DiaMedica Therapeutics Inc. Aktie

Good morning, ladies and gentlemen, and welcome to the DiaMedica Therapeutics First Quarter 2026 Earnings Conference Call. An audio recording of this webcast will be made available shortly after the call today on DiaMedica's website at www.diamedica.com in the Investor Relations section.

Before the company proceeds with its remarks, please note that the company will be making forward-looking statements on today's call. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these statements. More information, including factors that could cause actual results to differ from projected results appear in the sections entitled Cautionary Statement Notes regarding Forward-Looking Statements in the company's press release issued yesterday under the heading Risk Factors in DiaMedica's most recent annual report on Form 10-K and most recent quarterly report on Form 10-Q. DiaMedica's SEC filings are available at www.sec.gov and on its website. Please note that any comments made on today's call speak only as of today, May 7, 2026, and may no longer be accurate at the time of any replay or transcript rereading. Please -- following management's remarks, we will open the phone lines for questions.

I would now like to introduce your host for today's call, Rick Pauls, DiaMedica's President and Chief Executive Officer. Mr. Pauls, you may begin.

Thank you, operator, and thank you all for joining us today. With me this morning are Dr. Julie Krop, our Chief Medical Officer; and Scott Kellen, our Chief Financial Officer. Given that our last call was only 5 weeks ago, we'll try to keep our remarks short. We are pleased with the progress we've made so far in 2026 as we continue to advance DM199 across both our preeclampsia and acute ischemic stroke programs. Most importantly, for our shareholders, we're poised to deliver multiple clinical milestones between now and the end of 2027, all of which could provide significant validation of the value of DM199. We also weigh the risks and advantages of providing interim updates as clinically meaningful data emerges ahead of formal readouts.

We're particularly interested in completing the interim analysis for our stroke program. We've been working diligently on the ReMEDy2 stroke trial for a long time, battling through some significant challenges emanating from the COVID pandemic. With enrollment having surpassed 70%, we expect that the interim analysis will validate all of the hard work that has gone into the program.

I now turn the call over to Julie to provide additional detail on our preeclampsia and stroke programs.

Thank you, Rick. In the Phase II investigator-sponsored trial, enrollment is near completion in the extension cohort for the Part 1a dose escalation study in late-onset preeclampsia patients. Late onset patients are planned to deliver within 72 hours. This cohort will allow us to detect the dose or doses we plan to use for the upcoming cohorts of the IST. We expect to complete this cohort and provide a data update later this quarter. As you may recall, the interim results from this study demonstrated DM199's potential to reduce blood pressure and improve placental perfusion without crossing the placental barrier. While we only have data in a relatively small number of patients, the results we observed were highly consistent and encouraging.

We look forward to sharing the data from the extension cohort to further support the interim results. Additionally, learnings from Part 1a are guiding protocol amendments for the 2 remaining preeclampsia study groups. The first group referred to as Part 1b is an expansion study with up to 30 additional late-onset preeclampsia patients who will receive DM199 as a continuous IV infusion until delivery. In this cohort, we hope to learn more about the ability of doctors to use DM199 to effectively support blood pressure control management at this late stage of the disease. The second part referred to as Part 2 will study up to 30 early onset preeclampsia patients. Three doses will be evaluated to support dosing for a Phase III trial and an optimal dose level to extend the time mom is able to carry the baby, increasing the gestational age at the delivery.

As you've seen in our investor presentations, the medical complications for the baby are expected to decrease significantly the longer mom carries the baby. With the potential for DM199 to help manage blood pressure and improve blood flow to the placenta, we believe DM199 has a chance to be a transformative therapy for preeclampsia. Initiation of these 2 preeclampsia cohorts which will recruit concurrently, is expected to begin after the completion of the ongoing Part 1a extension cohort.

The IST also includes a study in women experiencing fetal growth restriction. In this group, we will be evaluating the effects of DM199 on fetal growth restriction in patients without preeclampsia. FGR is a condition with diminished fetal growth due to a poorly functioning placenta, the life support system of the unborn child. FGR is the leading cause of stillbirth and for infants that survive the FGR pregnancy, it is associated with enduring adverse health effects over the child's lifespan. In this cohort, we will evaluate the potential for DM199 to increase placental perfusion and improve fetal development.

Enrollment of the first patient for this study is expected in the current quarter. In parallel with the IST, we are advancing our global Phase II study in early onset preeclampsia. We intend to conduct this study in North America, both the United States and Canada and the United Kingdom. In March 2026, we received approval from Health Canada to initiate this study and study sites have been selected. We are working to initiate enrollment in Canada by the end of this year. We expect to file a clinical trial application in the U.K. in the current quarter. With respect to the status of the IND submission in the United States, as we discussed previously, the FDA requested an additional nonclinical 10-day modified embryo fetal development and pre- and postnatal development study in a rabbit model. Results of a non-GLP dose-ranging study in rabbit suggest that the animals developed an adverse immune response to DM199, preventing us from completing the requested modified pre- and postnatal development study in a rabbit model.

We have proposed to the FDA performing this study in a second rodent model and are awaiting their response. That said, I would highlight for everyone that we are moving forward in parallel with the study in Canada and are planning to add U.K. sites while we complete any additional preclinical work requested by the FDA. This study will evaluate 3 dose groups of DM199 in patients with early onset preeclampsia to further establish safety, pharmacokinetics and pharmacodynamics in a more ethnically diverse patient group prior to initiating a registration study.

Turning now to our stroke program. We are encouraged by the continued progress on the ReMEDy2 trial. Enrollment has now surpassed 70% of the target required for the interim analysis. Site activations and enrollments have recently commenced in Europe as well. In addition to the United States, Canada and the U.K., we've added 6 additional European countries and now have approximately 70 sites activated. In April, we sponsored an investigator meeting for our European study team that was well attended and had many productive sessions and discussions, which we believe are the key to getting the study teams excited about and focused on patient enrollment.

And we are reiterating our intention to complete the interim analysis by the end of 2026. As a reminder, in the Phase II ReMEDy1 stroke study, treatment with DM199 was associated with clinically meaningful improvements in functional outcomes for the patient group that most closely resembles the patients enrolling in our ReMEDy2 trial. In the subset of patients that did not undergo a thrombectomy, we observed a 15% absolute increase over placebo in the proportion of patients achieving favorable recovery as measured by a score of 0 or 1 on the modified Rankin Scale. Furthermore, ReMEDy2 is enrolling patients presenting with moderate stroke severity defined as an NIHSS score between 5 and 15. Looking at that subgroup in the ReMEDy1 study, there was a 19% absolute improvement over placebo in functional outcomes. There was also a 50% reduction in the number of patient deaths and a 13.3% reduction in recurrent strokes compared to placebo. These data inform the design and powering assumptions for the ongoing ReMEDy2 trial. I think you can understand why we are eagerly awaiting the results of the interim analysis.

Let me now turn the call back to Rick.

Thanks, Julie. I'd like to now ask Scott to review the financial results for the quarter.

Thank you, Rick, and good morning, everyone. We announced our first quarter 2026 financial results and filed our quarterly report on Form 10-Q yesterday after the markets closed. As of March 31, 2026, our cash, cash equivalents and short-term investments were $51.3 million, current liabilities were $5.7 million and working capital was $46.6 million compared to cash and investments of $59.9 million, current liabilities of $5.1 million and working capital of $55.5 million as of December 31, 2025. We anticipate that our current cash and investments will be sufficient to fund our planned clinical studies and operations through 2027. Net cash used in operating activities for the first quarter of '26 was $9.1 million compared to $7.1 million for the first quarter of 2025.

The increase in cash used in operating activities resulted primarily from the increased net loss for the current year period, partially offset by changes in operating assets and liabilities during the current year quarter.

Turning to the income statement. Our research and development expenses increased to $8 million for the 3 months ended March 31, 2026, up from $5.7 million for the same period in the prior year. The increase is due primarily to the increased costs resulting from the continuation of our ReMEDy2 clinical trial and its global expansion, the expansion of our clinical team and costs related to additional reproductive toxicity testing being performed in support of our PE program in the United States. These increases were partially offset by net cost reductions in manufacturing development activity related to work performed and completed in the prior year period.

We expect that our R&D expenses will moderately increase in future periods relative to recent prior periods as we continue our ReMEDy2 trial and continue to advance our DM199 clinical development program into PE. Our general and administrative expenses were $2.5 million for the 3 months ended March 31, 2026, and 2025. While small changes occurred within a number of expense categories, the differences were not material individually or in the aggregate and the overall net changes offset each other. We expect G&A expenses to remain relatively consistent in future periods as compared to recent prior periods.

With that, let me ask the operator to open the lines for questions.

Your first question is from the line of Josh Schimmer with Cantor.

The preeclampsia data updates that we'll get this quarter for the late onset cohort, what incremental observations should we be looking for beyond blood pressure control? Obviously, preeclampsia can affect urine output, kidney function, liver function platelets and biomarkers like sFlt. At what point will you have data to share on those parameters?

Yes. Thanks, Josh. So the expansion cohort that we're running is going to be 12 additional patients. We're almost completing that right now. It's going to be at the cohort 10 from the Part 1a. And so it's really just going to give us additional clarification here, particularly on blood pressure, dilation of the intrauterine arteries. At this point, we're really not expecting any changes in some of the biomarkers like sFlt because these patients really only got 2 doses. It's really we believe that having the drug on board for ideally a week, 2 weeks that we really would see some of those biomarkers improve.

Okay. Got it. So I think at one point, the lead investigators suggested that there was an improvement in edema at the very least maybe might be something that can improve within a short period of time. Is that something you're looking for?

Yes, that's something that if there is an improvement in endothelial health, and it is something that Dr. Cathy Cluver very clearly seen in some of these patients that the edema did resolve even within 12 to 24 hours of getting DM199, which is encouraging. It's a small number of patients, but we'll be looking to see maybe there's some additional insight there as well.

Just a couple of other quick questions, if I may. What are the steps to start initiating enrollment in the early onset preeclampsia study? Why is that not going to occur until later this year?

Yes. Julie, do you want to take that one?

Yes. Are you referring to the IST cohort? Or are you referring to the -- to our sponsored trial?

Sponsored trial.

Yes. We are in the midst of getting our dosing data from -- again, from the IST study before we select our final doses for that protocol as well as getting sites contracted up and running and our CRO selection process, all of that completed and then we'll be initiating. So it's a combination of factors, but we should be again in Canada later this year.

And then last sorry...

Sorry, if I can add. And so importantly, as we mentioned, so we have selected the 2 sites in Canada and one site in particular, is already in our stroke trial. So we're looking forward to leveraging the relationships, the existing contract that we have to basically doing what we can to expedite and get those sites activated as soon as we can.

Got it. And then last question, timelines for completing the second animal toxicology study and then ultimately reengaging with the FDA for IND.

Yes. So it will really depend on the feedback that we get from the FDA. And so it is a rat study that we proposed. And if they agree to that, that's a matter of a few months, probably 3 to 4 months to complete. And so again, while that's all happening, we'll be running the Phase II in Canada and then expanding to the U.K.

Your next question is from the line of Stacy Ku with TD Cowen.

So we have a couple of questions. So I guess, first, follow-ups. When could you expect to hear from the FDA on the mouse study? And is there a possibility the FDA could ask for another animal model? And how are you looking to prepare for all these different scenarios? It sounds like the rat study is pretty straightforward, but just help us understand how you view the next 2 necessary steps.

And again, just to clarify, it sounds like you are expecting a potential study initiation of the global Phase II by year-end. Just want to make sure you're reiterating that time line. And then we're looking forward to the updated preeclampsia results in Q2. But as we think about the early onset preeclampsia or fetal growth restriction subgroups of the IST, could we think about any potential for low-dose updates by year-end for either of these groups?

And then, Julie, just a clarification again, what is the timing of potentially starting the early onset preeclampsia IST?

And then last, just a reminder, what's the go and no-go decisions on the interim results for stroke? I can repeat some of these questions.

Okay. Great. So we'll try to take those. I'll start off here. Maybe Julie, you can help me out here. So in terms of the -- we did our submission to the FDA over a month ago. And so we're just waiting to hear the feedback. So as soon as we get clarity from the FDA, we'll provide an update. We have looked at alternative kind of backup plans in case they want something different. But we think we've got a very strong rationale for the proposed rat study. And I think it's encouraged that the Health Canada has already approved us to start the trial in Canada.

With the PE trial in terms of, yes, potential that we could get some data as soon as we have a cohort that's completed and we see some compelling data, we would look at potentially press releasing or getting that at a late-breaking conference.

And the last question that you had with regards to the outcomes of the interim analysis for the stroke program. First, we'll do a futility analysis. So if there's not a drug effect, we'll terminate. Otherwise, there'll be a resample size. And the resample size will be between 300 and 700 patients. And we believe if we see a drug effect comparable to what we see from our Phase II, which is comparable to the data we've seen with the data with the human urinary form in China, and there's about 1 million patients either being treated with that form. We would look at completing the enrollment in the following quarter.

Your next question is from the line of Thomas Flaten with Lake Street.

Rick, just following up on that last response, just to clarify, given that you've got 70-plus sites and 70% enrolled, if you -- when you said we're going to complete enrollment in the following quarter, do you mean the first quarter of '27 or the -- which quarter were you referring to on the full enrollment?

Yes. So assuming that we have the interim analysis at the end of this year, then we would anticipate completing the enrollment the following quarter, so the Q1 of next year.

And does that assume an upsize in the total population? Because it seems to me it's only May. And by year-end, when the interim analysis reads out, you should be pretty close to full enrollment on the original study size, right?

We will be. So that after patient 200 is dosed, there'll be a 30 -- sorry, a 90-day window here for the primary endpoint and then another approximately 4 weeks for the interim analysis to occur. And during that approximately 4 months, we'll be continuing to enroll. So we'll be getting closer to the 300 patient number during that period of time.

Got it. And then just to clarify a prior response. So once you get the Part 1a expansion data out this quarter, there's -- is it reasonable to assume that you would start Part 1b and Part 2 in the third quarter? Or should we expect maybe a fourth quarter start on that?

No, those should be starting here this summer. And so we're just -- we finalized the dosing that will be going into those cohorts. So we'll be doing 3 doses at 5, 10 and 15 micrograms per kg subcutaneous every 3 days until delivery. So those cohorts should be starting very soon. We had some -- we've now got our sites, Cape Town South Africa has had some challenges with some staffing and they've added some new staff. And so they've been very active recently in the Part 1a expansion study. So we feel very good that, that study will be enrolling soon.

Your next question is from the line of Jason (sic) [ Chase ] Knickerbocker with Craig-Hallum Capital Group.

One for Scott. I appreciate your comments on forward R&D, but maybe just a little bit more color there. You said kind of modest increase. I would imagine kind of enrollment is still picking up on an absolute number for stroke. And then can you just give us an idea kind of what the magnitude of that increase you expect sequentially in stroke and then kind of the incremental costs you expect for PE through the year.

Sure. Thanks, Chase. Yes, with respect to the stroke, modest increases. I mean the -- and you're correct, it's all going to be driven by the enrollment rates. And to some extent, it depends on whether those patients are enrolled in the U.S. or Europe. U.S. is probably the most expensive followed by U.K., Canada and Europe. And then with respect to the incremental cost for PE, there'll be -- well, we're still working on the estimates for the Phase II trial. The financial support we provide for the IST is very modest. It's an incredible bargain. So again, moderate -- modest to moderate increases, nothing order of magnitude change-wise.

Could you just define modest or moderate for us, if you don't mind? And then just one for Rick. Just as we think about the resample, should we kind of just expect to receive the number on the resample or anything else at that point that we'll be able to provide?

Sure. For the interim analysis, we'll be providing an update on the expected timelines to complete the enrollments.

Chase, it's hard to give a specific number because there's movement inside all the different expense categories. I mean I wouldn't expect it to go up more than 10% a quarter.

I will now hand today's call over to Rick Pauls for any closing remarks.

All right. Well, thank you all for joining us today. We greatly appreciate your interest in DiaMedica and hope that you enjoy the rest of the day. This concludes our call today. Thank you.

Thank you for joining. You may now disconnect your lines.

Good morning, ladies and gentlemen, and welcome to the DiaMedica Therapeutics Full Year 2025 Earnings Conference Call. An audio recording of this webcast will be available shortly after the call today on DiaMedica's website at www.diamedica.com in the Investor Relations section.

Before the company proceeds with its remarks, please note that the company will be making forward-looking statements on today's call. These statements are subject to risks and uncertainties that could cause the actual results to differ materially from those projected in these statements. More information, including factors that could cause actual results to differ from projected results appear in the section entitled Cautionary Statement Note regarding Forward-Looking Statements in the company's press release issued yesterday and under the heading Risk Factors in DiaMedica's most recent annual report on Form 10-K.

DiaMedica's SEC filings are available at www.sec.gov and on its website. Please also note that any comments made on today's call speak only as of today, March 31, 2026, and may no longer be accurate at the time of any replay or transcript rereading. DiaMedica disclaims any duty to update its forward-looking statements. Following the prepared remarks, we will open the phone lines for questions. I would now like to introduce your host for today's call, Rick Pauls, DiaMedica's President and Chief Executive Officer. Mr. Pauls, you may begin.

Thank you, Morgan, and thank you all for joining us for our fiscal year 2025 earnings call. With me this morning are Dr. Julie Krop, our Chief Medical Officer; and Scott Kellen, our Chief Financial Officer.

Looking back for a moment, 2025 is a year in which we made significant progress across our pipeline, achieving a number of key milestones. As most of you know, our lead candidate, DM199, is a recombinant form of the naturally occurring KLK1 protein, a serum protease that acts through the bradykinin 2 receptors in the walls or endothelium of our blood vessels to increase the level of nitric oxide, prostacyclin and endothelial-derived hyperpolarizing factor.

The combination of these factors has the potential to more effectively enhance blood flow and vascular health than any other factor given by itself. We believe that this mechanism is why DM199 is so well suited to improve patient outcomes for preeclampsia, fetal growth restriction, acute ischemic stroke and other indications associated with vascular pathology. I'll now turn the call over to Julie to provide an update on our preeclampsia and stroke programs.

Thanks, Rick, and good morning, everyone. Starting with our preeclampsia program, 2025 marked a very strong year of progress. In July, we announced positive interim results from Part 1a, the ascending dose portion of our investigator-sponsored Phase II trial being conducted in South Africa. These results showed that DM199 produced statistically significant reductions in blood pressure and in the uterine artery pulsatility index, consistent with reductions in vascular resistance that suggest a potential improvement in blood flow to the placenta.

Importantly, the interim data demonstrated that DM199 did not cross the placental barrier. These interim results were observed in hypertensive women expected to deliver within the next 72 hours. We believe these results demonstrate an on-target mechanistic response, which supports DM199's potential to be a first-in-class disease-modifying therapy for preeclampsia.

Key findings from the interim analysis of Part 1a, specifically from Cohorts 6 through 9 in pregnant women with preeclampsia planned for delivery within 72 hours include the following: First, blood pressure data demonstrated clear dose-dependent and statistically significant sustained reductions in both systolic and diastolic blood pressure, underscoring DM199's potential to control maternal hypertension associated with preeclampsia. Second, DM199 significantly reduced the uterine artery pulsatility index, a Doppler-based measure of arterial resistance that suggests improved uteroplacental perfusion. Third and most importantly, DM199 did not cross the placental barrier, placing it in a unique position with respect to safety and reduced fetal risk in this highly vulnerable patient population.

Through additional analysis, we have also demonstrated that DM199 does not pass to babies through breast milk, further reinforcing its confinement to the maternal circulation. This advantageous safety profile combined with DM199's novel mechanism of action may enable earlier initiation and longer treatment duration, which has the potential to drive meaningful prolongation of pregnancy without added safety burden. We believe the observed improvements in vascular resistance reflect restoration of normal endothelial function, consistent with an on-target mechanistic response to DM199 therapy.

By improving endothelial health, DM199 has the potential to address the underlying vascular dysfunction driving the disease that should result in stabilization of maternal vascular pathology and prolonged pregnancy as opposed to current therapies that simply manage symptoms. Taken together, the ability to reduce blood pressure, improve uterine placental perfusion and restore endothelial function reinforces our belief in DM199's potential to be a first-in-class disease-modifying therapy for this life-threatening condition for which there are currently no approved treatment options.

During the fourth quarter, under the leadership of Professor Cluver, enrollment continued in the Part 1a expansion cohort, which will include up to 12 additional patients to provide us with a more comprehensive data set. We anticipate completion of this cohort in the first half of 2026. Protocol amendments are being finalized for Part 1b and 2 of the study. Part 1b will enroll up to 30 hypertensive women with late-stage preeclampsia expected to deliver within 72 hours to further confirm the Part 1a results. These participants will receive continuous IV administration of DM199 that will be titrated to maintain blood pressure in the targeted range.

Part 2 will enroll up to 30 women with early onset preeclampsia, who are candidates for expected management where the therapeutic goal is to prolong the pregnancy as long as possible while also providing increased blood flow to promote larger, healthier babies. These protocol amendments represent refinements to the previous treatment regimens based upon learnings from Part 1a. The fetal growth restriction cohort will be enrolling patients without preeclampsia, but with impaired placental function, further expanding the potential application of DM199 across placental vascular disorders. The first patient in that cohort is anticipated to be dosed in Q2 2026.

Importantly, we have also recently received regulatory clearance from Health Canada to initiate a global Phase II clinical trial of DM199 in early onset preeclampsia. This is an important regulatory milestone for our PE program. We are currently finalizing plans to commence site activation in the second half of the year. We intend this trial to be a global Phase II study. It is an open-label dose-finding trial designed to enroll approximately 30 participants with early onset preeclampsia between 24 and 32 weeks of gestation. This expected management population represents patients with the greatest unmet medical need where safely prolonging pregnancy can have the most meaningful maternal and neonatal impact. The study will evaluate the safety, tolerability and preliminary efficacy of DM199 with dosing anticipated to continue until delivery. We are assessing 3 dose levels to inform dose selection of the optimal regimen for Phase III.

Primary study endpoints include maternal pharmacokinetics and further confirmation that DM199 does not cross the placental barrier, an important safety consideration for both regulatory review and patient acceptance. In addition, we will evaluate clinical and biomarker outcomes, including prolongation of pregnancy, blood pressure control, uterine artery blood flow, circulating pathogenic biomarkers and renal function. We are also preparing to seek approval to expand the study to include sites in the U.K.

And with respect to the additional reproductive tox study in rabbits requested by the FDA, preliminary results from a dose range finding study in rabbits suggests that rabbits may not be a suitable animal model for reproductive toxicology studies with DM199. This is likely due to an unusual immune response to the recombinant human protein unique to rabbits that has not been seen in rats, monkeys or humans thus far. Most importantly, from our perspective, there were no teratogenic effects observed in the approximately 200 pups or baby rabbits produced in a prior study. This included no external visceral or skeletal malformations. We are currently evaluating an alternative animal model to address the FDA's request, and we will work with FDA to find a solution in parallel to initiating the Phase II trial in Canada and other potential jurisdictions.

Turning to our ReMEDy2 trial. 2025 was also a good year for our stroke program. Over the past several months, we have intensified our engagement with study sites to share best practices and build friendly competition. We've also added additional resources to support sites through the enrollment and follow-up process, and we continue to work on additional ways to support our study sites. These activities, along with increased site activations globally have resulted in encouraging enrollment momentum over the last few months.

At present, I'm very pleased to report that with these additional efforts in the United States and Canada, along with expansion into the U.K. and Europe, we have achieved almost 70% of the required enrollment of 200 participants for the interim analysis. We currently have close to 61 active sites, including 4 in the U.K. and an additional 12 across Europe, and approximately 25 more sites are expected to activate in the coming quarter. With our recent progress, we are reiterating our guidance to complete the interim analysis by the second half of 2026.

Since the last earnings call, an independent Data Safety Monitoring Board meeting was conducted after the enrollment of 100 patients. Following review of the safety data from these participants, the independent DSMB unanimously recommended that enrollment continue without modification. I will now turn the call back to Rick.

Thanks, Julie. We're also pleased to note the paper titled Endothelial Triple Pathway Basal Relaxation as an adjuvant strategy in resistant hypertension was recently published in the Journal of Hypertension. The article authors included Dr. Luke Laffin, a recognized key opinion leader in the treatment of resistant hypertension.

This publication underscores the need for new treatment approaches to lower blood pressure in patients with chronic kidney disease. It also highlights findings from our prior Phase II REDUX trial, which demonstrated DM199's ability to significantly reduce blood pressure in patients with elevated levels over a 3-month treatment period. DM199 was also observed to lower serum potassium levels in patients whose potassium levels were elevated, placing these patients at risk of developing hyperkalemia. We look forward to sharing more on the potential use of DM199 to control blood pressure in patients with chronic kidney disease in the future.

I would like to now ask Scott to review the financial results for the quarter.

Thank you, Rick, and good morning, everyone. We announced our full year financial results for 2025 and filed our annual report on Form 10-K yesterday. As of December 31, 2025, our cash, cash equivalents and short-term investments were $59.9 million. Current liabilities were $5.1 million and working capital of $55.5 million compared to cash and investments of $44.1 million, current liabilities of $5.4 million and working capital of $39.2 million as of December 31, 2024.

The increase in cash and short-term investments is due to the net proceeds received from the sale of common shares in the company's July 2025 private placement and under its at-the-market offering program. We feel confident about our cash position and anticipate it will fund our planned clinical studies and corporate operations through the end of 2027. Net cash used in operating activities for the full year 2025 was $29.1 million compared to $22.1 million for the full year of 2024. This increase is primarily a result of the increase in net loss for the full year of 2025 as compared to the prior year period.

Turning to the income statement. Our research and development expenses increased to $24.6 million for the year ended December 31, 2025, up from $19.1 million for the prior year. This $5.5 million increase is driven by a combination of factors, including the continuation of our ReMEDy2 clinical trial and its global expansion, the expansion of our clinical team in both the prior and current year periods and increased noncash share-based compensation costs. These increases were partially offset by cost reductions related to manufacturing process development work performed and completed in the prior year period.

Our general and administrative expenses were $9.8 million for the full year 2025, up from $7.6 million for the full year 2024. G&A expenses increased by $2.2 million due to a number of factors, including increased noncash share-based compensation expense, increased personnel costs, increased investor relations expenses and increased patent prosecution costs.

With that, let me ask the operator to open the lines for questions.

[Operator Instructions]

Your first question comes from Stacy Ku with TD Cowen.

So we have a couple. If we could just stay with preeclampsia for now. The first question is on kind of your update with the rabbit preclinical trials for the U.S. IND approval. So just help us understand what are your early thoughts on the alternative species with the FDA? Are there -- what other preclinical models are best for reproductive tox studies? So that's the first question. If you could maybe further elaborate there.

And then as we think about the ISP and clearly, a lot of great signals that we're going to get -- continue to get there, what key learnings are you hoping to carry into the early onset preeclampsia kind of cohort? As we think about Part 2 and Part 3 so fetal growth as well. Is there any potential that we can get an update later this year? So just help us understand where you all are in potential timing there?

And then, of course, ahead of the U.S. trial, Julia, we kind of heard all the high level of preparation ahead of moving forward in the U.S., but just help us understand how our conversations progressing? What criteria is the team focused on when it comes to enrolling the right preeclampsia study investigators. And then if I could sneak in a tiny question on CKD. Clearly, a big opportunity. When could we expect a detailed plan or a more detailed plan for pursuing DM199 in treatment-resistant hypertension in CKD patients?

So I'll start off maybe with the CKD, the fourth question is that we're very excited about the opportunity for our drug to lower blood pressure. We've clearly seen it in numerous trials. I think there's a huge clinical need, in particular in patients with chronic kidney disease as many of these patients have elevated levels of potassium that puts these patients at risk of hyperkalemia. So I think first, we can treat these patients, control their blood pressure when they frankly don't have a lot of options and what we did see in our previous trial, the ability to lower potassium levels, which could be a very exciting opportunity.

Right now, really the focus though is on our preeclampsia and stroke program. And at the appropriate time, we'll look at potentially advancing into CKD. But right now, we want to make sure we're really focused here near term on our other 2 programs. And then maybe I'll hand it off to Julie.

Yes. Stacy, all very good questions. I think it's premature right now to tell -- to say exactly which species that we're going to focus on. We want to first be able to -- we submitted a package to the FDA, and we're having a discussion with them further on appropriate models. There are several appropriate models we're considering. But again, we'll hold back until we will give an update once we have that discussion.

And then with regards to your question around what have we learned from previous cohorts, I think I think we understand the PK better after running the initial studies. And one -- one of the learnings we're taking forward is for our early onset studies using the subcutaneous only and probably reserving the IV for the later onset as we've been doing previously. So that was one element.

I think as far as site selection, we are highly focused on selecting sites that have both experience with preeclampsia studies as well as a practice that's well suited for early onset expectant management, which is something -- some sites are very adept at and other sites are more conservative about when to deliver patients. So again, it's that tight rope between treating -- between the mother's health and the baby's health and making sure that we select centers that are comfortable keeping the mother even though there's some severe -- there's potentially severe complications going on, it feels like they can stabilize them enough to prolong the pregnancy. So those are kind of the considerations that we're focused on.

Your next question comes from Josh Schimmer with Cantor.

Two quick ones. For the evaluation of DM199 in earlier onset preeclampsia, how do you think about the potential risk of the protein crossing the placental barrier at that stage? And what evidence do you have to suggest that it in that setting as well will not cross in any meaningful extent to the placenta? And then for the interim analysis for the Phase II/III stroke program, what are the potential outcomes there? Are there stopping criteria either positive or negative or resizing criteria? Maybe you can share a little bit more about what you expect the interim to inform?

Sure. Thanks, Josh. So starting off with the early onset and crossing of the placenta. We don't think it will happen. I mean we've done now over 35-plus patients with more late onset preeclampsia where we didn't see this crossing. To cross the placental barrier is about -- the size to cross will be about 500 daltons, where our protein is about 26 kilodaltos, so 50x larger. So it would be very shocking if it did occur. We also did an earlier study in the rat model, we also did not see it. So it's just -- I think we're at this point here, another check the box, but we feel very good the fact that in the South African patient population, we didn't see it.

With regards to your second question, the ongoing Phase II/III stroke program, for the interim analysis, first off, if we're not seeing a drug effect, we will terminate the study for lack of efficacy. Otherwise, there'll be a resample size and the sample size will range from 300 to 728. How we designed this trial, and we believe a base case that if we're seeing a drug effect that's comparable to our Phase II, which is comparable to the many studies that have been shown with the human urinary form of the study in China.

Looking at the modified ranking score of 0 to 1 as the primary endpoint, we're anticipating that if we see, again, a drug effect comparable, we'll be looking at something ideally in the 300 to 350 range. If we need to go above 500 patients, we'll have to really evaluate the next steps for the program in light of the high prospects we think as well for the preeclampsia program.

Your next question comes from Thomas Flaten with Lake Street.

Just a question on the Part 1a expansion cohort. It strikes me that it's taking a bit longer than I might have thought in my mind given how many patients Dr. Cluver sees on a weekly basis. Is this a slow and deliberate approach she's taking? Or has something else been going on there? Just some additional color on that expansion cohort would be great?

Sure. Yes, it's a good question. It really has been a result of some staffing challenges that Cathy Cluver has had at her site. We've recently provided some additional financial support. And with the hiring of a couple of new nurses just in the last few weeks, we anticipate that enrollment is going to pick up again.

And then following on from that, if I understood the press release and your commentary correctly, are Parts 2 and 3 -- are Parts 1b and 2, sorry, dependent on the completion of the expansion cohort? Or will they initiate prior to the full completion of that cohort?

Those -- so we've made a few protocol amendments that are going through shortly. And so we're anticipating later in Q2 that those 2 cohorts should initiate. Part 1a expansion study is ongoing and will be completed as well in Q2.

Got it. Understood. And then just a quick one on ReMEDy2. You mentioned some acceleration or some momentum building. I was wondering if you could just give us a sense of in the first quarter of this year, how many patients did you enroll compared to what you did in the fourth quarter of last year, just to give us some kind of scope and scale of that momentum?

Yes. I would just say at a high level, the enrollment increase really has been more so it's been this year. So even going into the end of 2025, it was still relatively slow, but it really has picked up substantially in the last month, last 2 months. But really, the more recent months is where we've seen the really uptick. And that also correlates to where we've had the increase in sites and all the work that Julia and her team have been doing has been wonderful. And I think we're now starting to see the benefits of all that work.

Your next question comes from Matthew Caufield with H.C. Wainwright.

For the ReMEDy2 trial, there had been some prior discussion of some challenges with stroke enrollment formally being slower in the U.S. due to initial triage in the community hospitals. Kind of thinking bigger picture, do you ultimately foresee any limitations for real-world access if or when DM199 could ultimately be approved for the AIS indication?

Yes. Good question. So I think there's a difference between the challenges that we had been seeing with enrolling at more of these hub-and-spoke hospitals. But ultimately, for commercialization, the wonderful thing about our drug is the safety profile should be great in being able to be used very broadly at small community hospitals and big academic centers. So I think that the previous challenge we're having is really more with enrolling patients at the large academic centers. But in terms of -- again, at the commercial side, I think it will be a wonderful drug because of that safety profile.

Your next question comes from Chase Knickerbocker with Craig-Hallum.

I was just hoping to work one more in on the nonclinical side here. Can you just maybe walk us through kind of the differences in your prior nonclinical rabbit study that you had kind of mentioned where you didn't see any toxicity in this one? Was there kind of a different species used here? Or maybe just kind of your biological rationale as to why this antibody response arose?

Yes, Julie, can you take that one?

Yes. So that's a very good question. The first study was a different gestational age time period for the pre- and postnatal rabbit study. We studied an earlier -- I mean, a slightly later gestational age as well as a slightly different duration of treatment, different doses. So it's hard to explain. We did see maternal toxicity in that study as well. It wasn't quite as significant.

But I think the difference here and the issue really with the FDA is not related to concern on the part of the fetus -- I mean, sorry, the pups, if you will. The pups really did not show any increase in malformations or teratogenicity from the control group in either study. But I think the concern with the FDA is finding a NOAEL effect dose where they don't see any adverse effects and the maternal toxicity that we saw, which we believe is due to immunogenicity, which is not uncommon to see in rabbits and immune responses very quickly to human proteins. So I think really, it was in both studies, we weren't -- we had maternal toxicity.

So I don't think they were really that different other than gestational ages being different and the FDA wanting us to dose primarily after the first trimester after the development -- the early development of the fetus because that's closer to the way we're going to dose humans. So it just turns out, I think the rabbits just are not a good species, and we're going to just have to do it in a different species.

Got it. And then just maybe a little bit on time lines as far as when you'd expect to get that feedback that you need to continue with the different species or just kind of color from FDA on what they would like to move forward. Do you have a meeting scheduled in Q2? Maybe just walk us through time lines there.

So we are going to -- we'll provide an update as soon as we have something to update. I don't think we're giving a forecast yet until we understand and get alignment from the FDA on the path forward.

Understood. And then just last for me, Rick, on the stroke timing, could you just give us a little bit more color as to kind of what you're seeing from an enrollment rate perspective? I mean, is it kind of being driven by kind of breadth increasing? Or is that depth really kind of increasing as we thought it would to kind of drive this acceleration in enrollment in the stroke study?

Yes. And it's a combination of, in particular, over the last few months, an increase in the enrollment rate per site and also for a greater number of sites. And then with being at 61 sites now and having sites having a chance to be in the trial and understand some of the challenges and opportunities of running the trial. And then I think also having a number of sites that are also on the verge of coming on board here in the coming weeks, we feel good about reiterating our guidance for this year.

That concludes our question-and-answer session. I would like to now turn the conference back over to Rick Pauls, DiaMedica's President and Chief Executive Officer, for closing remarks.

Well, thank you all for joining us today. We greatly appreciate your interest in DiaMedica and hope you enjoy the rest of the day. This concludes our call. Thank you.

This concludes today's call. Thank you so much for attending. You may now disconnect, and have a wonderful rest of your day.

Good morning, ladies and gentlemen, and welcome to the DiaMedica Therapeutics Q3, 2025 Earnings Conference Call. An audio recording of this webcast will be available shortly after the call today on DiaMedica's website at www.diamedica.com in the Investor Relations section.

After our speakers' remarks, there will be a question-and-answer session. [Operator Instructions] Before the company proceeds with its remarks, please note that the company will be making forward-looking statements on today's call.

These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these statements. More information, including factors that could cause actual results to differ from projected results appear in the section entitled Cautionary Statement Note Regarding Forward-Looking Statements in the company's press release issued yesterday and under the heading Risk Factors in DiaMedica's most recent annual report on Form 10-K and most recent quarterly report on Form 10-Q.

DiaMedica's SEC filings are available at www.sec.gov and on its website. Please also note that any comments made on today's call speak only as of today, November 13, 2025, and may no longer be accurate at the time of any replay or transcript rereading. DiaMedica disclaims any duty to update its forward-looking statements.

Following the prepared remarks, we will open the phone lines for questions. I would now like to introduce your host for today's call, Rick Pauls, DiaMedica's President and Chief Executive Officer. Mr. Pauls, you may begin.

Thank you all for joining us for our Q3 2025 earnings call. I am joined this morning by Dr. Julie Krop, our Chief Medical Officer; and Scott Kellen, our Chief Financial Officer. We've continued to make meaningful progress across both our clinical programs since Q2, and I'm pleased to share our recent developments and upcoming milestones with you today.

As most of you know, DM199 is our lead product candidate, is a recombinant form of the naturally occurring human tissue KLK1 protein. KLK1 enhances blood flow and vascular health by increasing levels of 3 key endothelium-derived vasodilating factors through activation of the bradykinin pathway.

These are nitric oxide, prostacyclin and endothelum-derived hyperpolarizing factor. We believe that this mechanism is why DM199 is well suited to improve patient outcomes for preeclampsia, fetal growth restriction and acute ischemic stroke, indications associated with vascular pathology.

Starting with the preeclampsia program. Meaningful progress has been made, since we announced the positive interim results in July from Part 1a of our investigator-sponsored Phase 2 trial being conducted in South Africa. We believe that these interim results validate the biological activity of DM199 and provide a strong basis for the expansion of this clinical study into the early onset preeclampsia and fetal growth restriction cohorts.

Additionally, this data, which includes the confirmation that DM199 did not cross the placental barrier places DM199 in an unique position with respect to safety and reduced risk in this very vulnerable patient population. We're grateful for Professor Cluver and her team as their work helped us tremendously as we prepare for our planned upcoming U.S. trial.

Just to briefly review the interim results Part 1a of the study was conducted in pregnant women with preeclampsia planned for delivery within 72 hours. We continue to believe that these interim results demonstrate that DM199 has the potential to be a first-in-class disease-modifying treatment option for preeclampsia.

We based our assessment on 3 key factors: First, blood-pressure data from cohorts 6 through 9 demonstrated clear dose-dependent and statistically significant reductions in both systolic and diastolic blood pressure.

Signaling DM199's potential to control maternal hypertension associated with preeclampsia. I would point out the importance of this, given the results of one of the more recent preeclampsia trials the PRESERVE-1 antithrombin study, in which approximately half of deliveries were initiated due to out-of-control hypertension. Suggesting that better control of blood pressure could have prolonged pregnancies in these patients.

2, improve placental perfusion. In Part 1a of our recent Phase 2 results, DM199 treatment produced a statistically significant reduction in the uterine artery pulsatility index, a doppler-based assessment of arterial resistance, suggesting improved uterine artery blood flow and enhanced placenta perfusion.

And 3, we believe that these improvements were driven by improving endothelial function believe to be an on-target mechanistic response to DM199 therapy. By improving or restoring endothelial function (sic) [ dysfunction ], DM199 has the potential to reverse vascular injury caused by preeclampsia.

Having the potential to control hypertension, improve endothelia dysfunction and improve placental perfusion, supports our belief in the potential for DM199 to be a first-in-class disease-modifying therapy for this life-threatening condition, which has no available treatment options.

During the third quarter, Professor Cluver advanced and completed Cohort 10 of Part 1a, which dose participants at 2.5 micrograms per kg IV and 15 micrograms per kg subcutaneously and further initiated dosing in the expansion cohorts of an up to 12 additional patients at the expected therapeutic dose level. We anticipate completion of this expansion cohort in the first half of 2026.

For Parts 1b and 2 protocol amendments are being implemented based on clinical learnings from Part 1a to refine the treatment regimen. Part 1b includes patients, who will be delivering within 72 hours. Part 2 will enroll women with early onset preeclampsia, who are cannabis for expected management or prolongation of pregnancy.

Part 3, the fetal growth restriction cohort includes participants with fetal growth restriction, but who do not have preeclampsia, we anticipate screening to start in the coming weeks. We're also preparing to conduct a Phase II preeclampsia trial in the U.S. We completed an in-person pre-IND meeting with the FDA, where we believe we've had a productive meeting, and we look forward to providing an update after receiving the final meeting minutes.

We anticipate the upcoming U.S. Phase 2 trial will be conducted in early onset preeclampsia patients. This treatment for this group is referred to as expected management, which is the preeclampsia patient population with the greatest unmet medical need.

Turning to our stroke program. Let me ask Julie to provide an update.

Thanks, Rick, and good morning, everyone. We continue to make steady progress in operationalizing our Phase 2b/3 ReMEDy2 stroke trial. As the trial has progressed, it's become clear that current enrollment rates are lower than what we initially projected based on historical enrollment data.

We believe this is primarily due to changes in stroke referral patterns driven by the adoption of technologies such as this AI and increases in the use of tele neurology. When patients present to smaller community hospitals and are not eligible for mechanical thrombectomy, they are currently more likely than in the past to remain at those hospitals rather than get transferred to the larger comprehensive stroke centers that typically serve as our research sites.

As a result, our participating centers are now seeing fewer of our target patient population than they did 5 or more years ago. The team continues to develop and implement strategies to offset these challenges and support our clinical sites. Based on this information, we recently updated our ReMEDy2 enrollment forecast using actual enrollment rates from our current clinical trial sites in lieu of the historical rates we originally used.

That said, there remains a lot of enthusiasm among the investigators, who are highly motivated to find additional treatment options for this high unmet medical need. We continue to make steady progress with enrollment. And as of today, are approaching 50% of our enrollment target for our interim futility analysis that includes a sample size reestimation. We now expect the interim analysis based on the first 200 patients to be completed in the second half of 2026.

As a reminder, after reviewing safety data from the first 50 participants in the study, the independent Data Safety Monitoring Board reported no safety concerns and unanimously recommended that enrollment continue without modification.

Thanks, Julie. I would like to now ask Scott to review the financial results for the quarter.

Thanks, Rick, and good morning, everyone. As of September 30, 2025, our cash, cash equivalents and short-term investments were $55.3 million, this compared to $30 million as of June 30, 2025, and $44.1 million as of our prior year-end.

Our current cash includes the net proceeds from our July private placement. We feel confident that our current cash position will fund our planned clinical studies and corporate operations into the second half of 2027. We used $21.3 million of net cash in operating activities for the 9 months ended September 30, 2025 compared to $15.6 million for the same period in 2024.

This increase is primarily a result of the increase in net loss in the first 9 months of 2025 compared to the prior year period, partially offset by changes in operating assets and liabilities during the current year period. Our R&D expenses were $6.4 million and $17.9 million for the 3- and 9-month periods ending September 30, 2025. This was an increase from $5 million and $12.6 million for the same time periods in the prior year.

Both increases were due primarily to cost increases resulting from the continued progress of the ReMEDy2 clinical trial including its global expansion, progress with the Phase 2 investigator-sponsored trial in preeclampsia and the expansion of our clinical team during the current and prior-year periods. These increases were partially offset by cost reductions related to manufacturing process development work performed and completed in the prior-year periods.

Our general and administrative expenses were $2.6 million and $7.3 million for the 3- and 9-month periods ending September 30, 2025. These expenses increased compared to the same time period in 2024, which were $1.9 million and $5.7 million, respectively. The increases in both periods resulted primarily from increased noncash share-based compensation and increased personnel costs incurred in conjunction with expanding our team.

Increases in investor relations, patents and professional fees also contributed to the increases in both periods. Overall, our net losses were $8.6 million and $24.0 million for the 3- and 9-month periods ending September 30, 2025. These are higher than the $6.3 million and $16.5 million reported during the same period in 2024. Now let me turn the call back over to Rick.

Thank you, Scott. We'd like to now open the call for questions. Operator, if you could please introduce the first analyst.

Your first question comes from Stacy Ku with TD Cowen.

Congrats on the progress. So first, as we go a little bigger picture, maybe as we await the minutes from the pre-IND FDA meeting, can you talk about the work that you are doing with the preeclampsia KOL community and clinical trialists to increase awareness of what you've seen so far with the DM199 proof of concept.

Specifically, when it comes to U.S. clinical development, maybe also talk about the key factors you're considering right now for trial sites. That's the first question. And then second, as it relates to the protocol amendments, maybe can you go into a little bit more detail what you are thinking maybe talk a little bit more about the doses and outcomes that you all are seeing so far. Just help us understand that piece.

Sure. Great, Stacy. So starting off with the KOLs. So we've been doing quite extensive reach out with the KOLs really across the U.S. and also basically globally for that matter. And the feedback that we've been getting has been very encouraging. There hasn't been a drug in development for preeclampsia for a number of years.

And I think, first off, the feedback we're getting is the fact that the drug is not crossing the placental barrier is just a very critical safety profile. And just to see that as very encouraging and immediate drops in blood pressure and the fact that we're seeing that very consistently amongst pretty much every patient.

And then I think the upside is also encouraging, but still early is the signals of dilation of the intrauterine arteries. And so if this can consist into later-stage studies, I think, this is a clear sign of being disease-modifying.

With regards to the protocol, changes that we're looking at. So first for the Part 1b, what we're looking at doing is IV only, in IV into delivery with the ability of the positions to adjust the dosing as needed. And it's almost to be able to dial in the blood pressure to where it needs to be ahead of delivery. And then for the Part 2, we're still working on some adjustments on that. Right now, we're looking at likely using Cohort 10 from the recently completed Part 1a of the study.

In part -- in Cohort 10, we see very consistent and very clear drops in blood pressure as we've seen from cohort 6 to 9.

The next question comes from Thomas Flaten with Lake Street Capital Markets.

Just a follow-up, Rick, on the Part 1b. You kind of wedged in this 12-patient expansion cohort from Part 1a, was that intended to kind of supplement what you had originally intended to do with Part 1b, where you were going to do basically a dose expansion cohort? I'm trying to understand the purpose about the 12-patient cohort given the changes you're contemplating for Part 1b?

Yes, that's exactly it. So this cohort expansion we've done is at Cohort 10, so that's the highest dose we've gone to. And so I'd call this kind of additional work that would really replace what was previously planned for the Part 1b. And then when the Part 1b now will be IV only.

Got it. And then as you ramp-up towards a Phase 2 study here in the U.S., what is the trigger? What data are you waiting for from Dr. Cluver before you actually initiate the study here in the U.S. Is there anything in particular you're waiting for?

No. We've been analyzing the data that we received up to date. We'll be continuing to dosing more patients before that study gets initiated and not just the efficacy and the safety data, but the PK data is also very important that we've been analyzing as well. So we feel we have the data that we need to proceed.

But of course, if we get any additional data along the way, that could further help us to refine the -- that protocol is needed. And right now, the plan is for the -- that Phase 2 would be up to approximately 30 participants for the U.S. study.

The next question comes from Chase Knickerbacher with Craig Hallum.

Maybe just first, Rick. Any more specifics you'd be willing to give on what you saw in Cohort 10 that kind of led to those additional 12 patients? And then that comment on potentially that being the dose we're going to take into Part 2, just any additional detail you'd be willing to give on what you've seen in the patients you've dosed in that cohort so far?

Yes. I mean, I think what we're seeing, Chase is just very clear and immediate drop in blood pressure. Some of these patients in Cohort 10 and even in those that are in the cohort 6 to 9, these patients are all resistant hypertension. They've been on maximum tolerable alpha beta blockers, calcium channel blockers and they're refractory. They're not seeing any improvement.

Some of these patients are coming in there on, they're on short-acting IV labetalol, and there's no change in blood pressure. And frankly, within minutes of getting DM199, blood pressure is coming down very, very rapidly. And so we're just really encouraged that pretty much every patient is seeing an immediate reduction in blood pressure. So it just gives us a lot of opening statement for this treatment.

And so you've seen an incremental dose response in that tenth cohort? And then just second, on stroke, if I can. I mean, can you just maybe walk us through Rick, kind of what your expectations for enrollment rate was and kind of where it sits today? And then if you could give us an update kind of where the site activation situation sits, including kind of OUS?

Yes. As Julie had mentioned in the prepared remarks, the historical stroke enrollment rates we were looking at around 0.25 that we had previously using, and we're seeing a little less than this. And so we wanted to provide an update here revising the guidance. We currently have a little over 35 sites activated. We've got a number that are coming on board. We recently had regulatory clearance in the U.K. We believe we've got Europe coming on board as well here soon.

And so I think it's important for us here now that in past instead of looking at historical rates, we're using specific rates that we're seeing at our current sites. So that gives us a little more comfort here in terms of the revised forecast today.

What is the enrollment rhetoric that you're assuming to get to the second half target at this point?

We're not providing that at this point in time, Chase.

The next question comes from Matthew Caufield with H.C. Wainwright.

Rick and team -- so as the progress is made towards the AIS interim analysis for reaching those target 200 patients, -- regarding the Modified Rankin Scale score, what would reflect the meaningful change there in your view at the time of the interim analysis?

Sure. So we had initially the powering and really following what we saw in Phase 2. So in our Phase 2 trial, in the patients not pretreated with mechanical thrombectomy, there was a 15% absolute improvement in the MRS score of 0 to 1. And we also had made an adjustment to the protocol, excluding those with severe, severity stroke patients when they come in.

And so when we exclude those patients, we saw a 19% -- but how the study is currently powered is that we see around that 15%, we'd be looking at 300 to 350 patients for the final sample size.

This concludes the question-and-answer session. I'll turn the call to Rick for closing remarks.

Great. Well, thank you all for joining us today. We greatly appreciate your interest in DiaMedica and hope you enjoy the rest of the day. This concludes our call. Thank you.

This concludes today's conference call. Thank you for joining. You may now disconnect.

Good morning, ladies and gentlemen, and welcome to the DiaMedica Therapeutics Q2 2025 Earnings Conference Call. An audio recording of this webcast will be available shortly after the call today on DiaMedica's website at www.diamedica.com in the Investor Relations section. Before the company proceeds with its remarks, please note that the company will be making forward-looking statements on today's call. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these statements. More information, including factors that could cause actual results to differ from projected results appears in the section entitled Cautionary Statement Note regarding forward-looking statements in the company's press release issued yesterday and under the heading Risk Factors in DiaMedica's most recent annual report on Form 10-K and most recent quarterly report on Form 10-Q.

DiaMedica's SEC filings are available at www.sec.gov and on its website. Please also note that any comments made on today's call speak only as of today, August 13, 2025, and may no longer be accurate at the time of any replay or transcript rereading. DiaMedica disclaims any duty to update its forward-looking statements. Following the prepared remarks, we will open the phone lines for questions. I would now like to introduce you for your host for today's call, Rick Pauls, DiaMedica's President and Chief Executive Officer. Mr. Pauls, you may begin.

Thank you all for joining us for our Q2 2025 earnings call I am joined this morning by Scott Kellen, our Chief Financial Officer; and our new Chief Medical Officer, Dr. Julie Krop. We truly have made significant progress since Q1, and I'm happy to be able to share that with you today. Starting with our preeclampsia program. In July, we announced very positive interim results from Part 1a, the ascending dose portion of our investigator-sponsored Phase II trial of DM199 for the treatment of preeclampsia.

As a reminder, DM199 is our lead candidate and the recombinant form of the KLK1 protein, which enhances blood flow and vascular health by increasing levels of 3 key endothelial-derived basal diluting factors through the bradykinin pathway. These are nitric oxide, prostacyclin and endothelial-derived hyperpolarizing factor. Preeclampsia is an ischemic condition that affects millions of women worldwide and has no approved treatments and really no viable therapeutic options to target the underlying vascular dysfunction.

We held a key opinion leader webinar back in May on the unmet need in preeclampsia and on the potential of DM199 in this indication with professors Baha Sibai, Stephen Tang and Susan Walker, A recording of this webinar is available on DiaMedica website in the Investor Relations section. Based on the interim results from the Part 1a of our Phase II study, we believe that DM199 has the potential to be the first-in-class disease-modifying treatment for preeclampsia. In dosing cohort 6 to 9 of the study, DM199 demonstrated highly statistically significant and clinically meaningful reductions in both systolic and diastolic blood pressure, highlighting its potential efficacy in managing maternal hypertension associated with the disease.

DM199 was also found to be safe and generally well tolerated with no evidence of placental transfer at any of the dose levels. a key safety indicator in the development of a treatment for pregnant women. Additionally, treatment with DM199 led to a statistically significant reduction in the uterine artery pulsatility index, suggesting improved uterine artery blood flow and enhanced placental perfusion. Improved perfusion may be a key in reducing placental hypoxia, supporting the potential for DM199 to be a disease-modifying treatment, as well as a treatment for fetal growth restriction. Based on the interim results and recent analysis of the pharmacokinetics, a decision was made to advance to and enroll cohort 10 in Part Ia of the ongoing Phase II trial.

From there, we plan to finalize a dosing regimen for the Part 1b as well as for the Part 2 preeclampsia expected management and the Part III fetal growth restriction cohorts, all of which can be enrolled concurrently. For clarity, the remaining parts of the investigator-sponsored preeclampsia trial include Part 1b, an expansion cohort of 30 preeclampsia patients, where the decision has been made to deliver within the next 72 hours, a patient population similar to those dosed in the Part 1a. Part 2, a cohort of 30 patients evaluating DM199 in early onset preeclampsia. In this cohort, patients will start receiving DM199 at first diagnosis with intent to dose DM199 until delivery and demonstrate extension of gestational days along with other key clinical and safety end points.

Part 3, a cohort of 30 patients who are experiencing fetal growth restriction or FTR. FTR is a condition in which the fetus is not growing as expected, due to lack of blood flow, oxygen and critical nutrients. The expansion to this indication, which is related to Preeclampsia, is based on our recently announced interim results in which we measure a statistically significant reduction in the pulsatility index, suggesting improved dilation of intrauterine arteries and placental perfusion. In addition, we are now preparing to conduct a Phase IIb pre-game trial in the United States and other countries and are currently preparing our FDA IND application.

We look forward to sharing upcoming updates on these cohorts and the new preeclampsia trial. Additional details of the interim Phase II Part 1a results, including a replay of the investor call discussion of the results are available on our website under the Investor Relations tab and can be found in our July 17 results press release. Following the announcement of the positive interim results from Part 1a of the preeclampsia last month, we completed a [ 30 ] million private placement of common shares, which extends our cash runway into the second half of 2027. We intend to use this capital to also fund the new Phase IIb study of DM199 in the United States and other countries for the continued development of our ongoing stroke and preeclampsia programs.

Turning to our stroke program. We had a poster presented at this year's 11th European Stroke Organization Conference held in May in Finland. The poster was presented by Dr. J. Volpi from Houston Methodist and cover the safety and clinically relevant outcomes from a ReMEDy1 Phase II clinical trial evaluating DM199 in patients with acute ischemic stroke and pretreated with TPA. We'd like to remind people that in patients pretreated with TPA, DM199 demonstrated a significant improvement in full recoveries when compared to placebo.

Turning to our current ReMEDy2 stroke trial. We continue to make progress as enrollment continues, and we expect the interim analysis of the first 200 patients to be completed in Q2 2026. I wanted to take a moment to clarify our communication practices for ReMEDy2 enrollment milestones. We will provide updates during our quarterly conference calls when we have achieved 50% and 75% and of the interim enrollment sample size and press release when we enroll our 200th patient. At present, enrollment is now tracking well above the 25th percent milestone and steadily advancing towards the halfway mark.

I would also note that we completed the Data System Monitoring Board or DSMB meeting to review the safety profile required after the first 50 ReMEDy2 participants. The meeting is positive, meaning no safety concerns and at the conclusion of the meeting, the DSMB unanimously concluded that ReMEDy1 enrollment should continue. In other developments, DiaMedica was added to the U.S. small-cap Russell 2000 and the Russell 3000 indexes, enhancing our visibility among the broader investment community, including institutional investors.

Finally, Dr. Julie Krop joined our team as Chief Medical Officer this month. She has extensive experience in the biopharma industry working with both clinical and commercial stage organizations and was also previously involved in the development of an orphan drug candidate for the treatment of severe preeclampsia. Dr. Krop adds invaluable experience to our team as we invent DM199 to address the significant unmet needs for both of our key programs. I would now like to ask Scott Kellen, our Chief Financial Officer, to review the financial results for the quarter.

Thank you, Rick, and good morning, everyone. As of June 30, 2025, our cash, cash equivalents and short-term investments were $30 million. compared to $44.1 million as of December 31, 2024. However, including net proceeds from the July private placement, our pro forma cash position is approximately $60 million. As Rick mentioned previously, we feel confident about our current cash position and anticipate that it will fund our planned clinical studies incorporate operations into the second half of 2027.

We used $14.7 million of cash in net operating activities for the 6 months ended June 30, 2025, compared to $11.2 million for the same period in 2024. This increase is primarily a result of the increased net loss in the first half of 2025 compared to the prior year period. Our R&D expenses were $5.8 million and $11.5 million for the 3- and 6-month time periods ended June 30, 2025. This was an increase from $3.9 million and $7.6 million for the same time period in the prior year. The increases were due primarily to cost increases resulting from the continued progress of our ReMEDy2 clinical trial, including its global expansion as well as the expansion of the clinical team during the current and prior year periods.

These increases were partially offset by cost reductions related to end-use study work performed and completed in the prior year periods. Our general and administrative expenses were $2.2 million and $4.7 million for the 3- and 6-month time periods ended June 30, 2025. These expenses also increased compared to the same time periods in 2024, which were $1.7 million and $3.8 million, respectively. These increases resulted primarily from additional noncash share-based compensation and increased personnel costs, partially offset by reductions in legal fees incurred in connection with our lawsuit against PRA Netherlands.

Overall, our net losses were $7.7 million and $15.4 million for the 3- and 6-month periods ending June 30, 2025. These are higher than the $5.1 million and the $10.3 million reported during the same periods in 2024. Now let me turn the call back over to Rick.

Thank you, Scott. We would like to open the call for questions. Operator, if you could please introduce the first analyst.

[Operator Instructions] Your first question comes from Thomas Flaten with Lake Street.

Maybe, Julie, if I can start with you, I'm curious to kind of get your take on why you joined the company particularly in light of your past experience with preeclampsia, but then perhaps even more importantly, your thoughts on the stroke program, which I know is going on in the background.

Yes. Thanks for the question. Hello, everyone. Really having worked in the space of women's health before I really have a strong commitment to this area and really I'm excited by the program that I saw the programs really that I saw at DiaMedica as well as, I think, the team that's in place to execute upon them. So I think preeclampsia and ischemic stroke are both areas of large unmet need. There's de-risked biology, I believe, with the known role of KLK1 protein as both a vasodilator and it's also its role in vascular repair. And I think this product really addresses the underlying pathophysiology of both conditions and has already shown promising clinical data and really evidence even of some biologic activity. So this really excited me when I saw this. So I think for both programs, I'm really excited to be here.

Excellent. And then, Rick, I was -- I know you've got a lot of work that's going to kick off here in preeclampsia. I was wondering if you could maybe map out kind of a calendar for us, right? I'm assuming each of the cohorts in South Africa will enroll at a slightly different rates, given that there are different patients, different types of patients? And then maybe you could clarify the U.S. Phase IIb study, what exactly will be the target indication for that?

Sure. Thanks, Thomas. So in terms of what's coming up next, so the -- we've -- as I mentioned on the prepared remarks, moving into Cohort 10 of the Part 1b that should be starting next week. And we wanted to push the dosing a little bit higher to seeing if we can see any further improvement than what we've already seen which would be wonderful. And then based upon that and some of the pharmacokinetics data that we have already we'll be analyzing that to be moving into the Part 1b. And we'll be able to also be moving into the Part 2, so that will be the expected management. And by expected management, we mean that these patients are first diagnosed, they'll start being treated.

And those will be typically early onset patients. And then that's the third cohort that we talked about is the fetal growth restriction. So all 3 of these cohorts can be dosed concurrently. And so as we get -- those studies start, we'll have more updates in terms of some of the time lines. We do know that our site in South Africa, Dr. Cluver just a very unique scenario that if these patients in Cape Town have preeclampsia . They basically all filter into Cathy Cluver' site.

And so she gets 4 to 5 preeclampsia a day so we're very encouraged on how rapidly we can get these patients dosed, but we'll have more as the study gets started. For the U.S. study, we're currently planning to file a pre-IND request to the FDA, and that will be followed immediately after with an IND and then looking at getting that study started next year. And we're currently kind of finalizing the protocol. And as we get more clarity and finalize, we'll be sharing that details with the market.

Your next question comes from Chase Knickerbocker with Craig Hallum.

Maybe, Rick, just to start, can you give us an update on current active sites and how enrollment rates are trending in the stroke study? And just secondly, as we're now well across the 25% kind of milestone here. How are you kind of feeling about this new expectation for 2Q '26? Do you feel like it's firmed up at this point? You've got a lot more visibility or just kind of general thoughts there.

Sure. So we're currently at approximately 40 sites. We are at the point now where we're actually dropping off sites that are performing I think that's important with setting the right message to the sites. And then on top of that, we are working to having sites the U.K. and Europe come on board. And so I would say that coming through to last year coming early into the new year, things were very slow with the trial. And we've definitely seen a very encouraging uptick in the last few months. that gives us comfort here with the guidance of Q2 of 2026.

Any thoughts around kind of current enrollment rates?

It really does vary. I mean we haven't publicly stated. I mean what we are seeing kind of a bit of the 80-20 role where we've got smaller number of sites that are producing a large number of patients. And I will mention that last quarter as well, we had an investigators meeting that was really helpful. We had maybe 80, 90 participants from across the country in Canada. And I think that really helped with awareness. And I think that some of these aspects that we're taking, I think, are really going to help us here with continuing the momentum that we're building.

Got it. And then just on preeclampsia. On the U.S. study, I mean, is it a fair -- I think it's probably a fair assumption this will be in expected management. And any sort of additional detail that you would need from Part 1b and Part 2 of the South African study to put that IND in front of FDA? Or do you feel like you kind of have what you mean? .

Yes. So definitely, it's going to be the expected management. That's where we see the real need for this patient population. And so no, I think we -- I mean, the data we've announced here a few weeks ago was just fantastic. I mean we really could not have expected anything better than what we saw. So very encouraged by that. We just thought here that we've got an opportunity here to add in another cohort. So let's do it. And let's see if there's any change, and that may help us to tweak the dosing a little bit more. But we do feel that for this patient population, it's very severe. I mean these are very sick mothers. They have very severe endosteal dysfunction and a lot of basal constrictor. So we do see some value and potentially going a little bit higher on the dose. But what we've seen already, we'd be very happy with going ahead with the dosing in cohort 6 to 9 that we recently announced for the U.S. IND.

And then just last for me, Rick. Could we see something in the Phase IIb where we have a primary endpoint in the study that closely reflects what a pivotal regulatory endpoint will be in a Phase III study? Or just kind of think about -- how should we think about kind of the data generation in that U.S. study?

Yes. I think give us a little bit more time here as we finalize the protocol. We want to make sure we get the right expert opinions around this, and then we'll come out with a very clear path. We feel very comfortable in terms of some recent feedback we've had from the FDA on the primary endpoint. But we wanted to nail this down here before we publicly share what that endpoint will look like.

There are no further questions at this time. I would like to hand the call back over to Rick Pauls for any closing remarks.

All right. Thank you all for joining us today. We greatly appreciate your interest in DiaMedica and hope you enjoy the rest of the day. This concludes our call. Thank you.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good morning, ladies and gentlemen, and welcome to the DiaMedica Therapeutics Conference Call reviewing the interim Phase II preeclampsia results. An audio recording of the webcast will be available shortly after the call today on DiaMedica's website at www.diamedica.com in the Investor Relations section.

Before DiaMedica proceeds with its remarks, please note that the company will be making forward-looking statements on today's call. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these statements. More information, including factors that could cause actual results to differ from projected results appear in the section entitled Cautionary Note regarding Forward-Looking Statements in the company's press release issued today and under the heading Risk Factors in the company's most recent annual report on Form 10-K and the most recent quarterly report Form 10-Q. DiaMedica's SEC filings are available on the SEC's website, www.sec.gov, and on its website, www.diamedica.com.

Please also note that any comments made on today's call speak only as of today, July 17, 2025, and may no longer be accurate at the time of any replay or transcript rereading. DiaMedica disclaims any duty to update its forward-looking statements. Following the prepared remarks, the phone lines will be open for questions.

I would now like to turn you over to your host for today's call, Mr. Rick Pauls, DiaMedica's President and Chief Executive Officer. Mr. Pauls?

Good afternoon, everyone. Thank you for joining our call today. We're here to review the interim results from our Phase II Part 1a clinical trial of DM199 for preeclampsia. These findings mark a critical milestone in our mission to transform care for hypertensive disorders of preeclampsia. I'm thrilled to be sharing with you the results that have exceeded our expectations.

I'm joined today by Dr. Cathy Cluver, the principal investigator for the trial. Dr. Cluver is Professor of Maternal/Fetal Medicine at Stellenbosch University, South Africa. Also joining us is David Wambeke, our Chief Business Development Officer. Our Chief Medical Officer, Dr. Lorianne Masuoka, is not able to join as she is on medical leave.

Preeclampsia, as many of you know, is a life-threatening disorder of high blood pressure with multi-organ damage occurring during pregnancy, often involving kidney dysfunction. The disease afflicts more than 10 million women every year globally. In the U.S., there are nearly 200,000 pregnancies annually with the greatest need for treating in the early onset. That is within 34 weeks of pregnancy. Half of these early deliveries are driven by refractory hypertension despite maximum blood pressure treatment.

Major challenge for these mothers and their babies is that they cannot use some of the most commonly used treatments like ACE inhibitors and ARBs as they've been shown to cross the placental barrier and cause serious harm to the baby. Thus, we believe DM199 could offer an important safe treatment.

We also announced today plans to expand into fetal growth restriction, a related disease of early pregnancy where babies are not growing and are expected -- as expected, which is also a huge unmet medical need with no FDA treatment options today. Thus, we believe that DM199 is uniquely positioned to address both preeclampsia and fetal growth restriction.

So for the data that was just announced this morning, we had set out three key objectives for the trial that have been clearly met. So first, and importantly, there was no placental transfer of DM199. These patients were also well tolerated with no treatment serious adverse events. Second, we look at blood pressure. We previously had indicated a target of a 10-millimeter or greater drop in systolic blood pressure and 5 millimeters drop in diastolic in at least half the patients.

I'm excited to report that we had a dose response -- a dose-dependent reductions in both systolic and diastolic. The greatest effect actually occurred in Cohort 9, which was the highest dose tested. In this cohort, we had a 35 millimeters drop in systolic blood pressure and a 15-millimeter drop in diastolic at the 5-minute time point. As we look further at the data, we have pooled cohort 6 to 9 is where we're going to be focusing our upcoming clinical trials. In these cohorts combined together, what we saw at the 5-minute time point was a 25-millimeter drop in systolic and 13-millimeter drop in diastolic. Moving to the 30-minute time point, we had a 15-point drop in systolic and 13 in the diastolic. And then moving on to the 24-hour time point, we had 20 points drop in systolic and 10 in the diastolic. As you can see from each of these time points, there's very low p-value, indicating that almost all of these patients were moving in the right direction.

Third is the dilation of the uterine arteries. At our recent preeclampsia KOL event, it was discussed that a 10% reduction in the pulsatility index in at least half the patients would be considered clinically meaningful. As we can show here, there actually was a 13% reduction in the pulsatility index, a measure of blood flow resistance. This is an early sign of increasing placental perfusion and could be a future indication of disease-modifying effects of our therapy. Importantly, the study clearly met and exceeded the expectations that we had set for the trial.

Dr. Cluver, could you now take us through the study design and the demographics?

I definitely can. Thank you so much, Rick. So as Rick has said, the intention of this Part 1a study was really to assess safety and to determine if we could find an effective dose. And because of this, we were not looking to see if we could prolong pregnancy. We specifically chose a group of women that needed to be delivered within 72 hours and had very severe preeclampsia. And we wanted to make sure that the drug was safe for moms and for babies. And to do this, we wanted to have a short exposure time, and we wanted to also be able to collect cord blood to make sure that DM199 didn't cross the placenta.

The women that we included in this study were between 27 and 42 weeks pregnant and they had very high blood pressure. So they had systolic blood pressures above 150 millimeters mercury. They were all receiving standard of care. And so we didn't stop any treatments for these women, and all of them already were planned to have a delivery within 72 hours.

The study design was a dose escalation study design, and we wanted to play it safe. So in Cohort 1, we started with an ultra-low dose, and we only gave an IV dose. And then in Cohort 2, we started with an ultra-low IV dose and then added a subcutaneous dose. And then slowly with three patients in each cohort, we then increased the dose until we found what we thought would be an effective dose.

Next slide, please. This slide explains in a little bit more detail how we did the study. So what we did is we made sure we screened all the participants, made sure that they met the eligibility criteria then consented them and enrolled them in the trial. As soon as they were enrolled and everything was ready, we then did a baseline recording of their blood pressure and all blood pressure recordings were done 3x. They were done 3x because we know blood pressures can vary, and we took a mean of the three blood pressure measurements. And we also made sure that we used the blood pressure device that was validated for use in pregnancy and specifically for use in preeclampsia.

We prespecified a number of endpoints. So we prespecified blood pressure endpoints as being five minutes after we've completed the IV infusion, half an hour after we completed the infusion and 24 hours after completing the infusion. And the reason why we specified these as endpoints was because they were approximately the same as the Tmax of the IV and the subcut doses in healthy nonpregnant controls. We also embedded intense pharmacokinetic studies into this, and we did uterine artery doppler studies. So when we did the baseline recording before giving the drug, we also measured the blood flow in both uterine arteries and took an average. And then at the 2-hour time point, we again repeated the uterine artery dopplers.

So the patient would come in, she would be consented. Once she was consented, we do the baseline recording of the blood pressures. We then start with the IV infusion of DM199. And then once the DM199 infusion was stopped, we then take the blood pressures at 5 minutes, 30 minutes and then again at 24 hours for the prespecified time points. And we also recorded blood pressures in a number of other time points for safety reasons and also to have a good idea of what was happening with blood pressure variability. The subcut dose was given usually one hour after completing the IV infusion dose.

Next slide, please. This slide describes the baseline demographics of our participants. What you'll see here is that the median gestation at enrollment was around about 37 weeks of gestation. So the majority of them were at a later gestation. You can see as well that the woman had very high blood pressures. You can see the blood pressures met the criteria of the American College of Obstetricians and Gynecologists' definition of severe hypertension with systolic blood pressures of over 160 millimeters mercury.

The race of the participants was mostly black and mixed race. And this really represents the population that we see at our Preeclampsia Center of Excellence here in Cape Town, South Africa. The majority of women were already taking two or more antihypertensive medications before they were started on DM199 and nearly all of the patients received magnesium sulfate and the magnesium sulfate was usually started more than 24 hours before the DM199 was started. In this cohort, only 1 patient received corticosteroids. And the reason for getting the corticosteroids was because the gestational age was before 34 weeks. So it was for fecal lung maturity.

Next slide, please. Before I present the delivery and characteristics, I think it's always very important to provide some context. These women are not experiencing what we would consider a healthy pregnancy. They're all severely ill with a life-threatening complication of pregnancy. Again, some of them are sitting with systolic blood pressures above 180. Others are so swollen that they're unable to even open their eyes at times. And this also makes it extremely difficult for us to cite lines because they're so swollen and so edematous. So it really is expected that we have a high cesarean section infection rate in these women because of the disease of preeclampsia. And what you'll see is the cesarean infection rate for these women was around about 70%. And again, these women had a planned delivery within 72 hours. So it is expected that 80% of them delivered within 24 hours.

Next slide, please. Again, earlier, I was explaining that these women are severely ill. And you can see the expected events of preeclampsia, which we actually defined in our protocol, there were some quite severe adverse or severe expected events. And these included eclampsia, HELLP Syndrome and pulmonary edema. And these are really related to the pathophysiology of preeclampsia. But I must say, in my experience, usually women with such severe disease, the chances of them developing these complications is much higher than what I actually saw in this study. And I was pleasantly surprised that the number of women developing end organ complications like HELLP Syndrome pulmonary edema or even eclampsia was lower than what I was expecting.

So one case of eclampsia actually occurred in a woman who was postpartum. She had actually already been discharged and received DM199 more than 72 hours before she developed her eclamptic seizure. We did have some, what we call treatment-emergent adverse events, and these included nausea, headache and flushing. But these side effects were really well tolerated. The patients expressed that they had a headache or they felt they were flushed. And usually what we did in these cases is we gave them the fluid bolus and straight after the fluid bolus, the patients felt very well. We had no events of hypotension. No patients paused or discontinued the treatment. And we had no indication that DM199 was associated with early labor or any other complications.

Next slide. And I think I'm handing over to Dave now. Is that correct?

This is Rick. Thank you, Dr. Cluver.

Rick, are you taking over, Okay. Fantastic.

Thank you. Great. Well, so this slide here shows the levels of DM199 that was measured by cohort in both the mother and in the cord blood. So after the delivery of the baby in the placenta, the cord bloods clamped in both ends and then sent into our laboratory to measure to determine if there was any DM199 detected. And importantly, while we did not expect to see any DM199 in the cord, we did not. And so this was very important for us to confirm. And as we looked at initially going into the disease of preeclampsia, one of our main hypothesis is that our drug should not cross the placenta barrier, which just provides a huge safety profile for this drug.

What we know today is that drugs like ACE inhibitors and ARBs are contraindicated and have been shown to cause damage to the baby.

So as we can see here, there's a clear increase in the levels of DM199 in the mother, but none detected in the cord blood. And as I said, this was anticipated.

Going to the next slide. First, we're looking at the prespecified time point of five minutes post infusion, we can see here a very clear dose response curve for both the systolic and the diastolic blood pressure. Importantly, as we look at going forward, we're going to be focusing on the dose range between the 6 and Cohort 9. We are currently waiting for the pharmacokinetics data, the PK data so that we can really analyze that and determine where do we go next in terms of dosing, but we really do see a clear effect in this range -- in the cohort 6 to 9. The greatest effect we saw was in Cohort 9, as I mentioned earlier, where there was a 35 millimeters drop in systolic and 15 in the diastolic. When we combine Cohort 6 to 9 together, we see 25 millimeters drop in systolic and 15 in the diastolic.

So this -- yes, so moving now to the next slide. So at 30 minutes, we see a less steep curve as we did in the previous slide, and that really has been driven by the patients in Cohort 9. These three patients had an average baseline systolic blood pressure of above 180, and they were very sick. And so one of the learnings from this study that we'll be looking more into future studies is that looking at increasing -- potentially increasing the IV infusion for a longer period of time, so we can really hold down the blood pressure while we wait for the effects of the subcutaneous dosing to kick in and start showing an effect for these patients.

On Slide 14, here's combining the results from Cohort 6 to 9 together. And so here are just some additional time points above the prespecified time points that we had previously shown. So as you can see here, within five minutes, we can see a 25 millimeters drop. And really at each of these time points, I think what we are most excited about is that none of these time points did we see the systolic blood pressure go above 160. And as that blood pressure does get above 160, this is when physicians are really getting worried and starting to prepare for the need for delivery.

Next slide, please. And so here, we're looking at the same patients, but now looking at the diastolic. And you can see that here, we had immediately a 13-millimeter drop. We were looking for a dose that had 5 millimeters. So the fact that we're seeing 13 and really stable throughout each of the time points, we were just thrilled to see this early data.

So turning to the uterine artery resistance and the blood flow to the placenta. So this is using a Doppler, and we're measuring what's called the pulsatility index. So this is a measure of resistance, and this was done at the 2-hour point -- time point post infusion. And as you can see here, there was a 13% average drop overall and a very low p-value. So suggesting that DM199 is actually increasing placental perfusion. And I think this is very important because as more blood flow gets to the placenta, this should translate into better oxygen and nutrient delivery to the fetus, which should be involved in reducing ischemia to the placental bed. And with treating over several days and weeks in future studies, we would ideally anticipate seeing larger, healthier babies with prolonged gestational days and fewer neonatal events as well from this data suggests that we're going to be moving ahead with a cohort in the ongoing study for patients with fetal growth restriction, that's being led by Dr. Cluver.

So just to summarize here. So DM199 delivered very clear and statistically significant reductions in blood pressure at multiple time points that were prespecified. There was also a dose-dependent response across the ascending cohorts.

The blood pressure measurement was also important as being on target because we believe that from a mechanistic perspective, lowering blood pressure should also then be involved in helping to improve endothelial health and protection for the mothers and the babies.

The enhanced placental perfusion that we're seeing is also showing some early potential signs of disease modifying. That's very encouraging. And maybe even most importantly, overall, just having a very strong safety profile and not passing the placental barrier.

So with these results, we feel DM199 is emerging as a potential breakthrough candidate for both preeclampsia and maybe even fetal growth restriction.

So as we look into what's next, there's three additional parts to the ongoing study that Dr. Cluver is running. The Part 1b is an expansion cohort to confirm the dosing and the efficacy in 30 additional patients with planned delivery. Part 2, in terms of expected management arm. So this is going to be early onset patients with repeated subcutaneous delivery -- subcutaneous dosing until delivery. And then Part 3 that we plan to also expand is with fetal growth restriction. And in particular, with the dilation of the inter uterine arteries, we're very excited to expand into this patient population as well.

So with regards to fetal growth restriction, this is really a disease that's resulting from impaired blood flow to the placenta as you can see here. There are currently no approved FDA treatments, which we see also for preeclampsia. And the pulsatility index is actually one of the tools that's measured for the disease. And so we feel here that the ability to dilate the intrauterine arteries is a very strong rationale to expand into this patient cohort.

And so with that, operator, could you please open the lines for questions?

[Operator Instructions] Your first question comes from the line of Thomas Flaten from Lake Street.

Rick, first one on the expected management grouping. Given that you saw efficacy in Cohort 6 through 9, have you guys given any thought to maybe using multiple doses or allowing Dr. Cluver to updose patients which she's not seeing efficacy with instead of starting at perhaps Cohort 9 dosing?

Sure. Yes, Thomas. Thank you. So, yes, excellent question. And so this is part of the analysis that we'll be doing over the coming weeks. And so we'll be looking more closely as we look more closely at each of the cohorts. We also want to look at the PK levels, so looking at the drug profile, and that's really going to help us to define where we go for dosing. And one of the things that we will look at doing is the potential for titrating the dose, realizing that not every patient is the same. And in particular, those patients that have higher baseline blood pressure, it's possible they may need higher dosing. But that's something that will be very important that we'll be analyzing and spending a lot of time to making sure we really narrow down and getting the dosing right.

Got it. And then just off the top of your head, do you know the overlap of patients with both fetal growth restriction and preeclampsia, how often those co-occur?

So in early onset preeclampsia, the co-occurrence is quite frequent. And so it's up to -- if you're going less than 32 weeks, it could be 50% to 75% of patients will have intrauterine growth restriction.

And maybe I can add there as well. I can also add that a lot of patients that present with early onset fetal growth restriction then develop preeclampsia at a later stage. So the pathophysiology is definitely overlapping for some, but not all.

No, that's super helpful. And then just out of curiosity, Rick, I had a couple of teeny tiny questions. Why were there four patients in Cohort 4?

And then the second kind of nitpicky question was you made a very definitive statement about there being no placental transfer. But then on the slide where you have the data, it says that the data suggests, which is not quite as definitive. So I just wanted to ferret that out a little bit.

I can maybe answer the four patients. That was actually one of our thoughts and lands up being a protocol violation. What we did is we draw up the dose when we give it IV from a -- we dilute it in a saline bag. And then when we give the dose subcut, we draw directly from the vial. And what the study nurse did by mistake was she drew up the subcut dose from the saline bag. So we underdosed one of the participants there. And so we spoke with the Data Monitoring and Safety Committee, and they actually recommended that we rather include another patient at the correct dose. And that's why we had four patients in that cohort.

I'll answer the second part of your question, Thomas. It really has to do with the level of detection of our assay. So it goes down to 0.5 nanograms per milliliter. The highest sample that we found in the maternal plasma was 5 nanograms per milliliter. So we covered down to a 10x. But we -- since we can't go lower than 0.5, it's always possible that there's 0.1. And so that's where we just can't say with 100% certainty that is not crossing the placental barrier. But if you look back a little bit, I mean if you think about it a little bit more, our protein size is 26 kilodaltons. What passively diffuses is around 500 daltons. Drugs like low-molecular-heparin are 4 to 6 kilodaltons they're given in pregnancy and they don't cross the placental barrier.

So the data in totality and just the -- the kind of the chemical profile strongly suggests that we don't cross the placental barrier. But because, again, we can't go down to zero, our limited detection is 0.5. We just have to say it's suggestive.

Super helpful, Dave. And then finally, just Dr. Cluver, since we have you on the call, I was just curious if you would share with us any anecdotal experience you had with the patients themselves. You mentioned the one patient in your prepared remarks who was very swollen. I'm just curious what you saw in actually treating these patients. I know it was a limited treatment window, but anything you could share there would be super helpful.

I mean I'm obviously a little -- I'm not blinded, so -- and it's not a placebo-controlled trial. So one has to take that into consideration. But a number of the patients that were included in the trial, I was convinced that they were going to get much sicker. I was waiting for them to go into renal failure and pulmonary edema and some of these patients actually -- they became less swollen sort of in front of my eyes, which is something that I don't usually see with women with such severe disease. The women also weren't complaining of symptoms that they often do complain of. Even though there were a few cases of headaches, the majority of women really felt well on the study. And so many of the women were so thankful that there was a possibility that they could actually be included in this study.

So from my side, I feel extremely positive about the potential of DM199.

Your next question comes from the line of Matthew Caufield from H.C. Wainwright.

Great to see the interim data. For the treatment stage, patients received DM199 IV infusion and then Cohorts 2 through 9 received subcutaneous DM199 1 hour post IV. Can you remind us of the implications for IV infusion followed by subcu delivery? And if that's the intended treatment design going forward? And then I just had one separate follow-up.

Sure, Matthew. I can take it. Yes. So as Dr. Cluver mentioned, the purpose of this trial here is, first and foremost, to determine if our drug passed the placental barrier. And the only way to do that is to deliver the baby in the placenta. And so this was proof of concept.

On future studies, we're going to be looking at the expected management where we will start off with the IV infusion, and then we will do subcutaneous dosing until delivery.

Understood. And then separately, I know you mentioned exploring the PK data. Do you have any thoughts at least at this stage on potential dosing beyond Cohort 9, I mean, based on the results we've seen so far?

We're still looking at this. I think we really do want to see what that PK data looks like. From a safety tolerability, I think we'd be comfortable going higher and particularly on the subcutaneous, but we really do want to see what that PK data looks like first before commenting any further.

Got it. Very helpful. And great to see the data guys, congrats.

Our next question comes from the line of Chase Knickerbocker from Craig-Hallum.

Congrats on the data. Maybe first, just for Dr. Cluver. Can you help us sort of establish kind of the clinical relevance of kind of level of PI reduction? I mean is there kind of some data sets that you kind of hang your hat on as far as this level of reduction drove more gestational days or healthier baby, bigger baby. I mean, anything that you can kind of give us from previous data sets that you're familiar with to kind of establish that level for us?

Yes. So I think it's -- this is all very new and very novel. And as Rick said, we've never had a drug before that can actually decrease the pulsatility index in the uterine artery doppler. So again, it's very difficult to be able to reference data because we don't have data on a drug that does this. So it's quite novel and it's quite new.

What we do know is that as the pulsatility index increases in the uterine arteries, it basically shows us that there's reduced flow to the placenta and more ischemia. So one would think that by increasing flow, one may be able to improve outcomes and potentially prolong pregnancy in case there's a fetal growth restriction. But again, this is very new and very exciting.

Thanks. And then maybe another one for you. Just as you think about the blood pressure reduction that we saw in the study, particularly in the higher cohorts, what interpretations do you think is fair to draw or what kind of excites you for using this drug in expected management patients? I mean, is there anything there where you kind of hang your hat on this level of systolic or diastolic reduction should allow me to continue to keep this patient in expected management?

I think the first thing that excited me before we started actually looking at this was the fact that we can give this as a subcut injection and that it's got such a long half-life because that means that the woman can actually get a subcut injection and she doesn't have to repeatedly be taking tablets.

So number one, the fact that it can be given as a subcut injection, and it's got a relatively long half-life made me very excited.

The second thing that, again, mothers are also very excited about is the fact that it's a drug that doesn't pass the placenta, where if you think of all the other antihypertensive drugs, they're all small molecules. So they're all crossing the placenta and going to the baby. So that's the second thing that makes me very excited about this drug.

The third thing is all the other antihypertensive that we are using are really just antihypertensive drugs. They're not doing anything to the pathophysiology of preeclampsia, where DM199 is different. DM199 is actually improving endothelial dysfunction. So I think DM199 has much more potential than any of the other antihypertensive drugs for treating preeclampsia.

Got it. And then maybe just one for you, Rick, on as far as kind of time lines. Any update on kind of how -- what we should expect from an enrollment perspective in Ib? And kind of how quickly do you think we can kind of get to Stage 2 to start getting some data on -- in the expected management setting?

Yes, sure. Let us get back to you as we start getting those patients dosed, and we really want to talk to Dr. Cluver in terms of the time line. So I don't want to set any expectations today. I will say, though, that I mean, Dr. Cluver really did enroll these patients rapidly, but we just don't want to set any expectations until we get the study going.

So, we'll, in the coming months, we'll provide further updates after we have alignment on those time lines.

Understood. And then maybe just as far as kind of when you think it's appropriate for you to engage with FDA around potentially a global larger Phase II/III study here? Is it kind of post the second phase here? Or will you even take some of this data to them after the Ib? How are you kind of thinking about that?

Yes. So we're preparing what that will look like here right now, and we'll plan to do a submission to the FDA later this year.

And that concludes our question-and-answer session. I will now turn the call back over to Mr. Pauls for closing remarks.

Great. Well, we'd like to thank everybody for joining us this afternoon. In particular, I do want to thank Dr. Cluver for joining. I know it's very late your time in South Africa today.

So we do believe that DM199 could become the first disease-modifying treatment for preeclampsia and for improving fetal outcomes. And I just want to summarize today what we've been able to show to demonstrate importantly, the safety profile of DM199 in pregnant mothers and in particular, not crossing the placental barrier. We've shown some very highly statistically significant drops in systolic and diastolic blood pressure. We see these drops minutes after the IV begins. So very, very clear effect, while also showing the ability to dilate the intrauterine arteries that could result in potentially one day treating the root cause of the disease of preeclampsia, that being a hypoxic placenta.

So we look forward to sharing further updates with you soon. And thank you again. And with this, this concludes our call today.

This concludes today's conference call. Thank you for your participation, and you may now disconnect.

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.

Good morning, everyone, and thank you for taking the time to join our call today. We sincerely appreciate your interest. We've 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 it's still a major gap in understanding its underlying causes and how it's 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. And 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 3 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 are major honors, including the SMFMs Achievement Award and the ACOG 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 is 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. Then Dr. Sue Walker is Head of the Obstetics 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 will 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. So 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% to 8% of all pregnancies in the United States. And this rate is increasing about 180,000 to 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 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 that for the mother and the baby. Also, you'll see excess protein in the urine, a decreased activity of liver function, fluid in the lungs or 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 at the placenta, often leading to premature delivery. Next slide. The management of these patients, usually, we give them steroids, control maternal blood pressure, give medication to prevent seizures, and deliver the baby. However, even after delivering the baby, despite the use of steroids, there are still significant morbidity that affects these babies; bleeding in the brain known as intraventricular hemorrhage, bleeding in certain vascular [indiscernible] known as periventricular leukomalacia, necrotizing enterocolitis, this is a condition that affects the bowel of the fetus and [indiscernible]. 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 application long term for the baby, months after delivery, or the baby could die. Even when the babies survive, they are more likely to stay a significant number of days in the intensive care unit. And once they leave 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 after the baby surviving having significant neurologic morbidity is depend on gestational interval. Babies delivered at 24 weeks have almost 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 transfer into a significant reduction in the likelihood of the baby dying as well as the likelihood of the baby surviving without significant morbidity. And this is why extending or prolonging gestation, this early in pregnancy has significant clinical implications whether the baby is 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 intensive care unit plus long-term application to take care of a baby that has problems with their hearing, problem with their lungs, having cerebral palsy as well as having problem with their vision. Next slide, please. Listed here the rate of these complications that have a huge economic impact, as well emotional and psychological impact, that the family and more importantly, the cost for the whole to the cost 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 breathing in the baby's brain are all significant complications, and babies born at 24 to 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 include cerebral palsy, and this is a condition that affects really the baby all their life and has implications regarding cost as well problems and impact on the family as such. Then 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. Any time we try to expect a management with trying to prolong gestation. And this is really for fetal benefit, but that has significant risk to the mother. And these problems include pulmonary edema, a woman developing DIC where they can bleed to death, developing a condition called Harp syndrome that affects the maternal liver and leading to other several organs such as the kidneys, the brain in the form of stroke, and eclampsia where these women could have seizure. In some situation, this will lead to maternal death. Next please. This graphic again, 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 may be fatal, and some of them will lead to long-term deficits, development of seizures. This is a patient where you have got biting of the tongue, significant bleeding in the brain, involvement of the liver, where patients could have subcapsular liver hematoma, bleeding from everywhere, developing of abruptio placentae, 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 [indiscernible] and the need for multiple blood and blood products. This is how a liver hematoma looks at surgery, also involve development of a condition in the brain that is similar to stroke and having fluids in the lung. Next slide. 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 developed fetal growth restriction at 25 weeks after we spent a lot of time effort trying to prolong gestation and ended up having dying in the intensive care unit at the age 276 days. This is another baby that survived at 25 weeks IgAN, and at that time, it was 3 years old. However, this baby is having significant neurologic problems and pulmonary issues despite the fact that the baby is still alive. This is a baby, despite all of our efforts, ended up dying. So these are really just an example where this condition happened very early gestation, how it affects the fetus, whether the fetus is going to survive, and if the baby survives, what are the implications for the baby. Next, please. Again, this is a graphic of the patient. 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 that had dementia. She developed severe IgAN at 23 and 4 days and was able to prolong her gestation by about 9 days. However, she [indiscernible] delivery because she had a health syndrome, the baby was born at 470 grams. Unfortunately, the baby died in the intensive care unit at 14 months. Next, please.

All right. Thank you. So I appreciate that a very important overview. We'd now like to turn the call over to Dr. Tong to talk about how preeclampsia evolves and the mechanism of action with DM199.

Well, thank you very much, Rick. So my name is Professor Stephen Tong, and I'm based in Melbourne. So first, I'd like to start by explaining how preeclampsia arises. And there are 2 stages in its evolution. Stage 1 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 to tenfold, and this promotes plentiful blood flow to the placenta, providing it with all the oxygen and nutrients it needs to grow a healthy baby. But in preeclampsia, this all goes awry. The pre-eclamptic placenta fails to embed properly in the wall of the uterus. The spinal 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, and such early events sets the stage for preeclampsia. Stage 2 of preeclampsia occurs after the 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 sFLT1. But the placenta also releases many other factors aside from sFLT1 that are highly damaging to blood vessels, such as pro-inflammatory cytokines and molecules. And the damage caused by these noxious factors on the maternal circuitry 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. And 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. And 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. So 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. So the diagram on the left is a cross-section of a blood vessel, sort of a cross-section of a blood vessel. And 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 the 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. And this switches on internal molecular circuitry within the endothelial cell that activates all 3 of the main pathways involved in reducing blood pressure, nitric oxide, prostacyclin, endothelial-derived hyperopolarizing factor. And 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 increase, supplying distant organs with the oxygen and nutrients they need. Hence, bradykinin signaling would be a really useful strategy to treat preeclampsia. But 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. So 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 2 decades of biological research detailing the potential of tissue kallikrein 1 or DM199 to promote blood vessel health, and it all points to DM199 acting in 2 places to combat preeclampsia, mom's blood vessels, and maybe in the uterus itself. First, mom's blood vessels. Next slide. So 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. So I'll just give you one such example of many. So DM199 might have a pretty interesting effect that it may overcome the adverse effects of that molecule called sFLT1. So as I mentioned before, sFLT1 is a disease driver of preeclampsia. It's released from the disease pre-eclamptic placenta in very high amounts, and it prevents a receptor called VEGF receptor 2 from switching on, and 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. And if this is true, then DM199 may remarkably overcome the effects of this FLT in preeclampsia to restore blood vessel health. But aside from its many positive actions on the lungs' 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. So placental hypoxia or low placental oxygenation is a key feature of preeclampsia. It's possible DM199 can open blood vessels in the uterus itself. If so, this could increase oxygen to the placenta, reducing that placental hypoxia. And reducing placental hypoxia will stop the excess release of the noctis 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. And 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 preeclancy 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. And if so, it could save a lot of lives. And 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. But this inflicts all those nasty, terrible effects of prepaturuory on the baby or those poor neonatal outcomes, which were described before. But if DM199 can wash the damage caused by preeclampsia, it could be given to women with preterm preeclampsia to safely prolong the pregnancy. And if -- with pregnancy prolonged, the baby could be birth at a less preterm gestation, dodge all those poor neonatal outcomes associated with being born premature, with better lifelong outcomes. So 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. And 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. And 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 a potential health risk. But in contrast, DM199 is a protein, and proteins cannot breach the surface of the placental barrier, a continuous border of cell membranes. Proteins are just too big. So it's just like adding whole almonds to a sieve; they just won't pass through. Hence, being a protein, DM199 will likely stay out of the placenta. It will never reach the fetal circulation. And if so, this could wipe away teratogenic concerns and any other concerns arising from direct fetal exposure. So DiaMedica to look into this commission rodent placental transfer studies. And these studies, the diagram on the right shows a nice rise and fall of DM199 in the maternal circulation, but DM199 remain 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 near-magical qualities of having multiple actions to treat preeclampsia without even needing to enter the placenta, the very organ causing the disease. And that's 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 review of our -- of the ongoing Phase II clinical trial.

Well, thank you, Rick, and good morning, everybody. So where are we in 2025? So 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. And 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. So what are our current treatments for preeclampsia? Well, we don't really have one. As Dr. Sibai has 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. So the first panel that you can see there are the antihypertensive. So 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. And while they control blood pressure, these agents don't improve endothelial health. The second row you can see there is that we give antiseizure medications, particularly magnesium sulfate, to reduce the risk of mom having a FSH or eclampsia. As you've heard, one of the most serious complications of preeclampsia. And then 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. But 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. And the PRESERVE trial investigated the role of a new agent to improve pregnancy outcomes in women between 23 and 30 weeks with preterm preeclampsia. So 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. Now, the medication that was trialed didn't demonstrate any benefit, with the time to delivery about five to six days, and the babies were born very preterm. But you can see here in the highlighted yellow row that even with access to modern antihypertensive treatment, refractory hypertension was the leading precipitation for delivery in both arms of the trial, and this occurred in about half of the patients. So 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. And 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. And so I would suggest to you that the gap that we have here is the endothelium. So let's look at some of the existing treatments for blood pressure. So 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. But neither of these agents targets 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. And 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. So the question is, where do we take this to? Well, we need to take it to a clinical trial in pregnant women, and this is what's currently underway in our collaborative effort in Cape Town, South Africa. Next slide, please. So the first step in the first human trial in pregnancy is finding what is the right dose. And 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. And you can see here these rising blocks are showing that we're currently doing a gentle and steady dose escalation involving 30 patients and to achieve an adequate blood pressure response. We are currently at strata 8. So 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. So in terms of safety and tolerability, we're looking for a drop in blood pressure. But importantly, we are also doing cord blood assays of DM199 to ensure there's no transplacental passage. And then 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 pathogenic toxins such as soluble FSH and biomarkers of end-organ dysfunction, such as the creatinine, which is a measure of renal function. And 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. So perhaps if I could just summarize the key endpoints for the current study. The first thing is that we're looking at placental transfer. So, we're getting cord blood at the time of delivery to ensure lower undetectable levels of DM199, indicating that there hasn't been crossover through the placenta and going into the baby's bloodstream. And 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. And then 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 the source. So that's a bit of an overview of where we are and where we're going, and 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?

So please hold for a brief moment while we poll for questions. So, our first question comes from Thomas Flaten at Lake Street.

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 0 the only number that would make sense from a safety perspective?

Well, look, thanks for the question, Thomas. Obviously, what we would like to see is very minimal or no transplacental transfer. But I don't think that it needs to be 0 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. But 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 don't forget, we'll be using DM199 in a later gestation beyond the period where all the baby's organs have been made and matured. So, we're not thinking about using it in the first. We've got no reason to think that it will cause any of those problems because of all the reprotox studies that have been done. But nevertheless, we'll be using it at a later gestational age. And 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. And fortunately, in the early studies that we've already developed and are already underway, we are already doing a comprehensive evaluation of not just the maternal uterine arteries, but also all of the fetal vasculature. So, 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 are not seeing changes in response to medication even if it were to cross. But 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. And then just sticking with the endpoints, I guess, for whoever. To the point Rick made at the beginning, the investment community isn't really that familiar with preeclampsia drugs because there haven't really been any. But with respect to lowering blood pressure, obviously, in Part 1a, you're looking at women who will be delivering within 72 hours. So, the acute lowering of blood pressure is important. But what I'm curious about is, is there a definitive endpoint you need to get to? Or is it just an absolute drop? So, do you have to get below 130, for example? Or is that 20-point absolute drop sufficient regardless of where you started from?

Yes. Thanks, Thomas. That's a good question. Maybe what we actually can do is if we could advance, last year we provided a summary of what we thought would be clinically relevant data. Maybe if we could just jump to Slide 31. So, here's a summary of what we 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?

To answer Thomas' question, and thank you for the question, we recruit women where the blood pressures are really acutely very high. So 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. So, I think the first is a relative 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. But 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 millimeters of mercury or a little bit more, and a diastolic decrease of 5 to 10. But 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. So, the anticipated benefits of that go well beyond just blood pressure reduction. It may suggest that the blood vessels are getting healed. You should be able to see all those benefits of reduction in endothelial dysfunction. So, we're healing the blood vessels of the mom by giving this drug. And 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 to 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? So, in our current ongoing study, we've got 3 patients per cohort. I mean, how many patients would you want to see this 10-plus point drop in systolic blood pressure?

Well, as we increase the dose, we would hope to see essentially on upper doses, we would want to see a majority drop the blood pressure.

And then -- 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 had in the NICU for 267 days. 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 on this early is probably somewhere between $5,000 to $10,000 a day. If a baby stays 3 months or 4 months, and some of these babies celebrate their 1 year while they are in an ICU, we are talking about $2 million to $3 million 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 because these babies might be wheelchair born, they cannot walk, [indiscernible], some of them need some respiratory support, treatment of seizures, and dealing with cerebral palsy. So it's 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 lives was disrupted. Many of them ended up in the walls and so on. I cannot even mention to you some of the things that happened because all the efforts of the trial will be concentrated on dealing with such side. And if they have other children, these children will have no attention whatsoever.

Dr. Sibai, would you mind actually just adding 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 and the randomized trials that have been involved with and we conducted over the years, and they have been involved probably at least 4, maybe 6, trying to use different medications or different molecules to try to see if we can prolong gestation in these women. Unfortunately, almost all of these trials, more than 50% of patients, ended up being delivered because of what I call "uncontrolled blood pressure or resistant hypertension." And the main reason really has happened in the United States and in many parts in the world, there is a system called the maternal obstetric early warning sign, which we for sure [indiscernible]. And any time [indiscernible] blood pressure reaches 160 or more, [indiscernible] is triggered. Once this really happens in the hospital, a team of individuals, including nurses and doctors, have to rush to the bedside. And our biggest problem with preeclampsia apparently is that with the available blood pressure medications are used, this is very common. And in general, once 2 or more immunes are triggered, everybody starts using this as an indication for delivery. And this is why you see in these trials that have been published today, maternal indication for delivery, being uncontrolled hypertension, was the most important problem. And this is why an opinion, a molecule like this, or a drug like this is going to have great implications if it prevents these episodic elevations and 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 agent 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 delivering these patients is what I call fetal indication. And this is mainly as a result of reduced uteroplacental and blood flow. Based on the studies I have done looking at uterine artery in women who had early onset preeclampsia, almost 97% of these patients have increased resistance in uterine [indiscernible]. Having a medication that will target this part will have a huge implication because now, for the first time, we're having a medication that's not only controlling the endothelial and maternal blood pressure, but actually influencing uteroplacental blood flow. Both of these, I think, are unique. I'm not aware of any medication that they have tested or probably is going to be tested in the future that will have or play such an effect.

Maybe while we're on the same screen here, I mean Dr. Tong, can you maybe just also provide some color here on what would be clinically meaningful for the dilation of the intrauterine arteries?

Yes. So 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. And that's because there is no drug that can even rescue and improve the uterine artery blood flow. So we're really looking at a new horizon that no one's ever been to before. So we've got lots of drugs to try to reduce the blood pressure and a bit of experience there. But in contrast, we don't really have any drugs that rescue the uterine artery blood flow. But you would infer from animal studies, et cetera, that perhaps a 10% drop may be beneficial, but it's, in some ways, conjecture. What it's reflecting is the amount of blood flow in the uterus, and we're not sure how well that correlates to just how much beneficial blood flow there is to the placenta. But it's like a 10% could mean that there is a lot of blood flow to the placenta. So, 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.

Right. Dr. Walker, any other further comments on interdilation?

Yes. Look, thanks, Rick. I mean, as Stephen said, this is kind of a new horizon. So it's difficult for us to be definitive about the answer here. I mean, 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 3 such big green ticks that's, I guess, the thrust behind why we're really looking at DM199 for preeclampsia. But the signal from the uterine artery is certainly encouraging, and 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 than early preterm birth. So I guess we're arguing by analogy that given those changes that we see that if we are 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. And 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. And 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. So I guess that's kind of the hopeful optimism, and 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. So a bit similar to the philosophy on the PRESERVE trial that we've heard of. But then 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.

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 call what's good for the mother that might not be good for the fetus, what's good for the fetus might not be. Certain level of increased blood pressure in the mother is extremely important in women with preeclampsia have fetal growth restriction because really and perfusion is dependent on maternal blood pressure. Having a medication that really lowering maternal blood pressure and also reducing resistance in uterine artery is in my opinion, going to be the biggest breakthrough we have in obstetric as it relates to management of patients with IgAN 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 have an impact in uterine artery. This is why a drug that targets both of these pathways that has -- is going to have a significant implication for our success in prolonging gestation for such one.

Tara, is there any other questions?

Yes. We have a question from Matt Caufield at H.C. Wainwright.

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 have first Dr. Tong?

Well, thank you very much for the question. No, we would see that DM199 would be added to existing care. But what we anticipate and hope that with -- 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. And the other treatments that Sue Walker had mentioned, we give corticosteroids at the moment of birth, and we would probably still do that. But the hope is that the baby at giving the DM199, we can extend gestation. So 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. So it would be added to existing treatments with the caveat that there may be such benefits that you may need less of preexisting treatments.

Very helpful. I appreciate that. And then just lastly, curious of your thoughts on sildenafil previously in pregnancy trials. And then just any further thoughts on short-acting versus long-acting blood pressure meds in preeclampsia?

Can I 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. So perhaps there's more scope for good blood pressure control with DM199. So Sildenafil works on the nitric oxide, DM199, that prostaglandin and the endothelial hyperpolarizing factor pathway. So it spreads risk a bit, I suppose. And sildenafil has that solidary action, but 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. But I suppose the -- where sildenafil's ended up with really just underscores the potential of DM199. I don't know whether you know there was a worldwide effort and a very impressive effort where many countries did randomized trials to see whether sildenafil could be used to treat preterm fetal growth restriction. And unfortunately, the Netherlands arm 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 sildenafil could cause that. But this would have been caused because sildenafil is a small molecule, would have crossed the placenta with those possible harms in the fetus. And if DM199 is as we hypothesized, it won't cross the placental barrier, won't 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, preeclampsia was not shown to improve pregnancy outcome, and really early onset preeclampsia. And again, the main reason, as Dr. Tong said, it has really limited mechanism of action regarding only pathway. I don't think it's going to be the drug that's going to have the impact in the future.

And then the second question, Dr. Walker, do you want to take that one?

Thanks, Matt. So I think the question was just clarifying the role of our current antihypertensives, particularly the short-acting versus the long-acting, if I'm correct. Is that right?

Yes. Yes.

Yes. Great. No, thanks for the question. So you're right. I gave a bit of an overview of anti-hypertensives that are in current use and their mechanism of action. But you're 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. So a patient comes in 170, 180, 200, or 120, and we need to get that blood pressure down reasonably quickly. And that's often when we use an intravenous agent. So we, for example, would use something like intravenous labetalol or intravenous hydra, I think. Now these are good drugs because they get the blood pressure down fairly quickly, but they don't last for very long unless you have a continuous infusion. So they're very good for solving the acute severe crisis. But most of the time, when we're thinking about managing patients expectedly with preeclampsia, what we're using is long-acting agents. So these are things like nifedipine, labetalol, or Aldomet that are given orally and we usually give them in divided doses across the day with escalating doses as we start to see the blood pressure is starting to become higher and higher, and we're needing more agents to control the blood pressure. And I guess that's what Dr. Sibai was talking about when he was saying, look, there was uncontrollable hypertension. You've used multiple agents, and you've still got spikes of blood pressure. So you may then be needing to use a short-term agent because you've maxed out all your long-term agents. But 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 expected 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. So 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. So 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.

So we have time for one more follow-up question from Thomas Flaten at Lake Street.

I was just curious, and I guess this is a very open-ended question, and I apologize. But if I think about the patients in Part 1A and B, so the very acute setting of delivery within 72 hours and then moving into later phases of studies where you're in the expected management patients, what data should we be reading through from the very acute setting to maybe I don't want to call it chronic, but longer-term treatment and expected management? Are there endpoints or data points, or results you'd 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?

Yes, sure. So I mean, I think the patients where there has already been a decision made to deliver come of 2 sorts. When you've got preeclampsia term, we're not worried about the prematurity risks for the baby, and we start to say, well, no maternal risk is worth prolonging the pregnancy, and we should just get on and deliver. And we would use DM199, I guess, if you like, to the cover for the hypertension in these women who we've decided to make a decision for delivery. And 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. And we've already talked about what the endpoints might be for those studies. So we're really looking at safety, placental cord blood levels, blood pressure control, and looking at uterine artery Doppler. But if we're looking at the second group, that is where it's a group where we 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. But 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. And I guess in those sorts 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 care 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 to that child's life is in the long term. And we'll probably also have a maternal outcome, where we'll be saying, well, how long did it take, for example, until we got a severe complication or we developed some of those endpoints that have been looked at in other preterm preeclampsia to expectant management. I don't know, Stephen or Dr. Sibai, whether you want to advance on that?

Yes. And again, in these initial 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 expected management. And again, the number of days is very important based on gestation and age. I always say gaining an extra 4 or 5 days at 23 and 24 weeks is different than gaining 5 or 6 days when the baby is 32 and 34 weeks. This is why targeting a very early onset is important. But at the same time, maternal safety is going to be important. Improving outcome of the baby is not going to be good if, during expected management, you're going to have bad outcome to the mother. And some of the things we are going to be or needs to be looked at for the mother is going to be development of pulmonary edema, changes in maternal platelet count, whether the patient is going to have seizures or eclampsia, whether they're going to have any abnormality or dysfunction in the liver enzymes and how severe this is going to be. So these are what I call the maternal endpoints that will be or whether the patient is going to have a stroke or not. So this should be measured at the same time. And hopefully, this medication will show it's not only improved neonatal outcome, but it's also going to stabilize and even improve maternal outcome, which I really didn't mention and nobody has asked what is really the cost the mother, we all have been talking about the baby. There is a lot of cost even to the mother when we do the expected management. And 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 the patient having severe renal injury, which is 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.

Great. Thanks for the questions, Thomas. So this concludes the Q&A session for today. I'll now turn it back to Rick for closing remarks.

All right. This is great. Well, thank you, Dr. Sibai, Professor Tong, and Professor Walker. I truly do appreciate your insights 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 the 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. And so ideally, we'd like to first show a drop in systolic blood pressure of at least 10 millimeters of mercury and a diastolic drop of at least 5 millimeters. And we 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 2 lives here, the mother and her baby. That's why safety is absolutely paramount for this disease. And we need to see that DM199 is safe and generally well-tolerated by the mother. And just as importantly, that there is minimal to no transfer of DM199 across the placenta. And 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. And specifically, we talked about a drop of 10% or more in the Pulsatility Index in at least half of the majority of the patients. And 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, and 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 the baby and the mother. So if we can achieve these 3 key endpoints, we believe we're advancing something truly novel in the field that has seen very little innovation. I also want to highlight that with no FDA-approved treatments available today and limited therapeutic options on the horizon, the 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 multibillion-dollar market opportunity for DM199. Now we look forward to sharing the preliminary top-line results from the Part 1A of the current investigator-sponsored trial, which we anticipate releasing in the coming weeks. So thank you again for your time and engagement. And with that, this concludes our call today. Thank you.