We'll be right back.