Good morning and welcome to the DiaMedica Therapeutics 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 DiaMedica website following the conclusion of the event. I'd now like to turn the call over to Rick Pauls, President and Chief Executive Officer at DiaMedica Therapeutics. Please go ahead, Rick. Good morning, everyone, and thank you for taking the time to join our call today. We sincerely appreciate your interest. We have organized this event because in the coming weeks, we expect to share data from our ongoing investigator-sponsored clinical trial in preeclampsia. With so few therapies currently in development, we felt it was important to provide investors and others interested a chance to better understand the impact of preeclampsia on women and their unborn babies, and why it remains one of the most significant unmet medical needs today. With May being National Preeclampsia Awareness Month, the timing of this discussion feels especially fitting. Most people have heard of preeclampsia, but there is still a major gap in understanding its underlying causes and how it is currently treated. One of our key goals today is to help close that gap by shedding light on the disease and the limited treatment options available. We'll also walk through the efficacy and safety thresholds we believe are clinically meaningful in Part 1A of the ongoing phase II study, not just from a scientific perspective, but in terms of real-world impact on patients. Prior studies have clearly shown that DM199 can significantly reduce blood pressure. Reducing blood pressure in preeclampsia patients is critical to improving outcomes for both mothers and their babies. Today, we'll discuss what clinically meaningful data really means. We'll also explore the potential of DM199 to dilate the intrauterine arteries, which would increase blood flow to the placenta, which could be disease-modifying and lead to larger, healthier babies. Also, a key safety advantage of DM199 is that it is not expected to cross the placental barrier, or if it does, only in minimal concentrations, unlike small molecules that passively diffuse and reach the fetus. Thus, if we can safely show meaningful drops in blood pressure and possibly also dilate the intrauterine arteries, we believe it could represent a transformative moment, paving the way forward in our clinical development path of DM199 for what could one day become the first FDA-approved treatment for preeclampsia. Now, I'm honored to introduce our three distinguished OB-GYN physician speakers joining us today. Let me introduce them in the order that they'll be speaking. Dr. Baha Sibai is a world-renowned maternal-fetal medicine expert, a professor at the University of Texas Health in Houston, and director of the nation's largest maternal-fetal medicine fellowship. Professor Sibai is a world-recognized expert in maternal-fetal medicine with a specific focus on the study of hypertension and preeclampsia. He has published over 650 peer-reviewed articles, led NIH-funded trials, and earned major honors, including the SMFM's Achievement Award and the ACOG's Hall of Fame All-Star status. Dr. Sibai will offer his perspective on the current clinical challenges and the high unmet need in preeclampsia patients. Next, Dr. Stephen Tong is a clinician scientist at Mercy Hospital for Women and the University of Melbourne. He's also listed as one of the top 10 preeclampsia experts in the world by ExpertScape. Professor Tong currently serves as the Co-Director of Mercy Perinatal and has led global clinical trials for preeclampsia pregnancy treatments. With over 250 publications, NHMRC fellowships, and major grants, he's a leader in maternal-fetal innovation and diagnostics. Dr. Tong will discuss the evolution of preeclampsia and how DM199's mechanism of action could break new ground as a potential treatment for this very serious unmet medical need. Dr. Sue Walker is head of the obstetrics and gynecology at the University of Melbourne. She leads the perinatal medicine at Mercy Hospital and Victoria Fetal Therapy, a renowned expert in fetal growth disorders, preeclampsia, and stillbirth prevention. She has over 250 publications, major NHMRC funding, and co-chairs the RANZCOG committees. Dr. Walker will review the limited treatment options currently available and walk us through the design of the ongoing preeclampsia clinical trial. Following their presentations, we'll open up the floor for a Q&A session. Please also note that some of the images that will be shared today are clinically graphic in nature, as they depict real cases of preeclampsia and its consequences. They are being shared to underscore the seriousness of this condition and the urgent need for effective treatment options. With that, let's begin. Dr. Sibai, could you please start us off? You're on mute, Dr. Sibai. Good morning. My name is Baha Sibai, and today I'm going to go over some of the unmet needs in preeclampsia. First, the condition is a life-threatening high blood pressure disorder that occurs only during pregnancy and in the postpartum period. It affects somewhere about 5%- 8% of all pregnancies in the United States. This rate is increasing. About 180,000- 300,000 pregnant women will have the condition every year. The hallmark for the diagnosis of preeclampsia is elevated blood pressure that occurs after 20 weeks of gestation and in association with other organ abnormalities. One of them is the sudden spike in blood pressure that causes seizures, stroke, multiple organ failure, and even death for the mother and/or the baby. Also, you'll see excess protein in the urine, a decrease in kidney or liver function, fluid in the lungs called pulmonary edema, fetal growth restriction, hypoxia and stillbirth, and decreased levels of platelets in the blood, known as thrombocytopenia. At the present time, the only cure for preeclampsia to stop the disease is to deliver the fetus and the placenta, often leading to premature delivery. Next slide, please. The management of these patients usually involves giving them steroids, controlling maternal blood pressure, giving medication to prevent seizures, and delivering the baby. However, even after delivering the baby, despite the use of steroids, there are still significant morbidities that affect these babies: bleeding in the brain, known as intraventricular hemorrhage; bleeding in certain vascular areas of the neonatal brain, known as periventricular leukomalacia; necrotizing enterocolitis, and this is a condition that affects the bowel of the fetus and neonatal sections. In addition, these babies will require long-term ventilatory support, as well as develop a condition known as bronchopulmonary dysplasia. This condition will have clinical implications long-term for the baby, months after delivery. Or the baby could die. Even when the baby survived, they are more likely to stay a significant number of days in the neonatal intensive care unit. Once they leave the nursery, they're going to have significant long-term morbidity, including hearing disorders, visual disorders, cerebral palsy, and neurologic deficits. Next, please. There is no doubt both mortality for the baby as well as after the baby surviving having significant neurologic morbidity depends on gestational age and delivery. Babies delivered at 24 weeks have almost a 50% chance of dying, and many of these, even if survived, will have long-term deficits. As we improve gestational age on a weekly basis, this transfers into a significant reduction in the likelihood of the baby dying, as well as the likelihood of the baby surviving with significant morbidity or without significant morbidity. This is why extending or prolonging gestation this early in pregnancy has significant clinical implications, whether the baby's going to die and whether the baby is going to have a long-term morbidity. All of these cost a huge amount of money as it relates to the days spent in the neonatal intensive care unit, plus long-term implications to take care of a baby that has problems with their hearing, problems with their lungs, having cerebral palsy, as well as having problems with their vision. Next slide, please. Listed here, the rate of these complications that have a huge economic impact, as well as emotional and psychological impact, there's a family, and more importantly, there's a cost for the whole of the health system. Respiratory distress syndrome is one of the most significant complications. Bronchopulmonary dysplasia, necrotizing enterocolitis, this is a condition that affects the intestine of the baby, and bleeding in the baby's brain are all significant complications in babies born at 24-28 weeks gestation. This is why prolonging gestation at this gestational age has significant implications. Next, please. In addition, the rate of long-term deficits in infants born at less than 28 weeks includes cerebral palsy, and this is a condition that affects really the baby all their life and has implications regarding cost, as well as problems and impact on the family as such. Impaired vision and impaired neurological deficit, and more importantly, 40% of these babies will be disabled. Next, please. When we try to prolong gestation, and this is what we call expectant management, this is a protocol I really introduced more than 40 years ago, and this is very important. Anytime we try expectant management, we're trying to prolong gestation, and this is really for fetal benefit, but it has significant risks to the mother. These problems include pulmonary edema, a woman developing DIC, where they can lead to death, developing a condition called HELLP syndrome that affects the maternal liver, and leading to other injuries to several organs such as the kidneys, the brain in the form of stroke, and eclampsia, where this woman could have seizures. In some situations, this will lead to maternal death. Next, please. This graphic, you know, again, I have listed to you some of the cases I have seen over the years regarding complications in the mother when we try to prolong gestation, and this includes really bleeding in the brain, and this could be in various areas of the brain. Some of them might be fetal, and some of them will lead to long-term deficit, developing of seizures. This is a patient where they have got biting of the tongue, significant bleeding in the brain, involvement of the liver, where a patient could have subcapsular liver hematoma, bleeding from everywhere, developing of abruption placenta, which is premature separation of placenta. This will lead to fetal hypoxia and probably fetal death, and also will lead to patients have significant and major bleeding, including development of coagulation and the need for multiple blood and blood products. This is how a liver hematoma looks at surgery, also involvement, development of a condition in the brain that is similar to stroke and having fluids in the lungs. Next, please. In addition, there are a lot of things that happen when this condition develops very early in pregnancy, particularly when it is associated with fetal growth restriction. This is a baby that develops fetal growth restriction at 25 weeks, after we spent a lot of time and effort trying to prolong gestation and end up dying in the neonatal intensive care unit at the age of 276 days. This is another baby that survived at 25 weeks IUGR, and at that time, it was three years old. However, this baby is having significant neurologic problems and pulmonary issues despite the fact the baby is still alive. This is a baby, despite all of our efforts, ended up dying. These are really just an example where this condition happened very early in gestation, how it affects the fetus, whether the fetus is going to survive. If the baby survives, what are the implications for the baby? Next, please. Again, this is a graphic for patients, and as you know now, we are seeing more of these conditions, particularly as women really are delaying pregnancy to later maternal age, and with the impact really of obesity. A lot of women are having infertility problems and getting pregnant by IVF. This is a patient who had egg donation. She developed severe IUGR at 23 and four days. I was able to prolong her gestation by about nine days. However, she ultimately required delivery because she had HELLP syndrome. The baby was born at 470 g. Unfortunately, the baby died in the neonatal intensive care unit at 14 months of age. Next, please. All right. Thank you, Sibai. I appreciate that it is a very important overview. We now like to turn the call over to Dr. Tong to talk about how preeclampsia evolves and the mechanism of action with DM199. Thank you very much, Rick. My name is Professor Stephen Tong, and I'm based in Melbourne. First, I'd like to start by explaining how preeclampsia arises. There are two stages in its evolution. Stage one of preeclampsia occurs in early pregnancy during the first trimester. In normal pregnancies, the early placenta embeds in the lining of the uterus. It drastically remodels or renovates the blood vessels in the uterine walls called the spiral arteries. Placental cells widen these spiral arteries by a massive 5-fold-10-fold, and this promotes plentiful blood flow to the placenta, providing it with all the oxygen and nutrients it needs to grow a healthy baby. In preeclampsia, this all goes awry. The preeclamptic placenta fails to embed properly in the wall of the uterus. The spiral arteries are not properly remodeled. They fail to widen. The blood vessels supplying blood to the placenta remain narrow. The flow of blood, oxygen, and nutrients to the placenta is dangerously reduced for the rest of the pregnancy. Such early events set the stage for preeclampsia. Next slide, please. Stage 2 of preeclampsia occurs after 20 weeks of pregnancy. The stressed placenta, chronically starved of oxygen, releases noxious factors that spread through the mom's circulation, and these inflict widespread damage to her blood vessels. An important example of such a noxious factor is the anti-blood vessel protein called sFlt-1. The placenta also releases many other factors aside from sFlt-1 that are highly damaging to blood vessels, such as pro-inflammatory cytokines and molecules. The damage caused by these noxious factors on the maternal circulatory system is a pathological process known as endothelial dysfunction. Blood pressure rises sharply, and the vital organs supplied by these blood vessels do not receive the oxygen or nutrients they need. These organs in the mom then become dangerously sick. Brain injury can lead to stroke. The lungs can dangerously fill with fluid, compromising breathing. The liver can rupture. The kidneys can become sick, leak protein in the urine, and the kidneys can even fail. Once preeclampsia takes hold, there is no drug that can slow the disease progression. The only option, as Dr. Sibai mentioned, is to deliver the placenta. As Dr. Sibai said, at preterm gestations, this can inflict severe prematurity on the baby, beautifully presented by him just to show really the real terrible health impacts arising from needing to deliver the baby at a preterm gestation. I'm now pleased to explain the exciting potential of DM199 to be the first breakthrough treatment for preeclampsia, why DM199 could be the ideal drug treatment for preeclampsia, and why DM199 may be a drug in a class of its own. The diagram on the left is a cross-section of a blood vessel, sort of a cross-cut of a blood vessel. The outer layer is the vascular smooth muscle. The inside is where the blood flows, and the yellow rim is the single layer of endothelial cells, the inner lining of blood vessels. The middle picture zooms in on that endothelial cell layer. Bradykinin is a peptide in the bloodstream. Bradykinin, which is a short chain of amino acids, binds to and activates its receptor called the bradykinin 2 receptor on the surface of those endothelial cells. This switches on internal molecular circuitry within the endothelial cell that activates all three of the main pathways involved in reducing blood pressure: nitric oxide, prostacyclin, endothelial-derived hyperpolarizing factor. These molecules filter into the underlying smooth muscle layer of blood vessels and make muscles relax. Blood vessels widen, blood pressure falls, and the amount of blood flowing through the vessels increases, supplying distant organs with the oxygen and nutrients they need. Hence, bradykinin signaling would be a really useful strategy to treat preeclampsia. The problem is bradykinin only has a half-life of seconds. If you inject it intravenously, it would disappear before it even reached the top of the arm. DM199 made by DiaMedica Therapeutics is a protein that circulates in the bloodstream with a far longer half-life than bradykinin. Its function is essentially to make bradykinin. Hence, DM199 facilitates bradykinin signaling to reduce blood pressure and open up blood vessels. DM199 is simply a synthetic version of a natural protein called tissue kallikrein-1, but with slight modifications to enhance its stability. Being simply a drug version of a naturally occurring protein offers a critical advantage. It means that we already have two decades of biological research detailing the potential of tissue kallikrein-1 or DM199 to promote blood vessel health. It all points to DM199 acting in two places to combat preeclampsia: mom's blood vessels and maybe in the uterus itself. First, mom's blood vessels. Next slide. I refer you to the diagram on the right. As mentioned, DM199 might powerfully act to reduce blood pressure and open up blood vessels. Furthermore, research in the natural version of this molecule, tissue kallikrein-1, suggests that DM199 may have actions to reduce that endothelial dysfunction, and it can essentially restore blood vessel health beyond mere blood pressure reduction. I'll just give you one such example of many. DM199 might have the pretty interesting effect that it may overcome the adverse effects of that molecule called sFlt-1. As I mentioned before, sFlt-1 is a disease driver of preeclampsia. It's released from the diseased preeclamptic placenta in very high amounts, and it prevents a receptor called VEGF receptor-2 from switching on. That's bad because VEGF receptor-2 is a good guy. Its molecular role on the endothelium is to promote blood vessel health. Remarkably, it's likely that DM199 can relay signals inside the endothelial cell to switch VEGF receptor-2 back on. If this is true, then DM199 may remarkably overcome the effects of sFlt-1 in preeclampsia to restore blood vessel health. Aside from its many positive actions on mom's blood vessels, we think DM199 may have an important bonus action. DM199 may act within the uterus to stop preeclampsia at its source, and I now refer you to the diagram on the left. Placental hypoxia or low placental oxygenation is a key feature of preeclampsia. It is possible DM199 can open blood vessels in the uterus itself. If so, this could increase oxygen to the placenta, reducing that placental hypoxia. Reducing placental hypoxia will stop the excess release of the noxious factors causing the maternal vascular injury of preeclampsia. Thus, DM199 has the potential to switch off the release of those noxious agents right at its source, the placenta itself. In actual fact, we can test this premise in clinical trials. Doppler ultrasound can measure blood flow in the uterine arteries, and these are the big blood vessels supplying blood to the uterus and the placenta. In preeclampsia, in the clinic, Doppler ultrasound readily reveals increased blood flow resistance in these uterine arteries, suggesting that blood flow to the placenta is reduced. If DM199 can dilate blood vessels within the uterus, we can actually measure this by Doppler ultrasound. We could show, for instance, that giving DM199 reduces uterine artery blood flow resistance, meaning there's improved blood flow to the placenta. Hence, if I can summarize, the potential biological actions of DM199 to treat preeclampsia may be to powerfully reduce blood pressure, to open up blood vessels supplying more blood to mom's vital organs, to restore the health of maternal blood vessels generally by reducing endothelial dysfunction. Plus, the enticing possibility exists that it could increase blood flow to the placenta, stopping preeclampsia at its source. DM199 could be a revolutionary treatment that slows, stops, or even reverses the preeclampsia disease process. If so, it could save a lot of lives. For example, when preeclampsia occurs at an early preterm gestation, Dr. Sibai has beautifully outlined the case that we often need to deliver the placenta and baby preterm to save the mom. This inflicts all those nasty, terrible effects of prematurity on the baby, or those poor neonatal outcomes which were described before. If DM199 can quash the damage caused by preeclampsia, it could be given to women with preterm preeclampsia to safely prolong the pregnancy. If with pregnancy prolonged, the baby could be birthed at a less preterm gestation, dodge all those poor neonatal outcomes associated with being born premature with better lifelong outcomes. Finally, I want to tell you the potential point of difference of DM199 noted by Rick before, but it is a trait that no other drug proposed for the preeclampsia possesses as far as I know. The placental barrier is the surface of the placenta and keeps the maternal and fetal circulation separate. It tightly regulates what gets through the placenta and into the developing fetus, what gets in and what stays out. Small molecules, for instance, passively diffuse through the placental barrier, just like sugar through a sieve. Most drugs are small molecules. For instance, all those off-the-shelf tablets that you might just get at CVS Pharmacy, they're all small molecules. Nearly all drugs given during pregnancy, and I suppose outside of pregnancy, are small molecules. Those tablets are all small molecules. The issue then for small molecules is that it may enter the unborn baby where there may be potential health risks. In contrast, DM199 is a protein. Proteins cannot breach the surface of the placental barrier, a continuous border of cell membranes. Proteins are just too big. It is just like adding whole almonds to a sieve. They just will not pass through. Hence, being a protein, DM199 will likely stay out of the placenta. It will never reach the fetal circulation. If so, this could wipe away teratogenic concerns and any other concerns arising from direct fetal exposure. DiaMedica Therapeutics to look into this commissioned rodent placental transfer studies. These studies, the diagram on the right, shows a nice rise and fall of DM199 in the maternal circulation. DM199 remained undetectable in the fetal circulation. The implications, if DM199 in fact stays out of the fetal circulation, is perhaps pretty extraordinary. It means that DM199 may possess the neumagical qualities of having multiple actions to treat preeclampsia without even needing to enter the placenta, the very organ causing the disease. That is why we would argue that DM199 seems to be a drug in a class of its own. Hence, DM199 has the potential to be an ideal disease-modifying drug for preeclampsia. We therefore think DM199 is well worth evaluating in human clinical trials, and it just might represent a breakthrough drug that ends up saving a lot of lives. Thank you. Great. Thank you, Dr. Tong. That was a great overview. Next, I'd like to turn the call over to Dr. Walker, who's going to talk about the current limited treatment options and also a high-level overview of our ongoing phase II clinical trial. Thank you, Rick. Good morning, everybody. Where are we in 2025? We've heard from Dr. Sibai about the disease burden of preeclampsia and the risks to the mom, as well as the risks to her baby, particularly among those born severely preterm. Stephen has beautifully walked us through how the placental toxins cause and then amplify the disease process, which is characterized by endothelial dysfunction, causing hypertension and end-organ disease. We've heard why DM199 is particularly attractive as a novel treatment, given firstly, its action is on the end target of those toxins, the endothelium, and secondly, that it's not expected to cross the placenta. What are our current treatments for preeclampsia? We do not really have one. As Dr. Sibai said, we remove the source of the toxins, the placenta, and with that, the baby, sick, small, ready or not. The medications that we give in 2025 are to prevent the complications of the disease process rather than to address the disease process underlying it. The first panel that you can see there are the antihypertensives. We protect the mom from dangerous blood pressure spikes, for example, that can cause stroke with blood pressure drugs, alpha and beta blockers or calcium channel antagonists. While they control blood pressure, these agents do not improve endothelial health. The second row you can see there is that we give anti-seizure medications, particularly magnesium sulfate, to reduce the risk of mom having a fit or eclampsia, as you've heard, one of the most serious complications of preeclampsia. In the final row, you can see that if we have time, we do all we can to get the baby ready for premature birth by administering corticosteroids, which reduce the risk of complications from prematurity that Dr. Sibai has outlined to you: respiratory distress syndrome, intracranial hemorrhage, neonatal death, long-term morbidity. If I could have the next slide, please. These approaches really are insufficient. The data that I'm showing you here is from the PRESERVE trial, a trial in fact led by Dr. Sibai in an American network involving over 26 centers. The PRESERVE trial investigated the role of a new agent to improve pregnancy outcomes in women between 23 and 30 weeks with preterm preeclampsia. This trial gives us really contemporary data on what we call latency, the time to delivery from diagnosis until delivery, and the indications for delivery in preterm preeclampsia in America today. The medication that was trialed did not demonstrate any benefit, with the time to delivery about 5 days-6 days, and the babies were born very preterm. You can see here in the highlighted yellow row that even with access to modern antihypertensive treatment, refractory hypertension was the leading precipitant for delivery in both arms of the trial. This occurred in about half of the patients. I guess what this illustrates to us is we have a gap in achieving adequate blood pressure control for these patients with the current treatments I've described. The result is that we have an unmitigated risk to the mom of uncontrolled blood pressure and more preterm birth risks to the baby. If I could have the next slide, please. I would suggest to you that the gap that we have here is the endothelium. Let's look at some of the existing treatments for blood pressure. Antihypertensives currently used in pregnancies, such as nifedipine, work by causing smooth muscle relaxation, which lowers blood pressure by dropping vascular resistance. Agents like labetalol also drop vascular resistance and have an additional effect modifying heart rate and cardiac output. Neither of these agents target the endothelium, which, as Stephen has described, is the final destination of the toxins being released by the preeclamptic placenta, the endothelium being the master regulator of blood vessel health and function. What we've heard is that DM199 has multiple actions which address endothelial repair as well as blood pressure control through smooth muscle relaxation. Next slide, please. The question is, where do we take this to? We need to take it to a clinical trial in pregnant women. This is what's currently underway in our collaborative effort in Cape Town, South Africa. Next slide, please. The first step in the first human trial in pregnancy is finding what is the right dose. To do this, we're recruiting women with preeclampsia who have been determined to require delivery. These are women who are anywhere between 27 and 42 weeks who have severe hypertension, so more than 150 on 110, and they've been scheduled for delivery within 72 hours. You can see here these rising blocks are showing that we're currently doing a gentle and steady dose escalation involving 30 patients until we achieve an adequate blood pressure response. We are currently at strata eight. Our primary endpoints from this beginning, this early trial, the dose escalation, the dose finding trial here are firstly safety and tolerability. They're the most important outcomes in these early phase trials. In terms of safety and tolerability, we're looking for a drop in blood pressure. Importantly, we are also doing cord blood assays of DM199 to ensure there's no transplacental passage. We have exploratory outcomes. These are, as Stephen has mentioned, looking at the uterine artery blood flow with Doppler assessment and other measurements, including the levels of the pathogenic toxins such as soluble sFlt-1 and biomarkers of end-organ dysfunction, such as the creatinine, which is a measure of renal function. Once we've reached the optimal dose, we will then do an expansion cohort on a further 30 patients. If I could have the next slide, please. Perhaps if I could just summarize the key endpoints for the current study. The first thing is that we're looking at placental transfer. We're getting cord blood at the time of delivery to ensure lower undetectable levels of DM199, indicating that there hasn't been crossover of the placenta and going into the baby's bloodstream. As Stephen has said, if this is confirmed, this will be a significant reassurance. It's a highly significant safety signal that really can't be claimed by other small molecule therapeutics, which filter freely across the placenta. The second primary endpoint is achieving blood pressure control. Now, this is crucial. As we've seen in the PRESERVE trial that I presented, uncontrollable blood pressure is the single most common reason for abandoning expectant management and proceeding to preterm delivery. The pathways by which DM199 acts on the endothelium master regulatory system strongly suggest it could result in durable and sustained blood pressure control. Finally, we have our exploratory endpoint, which is the uterine artery Doppler measurement. This measures the resistance to maternal blood flow by the placental bed. High uterine artery resistance indicates poorer placental perfusion associated with fetal growth restriction and preterm birth. If uterine artery resistance drops, it suggests that DM199 may increase placental perfusion, meaning it can potentially ameliorate both preeclampsia and fetal growth restriction at their source. That is a bit of an overview of where we are and where we're going. I'd like to hand back to Rick. Great. Thank you, Dr. Walker. That was a very valuable overview. Tara, could we please open the line to the first question as we start off the Q&A session? Yes. We'll begin our Q&A session right now. Please hold for a brief moment while we pull for questions. Our first question comes from Thomas Flaten at Lake Street. Please go ahead, Thomas. Thank you. And thanks to all the doctors for joining this morning or this evening if you're in Australia. Dr. Walker, just following up on your last slide about the endpoints, I'm curious, given that KLK1 is an endogenous molecule, is there a larger safety margin if some of DM199 were to transfer through the placenta? Or is zero the only number that would make sense from a safety perspective? Thanks for the question, Thomas. I mean, obviously, what we would like to see is very minimal or no transplacental transfer. I don't think that it needs to be zero necessarily. I don't think that we would consider that a physiological molecule like this would necessarily mean that we couldn't be continuing to use DM199. I think we really have to gather the data first to try and get the indication of what transplacental passage there is. As Stephen has said, I guess there's a couple of things about transplacental passage. The first thing, of course, we all think about, I guess, in the lay audience is we think about things like thalidomide and causing birth defects. Now, do not forget, we will be using DM199 in a later gestation beyond the period where all the baby's organs have been made and matured. We are not thinking about using it in the first trimester. We have no reason to think that it will cause any of those problems because of all the reprotox studies that have been done. Nevertheless, we will be using it at a later gestational age. As you say, because it is a physiological molecule, we would just want to keep a bit of an eye on things like the blood flow patterns and the hemodynamics of the fetus and the newborn after birth. Fortunately, in the early studies that we've already developed and that are already underway, we are already doing comprehensive evaluation of not just the maternal uterine arteries, but also all of the fetal vasculature. This means we'll be able to look at things like umbilical artery blood flow, blood flow in the brain, blood flow in the heart and the liver and so forth, which I think then will be able to give us a very reassuring signal that we're not seeing changes in response to medication, even if it were to cross. Of course, what we're really hoping for is that we'll see that there's no or minimal transfer on those very first cord blood samples. Super helpful. Thank you for that detail. And then just sticking with the endpoints, I guess, for whoever, you know, to the point Rick made at the beginning, you know, the investment community isn't really that familiar with preeclampsia drugs because there haven't really been any. With respect to lowering of blood pressure, obviously Part 1A, you're looking at women who will be delivering within 72 hours. The acute lowering of blood pressure is important. What I'm curious about is, is there a definitive endpoint you need to get to, or is it just an absolute drop? Do you have to get below 130, for example, or is a 20-point absolute drop sufficient regardless of where you started from? Yeah, thanks, Thomas. That's a great question. Maybe what we actually can do is if we could advance, we actually, last year, we provided a summary of what we thought would be clinically relevant data. Maybe if we just jump to slide 31. Yeah, so here's a summary of what we had identified as the study was starting here in terms of what would be clinically meaningful results. Dr. Tong, would you mind just taking us through here in terms of blood pressure reduction and what you see as clinically meaningful? Yeah, sure. To answer Thomas' question, so thank you for the question. We recruit women where the blood pressures are really acutely very high. Just getting it under the threshold, which we would suggest a very high stroke risk, getting it under systolic 150 and getting it a diastolic well under 110 and hopefully under 100 would be an important goal. I think the first is a relatively drop from what we would call where clinicians would think would be a very dangerous level to a much more safer zone would be clinically relevant rather than always be a number. Just on average, we would suggest that what it may represent is something a bit like exactly as shown on the slide, a systolic blood pressure drop of 10 mm of mercury or a little bit more and a diastolic decrease of 5-10. What we hope to see is a consistent reduction in blood pressure of around those numbers with the administration of DM199 and a reliable expected drop of blood pressure with administration of the drug. I might also just reiterate that while these first studies, the early efficacy point we're looking at is blood pressure reduction, what I suppose excites me the most as a clinician scientist, which is the fact what it represents. A drop in blood pressure means that the drug is acting on the endothelium as we had expected. The anticipated benefits of that go well beyond just blood pressure reduction by it may suggest that the blood vessels are getting healed. You should be able to see all those benefits of reduction in endothelial dysfunction. We're healing the blood vessels of the mom by giving this drug. If you get one readout being a reduction in blood pressure, it would suggest plausibly that the biological machinery and the molecular mechanisms that you would expect DM199 to switch on are being switched on. You plausibly infer that there would be a rescue in endothelial dysfunction and an improvement in blood vessel health of the mom. Dr. Tong, can you just expand a little bit here? How many in our current ongoing study, we've got three patients per cohort. I mean, how many patients would you want to see this 10+ point drop in systolic blood pressure? As we increase the dose, we would hope to see essentially at the doses, which we on the upper doses, we would want to see a majority drop the blood pressure. Okay. That's helpful. What, sorry, Rick, one final one. I'll jump back in the queue. Dr. Sibai, you showed some relatively disturbing imagery of these poor young children. I was just curious looking at that. There was one child you'd had in the NICU for 267 days, I think it said. Can you, I mean, I don't know if you can, but can you enumerate for us what the cost of managing children in the NICU is long-term? Yes. I think when we talk about the cost, we talk about what I call the acute cost and the long-term cost. For the acute cost currently in the United States, the average cost for babies that are born this early is probably somewhere between $5,000-$10,000 a day. If a baby stays three months or four months, and some of these babies, they celebrate their one year while they are in an NICU, we are talking about $2 million-$3 million just for the bill for the acute care. Then you add to this the long-term implications. If these babies survive, which might be in the millions, millions, because these babies might be wheelchair-bound, they cannot work. Some of them, they are going to require some form of respiratory support, treatment of seizures, dealing with cerebral palsy. It is on and on. The other thing that worries me, when I started doing my expectant management study, as I said, 40 years ago, one of the concerns I had when we were following these babies is the impact on the family themselves, the emotional impact. So many of these families, their life was disrupted. Many of them ended up in divorce and so on. I cannot even mention to you some of the things that happened because all the efforts of the family will be concentrated on dealing with such a child. If they have other children, these children will have no attention whatsoever. Thank you very much. Dr. Sibai, would you mind actually, sorry, maybe just add on to that. Could you maybe just speak to the importance of maintaining systolic blood pressure below 160 for prolonging pregnancy? I think this is really one of the most important things. The randomized trials that I have been involved with and we conducted over the years, and they have been involved probably at least four, maybe six, trying to use different medications or different molecules to try to see if we can prolong gestation in these women. Fortunately, in almost all of these trials, more than 50% of patients ended up being delivered because of what I call, quote unquote, uncontrolled blood pressure or resistant hypertension. The main reason really this happened in the United States and in many parts in the world, there is a system called Maternal Obstetric Early Warning Sign, which we for short, we call it MOEWS. Anytime a systolic blood pressure reaches 160 or more, a MOEWS is triggered. Once this really happens in the hospital, a team of individuals, including nurses and doctors, have to rush to the bedside. Our biggest problem with preeclampsia currently is that with the available blood pressure medications we are using, this is very common. In general, once two or more MOEWS are triggered, everybody starts using this as an indication for delivery. This is why you see in these trials that have been published to date, maternal indication for delivery being uncontrolled hypertension was some most important problem. This is why, in my opinion, a molecule like this or a drug like this is going to be having great implications if it prevents these episodic elevations in systolic blood pressure, which by itself will lead to a major point to start to prolong gestation in such women. The other thing that's appealing about this drug, as I said, is not just about lowering blood pressure. It's really this benefit on repairing the age of endothelium. As of today, I have never seen any medication that is able to do this. The second thing that's very important based on my studies and the trials I have done, the second most common reason why I deliver these babies is what I call fetal indication. This is mainly as a result of reduced uteroplacental blood flow. Based on the studies I have done looking at uterine artery Doppler in women who had early onset preeclampsia, almost 97% of these patients have increased resistance in uterine artery. Having a medication that will target this part will have a huge implication because now, for the first time, we're having a fit of a medication that's not only controlling the endothelium and the maternal blood pressure, but actually influencing uteroplacental blood flow. Both of these, I think, are unique. I'm not aware of any medication that I have tested or probably is going to be tested in the future will have or play such an effect. Thank you, Sibai. That's very, very helpful. Maybe while we're on the same screen here, I mean, Dr. Tong, could you maybe just also provide some color here on what would be clinically meaningful for the dilation of the intrauterine arteries? Yep. We proposed that perhaps a drop of the resistance of 10% may be of clinical use. It's actually quite a bit of conjecture to figure out what drop will be beneficial. That's because there is no drug that can even rescue and improve the uterine artery blood flow. We're really looking at a new horizon that no one's ever been to before. We've got lots of drugs to try to reduce the blood pressure and a bit of experience there. In contrast, we don't really have any drugs which rescue the uterine artery blood flows. You would infer from animal studies, etc., that perhaps a 10% drop may be beneficial. It's, in some ways, conjecture. What it's reflecting is the amount of blood flow in the uterus. We're not sure how well that correlates to just how much beneficial blood flow there is to the placenta. Like a 10% could mean that there is a lot of blood flow to the placenta. Probably not answered that well. I'm not sure we know, but that's only because it's a new horizon. We don't have drugs to improve uterine artery blood flow to really guide us what would be therapeutically advantageous. All right. Thank you. Dr. Walker, any other further comments on the intrauterine dilation? Yeah. Look, thanks, Rick. I mean, as Stephen said, this is kind of a new horizon. It's difficult for us to be definitive about the answer here. I think, first of all, to have something that controls blood pressure, that rescues the endothelium, and that doesn't cross the placenta. I think there are three such big green ticks. That's, I guess, the thrust behind why we're really looking at DM199 for preeclampsia. The signal from the uterine artery is certainly encouraging. If we did get a reduction in vascular resistance in the uterine artery, we know that's part of the diagnostic criteria for early onset fetal growth restriction. We know that changes in the second to the third trimester of the uterine artery, if it improves, that there is a lower chance of growth-restricted babies and early preterm birth. I guess we're arguing by analogy that given those changes that we see, that if we were able to affect uterine artery dilatation, even as Stephen said, by a fairly modest amount, the physics is simply that if you can dilate it by a bit, you'll increase blood flow by a lot. Therefore, it gives us an opportunity to be optimistic that we'll be improving maternal blood flow through the placenta, improving oxygen and calorie uptake in the placenta, and therefore available to the baby. With that, the opportunity to improve fetal growth and to reduce the chance of us having to deliver a baby that is both sick and small and preterm. I guess that's kind of the hopeful optimism. It's the reason that we are looking at a cohort in these early phase trials. We've mentioned the group that are going to be delivered very soon, the group that we've made a decision for delivery because of severity of disease or they're very late in pregnancy. We've got a second group where we're going to be looking at DM199 for prolonging gestation. A bit similar to the philosophy behind the PRESERVE trial that we've heard of. There will be a third cohort of 30 patients where we'll be looking at patients with fetal growth restriction, whether or not they've got preeclampsia. Rick may I add to that? Yes, please. I think it's very important for a condition like preeclampsia. It's really a balance because what I called was good for the mother might not be very good for the fetus, what's good for the fetus might not be good. A certain level of increased blood pressure in the mother is extremely important in women with preeclampsia who have fetal growth restriction because really uteroplacental perfusion is dependent on maternal blood pressure. Having a medication that does really well, lowering maternal blood pressure and also reducing resistance in the uterine artery is, in my opinion, going to be the biggest breakthrough we have in obstetrics as it relates to management of patients with IUGR and/or preeclampsia. Because as Dr. Tong and Dr. Walker said, as of today, we have really nothing I'm aware of that have been successful and having an impact in uterine artery resistance. This is why a drug that targets both of these pathways, it is going to have a significant implication for our success in prolonging gestation in such women. Great. Thank you. That was a very helpful discussion. Tara, do you want to— is there any other questions? Yes, we have a question from Matt Caufield at H.C. Wainwright. Matt, please go ahead. Hi, good morning. Thank you. We actually had a couple of questions for the KOLs, if that's possible. Just the first one, do you see DM199 as possibly being additive to any of the attempts at standard of care, or do you foresee it acting more as a monotherapy if ultimately approved? And then we just had a couple of quick follow-ups. Thank you, Matt. Why don't we go to Dr. Tong? Thank you very much for the question. No, we would see that DM199 would be added to existing care. What we anticipate and hope is that if it has such a good— if it does have a good effect on blood pressure control, then there may be less need of those other therapies that are used to treat blood pressure, for instance. The other treatments that Sue Walker had mentioned, we give corticosteroids at the moment of birth, and we would probably still do that. The hope is that the baby, at giving the DM199, we can extend gestation. Even though you give the corticosteroids to help prepare birth, you would still have a much more favorable outcome because the baby is still going to be born at a less preterm gestation. It would be added to existing treatments with the caveat that there may be such benefits that you may need less of pre-existing treatments. Very helpful. I appreciate that. Lastly, curious of your thoughts on sildenafil previously in pregnancy trials. Any further thoughts on short-acting versus long-acting blood pressure meds in preeclampsia? I'm going to take the sildenafil question, Rick. Sildenafil was a hope, and we all fell behind it. It only acts on the nitric oxide pathway, whereas DM199 acts on the three pathways to drop blood pressure. Perhaps there's more scope for good blood pressure control with DM199. Sildenafil works on the nitric oxide, DM199, that prostaglandin, and the endothelial hyperpolarizing factor pathway. It spreads risk a bit, I suppose. Sildenafil has that solitary action. DM199, as I mentioned, may have a further benefit that it may have multiple actions to reduce endothelial dysfunction and improve endothelial health. I've mentioned one before. It actually decreases insulin resistance. It has many other things, reducing oxidative stress in the endothelial cells. It has multiple actions to restore blood vessel health, which I don't think sildenafil has. Where sildenafil has ended up really just underscores the potential of DM199. I don't know whether you know. There There was a worldwide effort, a very impressive effort, where many countries did randomized trials to see whether sildenafil could be used to treat preterm fetal growth restriction. Unfortunately, the Netherlands found that it was stopped prematurely because there was potential very significant harm in the newborn. It might have caused a condition called persistent pulmonary hypertension, so high blood pressure in the lungs of the newborn. It's a very rare condition. There is a plausible reason why the sildenafil could cause that. This would have been caused because sildenafil is a small molecule, would have crossed the placenta with those possible harms in the fetus. If DM199 is, as we hypothesize, it won't cross the placental barrier, won't get into the fetal blood, and therefore won't have such concerns on the fetus. May I add to that? Please. Again, in the two published trials that included really a limited number of subjects, sildenafil was not shown to improve pregnancy outcome in really early onset preeclampsia. The main reason, as Dr. Tong said, is it has really limited mechanism of action regarding only one pathway. I do not think it is going to be the drug that is going to have the impact in the future. Great. Thank you. The second question, Dr. Walker, do you want to take that one? Thanks, Matt. I think the question was just clarifying the role of our current antihypertensives, particularly the short-acting versus the long-acting, if I am correct. Is that right? Yes. Yes. Yep. Yep. Great. No, thanks for the question. You are right. I gave a bit of an overview of antihypertensives that are in current use and their mechanism of action. You are absolutely right. There are, I guess, two broad groups of antihypertensives. There's the short-acting ones that we generally use when we've got an acute episode of severe hypertension. A patient comes in 170, 180, 200, on 120, and we need to get that blood pressure down reasonably quickly. That's often when we use an intravenous agent. We, for example, would use something like intravenous labetalol or intravenous hydralazine. These are good drugs because they get the blood pressure down fairly quickly, but they do not last for very long unless you have a continuous infusion. They are very good for solving the acute severe crisis. Most of the time when we're thinking about managing patients expectantly with preeclampsia, what we're using is long-acting agents. These are things like nifedipine or labetalol or Aldomet that are given orally. We usually give them in divided doses across the day with escalating doses as we start to see that blood pressure is starting to become higher and higher, and we're needing more agents to control the blood pressure. I guess that's what Dr. Sibai was talking about when he's saying, "Look, there was uncontrollable hypertension. You've used multiple agents, and you've still got spikes of blood pressure." You may then be needing to use a short-term agent because you've maxed out all your long-term agents. I guess once we're starting to be in that situation, it's a situation Dr. Sibai was describing where we're really starting to say, "Look, we need to abandon expectant management. We've now got uncontrollable hypertension, and we now need to move towards delivery, remove that placenta, remove its toxins, and start turning this condition around. I guess the appeal for us with DM199 is that not only have we seen that it's an effective antihypertensive, but it's also improving the endothelial health, and it's potentially supporting the organ that's causing the problem in the first place by improving uterine artery blood flow and reducing placental hypoxia that is causing these toxins to be released. I guess it's a very fundamental difference in not just what the numbers are of the blood pressure, but how the agent is working to actually ameliorate the disease at its source and also at the target end organ, which is the endothelium. Very helpful. Thank you, guys. Great. Thanks for the questions, Matt. We have time for one more follow-up question from Thomas Flaten at Lake Street. Please go ahead, Thomas. Yep. Again, I was just curious, and I guess this is a very open-ended question, and I apologize. If I think about the patients Part 1A and 1B, so the very acute setting of delivery within 72 hours, and then moving into later phases of studies where you are in the expected management patients, what kind of data should we be reading through from the very acute setting to the maybe, I do not want to call it chronic, but longer-term treatment and expected management? Are there endpoints or data points or results you would like to see from this first data release that would give you comfort for the expected management patients? Sure. Dr. Walker, do you want to take that one? Yeah, sure. I mean, I think the patients where there has already been a decision made to deliver come of two sorts. When you've got preeclampsia at term, we're not worried about the prematurity risks for the baby. We start to say, "Well, no maternal risk is worth prolonging the pregnancy, and we should just get on and deliver." We would use DM199, I guess, if you like, for the cover for the hypertension in these women who we've decided to make a decision for delivery. That's what we're using in our dose escalation studies and what we'll use for the first phase in our expansion study of 30 patients. We've already talked about what the endpoints might be for those studies. We're really looking at safety, placental cord blood levels, blood pressure control, and looking at uterine artery Doppler. If we're looking at the second group, that is where it's a group where we've said, "Yes, we've got evidence of preeclampsia. We've got hypertension and end-organ dysfunction, whether it's proteinuria, renal dysfunction, liver dysfunction, or whatever." At the moment, we feel that we can press on to try and gain maturity for the baby. This is the expectant management group in preterm preeclampsia that Dr. Sibai's study addressed previously. I guess in those sort of studies, the sort of endpoints we might be looking at is what prolongation of gestation will we get from Dr. Sibai's study. We know roughly how long you'll get with expectant management with no treatment. I guess what we would like to see is that we get a prolongation of gestation, but moreover that we see less in the way of newborn complications, prematurity, babies being born very small, requiring high-dependency cares in the neonatal intensive care and so forth, both because of the cost of that in the short term, but most importantly, what the impact for that child's life is in the long term. We will probably also have a maternal outcome where we will be saying, "Look, how long did it take, for example, until we got a severe complication?" Or we develop some of those endpoints that have been looked at in other preterm preeclampsia expectant management. I do not know, Stephen or Dr. Sibai, whether you want to advance on that? Yes. In these sort of studies, I think it's going to be important to see how many extra days you are going to be able to prolong gestation with the expectant management. The number of days is very important based on gestational age. I always say gaining an extra four or five days at 23 and 24 weeks is different than gaining five or six days when the baby is 32 and 34 weeks. This is why targeting a very early onset preeclampsia is important. At the same time, maternal safety is going to be important. Improving outcome of the baby is not going to be good if during expectant management, you are going to have bad outcome to the mother. Some of the things we are going to be or need to be looked at for the mother are going to be development of pulmonary edema, changes in maternal platelet count, whether the patient is going to have seizures or eclampsia, whether they are going to have any abnormality or dysfunction in the liver enzymes, and how severe this is going to be. These are what I call the maternal endpoints that will be all whether the patient is going to have stroke or not. These should be measured at the same time. Hopefully, this medication will show it not only improves neonatal outcome, but it is also going to stabilize and even improve maternal outcome, which I really did not mention, and nobody has asked, what is really the cost for the mother who all have been talking about the baby? There is a lot, of course, even to the mother when we do the expected management. Then ultimately, our endpoint for delivery is pulmonary edema, kidney injury, liver injury, eclampsia, or stroke. All of these have significant implications regarding what happened to the mother acutely, plus also if the patient is having severe renal injury, she's going to require dialysis and even need for kidney transplant later on if they have pulmonary edema and they have pulmonary fibrosis because of severe hypoxia or they have a stroke. Even the mother will have both acute and long-term implications. That's very helpful. Thank you very much to everyone. Great. Thanks for the questions, Thomas. This concludes the Q&A session for today. I'll now turn it back to Rick for closing remarks. All right. This is great. Thank you, Dr. Sibai, Professor Tong, Professor Walker. I truly do appreciate your insight and thoughtful discussion today. Your contributions here are invaluable as we work to educate the broader investor and medical communities about preeclampsia and our investigational therapy, DM199. To everyone who joined us, thank you for taking the time to hear our preeclampsia story. We hope today's discussion has deepened your understanding of this serious condition and what also was meaningful progress looks like in terms of both safety and efficacy outcomes. I also just want to highlight from our conversation today what we believe the medical community is looking for with a new therapeutic like DM199. Ideally, we'd like to first show a drop in systolic blood pressure of at least 10 mm of mercury and a diastolic drop of at least 5 mm. We'd want to see this in more than half or the majority of patients at or near the targeted dose going forward. Second, and perhaps most critical from a drug development standpoint for preeclampsia, is that we're dealing with two lives here, the mother and her baby. That's why safety is absolutely paramount for this disease. We need to see that DM199 is safe and generally well tolerated by the mother. Just as importantly, there is minimal to no transfer of DM199 across the placenta. Finally, we see significant upside potential with our drug and the study endpoint if we do see any evidence of dilation of the intrauterine arteries. Specifically, we talked about a drop of 10% or more in the pulsatility index in at least half or the majority of the patients. In particular, we're looking for this in patients that have a high baseline pulsatility index. As we discussed, this index measures the resistance to blood flow. This could suggest improved placental perfusion or increased blood flow to the placenta. This could actually be a potential disease-modifying effect that could bring meaningful benefits to baby and the mother. If we can achieve these three key endpoints, we believe we're advancing something truly novel in a field that has seen very little innovation. I also just want to highlight that with no FDA-approved treatments available today and limited therapeutic options on the horizon, DM199's unique mechanism of action gives us the potential to meaningfully address this critical unmet need. Given the severity of preeclampsia and the lack of alternatives, we would expect strong adoption if this drug becomes approved, supporting our belief that this represents a multi-billion dollar market opportunity for DM199. Now, we look forward to sharing the preliminary top-line results from Part 1A of the current investigator-sponsored trial, which we anticipate releasing in the coming weeks. Thank you again for your time and engagement. With that, this concludes our call today. Thank you.