Our next company on today's RedChip Biotech Investor Conference is DiaMedica Therapeutics, ticker DMAC on the Nasdaq. Presenting today, Rick Pauls, CEO and President. Rick, are you there? I am. Good morning. I appreciate the opportunity. Good morning, Rick. Yeah. Good morning. Are you going to be displaying your presentation today? I sure will be. Hopefully, you can see my screen here. There you go. All right. As you're doing that, looks like you've already done it, let me go over the safe harbor statement very quickly. This segment may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements pertaining to future financial and/or operating results, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management, constitute forward-looking statements. Any statements that are not historical facts should also be considered forward-looking statements. Of course, forward-looking statements involve risks and uncertainties. Let me just add also that if you have any questions, please, audience, click the Q&A button at the bottom of your Zoom window. A text box will appear, then you can type in your question. We will consider it for today's show. All right, please go right ahead. Great. Well, I appreciate the opportunity, and we'll start off with the cautionary notes. DiaMedica, what we're developing is a synthetic or recombinant form of a critical protein called KLK1, tissue kallikrein. KLK1 is in all of us. It turns out that patients who have or at risk of preeclampsia, stroke, hypertension, kidney disease, have low levels. Sometimes in simple terms, we say we're doing is really protein replacement therapy. What I would say that's very unique about our protein is that there have been forms of this protein that have been treating patients for decades, and literally millions of patients over the years. Going back to the 1940s, Bayer, the German company, started isolating the KLK1 protein from pig pancreas in Japan for hypertension. Even today, there are several hundred thousand patients that are being treated with the porcine form in Japan. Similar number are also being treated in China for hypertension. More recently, in the last 15 years, a company in China, a Shanghai Pharma, started isolating the same protein from human urine for the treatment of acute ischemic stroke. That form of the protein today is treating almost one million patients a year. Sometimes I say the problem is solved, that we figured out how to manufacture the recombinant or synthetic form of this naturally occurring protein, as there's been numerous attempts over the years unsuccessful to make a form that could actually bring it into the clinic. What we're focusing today is our primary focus is on the treatment of preeclampsia. Last year, we had some very encouraging proof of concept data showing that our drug could very clearly lower blood pressure and increase blood flow to the placenta, potentially targeting the root cause of the disease, while we're also in a pivotal trial for acute ischemic stroke. Importantly here for the stroke program, we believe what our drug does is increasing blood flow to the ischemic area, that area at risk of dying following a stroke. We should have some meaningful data updates later this year. Importantly, we've got a very strong capital structure. We've got about $60 million in cash that give us a runway through the end of 2027, and a clean cap structure. There's no warrants and there's no debt. In terms of our pipeline, we'll start off with a preeclampsia program. We're just launching a phase II trial in the coming months. That'll be starting off in North America, initially in Canada. This will be early onset preeclampsia. Meanwhile, we've got an investigator-sponsored trial that's ongoing in Cape Town, South Africa. Throughout later this year and into next year, we should have an additional four clinical trial readouts. While that's all happening, we're also in a pivotal trial for acute ischemic stroke. We anticipate having our interim analysis before the end of this year. The interim analysis will be on the first 200 patients, in which case we'll either stop for futility or re-estimate sample size. If we see an effect size that's a drug effect that's comparable to our phase II data and for all the clinical use of this protein in Asia, we would look at completing the trial the following quarter. Starting off with preeclampsia, it's a disease many people have heard of but don't really understand well. Preeclampsia, in simple terms, is a hypertensive disease of pregnancy. Specifically, this typically happens sometimes after the 20th week when the demands of the blood flow, nutrients, oxygen outstrip the source that's getting to the baby. We're most interested in the early onset before 34 weeks. That's really where the greatest clinical need is. The rationale there is that if a mother develops preeclampsia at week 35, 36, typically just deliver the baby, and the baby and mother do well. However, if the baby is delivered at 28 weeks, that baby could be in the NICU for six months. Before 28 weeks, there's about 40% of these babies will have long-term disability. There's just a huge unmet medical need. In the U.S., there are about 200,000 patients a year that develop preeclampsia. Again, where the greatest need is the early onset, and there's about 30,000 of these patients in the U.S. There's also a related disease called fetal growth restriction, where the baby's not getting enough blood flow nutrients, and we think that our drug can also treat that patient population. There's another 20,000 patients there. What we look at is really the targeted patient population are about the 50,000 patients in the U.S. that have early onset preeclampsia and/or fetal growth restriction. The main reasons why these mothers have to deliver early is blood pressure. We'll talk about here in a few minutes why that's important and how our drug can address. This is just showing that every day that you can keep that baby and mother can have a significant effect in terms of reducing these very serious neonatal events, starting off with death and then looking at major morbidity. Just taking a little bit of a step back and just high level how this disease develops, just for context. Under a normal pregnancy, sometime after the 20th week, or sorry, in the first trimester, we've got these spiral arteries that open up. What happens is we've got trophoblast cells come in and strip the smooth muscle cells, strip the endothelial cells, and create basically this 10-lane highway. That's really where everything gets all the nutrients, blood flow, goes from the mom to the baby. For reasons we don't fully understand, this process does not develop well for preeclampsia patients and these spiral arteries do not open up. When that occurs, sometime after the 20th week, the demands of the baby, in terms of oxygen outstrip the supply, that then creates what we call a hypoxic placenta, and that then releases oxidative stress, which ultimately releases what we call these noxious factors. Things like sFlt-1, sEng, IL-6, they come in and damage the endothelium, and this ultimately is the first telltale signs is high blood pressure. Typically after systolic blood pressure gets over 160, that's really when the OB-GYN docs starting to prepare the delivery. They'll also look at other factors like eclampsia in the brain, hemorrhagic stroke, seizures, lungs. Proteinuria is really the other key factor that often occurs in these patients. What's important with our treatment pathway here is that we're targeting this, I mentioned this recombinant synthetic protein that produces nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factors that are all depressed in these patients. The difficulty with this disease is that we don't have a lot of treatment options today, and importantly, we can't use some of the best treatment options like ACE inhibitors, ARBs, because they're small molecules and they've been shown to cause harm to baby, and because of that, they're contraindicated. All we really have today is to help to control the blood pressure for literally a few extra days. Using labetalol and nifedipine, they can help to acutely lower blood pressure for a few days, but they don't address the underlying cause of the disease. A very important factor about our treatment is that we are developing a large molecule of protein that should not pass the placental barrier, and we've shown that. From a safety perspective, if our drug is not getting to the baby, it's a very critical safety profile while showing we can control blood pressure and get more blood flow to the placenta. Talking about our mechanism of action, first I'll just point out that the levels of our protein, the KLK1, are depressed in patients with both preeclampsia and also depressed in patients with preeclampsia with severe features where the levels are lower. Again, we see this sometimes as simply protein replacement therapy, restoring something that's in deficit. Again, recombinant human KLK1 protein is what we're developing. Through the production of bradykinin, activating the bradykinin two receptors, releases really three very critical vasodilatory factors, and those being nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factors that all work together to be increasing blood flow. Important to recognize that these three factors really target different arteries and conduits. If we're looking at nitric oxide, it's really the most relevant on the larger conduit arteries, where the EDHFs are really in the small arterioles. Really working together to, again, increase the blood flow and also lowering blood pressure. I showed you earlier a similar slide here. The premise is that if we can increase this whole pathway, so increasing levels of our protein, which then increases the nitric oxide, prostacyclin, EDHF, and VEGF, we think we can potentially be targeting the root cause of the disease. If we're getting more blood flow to the placenta, there should be less oxidative stress, there should be less of these noxious factors that are being released, and less damage happening to the endothelium. Usually the first telltale signs if our drug is active and is on target is that a reduction or control of blood pressure, while also improving and repairing the endothelium, improving maternal organ function and angiogenesis. I would also just like to mention is that I talked about earlier about these crude forms of this protein that are being used in Asia. We've been able to track down a number of publications showing the porcine form of our protein to really show very significant improvements in the outcomes for both the mothers and the babies. Again, all we're doing is manufacturing the synthetic form. Sometimes I say the analogy that I like is a bit like insulin. Insulin was initially marketed, commercialized by Eli Lilly. Genentech came along. They were able to figure out how do you manufacture the synthetic recombinant form of insulin, partnered up with Lilly, and then today all the insulin, in particular in the U.S., is all recombinant synthetic. A very good analogy of what we're trying to do here at DiaMedica. Turning to the results of our interim analysis data that we had, some proof of concept data that we shared last year. These are mothers that the plan is that they need to be delivered within 72 hours and often within 24 hours. Really what we wanted to determine, first and foremost, does our drug cross the placental barrier? The only way to really know that is to deliver the baby, deliver the placenta, look at the cord blood, and see if there's any of our drug DM199 in the cord blood. We would not expect it to cross, but really the only way to do it is to test it in patients. These mothers came in. They were all on maximum treatment options for preeclampsia, typically all on maximum labetalol and nifedipine. They'd come in, they'd get first dose IV. Then two hours later, they'd get a subcutaneous dose. We had three patients per cohort, and we really wanted to also see at what stage can we see a significant drop in blood pressure to tell us that our drug's on target. The other aspect we also wanted to look at is that can our drug increase the blood flow to the placenta? That's basically using a Doppler ultrasound, and they actually can look before and after and seeing if there's a reduction in what we call the resistance index, and a reduction in the resistance index directly correlates to more blood flow to the placenta. First, of course, in drug development, and particularly when you're dealing with pregnant mothers and their babies, is safety. Importantly, we had no serious treatment emergent events. What we did see for adverse events were really very consistent with this patient population. Potentially, a little bit of some facial flushing is what we did see with our drug, and which that all self-resolved. Then there were a number of expected events of preeclampsia, things like postpartum hemorrhage, eclampsia, HELLP syndrome, and pulmonary edema, but all in line with what you typically see in this very serious patient population. Importantly, from a safety perspective, we had no signs of hypotension, and so the main adverse event we have seen with our drug is that during that first IV infusion, if it's too rapid, we can cause a hypotensive event, so a large drop in blood pressure. When that has occurred, stop the infusion, and blood pressure goes back to baseline within a few minutes. The very important aspect of this is this is a naturally occurring protein that we just simply made the synthetic form. Turning to the placental crossing. What we can see here is that at each of the cohorts, you can see increased levels of our drug measured in the mother, but none detected in the cord blood. Just confirming that our drug doesn't get to the placenta and getting to the baby. We really don't have to worry about what that drug could be doing, causing some off-target effects. Turning to signs of efficacy, looking at blood pressure, so after the IV infusion, that was approximately over two hours, five minutes later, one of the key endpoints we had is that blood pressure measurements. As you can see here, there's a very clear dose response curve, and in particular, getting into cohort six and cohort nine, we see very significant drops. Keep in mind, these mothers are on this trajectory of blood pressure increasing very rapidly, and within minutes of receiving the IV infusion, we see very significant drops. When we combine cohort six to nine is really where we're going to be targeting for our next ongoing trial. We see a 25 millimeters drop in systolic, 13 in diastolic, and as you can see here, you can see a very clear drop and very small P values, indicating pretty much every patient responded. Just for a little bit of additional context, so if you take a step back and looking at all the time points that we had measured within 24 hours, we had kept the systolic blood pressure below 160. As soon as systolic gets over 160, the OB-GYN docs starting to prepare for delivery. You can see here very clearly we kept them below at each time point for both the systolic and the diastolic. Then the other part that we're also very excited about is that I talked about earlier about using Doppler ultrasound to remeasure the resistance index in the intrauterine arteries. As you can see here, just after two hours, there was a statistical significant drop of 13%. Again, low P value indicating most of these patients are all moving in the right direction. Importantly, when we go into the larger clinical trials where we'll be dosing for a longer period of time, if we could be dilating these intrauterine arteries for a few weeks ideally, we think we could see a profound impact in terms of having larger, healthier babies that stay in mom for a longer period of time. Really, as I mentioned earlier, every day you can delay delivery can have a very large impact in terms of how that baby turns out. Just to summarize, we think we have really the ideal drug profile for preeclampsia. We believe that we can improve blood flow to the placenta. We can control blood pressure. The last clinical trial for preeclampsia, the study failed, but the main reason some mothers had to deliver, over half, because that systolic blood pressure gets over 160. Importantly, it's how we do it. We do it by improving endothelial health. Most importantly, the safety profile is absolutely critical here when you're dealing with mother and her little baby. Again, very excellent safety profile. This is a naturally occurring protein, and very importantly, our drug does not cross the placental barrier. What's coming next here? We've got a phase II trial that's being initiated here right now over the coming months. This will be starting off in Canada, and then plan to move it into the U.K. and to the U.S., while we've got an ongoing study that is going on in Cape Town, South Africa. Really, between now and through the end of the year and into next year, we're anticipating to have five separate clinical readouts that will all help together to help us select which dose would go into the phase III. At phase III, right now we plan anticipating around 250 patients will likely be the base case. While that's all happening, we're also in a pivotal trial for acute ischemic stroke. Stroke has been a very difficult indication. There's been a lot of drugs have failed over the years. What we've learned is that things like oxidative stress, neuroprotectants, they haven't worked. What we do know that works for stroke is blood flow. If you're starting off with tPA, the clot buster is involved in dissolving the clot, blood flow gets reestablished, patients improve. tPA is used in about 10% of patients today, and the reason is you only have that 4.5-hour treatment window. Whereas mechanical thrombectomy is the other treatment. We come in with a clot retriever, pull out the clot, blood flow gets reestablished, and patients often improve immediately. That's only eligible for patients who have what's called a large vessel occlusion, and about 10% of patients there have also been treated. In total, for acute ischemic stroke, only about 20% of patients are being treated. With our therapy, by having a 24-hour treatment window. We think we can capture 500,000 patients that are not being treated today with our path here in terms of increasing blood flow. Without getting too much into the weeds in terms of the science, just at a very high level, what happens in the brain, you got these endothelial cells, and under normal conditions on those endothelial cells, you've got what's called bradykinin B2 receptors. What happens is that typically then native bradykinin comes and attaches and it vasodilates. What's very exciting, what happens following a stroke is that these bradykinin B2 receptors on endothelium are upregulated 35-fold. But what the body is missing is the ligand bradykinin. We come in, we give DM199 systemically, it releases bradykinin. Bradykinin attaches to those B2 receptors. Because those receptors are all upregulated on that side of the brain where there's a lack of blood flow, it focally vasodilates and pulls in blood flow from other parts of the body. If we zoom out from the cell level, we can see what happens here under early stroke. You've got the ischemia, the penumbra area, that's a risk of dying if you don't get blood flow reestablished. If you don't have a treatment like ours, if you don't get tPA, if you don't get mechanical thrombectomy, you're going to get a large infarct and permanent damage. All around here, if you can see where that clot is on the DM199 treatment here, you can see all in that little gray area here, those receptors are upregulated. Our drug releases bradykinin, focally vasodilates and actually pulls in blood flow from the other parts of the body, and that's why we believe patients improve and why we also think we can reduce the risk of having a recurrent stroke. What's unique about this whole program is that in China, there's a human urine form of the KLK1 protein currently being marketed today by Shanghai Pharma. Last year, almost 1 million patients were treated, and there's been a few hundred clinical studies showing the beneficial effects. We really looked at all of this data coming from China with the urine form, talking to experts there, talking to the neurologists, and we really call this our playbook in terms of which patients should we target, how long should we treat them for, and a lot of those factors that you could actually get caught up doing multiple phase II trials, we think we can be very targeted, so we think we can maximize the efficacy in our clinical trials. Turning to our phase II trial, what we saw is one of the learnings is that if a patient does receive mechanical thrombectomy, which is maybe 10% of patients today, giving our drug on top of that did not show a beneficial effect. Excluding those patients, what we saw was a 15% absolute improvement in what we call full recoveries. A modified Rankin score of 0 to 1 represents a full recovery. As we looked at our data a little closer, looked a little bit more at the data with the human urinary form, what we discovered is that patients coming in with severe stroke don't do as well in terms of getting to that full recovery. For our pivotal trial, we've excluded those patients, and looking at our phase II, we see a drug effect about 19%, which is very consistent to what we see with the human urinary form. Just to put this all into context, so tPA, the only drug approved for stroke today, initially got approved on a 13% absolute improvement versus placebo. Later, extension studies went out to four and a half hours where they see a drug effect of only 7%. We see that as really the clinical bar, because today, stroke neurologists will try to give tPA to pretty much every patient they can that can get to the hospital within four and a half hours, because even a 7% improvement versus no treatment can have a profound outcome in terms of these patients. It could impact their ability to speak, to walk, to even feed themselves. What we see from a clinical bar here is just 7%. We think with our therapy here, ideally high teens, maybe getting up closer to 20%, but most importantly, having a treatment option that can start within 24 hours so we can capture at least 90% of patients today who have a stroke. This is our pivotal trial design. This is again targeting moderate stroke severity patients. These are the ones we see the greatest effect with our drug, and we've seen with the human urinary form of the protein. Patients come in, they get first dose IV within 24 hours, and then they'll get a subcutaneous dose twice a week for a total of a 3-week treatment regimen with the primary endpoint at day 90, where again, we'll have the Modified Rankin score of 0-1. We're planning to do what we call an interim analysis after the first 200 patients. How that interim analysis will work, if we're not seeing a drug effect, we'll terminate the study, otherwise, we'll be doing a sample size re-estimation. We believe if we see a re-estimated sample size that's comparable to the phase II data I shared with you, which is very comparable to the data coming out of the human urinary form, we should be looking at close to 300 patients. We're planning to have that interim analysis by the end of the year. If it is 300 patients, we would then be looking at completing the enrollment in the following quarter. Just to summarize here, in terms of our IP protection here, so again, by being the first company to figure out how to manufacture this synthetic recombinant form, we did this discovery. It was a non-obvious discovery that really allowed us to have an issued composition of matter patents. We also got a series of formulation, with the subcutaneous, some dosing, and also we have some newer patents here that are pending in terms of treating diseases like pregnancy disorders, like preeclampsia, fetal growth restriction, while also knowing as a biologic, there's also 12 years of exclusivity with the FDA. Here's just pointing out to our team that's currently executing our trials. I'll mention that Julie Krop, our Chief Medical Officer in particular, has been involved in bringing several drugs through approval, including those in the women's health space. You can see the rest here of our directors. Last year, Dan O'Connor joined our board. He was at Ambrx and really did a nice job in terms of within 14 months, their company had a $2 billion acquisition. Just to summarize, I'll start off in terms of our capital structure, so $16 million in cash. Again, we've got a nice cash runway through 2027. Clean cap structure. There's no warrants, there's no debt, and we're really targeting two very large unmet medical needs. I'd say, unlike a lot of biotech companies that are developing drugs, we basically have a playbook coming from Asia with these two crude forms of the protein to really help us to guide us in terms of which patients to target. We think for either preeclampsia or stroke, I think both of these have a total addressable market of between $7 billion-$15 billion. Both indications where that if the drug gets approved, we think that physicians, hospitals will need to treat their patients because the alternative is very severe. With that, I'll open up to any questions. Thanks a lot, Rick. Thank you very much for an excellent presentation. We already have several questions for you. First one is, which analysts cover you currently? Yeah. Currently we've got five analysts. We have Josh Schimmer at Cantor. We have Stacy Ku at TD Cowen, and then we also have H.C. Wainwright. We have Lake Street, and then we also have Craig-Hallum. I understand that the mechanism for your drug is unique. Can you please describe how it works and why you believe it will be effective in preeclampsia and stroke? Yeah, it's a good question. I think in very simple terms, our drug safely increases blood flow. If you're starting off with preeclampsia, these patients have a hypoxic placenta, so they're not getting enough blood flow. That causes severe damage and requires these mothers to be delivered early. If we can simply increase the blood flow to the placenta while also lowering blood pressure, we think ideally, we could extend gestational days by weeks, when clinically, all we need is maybe five, six days, maybe even four days, to seeing a very clinically meaningful outcome. Then for stroke, what's very unique about our protein is blood flow again, but more so it is increasing collateral circulation in that ischemic area, that risk of dying, by the receptor activation that I mentioned earlier. Again, for both of these programs, there's all this data with the crude forms of the porcine form, the human urinary form, that really helps us to identify which patients we think ultimately will be the best responders. Rick, how do doctors react to DM199? Yeah. I've been doing this business for a while. Before this, I was running a venture capital fund, so I spent many years talking to different physicians over different diseases. I think starting off with preeclampsia, I had never seen the level of interest, in particular in preeclampsia, in terms of physicians' questions. The challenge there is that, these doctors are, basically every day, they're seeing the challenges of these mothers having to deliver early. They don't have any treatment options. They can give them labetalol, nifedipine to control blood pressures for five days maybe. They see these just horrendous outcomes. Their big question always is from a safety perspective. When they see that our drug does not cross the placental barrier, and then they're seeing that some dilation of the uterine arteries, they get very excited. I'd also mention a few years ago, just as context here, Viagra, so PDE5 inhibitors, did show some very encouraging improvements in these patients with preeclampsia. As a small molecule, later showed some very toxic effects, so it won't be used. The level of interest has just been fantastic. The same thing for stroke. Maybe not quite as the level of enthusiasm because they have been targeting a number of drugs over the years. When they better understand our mechanism of getting that collateral circulation, we share with them the data also, not just our data, but the data coming out of Asia with the human urinary form and even some of the more recent publications where you actually can see MRI scans. Where you actually can see before and after, that these patients, you can see the brain basically being lit up, which is showing there's getting more blood flow to the placenta. Again, for both of these indications, we're targeting patients. There's not a treatment option today, and the outcomes for these mothers and for these stroke patients is huge, and it's just a very sad situation. We'll wrap it up there as we rapidly approach the 30-minute, the bottom of the hour. Rick Pauls, thank you very much. Great. Well, thank you. Appreciate the opportunity to share our story with you all today. Glad you could make it today. Yep. Again, it's DiaMedica Therapeutics, ticker DMAC on the Nasdaq. If you'd like more information, call us at 1-800-RED-CHIP or email us.