Good morning. Welcome to the Tectonic Therapeutic Virtual KOL event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. 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 at Tectonic Therapeutic. Please go ahead, Alise. Thank you. Good morning and welcome to Tectonic's webcast to discuss TX2100, our differentiated approach to the treatment of Hereditary Hemorrhagic Telangiectasia, otherwise known as HHT. Next slide. In front of you is our forward-looking statement. If you can now go to the next slide. In terms of the order of today's Webex, I'm going to start with a brief introduction before I turn the presentation over to our distinguished guest, Dr. Hanny Al-Samkari, who will review HHT and the important unmet needs of patients with this disorder. Peter McNamara, our CSO, will introduce the discovery and rationale behind TX2100. Marcie Ruddy, our CMO, will provide a high-level update on our clinical program before we stop for Q&A. Next slide. Many of you listening in today are very familiar with Tectonic's story. For those of you, however, who are not, the company specializes in the development of both agonist and antagonist biologics targeting GPCRs. Our focus to date has been on diseases with high unmet need and limited to no therapeutic options, such as HHT. When we started the company, our goal was to have a robust product pipeline that enabled optionality and good database decisions. As of today, we have 2 programs in the clinic covering 3 indications, as well as a strong emerging preclinical pipeline. We have good clinical momentum, and we are well-capitalized to advance the pipeline. Next slide, please. Before I turn the presentation over to Hanny, I'm going to frame today's discussion. First, as you'll hear, HHT is the second most common genetic bleeding disorder and is a serious disease with major effects on quality of life and life expectancy. It is a potential multi-billion dollar market with no approved therapies. HHT is an orphan disease, and while VEGF inhibitors have been used off-label, they're limited by toxicity and sometimes the lack of durability. Our approach is novel. As APJ, the receptor for the peptide hormone apelin is a selective and specific anti-angiogenic target. It is tissue-selective and pathology-biased, as Peter will describe later this morning. Furthermore, we believe there's the potential to expand into a broader group of bleeding disorders caused by dysregulated angiogenesis. TX2100 is a potential first-in-class subcu-administered APJ antagonist with the goal of achieving the benefit of anti-angiogenic therapy with improved safety. Our probability of success is enhanced by the demonstration of efficacy in two separate preclinical models of HHT, which have previously been shown to have clinical translation. Our first-in-human study has been initiated in Australia, and Marcie is going to give a hot-off-the-press update to that during her presentation. Next slide. Turning now to Hanny Al-Samkari, who is a professor of medicine at MGH, it is not an understatement to describe Hanny as a true leader in the field. He's the head of the HHT Center of Excellence at MGH, and he has pushed the field forward in both endpoint and clinical trial design. As I think you'll hear, he's also a moving advocate for these patients and serves as a reminder to those of us in industry to put patients at the center of what we do. Turning it over now to you, Hanny. Wonderful. Thank you so much. It's a pleasure to be here. It's a pleasure to speak on HHT and the unmet need in HHT, which is really profound. I want to emphasize, this is a disease that has been neglected for a very long time. It is a disease that very clearly is among the greatest in terms of unmet need in the hematology space and very clearly near the top in the non-malignant hematology space. Let's dive in, I'll discuss what I mean by that. Here is a typical patient case with a patient with HHT, one of my patients. A 41-year-old man with severe nosebleeds and chronic intestinal bleeding, who works in the biomedical field, diagnosed with HHT in his 20s, but not cared for at an HHT Center, at least initially, right? Sent for regular nasal and intestinal cautery procedures that each worked for a couple of months, but provoked worse nose bleeding and worse gastrointestinal bleeding as time went on, as these procedures tend to do. Ultimately, went on disability, and his career was halted because of constant blood gushing from his face, limiting him at work; chronic severe anemia, despite regular intravenous iron infusions and occasional blood transfusions; constant emergency room visits for severe nosebleeds and hospitalizations from severe intestinal bleeding; and a diagnosis, unsurprisingly, of Major Depressive Disorder from the nose bleeding, from how profound it is and how much it impacted his life.... started on an antidepressant, a selective serotonin reuptake inhibitor, which reduces platelet function. It worsened his nose bleeding. The prescribing doctor, as most folks who prescribe SSRIs, didn't recognize that this was a side effect of this drug. He then saw me at the MGH HHT Center of Excellence, and he said, "I'm barely 40, but I feel like my life is nearly over. I just want to go back to work and maybe one day be able to have a girlfriend." Here's another typical patient case, also a patient of mine. 37-year-old man, father of three children, diagnosed with HHT 1 month prior to his visit with me. He came from Maine to the HHT Center of Excellence at MGH in Boston. He had gushing nosebleeds and chronic intestinal bleeding, causing severe anemia, resulting in severe fatigue, reducing his work hours, threatening his employment, he worked at a construction job, and therefore his ability to take care of his family. One of his sons died of a brain hemorrhage at birth. Another son had a brain hemorrhage shortly after birth but lived with disability. His daughter has recurrent nosebleeds, causing anxiety, distress, and social isolation at school. This is, these are two examples, right? This gentleman then saw me at the HHT Center of Excellence. He had just been diagnosed at 37, despite all of these other things happening in his family, the brain hemorrhages from brain arteriovenous malformations in his children, the epistaxis, causing major impacts for him and his daughter. I mean, this was somebody who was had no idea for the longest time what was going on with him. Finally, diagnosis was made, and we're able to get him on adequate therapy, seeing us at the HHT Center of Excellence and properly screen him to make sure he doesn't have a brain bleed like his two sons did. With that introduction, I just wanna explain to everyone how I think about inherited bleeding disorders and how I recommend that you think about inherited bleeding disorders. Inherited bleeding disorders are often thought of when people think of inherited bleeding disorders, the first disease that comes to mind is hemophilia. Hemophilia is our prototypical coagulation factor problem. It affects 1 in 5,000 males or 1 in 10,000 individuals. Most patients with hemophilia have moderate to severe bleeding, so certainly a very significant inherited bleeding disorder. We all recognize this. On the other end of the spectrum, we have HHT, Hereditary Hemorrhagic Telangiectasia, which the most recent prevalence assessment in North America was one in 3,800 people. Prevalence assessments for HHT usually bounce around one in 4,000 to one in 5,000 people, so around this sort of estimate, twice as common, at least, as hemophilia is. This is a disease where most patients have moderate to severe bleeding, like hemophilia. The site of bleeding is different. Patients with HHT have mucosal bleeding dominantly, right, in the gastrointestinal tract and from their face, right, epistaxis, which we cannot discount the importance of. Some people make the mistake of discounting the importance of recurrent bleeding from your face. My patients will tell you that they'd rather bleed from almost anywhere else. It makes it very, very difficult to live a normal life. In the middle, right, we have the most common bleeding disorder, which is von Willebrand disease. Von Willebrand disease, though, is characterized primarily by mild bleeding, right? I take care of all these patients, and, you know, most patients with VWD have mild bleeding. There are patients with more severe bleeding, but that's unusual. We have FDA-approved therapies for hemophilia and von Willebrand disease. We have many, certainly for hemophilia, which have transformed the field, and it made things very, very different for these patients than they used to be and much, much better, thankfully. We have multiple approved therapies for VWD. We have no FDA-approved therapies for HHT, no approved therapies worldwide for HHT. Getting to brass tacks, what is HHT? It is a multisystem inherited bleeding disorder with numerous morbid and potentially fatal manifestations. This is a disease that, most of the time in childhood, presents with people having more nosebleeds than other children, right? Children get nosebleeds. That's just sort of a common thing. It's not common, by the way, for adults to get nosebleeds, which is why I say recurrent nosebleeds in an adult is HHT until proven otherwise, because it usually is. These children, they have more nosebleeds than their peers, and then they start developing more and more bleeding over the course of their lives to the point where when patients are in their early adulthood, like the patients I showed you, they tend to have really problematic epistaxis, problematic nosebleeds. They may have developed gastrointestinal bleeding by that point. Almost everybody with HHT has recurrent nosebleeds. About one-third of patients with HHT develop clinically significant chronic gastrointestinal bleeding. The epistaxis is still the most important bleeding burden for these patients, the GI bleeding is obviously very important. Approximately one-third to two-thirds, the number is still being sorted out, of women with HHT have heavy menstrual bleeding, okay, that appears to be related to their HHT. All this bleeding causes a burden of iron deficiency anemia that's greater than any other bleeding disorder, really almost any other medical condition, right? You're just more likely to become iron deficient and have anemia when you're chronically bleeding from your nose, from your gut, so on and so forth. In addition to this, patients have visceral arteriovenous malformations, okay? Abnormal connections between artery and vein. These also cause the bleeding of mucosal surfaces. They're called telangiectasias when they're small and they're called AVMs when they're bigger, when they're more than a few millimeters to reaching a centimeter range in size. All of these lesions are what we call high-flow lesions because they connect artery, which has high pressure in it, to vein, which normally has low pressure, and is part of the reason why these patients bleed so much, because these lesions are really fragile and they burst, and they cause bleeding, right? The telangiectasias are very fragile, and they burst and they cause bleeding. Patients also have these lesions in their lung, liver, and brain. Most patients will have lesions in at least one of these organs. These are AVMs. About 20% of people have brain AVMs, 50% lung, 70% liver, and these cause all these other awful complications of this disease, right? Variably, each of these is, you know, 7%-10% or so of patients, when we talk about liver disease, pulmonary hypertension, pulmonary high output heart failure, things like this. Life-threatening pulmonary hemorrhage and certainly brain hemorrhage are the most feared manifestations of the disease. Even in spite all of these, like, very concerning visceral manifestations of the disease, patients rank bleeding as the most important clinical manifestation by quite a wide margin. HHT, as was already stated, is the second most common inherited bleeding disorder, all right? The most common one, again, von Willebrand disease, is mostly mild, right? This disease presents with it a huge amount, easily the greatest amount of unmet need in the entire bleeding disorder space, given that there are no approved therapies for it, and it causes rather substantial manifestations, including reduced overall survival. It is the most clinically significant and morbid inherited bleeding disorder of women, right? Because hemophilia is an X-linked disease and principally impacts men. HHT occurs in all sexes equally, and this disease affects 1.6 million people in the world. What causes HHT? HHT is really a problem with the physiologic brake pedal on angiogenesis, the development, growth, and maintenance of blood vessels. You have two pathways in your body that are part of what's called the transforming growth factor-beta signaling pathway, and one of these pathways, called the ALK1 pathway, is the brake pedal on angiogenesis. It keeps the growth of new blood vessels in check. The ALK5 pathway is the gas pedal on angiogenesis. What happens in HHT is that you have a lesioned brake pedal. This is an autosomal dominant disease, where patients have a mutation in one of the genes along the ALK1 pathway, either ALK1 itself, and that's the activin-like kinase, family member one, also called ACVRL1, or its critical co-receptor endoglin, right? These are the most common. These account for about 90% of all cases of HHT. When you have a loss of function in one allele, you have, you know, it's a haploinsufficiency problem. You have inadequate signaling through the pathway. Your brake pedal just isn't working as well as it should. From the time you are an embryo, you know, you have an excessive signal for blood vessel growth. You know, we know that patients with HHT tend to be born with the brain AVMs that they're going to have over the course of life, some aspects of this disease are more congenital. Other aspects develop over the course of life, mostly the latter. Ultimately, this puts these patients in a persistent pro-angiogenic state, that's why we are, you know, looking at anti-angiogenic mechanisms as a principal way to manage this disease. There are many mouse models of HHT. There is the anti-BMP9/10 immunoblock mouse model, where there are antibodies that bind the ligand for the ALK1 pathway. There is an endoglin-inducible knockout mouse model, an ALK1 inducible knockout mouse model, which has extremely profound manifestations, very severe GI bleeding. These mice die within two weeks of GI hemorrhage and pulmonary hemorrhage. There's also SMAD4 knockout mouse model. With prior therapies that we have looked at, we have recognized that response to drugs in these mice, these mouse models do tend to predict clinical efficacy in humans. There have been mouse models where bevacizumab, an anti-VEGF monoclonal antibody, has been used, a pazopanib analog has been used, and immunomodulatory IMiD drugs, including thalidomide, have been used. They work to restore some normalcy to the phenotype in the mouse model. They do improve the phenotype in the mouse model, and all of those drugs also do have efficacy in humans. You know, a paper was published in 2020 that showed this massive increase in prevalence in HHT in the United States, not because someone is going around and smacking people with an HHT stick, right? It's because of increased recognition and increased diagnosis. HHT now has federal funding from the U.S. government, like hemophilia does, like sickle cell disease does. It's long overdue, HHT Centers of Excellence are now federally funded, and more are being established and popping up throughout the country, and with that comes better education to community providers, who are then able to make more diagnoses of this disease. We used to say that about 80%-90% of patients with HHT out there were undiagnosed. Now, I would estimate that number is closer to 40%-50%. We still have work to do. This is an example of mucocutaneous telangiectasias in the gastrointestinal tract that ooze and bleed. This is not typically your brisk GI bleed, right, that we associate with, let's say, an ulcer in someone's stomach or duodenum. This is slow hemorrhage, whereby somebody might lose 30 cc of blood a day. It's enough to lose a gram or two of hemoglobin a week. It's enough to make the person absolutely dependent on parenteral hematologic support with IV iron and red cell transfusion. This is how this disease causes bleeding in the intestines. In the nose, these telangiectasias are extremely friable, very fragile. They are exposed to the environment every single day, they cause the greatest burden of bleeding in these patients that impacts their quality of life. Of course, we have the AVM, the arteriovenous malformations, in lung, liver, and brain, as I mentioned previously. The most feared complication of any bleeding disorder is, of course, intracranial hemorrhage. The Comprehensive HHT Outcomes Registry of the United States, or CHORUS, is the federally funded HHT registry. For those of you familiar with the hemophilia space, this is analogous to the American Thrombosis and Hemostasis Network, or ATHN registry, except for HHT, this was started in 2022. We recently presented the initial results from this registry, which showed intracranial hemorrhage rates in HHT of 3%, which is higher, about nine times higher than hemophilia A in 2026, right? These rates are similar to hemophilia in the 80s, before any routine prophylaxis, right? This was a top-line finding from this and just highlights, again, the importance of this disease and the unrecognized clinical need. When we talk about HHT, we're really primarily talking about the bleeding issues because they are the greatest unmet need. CHORUS also demonstrated that in the initial, in this initial report, that approximately three-quarters of patients had moderate to severe bleeding in HHT. Why is that important? Moderate to severe bleeding, this is the group of patients for whom treatment is very clearly indicated, right? Where if we had an effective, approved drug, we would be prescribing it to this group of patients. The mild patients, some of them would also be appropriate, just depending on the risk-benefit ratio of that drug. Very clearly, the moderate to severe patients are the people who need treatment, so most of these patients require treatment. This is an expensive disease as well. We did a financial analysis evaluating the mean per patient per year direct medical costs for HHT with colleagues at Diagonal, and this showed that all HHT patients, the mean per patient per cost was about $20,000 per year. Those patients with anemia, which is most patients, the mean per patient per cost was $27,000 per year, which is similar to muscular dystrophy. The mean per patient per cost for all patients was higher, about 20% higher than sickle cell disease. Those patients that require hematologic support, which is again, a large group of these patients, was $40,000 per patient per year, and that's similar to cystic fibrosis. Again, this is a disease, and the main drivers of cost were bleeding and its complications, hospitalizations for bleeding, intravenous iron infusions, off-label use of medications that are expensive and indicated only for patients with terminal cancer normally, and then, of course, procedures for epistaxis and other things that relate to the treatment of bleeding. This study had a sample of about 23,000 patients, right? Certainly not all of the patients in the U.S., still half a billion dollars in that sample. If we extrapolate that to the number of patients with HHT that are believed to be in the United States, that's about $2 billion per year in estimated cost. 12% of all diagnosed patients are hospitalized at least once per year. Just to show it, because it just shows the profound. It's quite wild, actually. There was one patient in this cohort that had gastrointestinal bleeding, for whom $21 million was spent on recombinant factor VIIa, which is a nonspecific hemostatic agent, right, that we use as a bypassing agent in hemophilia, but this was a patient treated outside an HHT Center. They're just desperately trying to prevent them from bleeding to death, they spent $21 million on the wrong medication. More findings from the first CHORUS report. I mentioned that three in four people develop moderate to severe mucosal bleeding. One in three with HHT develop chronic GI bleeding that is clinically relevant. There are more that develop GI bleeding that may not be as clinically relevant. At least one in three menopausal-age women develop heavy menstrual bleeding. seven in 10 people with HHT develop iron deficiency and/or anemia. One in four people with HHT develop severe enough anemia to merit red cell transfusion. One in 50 people with HHT, or 2%, develop pulmonary hemorrhage. One in 30, or 3%, develop intracranial hemorrhage, right? These are burst arteriovenous malformations, high-flow lesions, life-threatening, very, very scary. These are the people that lived, right? The people that died of these lesions before they could enroll in the registry were not represented here. One in 10 develop arterial thromboembolism, one in 10 develop serious cardiopulmonary complications, including pulmonary hypertension and/or heart failure, and one in five develop severe CNS complications, such as brain AVMs, stroke, intracranial hemorrhage, or epilepsy. All right? Again, I think I've hopefully convinced you, if you haven't heard of this disease before or hadn't heard too much about it, or heard it was just a hereditary nosebleed disease, right, that, well, first of all, the nose bleeding is extremely important and not just a thing to wave away, but also that this is a very significant multisystem inherited bleeding disorder. How do we treat people right now? We treat them, right, with off-label drugs. We, you know, make sure that we care for patients' iron deficiency and iron deficiency anemia. There's no group of patients that gets more intravenous iron and more red cell transfusions than people with HHT as a group. That includes, right, you know, a patient with HHT that's transfusion-dependent, right? That's not a huge percentage, right? That's 5%-10% of people with HHT, but nevertheless, somebody with HHT that's transfusion dependent, they're getting two, three units of blood a week, right, as compared with a transfusion-dependent patient with, say, thalassemia, who is gonna get at most two units every two weeks, right? This is a lot of blood. There's no other disease that requires the kind of blood burden that this disease does, and I have patients that are getting five units, six units a week. All right. Patients are managed right now with procedures. If they come into the emergency room and blood is gushing from their nose, or their hemoglobin is three because they have GI bleeding, right, we do what we have to do in that moment. We know that the more tissue injury you do in this disease by cauterizing, by lasering, by, you know, trying to eliminate these telangiectasias and mucosal surfaces, the more of a wound-healing response and angiogenic activation that you provoke, and therefore cause regrowth even worse than before of the telangiectasias that you were initially treating, right? This is why the paradigm in HHT has really shifted in the last decade away from these types of procedures. We use them when we need to. They're still used very frequently outside of centers of excellence, to be very clear, as sort of cyclical repeat procedures to the patient's detriment. It is done. It does happen, right? It is the reality, because outside of HHT Centers of Excellence, people are not interested in prescribing bevacizumab or pomalidomide for younger people who have decades left to live, when these drugs, in addition to being very expensive and sometimes being very difficult to get payer coverage for because they're off label, also have rather substantial side effect burden and are normally only used for a period of a few months to maybe a year or two in patients for whom they are approved. Nevertheless, if someone has mild to moderate bleeding, we tend to try oral antifibrinolytics, 6-8 horse pills per day, over every 6 hours. Very significant pill burden. You know, moderate efficacy. It's very difficult for people to take all of these pills. For people that have anything more than mild to moderate bleeding, we go to clinical trials or off-label systemic anti-angiogenic therapy like bevacizumab or pomalidomide. To be clear, the starting dose intensity for pomalidomide in HHT is actually 30% higher than it is in people with myeloma, right? We use higher doses of that drug in HHT than in myeloma. These drugs can be efficacious. They certainly don't work for everyone, and for the people that they do work, the efficacy is often limited by time, so people progress. We don't understand why that happens, but it definitely does with both of these drugs, with any of the off-label drugs that we use. Bevacizumab also has significant toxicity, as we recognize, right? Hypertension, proteinuria. We often buy one or two additional drugs when patients develop hypertension. They often have to get additional medications to try to manage that. Both of these drugs, Bev and Pom, have a thromboembolism risk. Pomalidomide causes quite a lot of neutropenia, causes rashes, neurologic side effects, really substantial constipation, right? We've published long-term data on pomalidomide. While it can be efficacious, certainly, and it does benefit a significant minority of patients who use it also is discontinued by a large percentage of patients because of this substantial toxicity. With that, I'll pass things over to Peter. Hi, everyone. I'm Peter McNamara, the CSO here at Tectonic. I've been in drug discovery for a little over 20 years. Our team here at Tectonic has worked extensively on the APJ program over the last few years. I'm really excited to walk you through the story behind TX-2100 and why we think it represents something genuinely differentiated. Next slide, please. TX-2100 is a potential first-in-class APJ antagonist for HHT and diseases involving dysregulated angiogenesis-driven bleeding. APJ is a G- protein-coupled receptor, the GPCR for the peptide hormone apelin. That biology underpins the rationale for this program. There are three key pillars to the TX-2100 story. First, it's a validated approach. Anti-angiogenic oncology drugs have been demonstrated to improve bleeding and anemia in HHT patients. However, the toxicity of these drugs makes them challenging for chronic use. Second, it's a differentiated target. APJ is endothelial-enriched. The pathway is activated in a pathology-biased manner. We believe that gives us the opportunity to deliver anti-angiogenic benefit to patients without the chronic tolerability issues that limit the other anti-angiogenic therapies, which are in clinical testing or used off-label. Third, the translation is de-risked. We see efficacy in multiple highly translatable mouse models of HHT, which include clinically meaningful endpoints like hemoglobin and bleeding. We have a clean, non-human primate GLP tox study and durable non-clinical PK. Our first- in-human trial has been initiated, and phase Ib and phase II proof of concept trials are planned. Next slide, please. APJ is a highly selective and highly specific anti-angiogenic target. It's an endothelial-enriched GPCR activated by the peptide hormone apelin. The pathway is upregulated in pathological angiogenic sprouting and is largely quiescent in normal vasculature, its blockade is expected to leave baseline vascular homeostasis intact. On the left-hand graphic, you can see what that looks like in disease. Excessive dysregulated angiogenesis that leads to the formation of arteriovenous malformations or AVMs. As Hanny said, these are fragile, disorganized vascular connections that underlie bleeding in HHT. What we see in our models is that when we antagonize APJ, we reduce this pathological sprouting and limit AVM formation. The vasculature becomes more normalized with fewer abnormal connections, improved structure, without disrupting baseline vascular homeostasis. This pathology-biased activation is what makes us believe in the potential for durable efficacy with improved safety. Next slide, please. What's striking in this story is how two independent scientific timelines have converged. Over the last three decades, we've come to understand the underlying genetic basis of HHT with the discovery in the mid-90s that the ALK1 pathway was mutated in patients. We have also come to understand the underlying angiogenesis etiology of this disease, as supported by the 2011 observation that bevacizumab showed clinical efficacy in HHT, and the real-world clinical experience that followed this, showing that multiple anti-angiogenic therapies work in HHT patients. HHT is now broadly accepted as a disease of dysregulated angiogenesis. In parallel, while apelin and APJ were discovered in the mid-90s and their role in angiogenesis defined in the early 2000s, pharma historically pursued APJ agonism in cardiovascular disease and heart failure. These programs didn't translate beyond early clinical studies with limited effects demonstrated in patients. For nearly three decades, these two bodies of science evolved independently. The HHT field validated anti-angiogenic therapy but never implicated APJ inhibition. The APJ field focused on agonism and cardiovascular disease. It was only by integrating these insights that Tectonic recognized that selective APJ antagonism could represent a targeted approach for HHT, and TX-2100 is the product of that insight. Next slide, please. The mechanistic proof of concept for anti-angiogenesis in HHT comes from the use of oncology drugs such as anti-VEGF therapies, which show improvements in bleeding, increased hemoglobin, and reduced need for transfusions. The problem, however, is that these drugs were never designed for long-term use in a non-malignant vascular disease. The solution is to develop a potent and selective APJ antagonist for the treatment of HHT and other angiogenesis-driven disorders that captures the benefit of anti-angiogenic therapy with an improved safety profile. Next slide. A big limitation of VEGF receptor antagonism is where VEGF sits in normal physiology. It's a core maintenance pathway for adult vascular beds. When you inhibit VEGF receptor systemically, you don't just blunt pathological angiogenesis, you also disrupt vascular homeostasis and repair, which drives the long-term safety issues which are seen clinically. That sets up the key question: Can we get anti-angiogenic benefit without shutting down essential vascular maintenance biology? That's where APJ is differentiated. APJ is endothelial cell-enriched, and the apelin APJ axis is most active in pathological sprouting angiogenesis, with low baseline activity in quiescent adult vasculature. APJ antagonism has the potential to deliver durable anti-angiogenic efficacy with a better safety profile than broad VEGF receptor blockade. Next slide, please. When you look at where these receptors are actually expressed, the difference becomes clearer. On the left, VEGF receptor 2 is expressed across multiple cell types and tissues, not just endothelial cells, which helps explain the broader on-target biology we see clinically. In contrast, on the right, APJ expression is much more concentrated in endothelial cells, with a relatively limited signal outside that compartment. That endothelial enrichment gives us the opportunity for more selective vascular targeting. Next slide, please. Targeting APJ is not only a selective and specific approach. The pathway has been shown to be upregulated in HHT pathobiology. Transcriptomic studies demonstrate a shared angiogenic signature across all of the key genetic mouse HHT models, and apelin consistently sits within that signature, then strongly upregulated in endothelial cells. We have our own in-house data, shown on the right, that also shows that apelin expression is upregulated in the anti-BMP9/10 model of HHT. Next slide, please. TX2100 is a highly potent, highly selective human APJ antagonist. It's a VHH-Fc fusion, which gives us excellent specificity, long half-life, and infrequent dosing. In vitro, TX2100 shows low nanomolar potency at APJ, with over a thousand-fold selectivity versus the most closely related GPCR. Functionally, it potently blocks APJ-mediated cyclic AMP signaling. Next slide, please. Importantly, because APJ is primarily expressed in endothelial cells, blocking it will lead to selective inhibition of AKT and ERK signaling in this cell type. The data on this slide shows that APJ antagonism potently blocks AKT and ERK activation. That's very different to VEGF inhibitors, tyrosine kinase inhibitors, or AKT inhibitors, which cause a much broader pathway expression of AKT and ERK signaling across many different cell types and tissues, which can drive the safety and tolerability issues seen in patients. Next slide, please. To evaluate APJ antagonism in vivo, we use TX1351, a mouse-reactive VHH- Fc surrogate antibody that's potency-matched to TX2100 at APJ. We tested the TX1351 across two complementary but increasingly stringent HHT models: the neonatal anti-BMP9 model and the severe adult inducible ALK1 knockout model. Across both models, APJ antagonism shows robust and durable efficacy, with reductions in AVMs and bleeding, and meaningful increases in hemoglobin. Importantly, these are clinically relevant endpoints, not just changes in vessel density, but improvements in bleeding and anemia that directly matter to patients, and I will walk you through these data in the next few slides. Next slide, please. In the neonatal anti-BMP9/10 model, TX1351 decreases AVM formation, increases hemoglobin, and reduces retinal bleeding. This is a real disease-modifying effect, not just a partial signal. Next slide, please. In contrast, in our hands, in this anti-BMP9/10 neonatal model, while both VEGF blockade and AKT inhibition can reduce AVM formation, shown in the graphs on the left, neither approach fully corrects the anemia phenotype, shown in the graphs on the right. VEGF inhibition, in particular, showed little to no improvement in hemoglobin. We were surprised by this, but the VEGF label states that an increase in bleeding is a potential side effect of VEGF inhibition, so this potentially explains the result. Next slide, please. In the most severe of the HHT models, the inducible ALK1 knockout mouse, the difference between APJ antagonism and VEGF blockade becomes very clear. On the left-hand part of this slide, you can see that on day 7, VEGF inhibition shows an initial ability to blunt the drop in hemoglobin, but that benefit wanes over time and is gone by day 12, looking at the gray bars in this graph. This is consistent with the lack of durability that can be seen in patients, as Hanny mentioned earlier. In contrast, APJ antagonism, shown in the orange bars, delivers sustained improvements in hemoglobin that are maintained through the end of the study. Importantly, this durability translates into bleeding outcomes measured on day 12, shown on the right of this slide. APJ antagonism significantly reduces GI bleeding, whereas anti-VEGF-treated animals continue to show evidence of substantial GI bleeding, despite modest hemoglobin benefit. Together, these data show that APJ antagonism not only improves anemia, but more effectively and persistently addresses the underlying bleeding pathology driving disease in this model. Next slide, please. Using latex blue dye perfusion, we can directly visualize vascular architecture in the GI tract of these mice. These data are shown in the four images on the left-hand side of this slide. The latex blue dye is injected into the arterial system of the mice, and due to the size of the latex bead, it can't pass through the capillaries. You can see that in the top left image, the no disease control group, where the latex dye is restricted to the arterial circulation. If you see latex blue dye in the venous circulation, that's indicative of AVM formation and shunting in the blood vessels. As you can see in the top right image, this is the disease control group treated with an isotype control antibody. In the bottom left image, you can see that the APJ antagonist TX1351 restores the blood vessels towards a more normal structure, reducing hypervascularization, hemorrhage, and abnormal vein dilation, and reducing the extent of latex blue dye getting to the venous circulation. This is compared to the isotype control group in the top right image. The graphs on the right quantify the effects of TX1351 on vascular density and vein diameter compared to the anti-VEGF antibody. Notably, APJ antagonism provides a more complete vascular rescue than VEGF-A antagonism in this model, as you can see in the graphs and comparing the bottom two images on the left. Next slide, please. Turning to safety. Across our internal preclinical program, TX2100 shows no molecule-specific or target-related safety findings. A reasonable question is whether prior published biology around the apelin APJ pathway creates any theoretical safety risk when you block the receptor. As I mentioned earlier, most of the published preclinical, physiological, and pharmacologic data comes from APJ agonist studies, often acute apelin peptide dosing, reporting effects on blood pressure, renal function, metabolism, and inflammation. Multiple APJ agonist programs were advanced into the clinic and were ultimately discontinued for lack of efficacy, but were generally safe and well-tolerated without major on-target liabilities. We tried to reproduce the described acute apelin agonist effects reported in the literature in us, looking for effects on cardiac function, on blood pressure, on glucose control, effects on platelets and fluid balance. In our hands, we were unable to reproduce these effects across multiple settings. Most importantly, this is supported by a 13-week GLP toxicology study in cynomolgus monkeys, along with GLP safety pharmacology studies also carried out in cynos. TX2100 was clean across cardiovascular, renal, metabolic, and hematologic systems, with a NOAEL of 100 mgs per kg per week, the highest dose tested. There were no test article-related findings identified at any dose level evaluated. Next slide, please. Stepping back, we've built a comprehensive preclinical package that supports entry into phase I. First, we've demonstrated robust preclinical efficacy across multiple highly translatable models of HHT, including endpoints that matter clinically, such as bleeding and hemoglobin. Second, in our IND-enabling GLP toxicology program, including a 13-week non-human primate study, we observed a clean safety profile with no molecule-specific or target-related safety signals. Third, we've identified a patient-friendly subcutaneous formulation, and importantly, our drug product shows the properties needed to support early clinical development. Taken together, we believe TX2100 is fully positioned for first-in-human evaluation. With that, I'll hand off to Marcie to walk you through the first-in-human study design and how we plan to generate early proof of mechanism and set up for proof of concept. Next slide. Thanks, Peter. I'm Marcie Ruddy, the Chief Medical Officer here at Tectonic, I will be reviewing our clinical plans for TX2100 over the next few minutes. Next slide, please. I'm very happy to report today that we have just successfully dosed our first two subjects in our phase I, first-in-human trial. Our clean toxicology studies enabled us to conduct this trial in healthy volunteers. This approach allows an efficient assessment of safety, tolerability, and pharmacokinetics of TX2100 after single ascending dose. We expect to report top-line results from this trial by 4Q 2026. We plan to initiate an open-label phase Ib trial in patients with severe HHT. In this trial, we will assess the safety and tolerability of TX2100 after multiple doses, and we will explore the effect of 2100 on a variety of efficacy endpoints. In addition, we are planning a phase II placebo-controlled proof-of-concept dose-ranging study in patients with moderate to severe HHT. Our primary endpoint will be an assessment of the change from baseline in epistaxis as compared with placebo. Secondary endpoints will include placebo-subtracted change from baseline in hemoglobin, hematologic support, and other relevant HHT patient-focused endpoints. Next slide, please. Before we close, we want to mention the potential of an additional opportunity to expand TX2100 to an additional patient population. We believe that the anti-angiogenic mechanism of TX2100 offers the opportunity to explore treatment of other bleeding disorders due to dysregulated angiogenesis. For these patients, small case studies and investigator-initiated trials have demonstrated signals of efficacy with other anti-angiogenic therapies, such as bevacizumab and thalidomide, and suggest that the anti-angiogenic effects of TX2100 may be a successful treatment approach. To explore this hypothesis, Tectonic conducted studies in a non-HHT preclinical model of dysregulated angiogenesis. These studies demonstrated that blockade of the APJ receptor results in reduced vascular hyperproliferation, confirming the potential effectiveness of this approach. We plan to present these preclinical data at an upcoming scientific congress. Next, please. Next slide, please. In conclusion, TX2100 is a potential first-in-class APJ antagonist for the treatment of HHT. As discussed, we propose that TX2100 would act as an anti-angiogenic agent in the setting of excessive dysregulated angiogenesis that's seen in HHT. This approach has been validated through off-label use of other anti-angiogenic agents, which improve bleeding and anemia in HHT. Blockade of the APJ receptor represents a differentiated target for the treatment of HHT. Apelin is typically elevated in the setting of pathologic angiogenesis, and because the APJ receptor has endothelial-enriched expression, TX-2100 offers the potential to provide pathology-biased, anti-angiogenic efficacy with the potential for improved safety. Given the experience of other anti-angiogenic agents, we believe TX-2100 has de-risked translation and a path to value. Our preclinical data presented today demonstrates efficacy of the approach in 2 validated preclinical HHT models. The tolerability and safety of this approach is informed by our toxicology program, which revealed no dose-limiting toxicities at the highest exposures evaluated. We have now begun our phase I trial and look forward to starting our phase II trial in HHT in a timely manner. We see a potential opportunity to expand TX-2100 to an adjacent condition associated with dysregulated angiogenesis. I'll now turn it back to Tara for questions. Great. Thank you, Marcie. Yes, at this time, we'll be conducting a question-and-answer session with our speakers. Please hold for a brief moment while we poll for questions. Our first question comes from David Risinger at Leerink. Please go ahead, David. Great. Thanks very much, Alise and team, really appreciate all of the high-level perspectives, and then the details on how far along you already are with this with this candidate. My questions are, could you just provide a little bit more color on the safety profile as you see it? I think you discussed how the APJ target is expressed on endothelial cells rather than regular cells, and you've obviously seen clean safety to date. If you could provide more color on that, and then anything that you might be watching for when you see human clinical trial results. With respect to your move straight into healthy volunteers, I think that's differentiated versus other candidates in development for HHT. If you could comment on that. Finally, if you could discuss the IP that you're developing for this specific candidate. Thank you. Why don't I just take the IP one? We're really not gonna talk about IP today, I do promise that we will have relevant updates in our regulatory filings. In terms of safety, I mean, you sort of summarized it, David. To date, based on our preclinical testing, we really haven't seen any safety issues of concern, right? The 12-week non-human primate studies were clean. There are reports of APJ agonism leading to increase in muscle mass. We looked specifically in our non-human primate studies at muscle, both the looking directly at the tissue as well as muscle mass, and we did not see any evidence of a diminishment of muscle mass. There's a whole variety just, you know, of general safety. We'll see what comes out of our early studies, that'll help direct the program going forward. You know, it's... I don't know of any drug that has a label that doesn't have any safety findings associated with it. I think we just need to see what we find in the clinic, but we feel quite comfortable where we are today. Excellent. Thank you very much. In terms of being able to go into normal, healthy volunteers, Marcie, you can take that one. Sure. as you know, it's a very efficient way of getting your initial safety tolerability and pharmacokinetics if you go into healthy volunteers. I believe Alnylam did. I think Diagonal is going straight into patients. I think you wanted to understand how unique this is. it obviously very standard in drug development to go into healthy volunteers for your first study. I think our preclinical data enable us to do that. You can't do that with some of the other agents because of the potential safety signals. Got it. All righty. Thank you again. Thanks for the questions, David. Our next question comes from Yasmeen Rahimi at Piper Sandler. Please go ahead, Yas. Good morning, team. Thank you so much for the very thoughtful presentation, and thank you to our KOL as well. I guess would love to hear from our KOL physician who provided such a thoughtful analysis, what his, you know, thoughts are on TX2100's mechanistic strong rationale, maybe also thoughts around onset of action, because I think that raises the next question. Once you enter the 1B portion, how soon could you see a proof of concept? Question 1 is mechanistic, his mechanistic thoughts. Question 2 is onset of action based on the mechanism, and then 3 is for you, team, is just what type of a POC data would you like to see in the 1B? I assume it's the phase Ib and the phase II going to be starting concurrently, or the phase Ib will finish and then phase II starts? I'd appreciate a clarification around that point as well, and then I'll jump back in the queue. Okay, I'm gonna turn it first to Hanny. Yeah. You know, in terms of mechanism, based on, right, the data that we have, set that were presented today, right? The mechanism seems very much in line with what we would anticipate would be efficacious in HHT. For me, you know, I sort of expect that this mechanism is efficacious, given the really profound impact on angiogenesis. For me, I obviously like to see the very positive safety data from all of the preclinical work that's been done. That is, you know, very reassuring, right? Because right now, you know, I suppose the drug that maybe is most similar, clinically, and the team can correct me if I'm wrong on this, would be bevacizumab. That's at least the way that it seems, based on, you know, the data that's been presented. You know, one of the major issues with bevacizumab, right, is all the off-target toxicity. If this drug, it manages to avoid that would be really substantial. In terms of onset of action, you know, that's obviously something that you only know once you know, once you've actually done the studies. I will say that, you know, different drugs, as they are right now, of these various off-label drugs that we do use, do have different onsets of action, and the fastest by a wide margin is bevacizumab in general. That's thought to be related to vascular permeability inhibition through the drug. You know, most patients on average begin responding to bevacizumab in 2-4 weeks, whereas for most of other vascular remodeling type drugs, including drugs like pomalidomide, it often takes longer, like, around, you know, 4-12 weeks, I would say, in terms of, typical onset of response. Thank you, Hanny. You, you did ask sort of a question. The phase IIb and the phase II will run in parallel. You know, we'll be looking for evidence of treatment effects such as epistaxis and change in requirements for iron transfusions and blood transfusions in that study. Thank you. Thank you, team. I'll jump back in the queue. Thanks for the questions, Yas. Our next question comes from Tyler Van Buren at TD Cowen. Please go ahead, Tyler. Hey there. Thanks for the very interesting presentations. Just given the preclinical data and what appears to be differentiation on durability of effect relative to VEGF inhibition, as well as to the improved effect on hemoglobin, can you just elaborate on why this APJ mechanism would have differential effects on durability and hemoglobin? Then a second question would just be a follow-up on the phase Ib. You know, we obviously wanna see you guys move this program forward as fast as possible. Is it possible to start the phase Ib before the phase II or the phase Ia data in Q4 or before the phase Ia is formally complete? Be helpful to understand how soon you could start the phase Ib in patients. Thanks. Okay, Peter. I'll let Peter take the first shot at the question about why we think there could be a difference in durability, as evidenced in our preclinical models. Yeah, I think as I kind of went through in the slides, you know, kind of the VEGF pathway and indeed aspects of the AKT pathway, they in addition to regulating angiogenesis, they also have effects on kind of normal vascular homeostasis. You know, kind of our thinking there is, while both of them may be having an anti-angiogenic approach, some of the effects on kind of normal vascular homeostasis, there could be a counterbalance there that's maybe blunting some of the efficacy. You know, I think that's our current thinking on it. Marcie, you wanna take the question about the phase Ib? Sure. We will need to get PK from our first- in-human study to decide the dose that we would do in the 1B, but we plan to get that study started as quickly as we can once we get some PK from our first- in-human study. The anticipated dosing interval at this point in time is? I think we got to, let us get some PK, and then we'll be happy to talk about it. Fair enough. Thank you. Great. Thank you for the questions, Tyler. Our next question comes from Uy Ear at Mizuho. Please go ahead. Hey, guys. Yeah, thanks for this great presentation. Maybe just help us sort of understand a little bit about. You know, I think you guys spoke about the VEGF having... There's also the homeostasis effect of this, and either for the company or for the, maybe also for the KOL, maybe just help us understand, you know, with other targets, such as ALK1 targeting, how does this particular targeting in I guess, can be used chronically, I guess? You know, how does that sort of, how do the other mechanisms, do you expect the other mechanism to also be safe, in terms of using chronically, considering that, you know, if you block angiogenesis in general, it would also impact other, it would impact the entire system chronically, and it could also lead to other kinds of conditions? Thanks. Uy Ear, are you asking about a specific mechanism, or are you talking about in general? Yeah, in general. Like, how does this allow you to use the drugs on a more chronic basis versus perhaps, your competitors that are, you know, targeting either, ALK1 or the Vidaris product or anything to that effect? Thanks. Why don't I let you take that, Peter? Okay. maybe let's talk about kinda AKT inhibitors, Vidaris and a number of other companies. You know, I think the issue you run into with AKT inhibition, that you run into the risk of abnormal glycemic control and skin rash, because obviously AKT is a key signaling node across many cell types and tissues, controlling a number of different physiological processes. You know, even if you try and get to kind of selective AKT1, for example, you may be able to dial out some of the effects on glucose and insulin, but you may not get away from some of the other physiological effects. Again, you're hitting the pathway globally, compared to our approach, which is kinda, you know, much more surgical, and we're really only inhibiting the upregulated apelin and APJ signal in endothelial cells. You also mentioned ALK1. I assume you're referring to the Diagonal approach, you know, which I think is a super interesting approach. It's also a potentially disease-modifying approach. You know, the difference, I think, is with the Diagonal approach, they're approaching the pathway, you know, upstream to try and fix the signaling in the pathway. Whereas our approach is downstream, and because we're actually targeting the, you know, the pathological disease driver of the disease, the angiogenesis. They're differentiated that way. You know, like any, like any drug discovery program, as Alise mentioned, you know, the data we have so far indicate that we have a very good preclinical safety profile, which gives us confidence, moving forward, that we will potentially be able to differentiate over safety compared to the other competitors. Okay, thanks. Thank you for the questions, Uy. Our next question comes from Gaurav Maini at LifeSci Capital. Please go ahead, Gaurav. Hey, everyone. Really appreciate the time going over HHT today, and congrats on initiating the phase I trial. Just a couple here from me. You know, as the team had highlighted in the slides here, with the multiple mouse models available for HHT, which is really encouraging to see, maybe could the team clarify kind of which models you view as most translationally predictive as it relates to human efficacy, especially given the differences in severity and tissue involvement that we see? A second one, maybe as it relates to downstream, as we kind of enter POC trial design and data in the future, you know, given HHT is phenotypically quite heterogeneous, how should we be thinking about patient selection for early efficacy studies? Will there be any sort of, enriching for a particular subgroup or anything surrounding that? Thank you. Peter, do you wanna take the first question? Sure, yeah. You know, the two animal models we used, as I mentioned, were the anti-BMP9/10 model and the ALK1 model. You know, the anti-BMP9/10 model, it's a neonatal model, but it, you know, based on the literature, it's mechanistically predictive, produces AVM phenotype. There's increased VEGF receptor activity in the model. You know, there's published data showing that if you block VEGF receptor signaling, it works pharmacologically in this model, so it, there's good translation. You know, with all of the... A lot of the models that are out there are neonatal models, one question we had was, you know, "Is there some sort of a developmental context to the model?" Which is why we moved into the adult inducible ALK1 model. We, you know, we picked the most severe model. As Hanny mentioned, these mice, they're really succumb to disease within a couple of weeks. The ALK1 model captures disease in the mature vasculature. And, you know, we were excited to see the kind of the efficacy we were able to achieve in terms of maintaining hemoglobin levels and, you know, in the context of vascular architecture, being able to see that we're able to revert the vasculature back to a more normal phenotype. Hanny, I don't know if there's anything. Did you want to add anything to that? I mean, any time a therapeutic is effective in the severe phenotype ALK1-inducible knockout mouse model, that's impressive. You know, just to add to the commentary, because again, those mice usually die within a couple weeks of fatal, horrible internal hemorrhage. Any efficacy signal you see there is good, and certainly if it's a very clear, promising subtype signal, that's quite good. I can also comment on the, you know, how to select patients for the POC, if you'd like. Sure. Yeah. You know, this is it's a little bit my bread and butter. No, you know, the population of patients that is in clear need here are those moderate to severe bleeders. There are a number of tools as well as criteria that have been established by a international consensus report on standardization, outcome criteria, definitions, and terminology in bleeding in HHT that was published last year. That really highlight how to properly select your patients for clinical trials in HHT, both the moderate and the severe group of patients. The thresholds there are very, they're validated, they're delineated. We're talking about, you know, a certain amount of iron infused or red cell units given over a certain period of time, you know, to define a certain threshold of overall bleeding severity. Tools like the Epistaxis Severity Score and epistaxis electronic diary applications that capture the frequency and duration and flow intensity of epistaxis. These things have been standardized and, you know, I can let the team comment on how they would potentially plan to employ them, but they are there, they exist, and they were developed for this exact purpose. Gaurav, I don't know if you were trying to go there, but we think we would work on all of the different genetic types of HHT, so there would be no patient selection, based on that. Gotcha. Appreciate the color. Thanks, guys. Thanks for the question, Gaurav. Our next question comes from Alex Nackenoff at Truist. Please go ahead, Alex. Hey, guys. Thanks for the call. I guess just a question on, and, you know, continuing on the course of questions on time, course of efficacy, over the course of phase Ib, phase II trials. Just kind of give us an idea of, like, the benchmark internally, for what you think is an achievable, efficacy on epistaxis that, and, you know, what you would consider a go, no-go consideration. Also, considering the mechanistic advantages over just targeting bleeding, you know, noting the Alnylam program, is there a potential to detect, the vascular malformations in the course of a clinical trial? Sorry for, if that's a naive question, just kind of curious what the time course of new malformations might be, and if there are clinical endpoints that would allow you to detect any impact on that. Thanks so much. Alex, in terms of our bar, I think it's too early in the program. We're not quite ready to set a bar for you. Stay tuned. Let us first get some phase Ia data, finalize our protocols, et cetera. You know, if you show less bleeding, in essence, you're having an effect on the telangiectasia, I think. You know, whether you can have over a 12 or 24-week study, an impact on these very large or larger, you know, year, several year-long AVMs, I think would be a tall order task. That doesn't mean that over time it couldn't happen, but I don't know, Hanny, if you have any other comments you wanna make on that. Yeah, it's a great question. The most important endpoint that needs to be evaluated in HHT clinical trials is bleeding, and very specifically, epistaxis. It is obviously of interest to have an impact on visceral AVMs, right? These are lesions that, as was mentioned, right, develop and grow over the course of years to decades. It remains to be seen, right, if one can have an impact on them over a three or six-month double-blind period. This is the kind of thing that you can look at much more, you know, intently in an open-label extension, right? Where you have potentially, for example, serial imaging of the liver, using specific methods that detect shunting through the liver, and you can quantify that shunting, which is, you know, a very clear, clinically relevant, demonstration of the impact of AVMs in the liver because there's huge amounts of shunting through them. You can do that, right, over one year, two years, three years in an open-label extension, quite a bit more readily. You don't have a placebo comparator, but these lesions don't shrink on their own. They don't involute on their own. The natural history is that they get worse and get worse and get worse. Any involution or reversal, right, would be considered extremely promising in that regard. Thanks so much for the color. Thanks for the questions, Alex. Our next question comes from Leland Gershell at Oppenheimer. Please go ahead, Leland. Thank you for this terrific presentation, looking forward to seeing more data from this program. Most of my questions have been asked and answered. Just a question, as there are multiple, you know, drivers of HHT in terms of the three different genes, just wondering, would you expect any difference in therapeutic effect across those different contributors? It seems like you wouldn't, given the commonality in the pathway, just felt like I should ask that question. Thank you. Correct, Leland. Our expectation going in is that we would have similar efficacy. Great. Then just actually one question for Dr. Al-Samkari. Commercial's obviously some time away, but nonetheless, you know, it seems like this is a market that's kind of waiting for the proper therapeutic, a targeted agent, you know, that'll actually, you know, really work and not have side effects. Would you believe that, you know, improvement in epistaxis frequency and severity would be enough kind of for this market to develop in favor of Tectonic? Would you think that physicians would need to see much further than that to be convinced of the therapeutic value here? Thank you. Hanny, take it from here. Yeah, 100% it would be enough to have improvements in epistaxis frequency, duration, intensity, the so-called parameters or domains of epistaxis severity. These patients, you know, as I kind of just gave you a little bit of color and flavor in my cases, I mean, these patients, 40% of them, 40%-50% of them have DSM-5 diagnosable psychiatric comorbidities, Major Depressive Disorder, a DSM-5 anxiety disorder like agoraphobia or generalized anxiety disorder or panic disorder, or even post-traumatic stress disorder. About 10% of all HHT patients have post-traumatic stress disorder. This is completely a result of epistaxis, okay? It's not because people are worried that their hemoglobin is gonna be low. It's not because they have AVMs in their liver, right? It is because they are just absolutely miserable about having bleeding from their face happen while they're at work, while they are with their children, while they're in public, while they're at dinner, while they're being, you know, sexually intimate. I mean, you name it, blood gushing from your face is a real, you know, problem in normal day-to-day life. This is an extremely patient-centric outcome, which is obviously very relevant for any new drug and for approvals. It is something that the data has already shown, that the epistaxis in HHT has the greatest impact on quality of life. There's no question in my mind that not just the first one or two or three drugs that we hopefully get approved in this disease, only need to show improvement in epistaxis. I would say, and by only, right, it's still, it's. I don't wanna make it seem like it's not a high bar. It is a, it is a very, very important bar to show very meaningful improvement in epistaxis. Not the easiest thing to do, which is why, again, we're using off-label cancer drugs that cost lots of money and cause lots of side effects to treat these patients. They're willing to do it, right? It's that miserable for them. The first five, six drugs, I would say, that get an approval, and hopefully we'll have that and more, will, the bar will be: Do you improve epistaxis significantly and do it with an acceptable safety profile, right? I want to see drugs, obviously, that also work on gastrointestinal bleeding and many of, you know, for all the reasons we've discussed, right, and have been discussed today, right? This is a mechanism that should work for that too. Obviously, we wanna see drugs that work for arteriovenous malformations, but it's not gonna be a question of, well, epistaxis is not good enough. That's not gonna be a question for a very long time, for a number of different agents with, you know, that are approved. You know, the expectation, right, is that we will need an armamentarium of drugs to treat this disease, for a number of reasons, and the most important thing right now remains, and will remain for some time, bleeding, and specifically epistaxis. Hanny, please correct me if I'm wrong. My understanding is there is some data even with bevacizumab, that it does impact the AVMs in the liver. That's correct. That's correct. AVMs in the lung and the brain can often be treated or surgically- With procedures, correct. Yeah. Not every lung AVM, not every brain AVM, most lung AVMs for sure, and a large percentage of brain AVMs can be successfully managed with procedures. It's not believed that those procedures provoke additional AVM formation, like the cautery-type procedures of the mucosal telangiectasias and AVMs that definitely do. You know, we have treatments for... We want obviously better treatments. We want medications, because procedures come with all sorts of risks and challenges, and very high cost. We would prefer medications, and obviously, hopefully, medications would be preventive as well- Right down the line. That is absolutely correct, and there's nothing for liver, okay, except for a modest, modest effect of bevacizumab on liver AVMs. That can be temporizing. That really is a bridge to liver transplant for these patients. Thanks. That's very helpful. Yeah. Thanks for the question, Leland. Our next question comes from Martin Auster at Raymond James. Please go ahead, Marty. Hey, guys. Thanks for taking the question. In the phase IIa, I know you'd said that apelin isn't particularly expressed during angiogenic quiescence. I was curious if there's any biomarkers that of relevance that you could look at to sort of understand pharmacodynamic activity? I guess the opposite of that, as you get into patient study, I was curious to the degree that apelin, and particularly the APJ receptor are overexpressed, and whether that's something that can be monitored in those early studies to kind of get an idea of what the impact is that you're having. High level is we don't expect biomarkers in our phase Ia. We will look, but we don't expect them. Marcie, why don't you take it from here on that? Sure. We have a number of biomarkers that we're exploring in our clinical patient studies. We hope to find a biomarker response, and so we'll be looking at a number of them. They are disease-related biomarkers. They're not specific to, they're not downstream of APJ. Got it. Okay. Thank you. Thanks for the question, Marty. Our final question comes from Ben Burnett at Wells Fargo. Please go ahead, Ben. Oh, great. Thanks so much. I want to just ask about the heterogeneity expected in severe, moderate to severe patients. For example, would you expect these patients to have, like, larger and more complex venous malformations, the AVMs? In those patients, would you anticipate needing a higher dose and longer exposure to have an impact? You want me to take the question? Yeah, go ahead, Hanny. Yep. Yeah, very good question. There is some correlation between the likelihood of having solid organ AVMs and the severity of those, as well as bleeding, primarily because of the progressive nature of the disease. If you are dealing with a population of patients in their 60s, 70s, and 80s, right, you're gonna have way more liver AVMs and more of a history of lung AVMs, and also more severe bleeding in, as a general statement. Really, truly, it's not what we've observed, right, with other therapeutics. There hasn't been a situation where we have used a therapeutic and it's only been, you know, for example, bevacizumab or pomalidomide, and it's only been effective in patients with more mild disease or what have you. It really... We actually just published a paper on predictors of response to pomalidomide, and having more severe bleeding at baseline actually predicts for a greater response. You know, it's not a circumstance where we would expect it to necessarily take a longer. It certainly, in every patient, there is, you know, some variability for how long it takes them to respond. In a general statement, right, for effective therapeutics, you tend to see a response within the two-to-three-month mark, right? Particularly if your mechanism is anti-angiogenic. If you're looking at a short duration, you know, initial proof of concept study, looking at, you know, by 12 or 16 weeks, you should see the signal for improvement. If you're talking about a pivotal phase III kind of study, right, about six months or so is the sweet spot there to give the arms very clear time to properly diverge, and give some of the slower responders time to have their response. You really can't keep these patients on a placebo for much longer than six or seven months. It's about that sweet spot there. To answer part of that question, Ben, we don't expect we need more higher doses, for example, in more severe patients. That's not our expectation. Okay, that's super helpful. If I could just squeeze in one just last one: Would you anticipate stratifying or enrolling based off bleed location? Not at this, you know. Not currently. Not at this time. Yeah. It's not something that has generally been done in the past. As a general statement, you wanna be sure that you don't have massive imbalance in where your GI bleeders are, but if you have a decently sized proof of concept study, that should not be an issue. Understood. Thanks so much. Thanks for the questions, Ben. I'll now turn it over to Alise for some quick closing remarks. Thank you very much for everybody for joining us. We really appreciate it. As you can hear, there's a lot of enthusiasm for the program, and we look forward to providing more updates in the future.