Good afternoon, and welcome to the Tectonic Therapeutic KOL Event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentation. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the Tectonic website following the conclusion of the event. I'd now like to turn the call over to Alise Reicin, President and Chief Executive Officer of Tectonic Therapeutic. Please go ahead, Alise. Thank you, Tara. If we could go to the next slide. And before we begin on this slide, you'll see our standard disclaimer language. Statements in this presentation and on this call may be forward-looking, including our plans, objectives, and expectations for our TX45 program. These matters involve risks and uncertainties, and the company's actual results may differ significantly due to a variety of factors that are discussed in detail in our SEC filings. Next slide. And if we could go just to the agenda. So good afternoon, and thank you for joining us today. We're fortunate to have with us two outstanding cardiology thought leaders who are both a part of the steering committee for our phase II study of TX45 and Group 2 pulmonary hypertension in the setting of preserved ejection fraction heart failure The program's going to start with the review of Group 2 pulmonary hypertension, and that will be given by Dr. Ray Benza, followed by a review of relaxin physiology and its potential role as a therapeutic in the treatment of Group 2 pulmonary hypertension. Marcie Ruddy, our Chief Medical Officer, will provide a high-level overview of the program for TX45, which is our long-acting relaxin, including how the results from our phase I-B study might inform the phase II outcome, and after that, we'll open it up for questions and answers. Dr. Raymond Benza is a Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York City, where he's Assistant Director of Pulmonary Hypertension. He's a recognized world leader in pulmonary hypertension, and he holds administrative positions in the Pulmonary Vascular Research Institute and the International Society of Heart and Lung Transplantation. He sits on multiple journal editorial committees and is on the steering committee for several industry trials in pulmonary hypertension, including ours. And just I'll end for him by saying he has a terrific YouTube on Group 2 pulmonary hypertension for those of you who want a deeper dive into the disease. Dr. John Teerlink is a Professor of Medicine at UCSF and a recognized world leader in heart failure. Dr. Teerlink has served on the U.S. FDA Cardiovascular and Renal Drug Review Committee and also serves as an editor of multiple medical journals. He has served on the steering committee of multiple clinical trials, including, most importantly for today, he served as the lead clinical investigator for the serelaxin development program, which he will be discussing further today. We are thrilled to have both of them here today. With that, I'm going to turn the program over to you, Dr. Benza. Thank you so much for that kind introduction. It's a pleasure to be here today. We're going to review the pathophysiology and the mechanisms that are underpinning Group 2 pulmonary hypertension. As many of you know, there are several forms of pulmonary hypertension segregated into five broad groups. Each of these groups are distinctive in that the triggers that cause the pulmonary hypertension are distinctly different. The largest group of pulmonary hypertension that we see in our clinic is that related to Group 2 disease, and this is, whose trigger is related to problems with the left heart, and this can either be heart failure preserved ejection fraction or heart failure reduced ejection fraction or left-sided valvular heart disease like aortic stenosis, mitral stenosis, or mitral insufficiency. However, the largest growing group of patients with pulmonary hypertension within Group 2 are those with heart failure with preserved ejection fraction who share a plethora of risk factors, including coronary artery disease, hypertension, type 2 diabetes, and hypercholesterolemia. As we see later in this presentation, there are two forms of Group 2 pulmonary hypertension: combined pre- and post-capillary pulmonary hypertension and isolated post-capillary pulmonary hypertension. And we'll get into the definition of those a little bit later when we go to the next slide. When we look at all five of these groups of pulmonary hypertension, you can clearly see on this slide that the largest number of patients afflicted with this disease are those owing to left heart disease as their primary trigger. Seven out of 10 patients that I and others see in clinic will always have this form of pulmonary hypertension, making it the most prominent form that we see in the world. In fact, if you look at the global population of patients, and you can go to the next slide, if you see, if you look at the population of heart failure within the United States, you could see there are many people afflicted with this disease, and if we look at patients with heart failure reduced ejection fraction, you can see that pulmonary hypertension involves 40%-80% of these patients. When we look at patients with heart failure preserved ejection fraction, up to 52% of these patients will be afflicted with pulmonary hypertension, so one of every two patients with heart failure preserved ejection fraction will have pulmonary hypertension accompanying them as a very important comorbidity. If there are 5 million people in the United States with heart failure, 2.7 with HFpEF and 2.3 with HFrEF, 62% of all patients with HFpEF and 52% of all patients with heart failure with reduced ejection fraction will have pulmonary hypertension. That means there are about 1.7 million U.S. citizens with heart failure with preserved ejection fraction pulmonary hypertension and 1.2 million U.S. citizens with heart failure with reduced ejection fraction and Group 2 pulmonary hypertension. We know when pulmonary hypertension complicates congestive heart failure, that survival that's associated with that heart failure is much, much worse. We have a significant number of patients burdened with this disease within the United States who are at higher risk of dying related to the pH associated with their heart failure. So it's important to try to find new therapeutics to mitigate this comorbidity to improve survival with this very large population of patients. If we can go to the next slide. Now, pulmonary hypertension is a disease defined by hemodynamics. And I just wanted to show you this general slide because we make reference to a lot of these hemodynamics, both in my presentation and in John's presentation, and to really understand the magic, the way this new molecule works, you really have to understand some of the principles behind the way we measure pressures in patients with pulmonary hypertension. Now, we usually do this with a catheter called a Swan-Ganz catheter, which we can float into the right side of the heart and make various pressures within the right atrium, the right ventricle, and the pulmonary artery. So the right atrial pressure is usually the first pressure that we will glean. And this is a very important pressure because it really tells us how the right ventricle is responding to the pulmonary pressure that's exerting backwards in it from the pulmonary arteries. When we float our catheter out to the pulmonary artery, this is where we get the main hemodynamic profiles that affect patients with pulmonary hypertension by measuring their systolic pulmonary artery pressure, their diastolic pulmonary artery pressure, and their mean pulmonary artery pressure. And this mean pulmonary artery pressure is very important because this is how we define the disease. Pulmonary hypertension, as I mentioned, is a hemodynamic disease that is defined as a mean pulmonary artery pressure that's greater than 20 millimeters of mercury. Now, we can also put our catheter into what we call the wedge position and be able to measure the direct pressure that is coming back from the left atrium. And this is called a pulmonary capillary wedge pressure. This is integrally important when you understand how the disease of Group 2 pulmonary hypertension really propagates. It's because of an elevation of this left atrial pressure from these left heart diseases that I mentioned before that causes this backup of pressure into the pulmonary circuit and actually winds up damaging the pulmonary arterioles and thus causing the pressure and resistance. And that's the next important measurement that we get is the pulmonary vascular resistance. This is really the hemodynamic that measures the intrinsic remodeling of the pulmonary arteries or how severely that artery has remodeled into response to this chronic bathing and high pressure coming back from the left atrium. Now, we don't have a pulmonary capillary wedge pressure in everyone all the time. And so one of the easier resistance measures we get is the total pulmonary resistance, which only takes us to have the mean pulmonary artery pressure and the cardiac output. And we can tell resistance is very easily using that principle also. If we can go to the next slide. As I mentioned earlier, there are two forms of Group 2 pulmonary hypertension. There is isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. So what's the difference in these two? As you can see on the left portion of this slide, the number of patients isolated post-capillary pulmonary hypertension really makes up the biggest part of this pie, with those with combined pre- and post-capillary pulmonary hypertension making up a much smaller piece. Now, that doesn't mean that isolated post-capillary pulmonary hypertension is more important. In fact, when you have patients who have the combined form of pulmonary hypertension and Group 2 disease, these people have the highest mortality associated with pulmonary hypertension when it's in the context of heart failure. But the pathophysiology of these two forms is very distinct and different. In isolated post-capillary pulmonary hypertension, the pressure in the pulmonary arteries is a direct reflection of the pressure coming back at it from the left side of the heart. In other words, a high pulmonary capillary wedge pressure. And this very high pressure can be exerted back onto the right ventricle and cause the right ventricle to be dysfunctional. In combined pre- and post-capillary pulmonary hypertension, the mechanism starts out exactly the same from a very high left atrial filling pressure or high wedge pressure. But these patients have been bathed in this pressure for years and years. And as a result, this higher pressure in the arteries has actually caused the arteries to become structurally different. The media of these vessels, which is the muscular part of the vessels, has expanded. The intima, which is the inner lining of the vessel, has also expanded. And the adventitial layer, which is the protective outer coating of the blood vessel, has become very thick. And it makes these vessels very, very non-compliant and comprised of a very high resistance. If we go to the next slide. So the hemodynamic definitions of these two forms are very different. In isolated post-capillary pulmonary hypertension, we have a very high back pressure, again defined as the pulmonary capillary wedge pressure, but we don't have this remodeling. So the resistance in these vessels is actually very low and normal. However, in the combined precapillary and postcapillary variant, again, we have this very high back pressure from the left heart. But due to the chronicity and the ultra-structural changes in the arteries, the vascular resistance within these arteries becomes very, very high. And this is where the very, very high mortality rate is associated with this form of Group 2 pulmonary hypertension. Now, 2 Wood units may not seem a lot to a lot of people, but I'll show you in subsequent slides that this is very, very important. And we can move on to the next slide. As you can see here, there's a relationship between this elevated pressure in the left heart or the pulmonary capillary wedge pressure and mortality, as there is a relationship between the vascular resistance remodeling and mortality. But you can see that the differences in survival are distinctly different between the two hemodynamic principles. There's a very linear increment in mortality associated with higher and higher pulmonary capillary wedge pressures. However, when you look at resistance, there's a clear step-off in mortality when the pulmonary vascular resistance exceeds 2.5 Wood units. So most people, again, that seems like a very low resistance. But in actuality, when resistance exceeds that, mortality markedly increases. And this is why we've pushed back the definition of pulmonary hypertension or CpcPH to include those with these lower resistances because we want to capture them early in the disease so they don't have this step-off in their mortality. We can go to the next slide. This kind of shows us the kind of pathways that lead to these various forms of Group 2 pulmonary hypertension using heart failure preserved ejection fraction, again, which is really the largest growing form of pulmonary hypertension in Western nations and thus the highest number of patients that I see with Group 2 pulmonary hypertension. The triggers that cause this heart failure preserved ejection fraction are aging, hypertension, obesity, diabetes, coronary artery disease. What these triggers do to the left ventricle is they make it very, very stiff. The contractile function is still normal. The heart is squeezing normally. When they relax to fill with blood, they relax with a much, much higher pressure per volume that comes into the left ventricle. This is because these triggers have caused thickening of the myocardium, fibrosis of the myocardium, changes in LV geometry and shape. What this stiffness does is it causes a much, much higher pressure that occurs in the left atrium or, again, the pulmonary capillary wedge pressure. This increases markedly when these patients try to do something. Just imagine a very stiff heart trying to contract very fast. The heart's still not going to be able to fill like it is. All that backup of pressure winds up in the lungs and raising the pressure there. When this pressure raises in the lungs, we get that remodeling that I showed you earlier that changes the architecture of these pulmonary vessels, leading to their damage and to the higher resistance that builds up within these arteries, which ultimately cause the right heart to fail. This is how people die with this form of pulmonary hypertension. Next slide. So if you look at our patients' journey, particularly those with heart failure with preserved ejection fraction, they usually come to the doctor with very vague symptoms: usually exertional shortness of breath or shortness of breath at rest. Sometimes they have swelling, and they're often misdiagnosed with much more common diseases like asthma. Or because many of these patients are overweight, they attribute it to their obesity. And so a lot of these patients really are lost in the community for a long time until they really start to manifest severe forms of heart failure, which can be picked up on a chest X-ray or an electrocardiogram. Or if someone checks an NT-proBNP, which is a sign of cardiovascular stress, these people can be then recognized. Now, once these people are recognized, we often will get an echocardiogram to determine the extent to which their diastolic function is impaired, but also to screen for pulmonary hypertension. As I mentioned, this is very common in this disease. So often what we'll see on the echocardiogram is a preserved ejection fraction, but a very thickened heart, a very large atrium because it's succumbing to this high pressure that's coming from the left ventricle, and usually the systolic pulmonary artery pressures on the echo are very, very high. And this is where we make the tentative diagnosis of Group 2 pulmonary hypertension, and this typically leads to a right heart catheterization that allows us to define the severity of the disease and how badly it's affecting the right heart. And then we try our best to treat this stiffness of the left heart using conventional medicines like SGLT2 inhibitors, mineralocorticoid receptor antagonists, ACE inhibitors, ARBs, and ARNIs, and diuretics. But unfortunately, none of these medicines will affect the changes in those pulmonary arteries that I showed you earlier, which is why there is a need for medications to not only try to lower the wedge pressure in these patients, which is the trigger for the disease, but at the same time to try to remodel the pulmonary arteries, which I try to highlight in this next slide. So the management of then treating pulmonary hypertension is really one central mechanism, which is really trying to lower the left atrial pressure or the pulmonary capillary wedge pressure. And at the same time, try to manage the underlying substrate to try to make that left heart relax better or contract better by using the conventional four-tier therapy that we have for heart failure with reduced ejection fraction or heart failure with preserved ejection fraction. And once we manage the underlying substrate and try lowering that pulmonary capillary wedge pressure, if we still have a lot of remodeling or resistance in the blood vessels, that's when we try to induce vascular remodeling. And then the long-term phase of the disease is treating all three of these principles at the same time. So I hope that brief explanation of what Group 2 pulmonary hypertension is, its frequency, the relationship with heart failure with preserved ejection fraction, the importance of managing the pulmonary capillary wedge pressure, left atrial pressure, and inducing vascular remodeling and changing the resistance, how it could be very, very important to our patients. Thank you very, very much, Dr. Benza. We'll get questions. We're going to take questions for all of the speakers at the end. So at this point, I'm going to turn it over to Dr. Teerlink. Fantastic. Thanks so much, Alise. And you know, I had such a privilege to have the opportunity to work with Dr. Benza on this program. And I just returned from a CVCT meeting in Washington, D.C., the Cardiovascular Clinical Trials meeting, where there was an entire session, actually, there were multiple sessions on pulmonary hypertension and multiple emphases on Group 2 pulmonary hypertension. One of the learnings that came out of that, one of the messages came out of that, is that it was essential that in this area, there was excellent collaboration between heart failure specialists and pulmonary hypertension specialists. It was really a great message that I think we're actualizing in this program. In addition, I'll have to apologize for my casual attire. I'm in between procedures for this meeting. And I'll also apologize perhaps for my enthusiasm for this. I've been involved in dealing with relaxin for probably around 20 years, over 20 years now. And so I'd love to give an introduction. Hopefully, at least approximately, it is as erudite as Dr. Benza's. You know, so relaxin was discovered back in 1926. And it was first discovered in guinea pigs as a hormone of pregnancy that was there to relax the pelvic ligaments during delivery. And then it clearly was a pregnancy hormone and recognized as such for a very long time. And the receptor itself wasn't even discovered until 2002. In the late 1980s, 1990s, it was evident that it could also provide a role in cardiovascular disease. That will be the main emphasis of my discussion here. One of the things that's important to understand about relaxin as we move along in this program is its importance and rather unique characteristics from a cellular and molecular biology characteristic. The natural relaxin is the natural ligand of the RXFP1 receptor. One of the unique aspects about the relaxin receptor is that when it is stimulated by relaxin, unlike many other G-protein coupled receptors, it's not actually internalized. What that means is it can be repeatedly stimulated over time, and there should be no desensitization or tachyphylaxis that we've seen, that we notice. And along those lines, it makes sense because relaxin levels are increased for nine months during pregnancy, and there's no evidence of desensitization in humans. So we have a good experimental model in terms of all of those women who have been pregnant. As I've noticed, as I've mentioned, it's been upregulated in pregnancy, and it's highly conserved in mammals. And so anytime you have such a highly conserved gene, one needs to try to figure out, well, why would that be? And it's clear that it provides a very, very important role in pregnancy. It goes up within one to two weeks of conception. And after that, it then continues on to be elevated even after delivery. And the levels that are there are about tenfold higher than in normal levels for both men and women. Its main role initially, when it was first discovered, was in cardiovascular sense, was as a pulmonary and systemic vasodilator. And this has many beneficial effects in the setting of pregnancy, in as much as it allows the heart to adapt to the necessity of an increased cardiac output with providing the additional placental blood flow in addition to the normal systemic needs of the woman. It allows it to address kind of the increasing metabolic demands of the fetus, as well as protecting the lungs against this large volume and increased blood flow through the lungs that occurs. So that's its predominant role initially. But then as we learn more and more about its role in pregnancy itself, it also turned out to be an anti-fibrotic agent. It actually does some of what it did in the guinea pigs in terms of preparing for parturition, but it also protects against the stimulation and possible fibrotic effects of pregnancy that can occur. And then this generalizes as well to an organ protection effect in as much as it protects the heart, kidney, liver in the pregnancy from the increased reactive oxygen species, inflammation, and increased blood flow and shear stresses that occur during pregnancy. So that's the initial standpoint. And then when we look at, well, yes, please, next slide. Good job, Tony. So when we look at kind of where to go, how this applies perhaps to the beneficial effects of TX45, specifically in pulmonary hypertension with heart failure and preserved ejection fraction or PH-HFpEF, we can see that the vasodilatory benefits of relaxin or TX45 can translate into reduced pulmonary and systemic vasoconstriction. One of the unique aspects of relaxin is that part of its vasodilatory capacity is through an endothelin B receptor-mediated vasorelaxation. And this then allows there to be a selective or a specific decrease in vascular beds that are already perhaps pathologically vasoconstricted as occurs in heart failure and pulmonary hypertension. So this vasodilation can occur in both the pulmonary and the systemic vasculatures. And as I mentioned, is modulated both by nitric oxide as well as decreasing endothelin-1 A signaling and actually improving vasorelaxation through the endothelin B receptor. All of these vasodilatory effects also can result in decreased right ventricular and left ventricular afterload, which provide a hemodynamic stimulus for reverse remodeling. As in heart failure patients, there is adverse remodeling with increased pathologic hypertrophy and ventricular dilatation on both the right and the left sides. And this provides the opportunity to actually reverse, provide that reverse remodeling from a hemodynamic standpoint. Then when we look at the possibilities of what TX45 can do with respect to the heart, relaxin acts as a lusitropic agent, actually increasing ventricular relaxation or improving diastolic function of the heart. And this has been demonstrated in multiple animal models and would translate into an improved left ventricular diastolic function, which would then get at one of the root causes, as Dr. Benza very eloquently described, of this heart failure with preserved ejection fraction related pulmonary hypertension. It's going to the root of the cause of the problem by trying to address left ventricular dysfunction. In addition, TX45 or relaxin is an anti-fibrotic agent. It increases the matrix metalloproteinase as well as decreasing TGF-beta signaling. One of the things that actually emerged from the CVCT conference was the important role of inflammation in this process, in the process of PH-HFpEF. It is important to know that relaxin can also be an anti-inflammatory agent. All of these factors, when working on the heart specifically, can result in reverse in a cellular reverse remodeling by reducing fibrosis and improving the compliance characteristics of the ventricle on a cellular level. In addition, the beneficial effects of relaxin or TX45 can translate to the renal system, the kidney system. In this area, it improves renal blood flow, but also provides direct kidney protection as organ protection, we believe through mechanisms of anti-fibrosis, anti-inflammatory, and protection against reactive oxygen species. All of these can result in improved sodium excretion, which is obviously also very important during pregnancy, as well as ultimately translating into reduced right ventricular and left ventricular preload. Hopefully, you can see how all of these combined can result in potential beneficial clinical improvement. Let's go to the next slide. So apologies because that last slide was rather long and complicated. So this is a very kind of direct discussion of how that might translate. The relaxation or vasodilatation related to relaxin and the anti-fibrotic and anti-inflammatory effects of relaxin have multiple ways that they can actually produce disease modification in PH-HFpEF. So this isn't just making a patient feel better, but actually potentially changing the course of disease. And when you look at the characteristics of PH-HFpEF, you can have pulmonary arterial narrowing, thickening and stiffening, and fibrotic remodeling, as Dr. Benza related. relaxin can change those by both directly through providing vasodilation as well as anti-inflammatory, anti-fibrotic remodeling effects. Similarly, relaxin or TX45 can have the same effects via the same mechanisms on the left and right ventricles. And so there can be that beneficial effect on both sides of the heart. In addition, the compromised kidney function, which is part and parcel of heart failure with preserved ejection fraction, you know, it's now we're thinking much more of cardiorenal disease, especially in the HFpEF area. And relaxin or TX45 can directly improve kidney function and natriuresis. So these things we believe are why TX45 can improve the outcomes of these patients with PH and HFpEF. We can go to the next slide, please. What is there some clinical evidence to support this? In fact, there was the program that I was very involved with, with serelaxin, which was a recombinant human relaxin that was administered intravenously. In this very nice hemodynamic study, 71 patients with acute heart failure who were enrolled in this hemodynamic trial 48 hours after presentation for acute heart failure, all of whom had to have a wedge pressure above 18 millimeters of mercury or 18 millimeters of mercury or above, were then given an infusion of serelaxin. This relaxin demonstrated a significant decrease in pulmonary capillary wedge pressure. This means it reduced the filling pressures of the left side of the heart, reducing some of the instigating factors in this acute setting for the pulmonary hypertension. This translated to the middle section where we looked at the change in mean pulmonary artery pressure, which once again, in the serelaxin group, which is represented by the orange line, was significantly reduced compared to the patients who just received placebo. So a rather dramatic decrease in the mean pulmonary artery pressure. And then, as Dr. Benza also referred to, he talked about the pulmonary vascular resistance. Now, he used the term Wood units. And Wood units, if you take Wood unit and multiply it by 80, that gives you dynes per second per centimeter to the fifth power. So in fact, that 160 is equivalent to 2 Wood units. So already, all of these patients in this acute setting have significant elevations in their pulmonary pressures. And what you see is the patients in the placebo group were now easily 2.5 -ish Wood units. Those patients, excuse me, actually closer to 3.5 Wood units. Those patients who were treated with serelaxin had a marked decrease in the pulmonary vascular resistance. This was in the setting of acute heart failure. This trial result demonstrates what can happen in this mixed picture because obviously patients in this program had both isolated and combined pulmonary hypertension. Let's go to the next slide, please. How did this translate, at least in the acute heart failure setting, to any clinical outcomes? These are some of the RELAX-AHF, these are all the RELAX-AHF clinical trials. The one on the bottom is the earliest and then progressing to the latest to the top. In pre-RELAX-AHF, we saw already a small signal based from five events versus 13 on a potential benefit in terms of reducing worsening heart failure. In fact, across the whole program, there was a 23% reduction in the risk of worsening heart failure at day five in these patients with acute heart failure. And this is highly significant across multiple programs. Now, there was the program, the RELAX-AHF 2 program, which is the program that was a 6,000 patient plus trial. And it did not meet this as an endpoint in terms of worsening, improving worsening heart failure at day five. And that was largely because the trial was focused as a mortality trial. And I do believe that kind of operational challenges and site selection interfered with us being able to selectively look at that specific endpoint. I'll also point out that RELAX-AHF, the second from the bottom in that list, was a phase III trial that met its primary endpoint of improving dyspnea. So we already had evidence of this agent of relaxin in this setting, improving patient outcomes not only in terms of their symptoms, but also in terms of their clinical outcomes. We can go to the next slide. So we heard a bit about the theoretical reasons why we think, you know, there should be an evidence of organ protection. And across the whole trial, the development program, we saw a significant decrease in creatinine compared to placebo in the relaxin-treated patients. And this decrease was highly significant across the board. In pre-RELAX-AHF, it did not hit that top, did not hit that value, but that's because we actually, it was a dose-finding study where the highest dose did actually cause some renal dysfunction, but that was almost two orders of magnitude higher than the level that we use in the trials. And this beneficial effect was still there at day five. So this is demonstrating that actually there is this beneficial organ protective effect with relaxin in the setting of acute heart failure. Parenthetically, there were also improvements in troponin, so evidence of cardiac protection, as well as left ventricular, sorry, left liver function tests, which showing hepatic protection and decreases in uric acid, showing which is one of the markers perhaps of inflammation. So we have actually real live clinical data to suggest that these protective effects are real. Let's go to the next slide, please. So when we first did pre-RELAX-AHF, we saw three events, three deaths in the serelaxin group and eight in the placebo group. And we said, well, that's interesting. But how can actually a two-day infusion of serelaxin decrease 180-day mortality? And we weren't really sure that it could. But the RELAX-AHF program did in fact show a significant decrease in all-cause mortality, a rather significant one of almost 37%. Because of this, many drove the RELAX-AHF-2 trial to have an all-cause mortality endpoint as the primary endpoint. And it did not meet this endpoint. But it still, when you look across the whole program, there is this suggestion of an improvement in mortality. Now, I'm not going to try to convince you to say that the two-hour infusion of serelaxin can actually improve long-term mortality. But I will suggest that it provides incontrovertible evidence of its safety in this very sick patient population. So I think that provides a very good kind of background on the evidence that exists so far with the relaxin program. We can go to the next slide. I hope I was able to elucidate for you some of the reasons why all of these pleiotropic effects of relaxin can increase the probability of success of TX45 in the setting of PH with HFpEF. It acts as a pulmonary and systemic vasodilator. It directly improves LV diastolic function and may improve RV and LV function and remodeling. It has anti-fibrotic and anti-inflammatory activity. While I applaud this group for going forward in PH for heart failure and preserved ejection fraction, I also strongly believe that TX45 could be very reasonably evaluated and very likely to be beneficial in multiple other therapeutic areas, including pulmonary hypertension related to heart failure with reduced ejection fraction and heart failure with preserved ejection fraction in and of itself, as well as heart failure with reduced ejection fraction in and of itself. Also its kidney protective effects, I think, are very reasonable to study in other contexts. I look forward to any questions that might emerge from this discussion, Alise. Thank you, Dr. Teerlink. I'm going to now turn it over to Marcie Ruddy, who's Chief Medical Officer at Tectonic. Thanks, Alise. I'll now take you through our development program in the next few minutes. As you know, TX45 is our long-acting Fc fusion protein, which has a half-life of approximately two to three weeks. This is a major difference from serelaxin, which had a half-life on the order of hours. We also think the half-life of TX45 distinguishes us among the other long-acting relaxin therapeutics currently in development. TX45 is formulated at 150 milligrams per mL concentration, which is suitable for subcutaneous administration. This allows us to comfortably administer a 300 milligram dose with a single 2 ml injection. While we believe that TX45 could be a pipeline and a product, the first indication we are exploring is the treatment of PH-HFpEF. Next slide, please. Here's an overview of our ongoing clinical development program for TX45. Our phase I trial is complete, and top-line data was presented at the American Heart Association in November. We are currently enrolling in both our I-B and phase II studies in patients with PH-HFpEF. Next slide. As detailed in our AHA poster, which you can find on our website, our phase I-A single ascending dose trial in healthy volunteers demonstrated that TX45 was well tolerated. We also define the half-life of TX45 to be approximately two to three weeks. The PK profiles by dose are depicted in the lower left figure. On the lower right, you can see the PKPD data from our trial. In this figure, the x-axis is TX45 concentration, and the y-axis is percent change from baseline in renal plasma flow. There are over 200 data points in this model from repeated renal plasma flow measurements at multiple time points post-dose for each subject across all dose levels. A robust nonlinear mixed effects Emax model was developed from these data. The Emax effect was determined to be a 33% increase in renal plasma flow, consistent with what has been demonstrated previously for this mechanism. This model then allowed us to select pharmacodynamically active subcutaneous doses for our phase II study. Our 300 milligram Q4 week dose will provide a steady state trough exposure of approximately 2.8 micrograms per ml, an exposure providing an EC80 at trough on renal plasma flow. This exposure is above the level associated with maximal efficacy in our chronic animal models of pulmonary hypertension, which was approximately 2 micrograms per ml. Our second dose, the 300 milligrams Q2 week dose, provides a steady state of exposure of approximately 8.6 micrograms per ml, which is greater than an EC90 at trough. We believe this dose should be maximally agonizing the RXFP1 receptor throughout the dosing interval, and therefore we consider this our no regret dose for capturing all potential efficacy of this mechanism. Next slide, please. As Dr. Teerlink showed you just a few minutes ago, serelaxin decreased both wedge pressure and pulmonary vascular resistance by approximately 15%-20% in the first eight hours of treatment in the setting of acute heart failure. Our phase I-B safety and hemodynamic trial is designed to explore the safety and acute hemodynamic changes of TX45 in patients with PH-HFpEF. We are looking to demonstrate hemodynamic changes consistent with an improvement in both left ventricular and pulmonary vascular dysfunction. We've enrolled both CpcPH and IpcPH patients in this trial. A simplified version of this trial is presented here. On day one, patients have a right heart catheterization and baseline hemodynamic measurements are obtained. We administer an IV dose of TX45 to quickly achieve maximal exposure levels. We then follow the hemodynamic effects of TX45 by repeated measures over eight hours. After this procedure, patients are discharged and followed for 29 days post-dose. Next slide, please. Sorry, excuse me. We're also currently enrolling in our phase II study. APEX is a 24-week study of patients in PH-HFpEF, which is enriched for patients with CpcPH. Our trial is designed as follows. After obtaining baseline hemodynamics via our right heart catheterization, patients are randomized in a one-to-one-to-one manner to receive subcutaneous dosing regimens of either placebo, 300 milligrams of TX45 Q2 weeks, or 300 milligrams Q4 weeks in a double-blind, double-dummy manner. After 24 weeks of treatment, patients will have a repeat hemodynamic assessment. Our primary endpoint is changed from baseline in pulmonary vascular resistance, and a key secondary is changed from baseline in wedge pressure. We are also assessing TX45's treatment effect in six-minute walk distance, though we're not fully powered in this study on that endpoint. We're aiming to have pipeline data from this trial in 2026. So next slide, please. Before we go to an open Q&A, I thought I would address a couple of questions that I'm sure you're going to ask. What would we consider to be a win in our phase I-B trial, and why do we think these data would increase the chance of future success, knowing that improvement in six-minute walk distance will be the registration endpoint for PH-HFpEF indication? As you heard earlier today, we believe that a successful therapy for PH-HFpEF should improve both left ventricular and pulmonary vascular dysfunction seen in these patients. We think it's important to demonstrate that TX45 lowers wedge pressure on the order of 15%-20% because improvement in wedge pressure has correlated with improvement in exercise capacity in trials of successful therapies for both HFpEF as well as HFrEF. In addition to lowering wedge in patients with CpcPH PH-HFpEF, we're also looking to lower PVR on the order of 15%-20%. Patients with IpcPH have near normal or normal PVR, so it may not be possible to see an improvement in PVR in that subgroup. As we have no successful therapies for PH-HFpEF, there is little data to tell us exactly how much lowering in PVR will translate into improvement in exercise capacity for this population. However, we know there's an important link between the two, as demonstrated by many successful trials in pulmonary arterial hypertension, or PAH. Across multiple mechanisms, therapies have demonstrated lowering of PVR on the order of 15%-20% is associated with a clinically significant improvement in six-minute walk distance in patients with PAH. For PH-HFpEF, however, lowering PVR alone is not enough to provide efficacy, as has been demonstrated in many failed trials looking to repurpose PH therapies for the PH-HFpEF population. Lastly, in this study, we are looking to explore the impact of TX45 on total pulmonary resistance, or TPR, which Dr. Benza mentioned earlier. This endpoint would be relevant for both the IPC and CPC patients. A reduction in TPR would be an indication that we have reduced right ventricular afterload, which should be an important indicator of improving exercise capacity in this condition. The limitation of this measurement, however, is that we're not aware of extensive literature linking this endpoint to changes in six-minute walk or outcomes. So, Marcie, this is John. Yeah, John. Sorry. I think I failed to kind of push this or emphasize this during my talk as well, because it's clear that if you hit a 15%-20% improvement in these, that's fantastic and clearly demonstrable of a compelling finding. I guess I would also remind folks that that 15%-20% is coming from an acute heart failure trial where you expect actually a lot of dynamic response in that setting, and in this setting of non-acute heart failure patients, I would actually be more comfortable, very comfortable with a 10%-15% change still demonstrating a meaningful and a go-forward type decision, but that's obviously, I don't write the checks. So anyway, I just want to add that perhaps here. That's really helpful, John, because as I said, there's not a lot of data in PH-HFpEF. What we've done is leverage what we know about, for example, PH-HFpEF in general. So why do we think 15%-20% decrease in wedge pressure is a reasonable target? Let's go to the next slide. A large registry study in PH-HFpEF concluded that elevated wedge pressure is the only hemodynamic parameter that predicted limitation in six-minute walk distance, and we know elevated wedge pressure is also shown to correlate with worse outcomes. We also know through the development of successful treatments for PH-HFpEF, lowering wedge pressure is associated with an improvement in exercise capacity, so, for example, trials with SGLT2 therapies have shown that a 20% decrease in wedge resulted in approximately a 20% improvement in six-minute walk distance. Now, these were trials in PH-HFpEF and did not specifically look at patients with PH-HFpEF. We hypothesize that addressing the pulmonary hypertension component of PH-HFpEF may further improve exercise capacity and outcomes in this population. Next slide, and there is some data with PH-HFpEF on the association of hemodynamics and exercise capacity as assessed by six-minute walk distance. In a registry of patients with PH-HFpEF, multiple hemodynamic parameters, including wedge pressure and PVR, correlated with six-minute walk. In the same registry, six-minute walk distance was also an important predictor of outcomes, including heart failure, hospitalizations, and death. Lastly, concomitant decreases in both wedge pressure and PVR were associated with a marked improvement in six-minute walk distance in CpcPH-HFpEF patients undergoing an experimental surgical procedure known as pulmonary artery denervation, or PADN. In the PADN-5 trial, patients with CpcPH-HFpEF who received the procedure demonstrated a decrease in wedge of about 19% and a decrease in PVR of about 30% as compared to patients who received a sham procedure. These changes were associated with a large increase in six-minute walk distance. Next slide. In summary, we believe that TX45 has a best-in-class profile. It is a long-acting relaxin-Fc fusion protein with optimized biophysical properties. It has demonstrated an appropriate pharmacodynamic activity on renal plasma flow in our phase I-A trial. We will present our top-line data from our phase I-B hemodynamic study in late 1Q, early 2Q 2025, and we expect to deliver data from our APEX trial in 2026. We believe that if our phase I-B study achieves our hemodynamic targets, these data should enhance the chance that six months of treatment will provide meaningful improvements for patients in our APEX trial and translate into improvements in exercise capacity as measured by six-minute walk distance in our later stage studies. With that, I'll turn it back over to Tara for Q&A. Thank you. Great. Thank you, Marcie. So, at this time, we'll be conducting a question-and-answer session with our speakers. So, as a reminder to the audience, if you'd like to submit a question, please use the Q&A text box at the bottom of the webcast player. Please hold for a brief moment before we pull for questions. So, our first question comes from Tyler Van Buren at TD Cowen. Please go ahead, Tyler. Hey, guys. Thanks very much for the presentations. Those were very informative. And to Dr. Benza and Teerlink in particular, I guess you guys were pretty clear about the potential, the expectations for the PVR and wedge pressure readout. But I guess in general, for Dr. Benza and Teerlink, do you believe TX45 is more likely to be successful in IpcPH or CpcPH? What population do you think is most attractive for TX45 development? So, I'll ask either Dr. Benza or Dr. Teerlink. Either one of you want to comment on that? I think it'd be an excellent therapeutic for both forms of pulmonary hypertension because we're expecting drops in wedge pressure and even improvements in diastology. I think this will be very, very helpful in patients with isolated post-capillary pulmonary hypertension. What I'm most excited about, though, even though that is the larger population that we see, is that the patients who have combined pre-capillary and post-capillary pulmonary hypertension, remember, this disease is as deadly as idiopathic pulmonary arterial hypertension with a 2.5-year mortality, 2.5-year life expectancy after diagnosis. This is a really serious disease, and we have nothing to treat it. And so, if this drug is successful, which I feel it is because of its characteristics and vascular remodeling, this will be a huge push forward for us in our disease state management. Dr. Teerlink, anything you want to add? Well, that was brilliant. And I agree with it as well. You know, I think, so for me, by more of the patients that I treat have the isolated, but the patients that are harder to treat are the patients with the combined. So, it would be a fantastic boon to be able to treat all the patients that I see with the isolated pulmonary hypertension in this setting of PH-HFpEF, but it would be a really tremendous advance forward in terms of overall therapeutics in this area to be able to take care of the combined patients. But I really believe, and hopefully I was able to express that why I believe that it should be effective and helpful in both groups. Okay. And just a second question. Again, you guys were so clear with the eight-hour hemodynamic measurement and what to expect there and how that translates to PVR and ultimately long-term outcomes. But as I understand it, I think there's going to be observations and visits up to 29 days in this study. So maybe you could just elaborate on what additional observations there will be in these patients and what you might hope to see up to 29 days. Yeah. Tyler, we are doing echocardiograms in the phase I-B study at various time points. But as evidenced by the variability in echo, I don't, you know, if we're very lucky, we'll see changes there. But until we see the variability, I don't want to make any promises about what we could see. The other thing is some of the patients were treated at lower doses that might not have exposures that are high enough to go out to day 29. So we'll be limited only to the patients who received the higher doses of the drug for those analyses. Marcie, I don't know if you have anything else you want to add on. No, we're following biomarkers as well, looking for trends and changes. But again, it's a small study, so it's very exploratory, some of the things that we're looking at. And of course, we're following for safety out to 29 days as well. Okay. Great. Thanks again for the presentations. Thanks for the questions, Tyler. So our next question comes from Edward Tan at Leerink. Please go ahead, Edward. Hi. Great presentation. Thank you for taking our questions. So on behalf of David Risinger from Leerink, I would like to ask, so can you provide your perspective of using PVR as an endpoint in phase II for both IpcPH and CpcPH patients? Thank you. So, Edward, I can comment on that. You know, right now, our phase II study, like all studies with pulmonary hypertension, has PVR as the primary endpoint. And we're going to, once we get our phase I-B data, we'll reassess that and choose what we think is the best endpoint for our phase II study. But if any of our thought leaders want to comment further on that, I think it'll bring down PVR in both populations, but I think you're going to get a floor effect in the IpcPH population. So we're going to have to see the magnitude of effect we see in the phase I-B in the overall population. Dr. Benza? I think what Marcie said, that, you know, in that trial, we are actually enriching for patients with CpcPH, which is why it's vitally important to have the PVR as the endpoint. We'll get a lot of information about the pulmonary capillary wedge pressure in these patients because it's often very elevated also. But the PVR was going to be the key thing because of that enrichment population that we had. Thank you. If I can ask another question, could you please compare and contrast, so Tyler says, mechanism of action and the utility in CpcPH relative to TX45, please? Thank you. Okay. I don't know if I can take a shot at that unless either one of our experts are familiar with. So, Tyler, Dr. Benza, do you want to start on that? Ray is very familiar. Yeah. The mechanism is very different. There's no similarities between the way two drugs. However, the end result is similar. You will get regression of the media of these vessels. You'll get regression of the adventitia of the vessels, and you'll get the same sort of vascular remodeling that sotatercept purports it does in patients with elevated PVRs. I guess I would just... Yeah, go ahead, John. I guess I would just add that it's not clear to me that the activin approach is going to be as active in the other organ protective effects that we see with the potential from relaxin. So I do agree that they both are really targeting very beautifully the pathophysiology within the pulmonary vasculature. But I really think both of these. We always think of, you know, I'm a heart failure doctor, and so you think of, well, it's the heart that's the problem. And people who are pulmonary hypertension, some people go right to the pulmonary thing. But both of these are actually systemic diseases. And having something that actually works very effectively systemically will also be important in this setting. And the other very important difference is that sotatercept does nothing to the myocardium that we know of right now. And that's a very important difference. Remember, we're treating with this new therapeutic both the substrate and the resulting vascular disease. So it's really a great combination of the two. Sotatercept works primarily just on the vasculature. So again, very, very different mechanisms of action with this particular new therapeutic favorably affecting both the substrate and the vascular tree. And lastly, just to comment, because they are such different mechanisms of actions, you would expect very different safety profiles. Yeah. I'll just point out a few things. And Dr. Benza, and Dr. Teerlink, first of all, there's no vasodilatory effect of sotatercept. So if both agents, for instance, worked, I think you'd get an onset of action that would be sooner because you'd get the vasodilatory and the lusitropic effects of ours. That may be one differentiator on efficacy. On safety, and hopefully Ray and John, please feel free to contradict me if my numbers are wrong, but the literature suggests 30%-60% of patients with PH-HFpEF have atrial fibrillation and therefore might be on anticoagulation. There may be some concerns about the use of sotatercept in patients on anticoagulation because some patients drop their platelets and the telangiectasias. sotatercept also can raise blood pressure, which is not an issue in PH patients, but could be an issue in patients with PH-HFpEF. Yeah. I think, you know, the point in terms of the safety profile of the relaxin agents or that, you know, we have billions of women who have had very high levels of relaxin for nine months during a particularly susceptible time period. And while the pharmacologic concentrations are a little higher, they're not that much higher. I think it's an important thing to try to take into account that we already have a lot of safety data with that. In addition, relaxin may improve atrial remodeling as well. It may, in the patients with PH-HFpEF, either decrease the burden of atrial fibrillation and perhaps even prevent the development of atrial fibrillation. Now, that's a very forward-looking statement, but there's certainly good biological plausibility for why that might be the case. And that certainly would not be the case with cytotoxic. Very, very helpful. Thank you. Thanks for the questions, Edward. So our next question comes from Yasmeen Rahimi at Piper Sandler. Please go ahead, Yas. Good afternoon, team. Thank you so much for the insightful discussion, especially from our experts. I guess the first question is, you know, the 1b that we're awaiting for as well as the APEX studies in PH Group 2, what could we be looking at in terms of signals out of these two studies that could give us confidence to really, for this mechanism to work in PH-HFpEF or PH-HFpEF in a broader population? Like, what should we be, you know, awaiting for? That's sort of question one. Question two is, you know, I think the thought around the utility of, you know, I think we have spoken a lot about six-minute walk tests, but if the expert could talk about KCCQ and what could be clinically meaningful differences in this PH Group 2 patient could be helpful. And then if I can squeeze a third question in that we're getting from clients always is, what would, in the expert's opinions, their view be on a registrational path? I appreciate to get color on these three questions. Okay. Why don't we take the second question first, and then we'll go to the third question, and we'll go to the first question. So the second question was, I think, views on KCCQ. Wait, Yasmeen, give me the second question again. Yeah. Yeah, that's right. KCCQ, we talked about what we want to see in PVR, but maybe six-minute walk test. We have a good understanding, but what do we want to see in KCCQ in this population, even if it's a trend? Okay. Dr. Benza, Dr. Teerlink? Well, as you know, the KCCQ is closely associated with outcome in patients with congestive heart failure. And because we expect to see improvements in pulmonary capillary wedge pressure as well as resistance, which often translates into improvement in functionality, I would think that the KCCQ would improve with these patients because they're less breathless, they're walking further, and their quality of life will be improved. And I would agree with that. There are a couple of caveats with the KCCQ. We've worked with John Spertus for years on this in multiple different clinical development programs and trials. It is a kind of an adage that it's hard to make an asymptomatic patient feel better. And so when somebody has a KCCQ, the KCCQ is a score that goes from zero to 100, with 100 being absolutely doing perfectly and zero being close to dead. And so we found that in patients who start out with KCCQ scores above 80 or so, it's difficult to move them much oftentimes. So you have to. It also depends on kind of your patient mix in terms of what you expect in terms of the responders within your study group. The other thing that's emerged is, at least in the heart failure community, we've considered the minimal clinically important difference to be five points on the KCCQ. It turns out that most of our lifesaving drugs in heart failure that clearly improve patients' outcomes and feeling, and they do great, have a KCCQ improvement of about one to two points. And then you have that compared to what happened in TRILUMINATE, the tricuspid regurgitation, which was an uncontrolled trial, and there they had 30-point improvements. So from a regulatory perspective, the FDA is moving more and more towards saying, well, you have to do an internal anchor for your own trial in terms of determining, well, what is the minimally clinically important difference? The challenge with that, though, is that especially if you have a smaller trial, that is going to be a very wide variability. And so it makes it hard for folks like you who are trying to decide go, no-go investment decisions to say, well, what's really enough? But during one of the major heart failure endpoint meetings that we had with the FDA, there was public discussion of functional endpoints. There was a very strong argument to say, well, if you just improve it by one or two points, that should be good in a large enough trial. So we aren't really sure what the—for this specific program, I at least am not sure what the right answer would be in terms of the number of KCCQ that would be, you know, clearly good in terms of the minimally clinically important difference. But any improvement, I think, would be showing an impact of the therapy on the patient's well-being. And I don't know if that helps clarify or muddies it further. Happy to ask if you have a clarifying question on what I just said. That was very helpful. Do you want to comment, Dr. Teerlink, Dr. Benza, on registration path? I'm sorry, say again, Alise. I think she was asking, Yasmeen was asking about the registration path. And I'm happy to comment on the interactions we've had with the FDA on that. But I don't know if you want to comment or Dr. Teerlink wants to comment first. You know, I think I'd leave that to one to you. So I think, Yasmeen, as you know, we have had communications with the FDA. Six-minute walk test is an approvable endpoint. Clearly, there are other things that we would consider including the KCCQ and maybe even some sort of composite endpoint in our phase III program. But I think we got to first get through phase II, and that'll help us define the phase III path. Great. Thank you. Thank you so much. Thanks for the questions, Yas. Our next question comes from Danielle Brill at Raymond James. Please go ahead, Danielle. Hi, good afternoon. Thank you for this event, and thanks so much for the questions. I have a couple of diverse questions. First, I wanted to ask on the antifibrotic effects. What clinical measure that will be implemented in the trials is most sensitive to detecting changes in cardiac fibrosis, and what's an appropriate time course to start seeing the antifibrotic effects? And then on the enrollment criteria for the KOLs, do you view there to be any risk in enrolling PH-HFpEF patients down to a 40% ejection fraction? How might patients with high or low ejection fractions respond differently to relaxin? Thank you. I think that the antithrombotic effects in the pulmonary vasculature are best going to be assessed by looking at hemodynamic variables like the pulmonary vascular resistance, the total pulmonary resistance, and the elastance, all of which will be gleaned from the right heart catheterization. As far as what we see in the heart, we're doing echocardiography, and we'll be able to look at a variety of measures of diastology that should correlate with improvement in ventricular stiffness. Those are some of the things that we'll be looking at. In terms of your question about, I believe, safety of the drug with lower ejection fractions, I don't foresee an issue with this. Most patients with heart failure with reduced ejection fraction also have problems with diastology. In fact, many of the patients that we see who have pulmonary hypertension already have almost restrictive physiology, which is a result of a fibrotic process in the heart, and so again, changes in diastology would be very helpful in assessing that. Yeah, and as an echo lab director, I will say that, you know, the measures of diastology in cardiac function are challenging in as much as you really need many numbers to be very confident in those. Those measures tend to be highly variable, and so you need, I will prepare people for having to look, hopefully not having to look, but we'll end up looking at trends rather than very significant definitive changes in that. If you do see definitive changes, that will be very remarkable and very impressive. The other thing I'll point out is that almost all of the heart failure with preserved ejection fraction trials have now been using and including heart failure with mid-range or mildly reduced ejection fraction, so 40% or above, and most of the agents that have been demonstrating to be beneficial in this setting have not shown a differential effect across that ejection fraction spectrum, so I think it's actually a really good idea to include these patients. It's opening up the potential for helping a larger group of patients who are in need of these kinds of therapies. Great. Thank you for the questions, Danielle, so our next question comes from Tiago Fauth at Wells Fargo. Please go ahead, Tiago. All right. Thanks for taking the question. I just want to go back to the debate of the phase I-B. So here's how to think about the extrapolation of the eight-hour hemodynamic models into the phase II, 24-week endpoints, how that translates usually how to take into account the different dose levels in patients enrolled, just trying to gauge how the risk in that dataset could actually be. And then just to confirm also relative to what's good enough for the phase I-B, and thanks again for outlining all those thresholds, but assuming the same criteria would apply to the phase II, I'm not sure if the bar moves at all just with longer dosing. I wouldn't expect it to be the case. I think you're also going to be looking at additional endpoints there, but just again, want to try to understand the translatability of the phase I-B to the phase II. Thank you. Okay. Who wants to take that one first? Dr. Benza, Dr. Teerlink. John, you're on mute. O n mute. Yeah. Yeah, I was just saying, actually, Ray, you can go ahead. You were at the beginning of the design of these programs. But so go ahead, and then I'll address. Yeah, I think these studies mesh very nicely. Looking at exercise improvement with the pharmacodynamics and pharmacokinetics, the trial that we've designed with the Group 2 pulmonary hypertension patients and the particular endpoints and some of the other secondary endpoints that we're looking at, including changes in risk scoring systems, will give us a nice composite profile of how relaxin moves these patients from an area of debility to an area of stabilization improvement. So I think all the things that we're looking at make a really nice transition between the two. Yeah, and I just want to completely agree and emphasize that I think this is a really fantastic chance to see, you know, there's the first look at, are there on-target, proof of concept kind of measures through the phase I-B, and then transitioning that into kind of looking more at the PD, the pharmacodynamic effects, and the clinical outcomes that might be affected by that on-target effect. And so it's a very rational development program. Tiago, I'll just add a couple of things. It is possible. So first of all, we haven't set targets for our phase II. Let us get the phase I-B data, digest that, and then we will set our targets for phase II. I think there's the possibility, so we expect that the effects we see acutely will absolutely be maintained. We know the renal blood flow effects are maintained over time. And as Dr. Teerlink said, there's no desensitization of the mechanism. There is the potential, though, that those hemodynamic effects could get better over time, and if we saw that, I think that would be evidence that there was an antifibrotic remodeling effect of the pulmonary vasculature and the myocardium as well. Got it. No, fair enough. Thanks again for the question. Thank you for the questions, Tiago. I'll now turn it over to Dan Ferry of LifeSci Advisors to read the remainder of the questions from the webcast. Thanks, Tara. Alise, so we do have a couple of written questions in from the audience. The first is, what percent reduction in PCWP and PVR would you define as a win for the phase I-B trial? Well, I think Marcie was very clear on that. What we've been saying is a 15%-20% reduction in the wedge pressure. In the PVR, also a 15%-20% reduction with a focus on the CpcPH population for that endpoint. Okay. Thanks, Alise. Yeah, hopefully they heard my attempt to say that I think there was a more reasonable range in the 10%-15%, given that these are not acutely decompensated patients. But we'll see how the rest of you all take that. Great. The follow-up question to that, Alise, is if TX45 meets 15%-20% improvement in PCWP and PVR in phase II, does this increase the probability of success for TX45 in phase II? And if so, why? I think Dr. Teerlink already addressed it. I think they're asking if we meet the targets we've met, John, do you think it increases the probability of success that our phase II will be successful? Absolutely. I hope I was clear in saying that, yeah, if you hit 15% and 20%, I think that's a very clear, compelling case for moving forward and a potential for benefit in the rest of the development program. My only point was, I think that that's pretty aggressive. And if you hit it, that's fantastic. And anything you want to add, Dr. Benza? No, I agree with John on this. I think we were very clear in the presentation what our expectations are and what we feel we can accomplish with this therapeutic. All right, Dan. Next question. Excellent. Thank you. I do have two questions here for the KOLs that are grouped together, Alise. The first one is heading into the hemodynamic study readout, what would keep you up at night regarding efficacy or safety? And then number two, can you hypothesize how long it might take to see evidence of reverse remodeling? Ray, you want to take that? Typically, it takes anywhere from four weeks to 12 weeks to really see true remodeling in the pulmonary vasculature. And we've learned that from a variety of different therapeutics, including sotatercept. And so as we mentioned, with that type of timeframe in remodeling and the effects that we expect to see in pulmonary capillary wedge pressure and PVR, I think those are really going to be the important markers that we see for efficacy. And there's a similar range for cardiac remodeling. It may extend a little bit beyond the 12 weeks in terms of seeing maximal effects continue to go on for months in terms of remodeling process. But you can see beginnings of it and indications of it early within the two to three months. What was the first part of the question, Dan? Yes. Heading into the hemodynamic study readout, what would keep you up at night regarding efficacy or safety? Does that mean keep me up like I'm so excited I can't wait to get back? My sense is, Ray, that's probably not what they were intending, even though I think we both feel that. From an efficacy fact, if we didn't see improvements in functionality and how the patient feels, obviously, that would be very disappointing. And I don't believe that's what we're going to see just based on the preclinical data that we've seen and the mechanisms of action and the way this molecule works in real life, as John highlighted for us. But if we didn't see modest improvements in six-minute walk distance on the order of 25, 30 meters, and we didn't see improvements in quality of life measures and measures of dyspnea, that would be disappointing. From a safety profile, I think I'll let John answer that particular one given his experience with other molecules of this class. Yeah. And I guess in terms of the efficacy part, I will just re-emphasize, I think it's dangerous to have. It's great to have a lot of enthusiasm, but dangerous to have unrealistic expectations. And so it will depend on what the characteristics of the patients are when they come in and how much of the characteristics are modifiable risk. And so if the patients are coming in with too high of a KCCQ or other issues along those lines, it's going to be hard to improve it. But I think the trial is designed to try to optimize those aspects. In terms of a safety, I think the biggest concern that I think most people will think of in regards to this is symptomatic hypotension. And that's something to consider as an issue because anytime you think of something that has vasodilatory possibilities can cause that. That was not a major issue in the serelaxin program. And that's in patients who were given large doses of intravenous diuretics, having major volume shifts, and all sorts of things going on during their acute heart failure hospitalization. And once again, this is a hormone that's around with women where causing hypotension would be clearly evolutionarily disadvantageous. So I think there's a low likelihood of that, but that would be something I'd want to look for in terms of major symptomatic hypotension. Did that answer your question? Actually, we don't know because it's online. Okay. There you go. We can take the next question, Dan. Thanks, Dr. Teerlink. Yeah. Just a few more here, Alise. For the KOLs, how should we think about the six-minute walk, 6MWD, as an endpoint across these differing patient populations, just HFpEF versus IpcPH versus CpcPH? Like differences in PVR described earlier, are there different thresholds of improvement you would consider to be clinically meaningful in one group versus another? Certainly, if we can drop PVRs below five, we should expect to see a resultant improvement in overall outcome similar to what we've seen in Group I pulmonary hypertension. That's an important threshold that I would like to see. As I mentioned, as we mentioned earlier, 20% reduction in PVR often results in a significant improvement in the way the right ventricle works. So that would be an important finding that we can glean from these trials. For isolated post-capillary pulmonary hypertension, I'm more interested to see the reduction in the wedge pressure, which is going to be incredibly important because that's what really the marker of IPCPH is, is it changes in filling pressure of the left ventricle that that's transmitted back to the pulmonary vascular tree. So that's the primary thing I'll be looking at for the IPCPH. Both will translate for each of these populations, wedge and PVR reduction into improvement in functionality, walk distances, NYHA class, and quality of life measures. Yeah, I don't really have a whole lot to add to that in terms of we do know in HFpEF that the six-minute walk and just isolated six-minute walk in isolated heart failure with preserved ejection fraction without adding the additional risk factor of the pulmonary hypertension, it's been a little challenging to show effective changes in six-minute walk tests. And that's why I'm worried about too high of expectations because I think any change in this patient group will be an advance over what we have so far. So that's kind of my heart failure perspective. And next question. We have time for one more. I think that's it, Alise. Okay. I want to thank Ray and John very much for joining us today. Those were terrific talks. I always learn when I hear both of you speaking, and I'm sure everybody online did as well. Thank you very much. Thank you for everybody who joined us today and participated.