DiaMedica Therapeutics Inc. (DMAC) Earnings Call Transcript & Summary

Good morning, and welcome to the DiaMedica Therapeutics Virtual KOL Event. [Operator Instructions] 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.

Welcome, everyone. I'm thrilled today to welcome you to our Preeclampsia Key Opinion Leader Call. It's a truly exciting day for us as we gather to share the latest advancement of our preeclampsia program. Before we begin, I wanted to highlight the standard reminders regarding forward-looking statements to be made on today's call. So I'd like to start today by sharing our agenda and expressing our enthusiasm for preeclampsia with our collaborators. On today's call, Dr. Sue Walker from The University of Melbourne, will share a background on preeclampsia. That will be followed by Dr. Lorianne Masuoka, our Chief Medical Officer, who will provide a case study and her actually direct experience, which I think will provide a very interesting perspective as a neurologist and the importance of basically keeping the baby in the womb room as long as possible. Then Dr. Stephen Tong from The University of Melbourne, will share the scientific background, and that will be followed up with Dr. Cathy Cluver from the University of Stellenbosch, who will talk about the trial design. Followed by that, we'll talk about the -- we'll have an opportunity for a Q&A session. So the takeaway from the call today should really hopefully provide a deeper understanding of the need for treatment for preeclampsia and the impact that we feel that our therapy, if successful, could provide to patients, these mothers and also their babies. So in terms of our mission is to provide life-transforming therapy for patients with severe ischemic diseases. And we're starting off here with stroke, and then also expand into preeclampsia. Now we're talking about a patient population that today that they don't have treatment option. And so it's an area where there's a huge unmet need, in particular now as we're looking at expanding into improving women's health and their babies. So here is a summary of our pipeline. So I think as many as you know, is that our lead focus has been for acute ischemic stroke, we're currently in the pivotal trial. Just a few weeks ago, we announced the expansion into preeclampsia, and looking at the complications of preeclampsia as a focus with the potential down the road to also expand into fetal growth restriction. Just a little bit of real quick background here for our program is that we actually started off, and sometimes they say the problem we've start -- we've done here is figure out how to manufacture a recombinant synthetic form of this naturally occurring protein. It's something that we believe that patients that have a risk of stroke, preeclampsia, hypertension, kidney disease have low levels. And so we believe we're simply restoring the levels of this critical protein. And by doing so, we think we can help out patients. From a capital perspective, the last reported $58 million is a pro forma cash that gets us a runway into Q3 2026, which allows us to get to very key value creation milestones for both preeclampsia and also, of course, for stroke. In terms of a background, so we've been looking at preeclampsia here for the last 3 years, as we're looking at where we go next beyond stroke. And it really was last June, where we had reached out to our collaborators on the call today. And in particular, we identified them as really world leaders in the research for preeclampsia. Back in 2021, our collaborators published in Lancet, a review paper on the overall preeclampsia market and need for therapies. And so we're really targeting really an underserved area in women's health, and in particular, hypertensive disorders of pregnancy that is just increasing at an alarming rate and really lack of treatment options. Importantly, while we're very excited about the preeclampsia program, we're able to run this trial as an investigator-sponsored trial that really allow our clinical team to continue focusing and not be a distraction to the stroke program. And so I really just want to thank everybody for joining our call today. And I would like to hand over the call to Dr. Sue Walker at The University of Melbourne.

Thanks, Rick, for those very warm words of introduction, and we're really honored to be with you this morning. Stephen and I are based at The University of Melbourne, and we're joining you from Australia, where it's just a touch after midnight. And Cathy is a Professor of Maternal-Fetal Medicine at Stellenbosch University, joining us from Cape Town in South Africa. The three of us have been working as a very tight coalition for over a decade in a comprehensive bench-to-bedside research program focused on preeclampsia, culminating in the setting up of a unique clinical trials unit in South Africa, where we have perhaps been the only team running successive clinical trials with a singular focus on the prevention and treatment of preeclampsia. I'm Sue Walker. I'm a professor of Maternal-Fetal Medicine, and I'm Head of Obstetrics, Gynaecology and Newborn Health at The University of Melbourne. My clinical leadership involves caring for high-risk pregnancies, shepherding women and their babies through some of the most serious complications that threaten their life and health. One such condition is preeclampsia. My research expertise is in the area of fetal growth restriction and preventable stillbirth, both of which are in inexorably linked to preeclampsia. This young woman on the left presented to [ Cape's hospital ] with severe hypertension and seizures. She represents the face of preeclampsia. And there is not an obstetrician in the world who would not recognize this photo and a life-threatening situation that she and her baby find themselves in. Preeclampsia is the most common and serious medical complication to occur in pregnancy, affecting some 5% to 8% of all pregnancies. It is characterized by high blood pressure after 20 weeks gestation, in association with evidence of multi-organ dysfunction, kidney damage, liver damage, the risk of seizures and stroke, clotting problems, heart failures and fluid in the lungs, fetal growth restriction and stillbirth. So preeclampsia thus represents a global human tragedy. Approximately every 10 minutes around the world, a woman dies from preeclampsia, which equates to about 50,000 maternal deaths each year. For every woman that dies, a further 5 suffer lifelong health complications. Almost every minute, a baby is lost to preeclampsia, resulting in 500,000 stillbirths and infant deaths every year. Among survivors of preeclamptic pregnancies, both the mom and her baby have a lifelong legacy with increased risks of heart disease. This will ultimately take the life of 2 out of 3 mothers. Now it's perhaps tempting to consider that these devastating statistics apply only to low- and middle-income countries. But preeclampsia is one of the leading causes of death in countries like Australia and the United States and all high-income countries as well. And indeed, this data shows that the maternal mortality rate in the U.S.A. is among the highest of all high-income countries. To provide a little more granularity here, let's delve into the most recent data from the CDC. As you can see on the left panel, hypertension and preeclampsia is rising among hospital admissions in the United States, with the highest prevalence among women aged over 35, Black women and American Indian/Alaska Native women. On the right panel, you can see that among deaths that occurred during the delivery hospitalization, about 1/3 had a diagnosis of a hypertensive disorder in pregnancy. Even back in 2012, the cost of preeclampsia to the health system within the first 12 months of delivery was estimated at $2.18 billion, approximately half of the mothers and half of the infants. But this cost, of course, was disproportionately borne by those births that occurred at lower gestational age. So what is preeclampsia and how does it occur? The disease of preeclampsia is characterized by a diseased or damaged placenta where the placenta fails to establish a good blood supply and is forced to exist in a low oxygen or hypoxic environment. Risk factors for this failure of successful placentation include genetic and immunological factors as well as maternal risk factors such as increasing age, increasing BMI; coexisting medical conditions, such as hypertension and diabetes; and risk factors unique to the pregnancy such as twins. But no matter the clinical antecedents or the underlying risk factors, the diseased placenta releases toxins into the maternal circulation. Summarized in the box on the left, these include soluble Flt, soluble endoglin, TNF-alpha and interleukin 6. Together, these agents act on the largest organ of our body, the endothelium found in the lining of every blood vessel. Endothelial damage is a hallmark of preeclampsia, resulting in blood vessel damage, causing vasoconstriction, resulting in severe hypertension; damaged and leaky blood vessels, resulting in reduced blood flow to organs, culminating in organ damage, hypertension, renal impairment, liver impairment, seizures and stroke, pulmonary edema in the lungs, bleeding with clotting failure. But the final organ affected is arguably the most important: the placenta, itself the cause of the mischief also gets impacted with progressive worsening of blood supply. This results in fetal growth restriction, placental abruption and increased stillbirth risk. But importantly, this results in a continued cycle of amplification. The placenta becomes more hypoxic. It responds by releasing more of these anti-angiogenic factors into the circulation, resulting in further organ dysfunction. It is a never-ending cycle. It is a perfect storm. Preeclampsia cannot get better until the placenta is delivered and thus the baby, sick, small, ready or not. So once the diagnosis of preeclampsia is made, clinicians face a dilemma, how long do we attempt to nurse the pregnancy along to gain every day and every gram we can for the baby, particularly at very preterm gestation without putting the life and health of the mom at risk? Now in most pregnancies, the decision to cut and run is usually made at around 34 weeks. But when the disease occurs much earlier than this, there is a balancing act. There may be a high price to be paid for delivering a baby too early against a maternal price to be paid for delivering too late. But of course, this doesn't just end in survival. Beyond the short-term outcome of survival to hospital discharge, the cost of prematurity to our children, their families and society is high. This graph shows the likelihood of a child requiring special education according to gestational age of both. And while the likelihood is much higher at extremes of preterm birth, there remains significant gains in terms of neurodevelopmental outcome in avoiding late preterm and early term birth. As of now, these births are currently unavoidable because we have no treatment for preeclampsia. There is no disease-modifying agent that can dampen down the placental disease and effectively prevent the blood vessel damage that ensues. The mainstay of management at the moment is stabilization and deliver, reducing blood pressure to safe levels to reduce stroke risk, giving medication to prevent seizures and preparing the baby for early birth and the aftermath by administering medication to help accelerate fetal lung maturity. But wouldn't it be great if there was an alternative? Wouldn't it be great if there was a medication that could reduce the endothelial damage, reduce the stress and vasoconstriction and inflammation, resulting in healthier blood vessels? Such an agent could enable the pregnancy to be safely extended, protect mom's organs from harm, enable the baby to grow and mature. That's exactly the agent you are going to hear about this morning. But first, I'd like to hand you over to Lorianne, the Chief Medical Officer of DiaMedica, who can share her own personal experience with preeclampsia. She shares the delicate gamble undertaken by patients and clinicians worldwide to maximize baby's gestation while protecting the mom from harm. I'll hand over to you, Lorianne.

Thanks, Dr. Walker. Yes. So DM199 and its development in preeclampsia is something that I personally feel very passionate about. When I was pregnant with my first daughter and only daughter that I actually gave birth to, at 28 weeks, my blood pressure was already out of control, at 160 over 95. So my preeclampsia became a problem very early in gestation. At 28 weeks, my blood pressure continued to increase. This is a progressive disorder where despite medical therapy with antihypertensive drugs which, by the way, are the old antihypertensive drugs which are the only ones that are approved for use in pregnancy, despite the use of these antihypertensive drugs, my blood pressure continued to rise in a very scary manner. I was put at bed rest. So I was a very active person working in the biotech industry, going to the gym every day. And so it was very difficult to be put at bed rest, and this was a strict bed rest for over a month while we try to keep my blood pressure as low as possible. And despite treatment with antihypertensive drugs, my blood pressure continued to rise. At 28 weeks, my doctors wanted to deliver the baby. But I refused knowing that at 28 weeks, there was a chance of significant brain damage due to bleeding. And I had taken care of patients in my clinic on Monday afternoons, it was an encephalopathy clinic. And I knew the bad effects of intracranial bleeding leading to seizures, mental, cognitive delay, spasticity, cerebral palsy, and I wanted to avoid that for my child to the greatest extent possible, not to mention GI disorders and breathing problems. So we continued to cross our fingers that the outcome would be all right. I was being told by the doctors that I risked placental abruption and then I risked having a significant stroke. And despite that, we continued on to 33 weeks. Unfortunately, at 33 weeks, my blood pressure soared to 220 over 120, which is a very dangerous blood pressure level. And my kidneys were in something called nephrotic syndrome. I was spilling 5 grams of protein every day. And just to give you a relative scale, 115 milligrams is considered quite serious. So my kidneys were shutting down, and the fetal amniotic fluid had decreased overnight by 50%. So it was an emergency. She was delivered by emergency C-section. And although she required help to breathe initially, luckily, she turned out to be a perfectly normal infant. And I strongly believe that wouldn't have been the case had we had to deliver at 28 weeks. So it's a constant fight between the health of the mother and the health of the child. And as a neurologist, I fought very hard for the health of my child. It was an incredibly scary time. I was terrified the entire time, and it's incredibly traumatic. This is one of the worst diseases imaginable, where you're not only taking a risk for your own health, but you're risking that of your precious baby. So this is a disease that desperately needs some kind of treatment so that women don't have to go through the kind of life-threatening decisions that I went through. Thank you.

Well, Lorianne? Thank you very much.

Thank you. With that, I'll hand it over to you.

Dr. Tong? Yes.

Okay. Thank you very much. So my name is Stephen Tong. I'm a Professor of Obstetrics at The University of Melbourne. I'm a clinician scientist. I'm a laboratory research trained, and I'm a practicing obstetrician. And my expertise is in preeclampsia, especially preeclampsia therapeutics. And this morning, I'm delighted 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. First, DM199 drops blood pressure. The diagram on the left is a cross-section of a blood vessel. The outer layer is the vascular smooth muscle. The inside is where blood flows, and the yellow rim is the single layer of endothelial cells, the inner lining of blood vessels. The middle picture zooms into the endothelial cell layer, and live bradykinin or bradykinin is a peptide in the bloodstream. Bradykinin binds to and activates its receptor, the bradykinin 2 receptor on the surface of endothelial cells. This switches on internal molecular circuitry within endothelial cells that activate all 3 of the main pathways involved in reducing blood pressure: nitric oxide, prostacyclin, endothelium derived hyperpolarizing factor. These molecules filter into the underlying smooth muscle cell layer of blood vessels and makes blood -- makes the muscles relax. Blood vessels widen, blood pressures falls and the amount of blood flowing through the vessel increases, supplying distant organs. Hence, bradykinin signaling would be a really useful strategy to treat preeclampsia. The problem, bradykinin only has a half-life of seconds. If you injected 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. It cleaves inactive kininogen to make active bradykinin. Hence, DM199 facilitates bradykinin signaling to reduce blood pressure and open blood vessels. DM199 is simply a synthetic version of a natural protein called kallikrein-1, or KLK1, but with slight modifications to enhance its stability. And being simply a drug version of the naturally occurring protein offers a critical advantage. It means there's already two decades of biological research in the potential of tissue kallikrein-1 to promote blood vessel health. Please note that DM199 is a synthetic version of tissue kallikrein-1. It is different to a protein with a similar sounding name, plasma kallikrein-1. Plasma kallikrein-1 does very different things. This diagram shows blood pressure trends over 95 days among participants in a DM199 trial of chronic kidney disease. All are given subcutaneous doses of DM199, and I wish to highlight two points. First, DM199 drops blood pressure in humans. It works. This is important for preeclampsia where high blood pressure is a universal feature, where severe hypertension needs prompt control. Secondly, DM199 only appears to drop blood pressure when it is high in the first place. The blue line at the bottom shows blood pressure trends among participants with a high starting blood pressure at the beginning of the trial, and these hypertensive participants had a sustained drop in blood pressures throughout the trial. And in contrast, those in the green were participants with normal blood pressures at the start of the trial. Blood pressures among these participants did not fall. And this means DM199 only drops blood pressure when it's high. And if this is true, this would be an important safety mechanism. It's known giving too many blood pressure medications or too high doses in preeclamptic women is a pitfall, because dropping blood pressure too low can cause acute fetal distress. But this might not happen or happen less if DM199 preferentially drops blood pressure only when it's high. In this chronic kidney disease trial, subcutaneous dosing was used, hence, blood pressure falls, you can see were quite gentle. Before preeclampsia, we sometimes need rapid control of very high blood pressures. Luckily, DM199 comes in an intravenous formulation as well as the subcutaneous formulation. Hence, for preeclampsia, we envisage the option of giving IV doses to obtain rapid blood pressure control, followed by regular subcutaneous dosing. So DM199 drops blood pressure in humans, but it may do far more to combat preeclampsia. DM199 may switch on molecular signals promoting maternal blood vessel health. Recall preeclampsia from Dr. Walker's presentation is a state where the mom's blood vessels are under constant assault from noxious factors released from the placenta. Preeclampsia is known what's called an anti-angiogenic state. So restoring blood vessel health could be a way to counter this assault. Vascular endothelial growth factor is one of the most important molecules promoting blood vessel health. It's like the ultimate multivitamin for blood vessels. Present in the circulation, VEGF binds through its receptor on the surface of endothelial cells, turning on a raft of molecular signals. And in preeclampsia, VEGF signaling is vastly reduced. Literature on the natural version of DM199, KLK1, suggests DM199 strongly increases VEGF signaling and does so in three ways. First, in a process called transactivation. It relays signals within the endothelial cell to switch on the VEGF 2 receptor. And this is a pretty astounding concept if you think about it. It means the receptor doesn't even need VEGF to switch on. Furthermore, bradykinin signaling issues the command to make more VEGF protein and make more of the VEGF-2 receptor. So enhancing VEGF signaling may be particularly useful in preeclampsia because sFlt, as Dr. Walker had mentioned before, is an important anti-angiogenic molecule released in excess from the preeclamptic placenta. It neutralizes VEGF in the blood. It knocks it out of the sky. Remarkably then, DM199 has the potential to overcome the sFlt block in preeclampsia. especially via transactivation, which makes the amount of sFlt and VEGF in the circulation, perhaps somewhat redundant. Hence, DM199 not only drops blood pressure, but it also promotes the health of existing blood vessels. However, DM199 may have even more actions to combat preeclampsia. DM199 may promote the growth of new blood vessels. The diagram shows an experiment in rodents. Tissue kallikrein-1, the natural version of DM199, is being delivered in this experiment in a muscle in the leg shown in the black bars. The delivery vehicle of DM199 is an adenovirus, which is a molecular technique where once injected, the local tissues make KLK1 protein in the muscle. You can see after 2 weeks compared to no KLK1 at the gray bars, giving KLK1 results in increased growth of capillaries, which are the small vessels, and arterioles, which are the larger vessels. And even after 8 weeks compared to no KLK1, there's still a significant increase of arterioles. Another group has confirmed this, showing that the administration of tissue KLK1 to heart muscle improves new blood vessel growth. Hence, DM199 may reduce blood pressure, promote the health of existing blood vessels and facilitate the growth of new blood vessels. So far, we've spoken about the potential of this drug to rescue the maternal disease of preeclampsia. We think it's plausible that DM199 could even rescue the placental disease, the very origins of the noxious factors causing preeclampsia in the first place. The picture in the middle depicts the arterial system in the uterus providing blood to the developing placenta. The big vessel on the left is the uterine artery, the main blood vessel supplying the uterus and placenta. Within the uterus, that vessel breaks down into smaller vessels, the arcuate, radial, then spiral arterioles. And rodent studies would suggest that their molecular regulation may be very different. The uterine artery mainly dilates in response to nitric oxide and prostacyclin, whereas the small arteries mainly dilate in response to endothelium derived hyperpolarizing factor. DM199, as we had mentioned before, upregulates all 3 of these molecules, and this means it could be effective in opening blood vessels of all types right across the uterus, allowing more blood to flow to the placenta. Hence, DM199 may potentially increase blood supply to the placenta. And this is exciting because it could rescue the placental disease of preeclampsia, and here's why. It is thought that placental hypoxia or low placental oxygenation is a key feature of preeclampsia. This placental hypoxia is thought to contribute to the release of the anti-angiogenic factors into the maternal circulation, such as sFlt, that causes all the blood vessel injury in the mom. By increasing blood flow to the placenta, placental hypoxia should reduce, and this could then reduce the release of these factors from the placenta, wiping away the maternal vascular injury. This slide summarizes so far the potential beneficial effects of DM199 that we have discussed. DM199 may plausibly reduce blood pressure, promote the health of existing blood vessels, promote the growth of new blood vessels, and all these could have the net effect of rescuing the maternal disease. Plus the enticing possibility exists that it could increase blood flow to the placenta, rescuing preeclampsia at its source, the placental disease. So finally, I want to tell you what is, for me, the wow factor of DM199. It's the reason why DM199 caught my attention from the first time DiaMedica Therapeutics reached out to our team. The placental barrier is the surface of the placenta bordering the maternal compartment. It tightly regulates what gets through the placenta and into the developing fetus, what gets in, what stays out. Small molecules, for instance, passively diffused through the placental barrier, just like sugar through a sieve. Most drugs are small molecules. Those off-the-shelf tablets prescribed by CVS Pharmacy as small molecules, nearly all drugs given during pregnancy are small molecules. The issue then for small molecules is that many can enter the unborn baby. For example, our team is evaluating metformin to treat preeclampsia, and we have a number of trials testing metformin. The issue is that the fetal blood levels of metformin can get quite high, and this is causing much debate, whether metformin is safe to give during pregnancy. In contrast, DM199 is a protein, a rare drug class, it would be unique for pregnancy conditions. Proteins cannot breach the surface of the placental barrier, a continuous border of cell membranes. They are just too big. It's like adding whole almonds to a sieve, they won't pass through. Hence, being a protein, DM199 will likely stay out of the placenta. It will never reach the fetus. And this wipes away to radiogenic risk or other risks arising from direct fetal exposure. And just to be sure, DiaMedica Therapeutics commissioned rodent placental transfer studies, and these studies showed a nice rise and fall of DM199 in the maternal circulation after administration, but DM199 remain undetectable in the fetal circulation. And the implications if DM199 stays well clear of the fetus in placenta is perhaps pretty extraordinary. It means that DM199 may possess the near magical qualities of having multiple actions to treat preeclampsia without even needing to enter the placenta, the very organ causing the disease. And this is why we would argue that DM199 seems to be a drug in a class of its own. So in summary, DM199 seems to be an excellent candidate treatment for preeclampsia. It could be very safe. As a protein, it's not expected to cross the placenta. It's already been tested in 275 humans. Reproductive toxicology studies in rodents have been completed, which did not reveal any safety concerns. It could combat the maternal vascular disease by reducing blood pressure, promoting the health of existing blood vessels, promoting new blood vessel growth. And all this may increase blood flow to maternal organs, helping them to heal while the pregnancy safely continues. Remarkably, DM199 may rescue preeclampsia at its source, the placental disease, and it could do this by increasing blood supply to the placenta. Hence, we, the team, Cathy, Sue, myself, believe DM199 has potential to be an ideal disease-modifying drug for preeclampsia. And we think that DM199 seems well worth evaluating in human clinical trials, and it just might represent a breakthrough drug that ends up saving a lot of lives. So now it's my absolute pleasure to hand over to Dr. Cathy Cluver to give you an overview of where we may run clinical trials and the exciting trials that we have planned of DM199. Thank you.

Good. Thank you so much, Stephen. My name is Cathy Cluver. I'm a Maternal-Fetal Medicine subspecialist, Professor in the Department of Obstetrics and Gynaecology at Stellenbosch University here in Cape Town, South Africa. And I've founded mainly the Preeclampsia Research Unit, which is the only unit in the world that's run successive randomized controlled trials, assessing novel treatments to treat preterm preeclampsia. So Sue has discussed the global human tragedy of preeclampsia and reminded us that we have no treatment apart from delivery for preeclampsia. Lorianne has shared her personal experience of preterm preeclampsia, and Stephen has explained why DM199 may be a breakthrough for the treatment of preeclampsia. It's now my job to explain, firstly, why are we going to run the first studies in our unit here in South Africa; and secondly, how we have planned and designed these trials. So why South Africa? South Africa is a country of diversity and inequality. It's estimated that only 10% to 20% of our population can afford private health care. That means that the majority of South Africans are served by state-funded health care systems that include Tygerberg Hospital, where I work. So what does this mean for the pregnant mother in South Africa? When she falls pregnant, she needs to go and get antenatal care, and that usually occurs in her local clinic in the community. She's then triaged either into a high-risk and a low-risk group. And if she falls into the highest risk group, she will then be triaged to receive her care at Tygerberg Hospital. And that will include all women who develop preeclampsia. At Tygerberg Hospital, we deliver over 9,000 high-risk pregnancies every year, and the majority of these women suffer with complications like preeclampsia. Now I didn't realize that this was really something different, and that this didn't occur in all hospitals. Until in 2013, I went to go do fellowship training at Mercy Hospital for Women in Melbourne, Australia under Sue Walker. It was during this time that I also met Stephen, and I was first introduced to the concept of bench-to-bedside research. During this year, we realized that we had a unique opportunity. We had the opportunity to translate bench research to clinical trials of novel therapeutics for preterm preeclampsia in South Africa. So with the support of Stephen and Sue, in 2014, I went back to South Africa to set up the Preeclampsia Research Unit. In 2018, we published our first randomized controlled trial, assessing esomeprazole to treat women with preterm preeclampsia. Here, we recruited 120 women. In 2022, we published our second randomized controlled trial, and we included a 180 women with preterm preeclampsia. We're currently nearly halfway through our third randomized controlled trial, and we've also set up international trial collaborations with researchers based in Sweden, particularly at Gothenburg University. Our Preeclampsia Research Unit also curates one of the largest preeclampsia biobanks, and has to date included over 2,000 women with preeclampsia. So why the Preeclampsia Research Unit at Tygerberg Hospital Cape Town? I'll put it to you. Firstly, our women and our participants want to be involved in research, and we have the numbers. We run trials fast and efficiently and to the highest international standards. We have exceptionally well-trained staff. We have a team of research nurses with experience in running treatment trials in preterm preeclampsia. We have PhD students, scientists and also medical students working with us. We have the experience. We are the only unit in the world to have completed successful preeclampsia treatment trials. And in these trials, we have embedded pharmacokinetic studies to assess the drugs in preterm preeclampsia. We also have the research infrastructure, including trial pharmacies, a biobank, a biorepository and our obstetrics department has the support of an ICU and a critical care obstetric unit. And to top it all off, because of our preeclampsia biobank, we also have the ability to have historic controls for women included in preeclampsia treatment trials. So how are we going to go about designing these trials? So firstly, we're going to have 2 parts. Part 1 will be divided into a dose-finding study followed by an expansion cohort. And in this, we want to assure the safety and show efficacy signals. Part 2 will be an efficacy study. Moving back to Part 1. What will we be doing here? We will be including women diagnosed with preeclampsia who need delivery within 72 hours. These women will have to have a systolic blood pressure above 150 millimeters mercury, and they will need to be between the gestation of 27 to 42 weeks. So something -- what, that's a little bit of a strange gestation, but it's not. Unfortunately, in our setting, viability is only reached at 27 weeks due to limited resources, and some women only present for antenatal care very late in pregnancy. All right. What we'll be doing in the dose-finding study is we'll do a traditional dose-finding study. We'll start with very low doses, and in sequential patients, we'll titrate the dose until we see signs of efficacy. These will include a decrease in blood pressure. But importantly, we will also be collecting maternal and cord blood samples so that we can study the pharmacokinetics of DM199 and confirm low or absent levels of DM199 in the fetal circulation. Once we've determined a dose, we'll then move to the expansion cohort. We'll be using the same inclusion criterias for the dose-finding study. But the aim of the expansion cohort will not only be safety, but also to look for signs and signals of efficacy. We'll be looking for blood pressure changes, and we'll be measuring the blood flow in the uterine arteries, specifically aiming to see if DM199 relaxes the smooth muscles and dilates the blood vessels, thereby increasing blood flow to the placenta. For part 2, we'll be including women undergoing expected management of preeclampsia. These are women like Lorianne, who put their own lives at risk, to try and improve the outcome of the unborn baby. For this study, we will be including women between the gestational ages of 27 and 33 weeks, because at 34 weeks in our setting, we would deliver all women because the benefit of delivery far outweighs the value of expectant management. The aim would be to see if we can gain as much time as possible before delivery is needed. I want you now to think back to Stephen's slide on the potential of DM199. And based on these outcomes, we've designed the endpoints for this study. Firstly, we want to see if DM199 can prolong pregnancy. We want to see if it can decrease blood pressure and a need for antihypertensive treatment. We wanted to see if it can dilate those uterine blood vessels over a longer time period. We'll also be collecting blood samples, maternal blood samples and core blood samples. And in the maternal blood samples, we'll be comparing the levels before and after treatment to see if we can decrease those biomarkers, the soluble Flt and the soluble endoglin. And we'll also collect urine so that we can measure the amount of protein that's excreted, and we'll be aiming to see if there's a trend for improvement in renal function. Based on this research, we will have enough data to plan a large randomized controlled trial to assess if DM199 will be a treatment for preeclampsia. Thank you.

Thank you, Dr. Cluver. So we'd like to now start with the Q&A session. If you would like to ask a question, please submit your request to [email protected]. Okay. So our first question, does kallikrein cause angioedema? Lorianne, could you take that one, please?

Sure, happy to. We don't actually believe that DM199 will cause angioedema in over 100 patients in our Phase II study outside of 1 case where there was a protocol violation. And the patient was taking an ACE inhibitor. We just don't see it. In pregnancy, ACE inhibitors are contraindicated due to harm to the baby, so nobody will be taking them. So we won't run into this problem at all with the clinical trial that Dr. Cluver just described. It's very important to distinguish between tissue kallikrein, which is our DM199, and plasma kallikrein, as Dr. Tong alluded to, which is not DM199. Tissue kallikrein has about 200 amino acids, plasma kallikrein has around 600. They are very different in structure and cleave different substrates to make bradykinin. Plasma kallikrein can also create plasmin, which activates the fibrinolytic and complement systems. Tissue kallikrein does not create plasmin. There are a lot of pharmas targeting hereditary angioedema. It's an ultra-rare disease with high unmet medical need. This is a genetically driven disease causing uncontrolled production of plasma kallikrein. We won't give DM199 to these patients. In fact, patients with hereditary angioedema are excluded from all of our trials. There are maybe 10,000 such patients in the United States. It's very rare in addition to that. Bradykinin is also linked to angioedema in patients taking ACE inhibitors and Entresto. These drugs inhibit enzymes that break down bradykinin, increasing its levels. So the good thing is there are tens of millions of people in the U.S. with cardiovascular disease benefiting from ACE inhibitors and another 0.5 million on Entresto. However, we are going to be excluding these patients from our clinical trials who are concomitantly taking these drugs. They have to wash out, and we have a lower infusion rate for those patients with a history of ACE inhibitors. And as I mentioned earlier, this is not a problem at all with pregnant women who do not take these medications. DM199 does not interfere with the natural regulators, bradykinin. And that's why we believe that at our targeted doses, we are using the appropriate dose to have just the right amount of bradykinin. We believe we won't cause angioedema. And as I mentioned earlier, we really haven't seen it.

Great. Thank you, Lorianne. Next question. How does your drug compare to RNAi-silencing approach for sFlt-1? Dr. Tong, do you want to take that one?

I think that's mentioning another candidate therapeutic proposed, I think, developed by Comanche Pharmaceuticals. And this is a siRNA which is meant to go to the placenta to reduce sFlt levels. So I'll start by actually saying that I strongly support innovation in finding new pregnancy complications, and siRNA targeting sFlt is indeed innovative and is indeed an exciting idea. And it might -- it absolutely might work. I mean it's very different mechanisms of action, isn't it? They want -- they're developing an RNA to enter the placenta deliberately to reduce the production of sFlt; whereas our drug is a protein, which stays in the blood vessel and have all the actions I've mentioned before. And the siRNA treatment might work and it's worthy of testing. I suppose a theoretical concern perhaps is that the siRNA needs to enter the placental surface. And the possible issue there is that the placental surface in humans continuously sheds, and it happens even far more quickly with preeclampsia. It's a bit like leaves shedding off at oak tree during autumn, where the drug target is the leaves themselves. And it is very different to liver because most siRNAs on the market, it targets the liver. The liver is a stable cell population that doesn't actively shed. And therefore, siRNA is targeting -- liver targets can act in the liver for many months. And so Comanche proposed 1 dose, and the possible risk of that is it may not be sufficient. It might just not stay in because it lands in the placental surface, but then it buds away and then the new layer is unaffected by the drug. But I'm just going to quickly note there that there's not a single disease-modifying drug for preeclampsia. And in my view, as an academic for preeclampsia, as a clinician, there's really easy room for 2 or 3 or more drugs for preeclampsia. And they could, for instance, be strong synergies in between siRNA knockdown of sFlt and DM199, and there are biological reasons to suspect they might be synergistic. So while there may be concerns, they are very different drugs, there may be synergism. And I would actually end to say that I strongly support innovation, and I support the siRNA concept being properly evaluating clinical trials. But I think that they're miles apart and there's a role for both.

Great. Thanks, Dr. Tong. Next question. What is the past experience using Viagra in pregnancy and why didn't it work? Dr. Walker?

Thanks, Rick. So sildenafil or Viagra increases the bioavailability of nitric oxide, which we've heard a lot about this afternoon. It's been used in a variety of indications in pregnancy. It's been used in very small populations of moms who've got a condition called pulmonary hypertension. It's also being used as a proposed treatment for fetuses with a congenital condition known as diaphragmatic hernia, where they also have pulmonary hypertension. And it's been examined for its potential tocolytic effect, that is to relax the uterus. But I guess the areas that we're most interested in, given the discussion that we've had this morning, is talking about what's its potential effect on placental health. And I think that's really been evaluated in three areas. The first is to look at, could it do what we are hoping DM199 may be able to do? Could it treat preeclampsia by targeting placental health? So there has been 1 trial that has looked at that in 100 women with preterm preeclampsia. And encouragingly, there was seen to be an extension of gestational age by about 4 days. So that is an encouraging signal. The second area, which has been encouraging is looking at giving sildenafil during labor to reduce the risk of fetal distress under the hypoxic challenge of labor. And it does appear that it improves your chance of a vaginal delivery and less of a chance of needing operative delivery for fetal compromise, but this needs to be confirmed in a current and ongoing trial. But perhaps the warning sign for sildenafil came from the mighty STRIDER trials. These were a series of trials that were looking to see if sildenafil could be used as a therapeutic to rescue preterm fetal growth restriction. And as Stephen has said that these great obstetric syndromes, we are in desperate need of new medications, and fetal growth restriction to date remains a condition for which there is not an effective treatment in pregnancy. So sildenafil was administered during pregnancy in a long-acting way, given in a sustained period to try and see if it would improve placental function and improve fetal growth. Unfortunately, the STRIDER trials were terminated prematurely because of an unexpected complication that caused increased morbidity to the newborns in a condition called persistent pulmonary hypertension of the newborns. And this may have been because there was a reaction to having been exposed to sildenafil during pregnancy, and then that drug being withdrawn and having pulmonary vasoconstriction after delivery. So I guess in summary, there are two things here. There is an encouraging message that maybe improving bioavailability of nitric oxide indeed can help in placental syndrome such as preeclampsia and fetal growth restriction. But the warning signal is this problem of drugs, as Stephen has said, that are small molecules that cross the placenta that, therefore, we have to be cautious about what may be expected or unexpected adverse effects on the fetus. And I think really after the STRIDER trials, really, there is not going be an appetite for continuing to investigate sildenafil on a prolonged basis, as was done in the STRIDER trials to try and rescue placental function and fix fetal growth restriction or preeclampsia.

Great. Thanks, Dr. Walker. Next question. In stroke, KLK1 is used in China. Is it the same for preeclampsia? I guess the question is, are there forms of KLK1 being used today in Asia? Lorianne, do you want to take that one?

Sure. So it is, in fact, true. Porcine KLK1 is being used in China to treat preeclampsia. We found 10 clinical papers that show really good results of porcine KLK1. They show that blood pressure is reduced. There's an increase in uterine blood flow, just as we were hoping to see with DM199. In Dr. Cluver's study, there was an improvement in kidney function and decrease in the negative preeclampsia biomarkers, including soluble Flt-1, soluble endoglin and IL-6, which are all inflammatory, along with improved delivery, meaning they actually extended gestation by an astonishing 2 weeks. So while we're incredibly encouraged to see these results with porcine KLK1, we know that we need to determine if our DM199 will show similarly encouraging effects in preeclampsia patients.

All right. Great. Thanks, Lorianne. The next question, are there any major unknowns regarding the ramp-up to mass production of DM199 following approval? I can take that one. That's pretty easy. Yes, we can definitely scale it up. We're currently doing 250-liter runs. We're doing that at Catalent. Each run will give us several hundred thousand doses. And it'd be very quick and easy for us to do multiple runs or to scale up to much larger runs. So absolutely, there will be no problem between our stroke program and preeclampsia to really source all of the full demand from this therapy. Next question we have here is, when will the trial start? So as background, we've recently received ethics clearance in South Africa to start. And then the final piece is getting regulatory clearance. And so that was submitted, I guess, early July, early this month, and we're anticipating to have feedback in Q4. And then we'll be in a position to shortly thereafter start dosing patients. So our plan still is to start dosing in Q4 of this year and to have top line results from the part -- from the Phase II part 1a to have those in the first half of next year. The next question is, do you have a dedicated ultrasound units and trained technicians to measure the blood flow in the uterine arteries? Dr. Cluver, do you want to take that one?

Yes, we do. So we've got a very much dedicated maternal fetal medicine center, dedicated ultrasound unit. So we will be able to do that.

That's great. Okay. So at this point, we'd like to also take some questions from our covering analysts.

So our first question comes from Thomas Flaten at Lake Street.

Thank you to Rick and the team for setting the call up, and thanks to the physicians for joining us, some of you at a terrible hour of the morning. So thanks for that. Dr. Tong, I had a question for you, and it goes back to the last question about the blood flow into the uterus placenta. Would that be a required factor for having an impact on fetal growth restriction? So if we don't see that improved blood flow to the placenta, would that be a negative finding against maybe having an impact on fetal growth restriction?

Well, thank you very much for that, Thomas. Yes, I would think that, that would be the case. It would be very hard to plausibly suggest that fetal growth would be substantially improved if we're not going to increase the blood flow to nourish the placenta and, therefore, the fetus. And that's why we've been so keen to embed a very detailed Doppler ultrasounds in the planned South African trials to really investigate that potential and maybe even open up the possibility of using DM199 for fetal growth restriction.

Got it. And then there was a question that Rick read out -- or sorry, that Lorianne pointed out about extension of gestation. And as we look into the maybe the preterm treatment, what's a clinically meaningful improvement in gestational days? Is it as simple as any days are good? Or is there something more maybe sophisticated than that?

Sue, do you want to take that one?

Yes. Thanks for the question, Thomas. So look, at very, very preterm gestations, every day matters. If you look at, I guess, in our setting and perhaps in your setting as well, we would say that the gestation of viability would be around about 22 to 23 weeks, where the chance of survival is extremely low, leading to 28 weeks where the survival will be about 90% to 95%. So you can see that with each day of gestation, you increase the chance of survival and intact survival by a few percent. But in terms of a meaningful number for increasing gestation, with our previous preeclampsia trials, we have always sort of said, "Look, we would like to aim for an increase in gestational age of perhaps 5 to 7 days because that will give you the multiplier of that, and that would be really a clinically meaningful gestation." And perhaps particularly in low- and middle-income countries that don't have the resources that we do in high-income countries for advanced neonatal care, that would be a substantial and meaningful increase.

Excellent. Then one final question for Dr. Cluver. In your prepared comments, doctor, you mentioned that you would be looking for low or nonexistent DM199 in fetal tissue. I hope I heard you correctly. That seems to imply that there's some acceptable level of DM199 that might cross the placental barrier. Did I understand that correctly? And if I didn't, could you please clarify?

Yes. So I think what DiaMedica is actually doing at the moment is they are designing, and Rick can actually add more info about that, is to look for a drug is always very difficult, particularly something like DM199, and they actually have invested into getting a more specific test. So the reason why I've said low or no is just because there may be some cross-reactivity when tested with the [ 4 ] DM199 levels. But ideally, if we get a very specific test, we'll be able to say no DM199 in the fetal circulation. And when we say fetal circulation, the sample that we'll be using there is when the baby is delivered, the placenta is delivered, and there's the umbilical cord. And what we do is we clamp the umbilical cord, and we take a sample from that umbilical cord. So we don't actually get fetal tissue, per se. It's actually a blood sample that we collect from the umbilical cord.

So our next question comes from Chase Knickerbocker at Craig-Hallum.

I'll echo Thomas, I appreciate you getting on, and really late here for you, guys. Just kind of first from me, we kind of talked a little bit about the data from the PDE5 inhibitors Do you guys have any firsthand experience with your team with PDE5 inhibitors? Or any other agents that would inform kind of the excitement that you all have over the potential profile of DM199 here as potentially disease-modifying treatment?

Dr. Tong, do you want to take that one?

So the question is whether we've seen or had experience with the sildenafil-type drugs or nitric oxide donors? Was that the question, Chase?

Or any other agents that kind of inform your excitement here that might act similarly or kind of inform your excitement over the profile.

Sure. Well, we've not done any trials of sildenafil. As Sue mentioned, there's the Trapani trial published in 2016, randomized 100 participants. We've tested esomeprazole. We published that, and there was a nonsignificant 3-day prolongation potentially. We published metformin in the British Medical Journal, which might be a disease-modifying drug for preeclampsia. That's mainly our clinical trials. But the message there is metformin might work, but has any of the drugs really caught my excitement? No, for the exact reason that I expressed quite honestly, the fact that it stays in the maternal compartment and has those multipronged actions. I don't know of any drug that can do that basically, I really don't.

Very helpful. And maybe just trying to understand a little bit more about the shortcomings with kind of the legacy antihypertensives that you all use today. Is it because they do so little to improve endothelial function and then not improving blood supply to the placenta, that eventually those anti-angiogenic factors overpower the control that you have over the hypertension from those antihypertensives? Or just speak to a little bit more about the cascade that eventually kind of leads to, again, uncontrolled hypertension in these patients.

Yes. I think you've now hit the nail on the head, Chase. So those tablets really treat, I suppose, the end symptoms of the blood vessel. It helps dilate the blood vessels. Dropping the blood pressure is good. We're just trying to prevent stroke here. But it really doesn't tackle the underlying disease. It's not really what we would regard a disease-modifying drug. So you're absolutely right, the disease progresses. So we would typically start on antihypertensives, and the blood pressure will go up and we'll increase the dose. And when we max out of one antihypertensive, we hop to the next one. And at Mercy Hospital, once we've added the third antihypertensives and we've maxed out in all three, we have to deliver the woman. So it's really not a disease modifier, it's just to control symptoms as best we can.

And then last from me. Dr. Cluver, can you talk a little bit more about the protocol as far as what other antihypertensives you're going to be using in line with DM199 and kind of the titration schedules that you'll be using there? And then two, when we think about part 2 of the study, what percentage of your preeclampsia patients do you kind of see before 34 weeks? And then maybe just kind of from a number perspective to inform potential enrollment, how many of those patients kind of 27 to 33 weeks do you typically see?

Perfect. So let's -- I'll tackle the first part. Thank you, Chase, for that question, which is drugs. So the drugs. So we have less drugs available to us being a low, middle-income country. So when we see someone who comes in with acutely high blood pressures, our first line of treatment is a calcium channel blocker. So that would be a short-acting Adalat or nifedipine. And that would be the first drug that we would be able to use to acutely decrease the blood pressure. We'd also start the women on alpha methyldopa and that's an alpha and beta blocker. If after sort of reaching maximum doses of the short-acting calcium channel blocker to try and drop the spikes, what we then can do is jump to an intravenous dose of Lipitor. We don't have access to [ oral Lipitor within ] our setting. And previously, we did have access to Hydralazine. But unfortunately now and due to the cost of Hydralazine, there's only limited access that we have to that. So those would be the typical drugs that we would be using in combination with DM199 to control blood pressure. Next was your question on numbers. Probably the easiest way to describe this is by using an example of our preeclampsia biobank. And on average, we are recruiting somewhere between -- we can recruit between 5 and 10 patients a day with preeclampsia at Tygerberg Hospital because we see so many. And for the preterm arm of the study, we, on average, the study that we're currently running, we recruit between -- somewhere between 2 and 4 patients a week. Did that answer your questions, Chase?

It certainly did.

So our final question comes from Frank Brisebois from Oppenheimer.

Just a quick one here. This is for Dr. Tong probably. I was wondering, Rick, I don't know if you can go back to Slide 22. That's easy for you guys to do that.

Sure.

Yes. So on Slide 22, it kind of discusses the impact that this drug can have depending on your baseline level of hypertension. And maybe Dr. Tong, if you can walk us through a little bit that green line versus the blue line. And maybe a better understanding of is it the rate of decrease that matters, because those might seem kind of similar. Or what happens at the very start there in terms of the spike on the green line and the decrease on the blue line and how important is that?

Cool. So I'll just preface very quickly that this is a chronic kidney disease trial for which they had a fixed subcutaneous dosing. It will be very different to what we envisage, both the dose and the formulation for preeclampsia. So if I could walk through this slide, the blue line shows 15 participants with the starting blood pressure where the top number was over 150. In fact, the average was 166.5. You can see it on the table on the right. And they had the most sustained reductions in blood pressure with regular subcutaneous dosing, right? At the end of the trial at day 95, they still had a drop of blood pressure compared to initial enrollment of 22 degrees of mercury. Those who had high-ish blood pressures, but less so is in the black line, and that was 33 with a starting blood pressure of over 140 but not over 150, and they had a more gentler decline in their blood pressure dropping down to 12.6 towards the end of the trial. And the next up is even more gentler starting blood pressure. There was 54 participants with an average baseline 146, and they dropped by 7 millimeters of mercury. And the green line are people with a starting blood pressure of around 120. So they are well in the normal range. And so this is 24 participants. And sure, there may be a nonsignificant spike, you could say increased blood pressure, but if their starting blood pressure is 120, that doesn't put them in the high blood pressure category. But really, it [ flutters ] around a little bit and is really not dropping blood pressure particularly much.

Okay. Great. No, that's very helpful. And then maybe, Rick, I don't know if you could comment on -- we talked about primary endpoints, secondary endpoints that we're looking at here for this trial, the two parts. But any discussions or any comfort in terms of maybe the FDA or ex U.S. in terms of regulatory endpoints, just given there's nothing out there. Is it clear cut in terms of what regulatory bodies will need for ultimate approval? Or is this a work in progress?

Sure. So as we look at some other trials and getting feedback from experts in the field, we feel that a clear primary endpoint for approval would be extending gestational days, but also seeing improvements in other factors like blood pressure, kidney function would all be very supportive. We will talk to the FDA about potential blood pressure as well as part of that. But at a high level, we really do believe if we can extend gestational days, that will support. Dr. Tong, maybe do you want to comment on that, too?

I don't have any further things to add with regards to FDA. That isn't my expertise other than the fact that we have designed this trial, yes, looking for safety. But we really have sensibly expanded a very thorough search to look at early efficacy signals in these first trials that are planned to enroll end of the year.

So this concludes our Q&A. I'll now turn it back over to Rick for closing remarks.

All right. Great. Well, thank you, everyone, for joining us today. We really look forward to keeping you updated on our progress for both preeclampsia and our stroke program. And I would also like to invite you to visit our website to learn more about preeclampsia. We've recently put up a white paper that goes into more detail into the scientific rationale. And so with that, I really want to thank our collaborators for today. I believe it's after midnight, and I really appreciate the time. So once again, thank you, everyone, for joining us today. And with that, this concludes our call.