All right. I think we're ready to get started. Welcome to day two of the Cantor Global Healthcare Conference. I'm Josh Schimmer, one of the biotech analysts at Cantor. Very pleased to introduce from DiaMedica Therapeutics, have Rick Paul's President and Chief Executive Officer and David Wimbekki, Chief Business Officer.
Gentlemen, welcome. Congrats on some of the recent encouraging data for your program in preeclampsia. Maybe give us a very quick snapshot of the company and DM199 and then we're going to try to cover everything we need to know about preeclampsia in half an hour and maybe even talk a little bit about stroke.
Okay. Well, great, Josh. Appreciate the opportunity to meet here today. So starting off, so Diomedical Therapeutics. So I would say starting off here, the the problem we've solved is how to manufacture a recombinant form of a critical protein called tissue calacrine, not to be confused with plasma calacrine.
This is a protein in all of us. It turns out that, we spent many years, trying to make the recombinant form and and part of the rationale is that over the years, you know, we're aware of at least five other companies, including some big pharma that have tried to make recombinant form and they were not successful, although many of those were were a few decades, ago. And so we've been able to manufacture this recombinant protein. We're currently it just announced some very encouraging data, phase two data for preeclampsia, very un an unmet need and a big part of the rationale going into preeclampsia is that the leading cause for having to deliver early is, is blood pressure. And so what we've seen repeatedly over multiple trials, very clear drops in blood pressure, while also we believe that our protein should be safe and well tolerated and as a large molecule should not pass the placental barrier, which is very important.
Preeclampsia, you know, we identified this as a $5 plus billion market opportunity in The U. S. Alone. There's very lack of treatment opportunities today and we'll touch upon that. We're also in a pivotal trial for acute ischemic stroke, another very large unmet medical need, been lots of failures over the years.
What I'll say that's really different here about our approach is that we believe our drug will increase collateral circulation in the penumbra area following a stroke. And so we know that does work for stroke is blood flow. So if you dissolve the clot, tPA patients improve. If you pull out the clot, mechanical thrombectomy patients improve. We think this could be the next modality by actually increasing that blood flow to the placenta.
Now you've got more blood flow, oxygen, and we think this is what drives, patient outcomes. And what's unique about this program and part of the rationale why we went into this is that there are two forms of this protein that are currently being used quite extensively in Asia, isolated from both pig pancreas and human urine. So today there's literally millions of patients being treated in both Japan and China with what we'll call crude forms of this protein.
And they're treated for which indications?
So today in China, there's a form isolated from human urine for just acute ischemic stroke. Last year, there were close to a million patients treated. And then also we know that there are multiple forms of the pig pancreas, multiple companies in Japan and China selling the porcine form predominantly for hypertension and some of the related diseases.
So how is tissue different than plasma kallikrein, and why does it matter?
Yep. I get to spend a lot of time distinguishing the two. So tissue kallikrein is about a two thirty eight amino acid sequence enzyme and it cleaves a substrate called low molecular weight kininogen. Plasma calacrine is an entirely different chemical entity six thirty eight amino acid sequence in size and it cleaves a different substrate called high molecular weight kininogen. So there are two entirely different enzymes.
I think what's important to note is for hereditary angioedema, there's a lot of companies that are targeting the six thousand or so patients that have hereditary angioedema. That's associated with the genetic defect for a serum protease inhibitor that down regulates or inhibits plasma kallikrein. And so there are six thousand of those patients. And so our drug isn't plasma kallikrein, it's tissue kallikrein. It's important to also note that plasma kallikrein is heavily involved in both the fibrolinitic and the contact and complement systems, whereas our drug is not involved in the fibrolinitic or contact or complement systems, specifically because we don't cleave plasminogen.
So plasma kallikrein will cleave plasminogen. Our drug does not cleave plasminogen. So, get to spend a lot of time distinguishing the two, but the short answer is they're completely separate and different entities.
All right. Let's dive into preeclampsia. What is it? How does it present? And, lots of questions to go through here, So, but let's start high
starting it off. So, preeclampsia is a hypertensive disorder of pregnancy. It typically happens after about twenty weeks of gestation and blood pressure starts to rise. And the diagnosis is high blood pressure, so systolic over 140, diastolic over 90, along with organ dysfunction, typically looking at kidney markers. Today, there's a real lack of, treatment options and part of the challenge is that some of the best medicines that we have today to treat blood pressure ACE inhibitors, ARBs are contraindicated because they're small molecules and they've been shown to cross the placental barrier and actually cause harm to the baby.
There's been other treatment options that have been tried over the years, things Viagra PD-five inhibitors and the challenge there is small molecules. They've been able to show beneficial effect but been able to actually cause, damage to the baby. And so today, really what we're left with in terms of treatment options are really alpha and beta blockers and calcium channel blockers. And unfortunately, those treatments have been able to really delay gestational days by maybe a week. And so when you're talking about a pregnant mother, I mean, literally every day that you can extend this gestational age when you're in that, you know, call it that, you know, twenty three to thirty four weeks can have a profound impact in terms
of outcomes. Okay. Do we know what causes it?
We do. The cause of preeclampsia really originates at the placenta, and so when you give birth, you effectively can cure the disease because it's a placental disease. And what causes preeclampsia, there arteries that feed the placenta called the spiral arteries, and they're meant to be remodeled. Effectively, they're meant to be widened into 10 lane highways so that we can facilitate a smooth, steady flow of blood to the placenta. And this process in preeclampsia during the first trimester is inadequately, completed.
And so these spiral arteries, I like to call them, they have their tonal activity, they're one lane highways, and then so as baby gets gets bigger, the blood flow of the placenta can't match the metabolic demands of the infant and then the placenta becomes hypoxic. So the root cause of preeclampsia is actually a hypoxic placenta that starts during the first trimester of pregnancy.
So, I know S FLT is used as a biomarker to diagnose preeclampsia. Is S FLT causal or correlative or part of the causality?
Yes. So, S FLT is it's caused by the hypoxic placenta. So, the tissue the placental tissue undergoes oxidative stress and it releases these factors like S FLT1, a whole host of other noxious agents, O2s, pro inflammatory cytokines such as tumor necrosis factor alpha, IL-six, RAS activating factors, so S FLT is definitely one of the bad actors that gets released, but it's the kind of the second hit. Like, the first hit is the hypoxic placenta that then mediates the release of these noxious factors that then damage mom's blood vessels and then you see all the maternal symptoms.
So, what is the typical course of a patient with preeclampsia, if there is one, and where is the unmet need that you're looking to address?
Maybe, yeah, to help kind of understand the patient journey. So oftentimes, one, I'll give an anecdote here. Mom's not feeling well. She's, say, twenty six weeks of pregnancy, no clue what preeclampsia is. She goes to our local community hospital.
She has some edema, maybe a headache, and she's not feeling well. But these are typical symptoms of preeclampsia. Edema is common. They slap a cuff on mom's arm, they see her blood pressure's high, they get startled, they slap a cuff on again, they repeat it, and they say it's still high. Then they measure protein, and they see that she's spilling a gram of protein into the urine.
And from there, they typically send you to a larger facility, if you're not already at one, that has a tier three NICU, because this is a very serious condition and it turn quickly. I mean, twenty four hours, you know, things can change. And so, yeah, it's becoming more well recognized, but that's like a tip, you know, how it come. I mean, you get the blood pressure and then from there they manage you expectantly in the hospital.
And when it does change quickly, as you describe, what happens quickly?
What are the
ramifications? So if, for instance, you see fetal distress or you see reverse or absent diastolic flow to the baby, I mean, those would be causes for immediate delivery. And so, like I mentioned, the cure for preeclampsia now is, you know, to deliver the baby because it's placental in origins. You know, but what you don't want those situations to happen. Typically, what happens is mom, you know, has initially symptoms, she goes into a hospital, she stays there inpatient and they start to manage you expectantly.
They monitor you very closely. They're continuously watching your blood pressure. They give you existing standard of care hypertensive alpha beta blockers. And what they're trying to do is to prolong the pregnancy safely. You know.
But eventually, if mom's blood pressure is sky high, she's starting to develop liver function abnormalities or other clinical manifestations that would necessitate birth, then they have to deliver prematurely.
And that's as much to protect the mother who may have severe complications if left untreated?
Yes. Every time, almost universally, they prioritize mom's life over that of the baby. And the catastrophic risk is stroke or developing eclampsia. Unfortunately, we just met with someone who, you know, his sister-in-law died during birth because she had preeclampsia and she had a stroke and died. So that's the catastrophic, you know, consequence.
That's why they don't like when blood pressure starts to go above 160 and stays there and they can't get managed, like, All right, it's time for baby to meet this world because the worst thing that they could have I mean, fetal mortality is horrible. But like I said, maternal mortality, she could have three other kids, I mean, she's got a family, and they always prioritize mom over baby.
Now, there is a spectrum of preeclampsia from early in pregnancy to later in pregnancy. So what percent of pregnancies have this complication and what are you focused on all of them or a subset, at least initially?
Sure. So in The U. S, there's somewhere between one hundred and eighty thousand and two hundred and fifty thousand patients with preeclampsia. If you're developing preeclampsia at thirty seven weeks, they're just going to deliver they're going to deliver the baby and that baby should do well. What we're really focusing on is that before that thirty four weeks.
That's really where the greatest need, that's where these mothers are going to be they're going to be, in the hospital, that baby is going to likely be in the NICU for weeks to months. So And we think in we see in The U. S. There's about thirty thousand of these patients that are that, you know, that pre-thirty four weeks and and that's really where we see the greatest need for our treatment and where we're initially going to focus. Longer term, you know, this is great that all mothers that are pregnant would have a treatment like this, but really the great need right now is that pre-thirty four week window.
So when patients that early on and they have onset of preeclampsia, managing with hydralazine, calcium channel blockers, magnesium if needed. How do the specialists make the decision when to induce? Like, when is it seems like a difficult balancing act, making sure that you're keeping mother and baby safe, at the same time giving the baby as much time to the fetus as much time to mature to be as healthy as possible in delivery.
Sure. So, you know, a after these, the mother has been diagnosed with preeclampsia, like you see, look at the alpha beta blockers, calcium channel blockers, and a few other related. But really, when that blood pressure gets above systolic of 160, that's really when when the doctors are saying, okay, we've got to start thinking about planning for delivery and that could happen, you know, literally any hour. That's the one part. And then, of course, on the on the baby side, so they're all continuously monitoring the fetus, in particular the heart rate.
And if all of sudden you've got variability and you've got some stress on the baby, then they need to get that baby delivered.
And even delivery is not immediately curative. It sounds like there can be complications even post partum. So, maybe talk a little bit about how that evolves for patients.
Yeah. I mean, we always for preeclampsia, we're always talking about, you know, the baby and, you know, the challenges that, you know, delivering earlier that baby could have both short term being in the NICU to longer term longer term over decades even. But often what's also not talked about much is how the how is the how is the mother. And so what we know is that mothers who've had preeclampsia, twenty five percent to thirty percent will develop chronic hypertension within a year of delivery.
Okay. And it doesn't go away right at delivery? Like, it sounds like it can take even a couple of days or even weeks to fully resolve?
Yeah. Correct. Yeah. There's I'd say half of the patients. Some of them, it can mediate or can resolve fairly quickly, you know, but I'd say half of them, it does take time.
And then for a different session, can talk about the paradox of postpartum preeclampsia that, you know, they didn't have preeclampsia. They delivered and then they developed it. And so, for a disease that's placental in origin and not having a placenta in developing eclampsia is a true clinical paradox.
So, what made you decide to pursue preeclampsia with DM199?
Sure. So, you know, initially, you know, we're, you know, we've been in a, you know, ongoing pivotal trial for stroke and, you know, we're very excited about that program. As we've seen that the momentum on enrollment is picking up there, about a year and a half ago, we wanted to look at where else could we go with this treatment. And what we know more than anything else with our therapy, very clear drops in blood pressure. We've seen it over multiple clinical trials.
We know the initial discovery actually Bayer, the German company, discovered this protein back in the 1940s that basically urine from dogs and human lowered blood pressure. So in the 1940s, Bayer actually started isolating this protein, from pig pancreas in Japan. So we just know definitively that this drug lowers blood pressure and so we looked at where is there a high value opportunity for controlling blood pressure. And so that was the initial hypothesis. We looked at resistant hypertension in patients with chronic kidney disease.
We looked at a number of other spaces but we kept coming back to preeclampsia and at the time it was like, this is a hard indication. I mean, is pregnant mothers, you've got two lives and the more we looked at it, we reached out to some experts in the field and we said, well, this drug will clearly lower blood pressure as a large molecule. Shouldn't pass the placenta barrier, but we wanted to find that out. As we looked at further in terms of the mechanism of action, we also discovered how it's lowering blood pressure and part of the effect is that improving endothelial health. So not just the blood pressure, but by improving the endothelium, we think that this should extend gestational days.
And then furthermore, looking at the mechanism, you know, what we realized is this drug should, dilate the intrauterine arteries, so it should drop the pulsatility index. And so we wanted to see that and so that was a big part of the study of the data we just announced in July.
So, then, a good segue into that trial, maybe frame the design and why you made the design decisions you did.
Sure. So, study running in Cape Town, South Africa, we're working with Doctor. Kathy Kluver who over the last three years has dosed probably 500 to 600 patients over different clinical trials and she has a very unique setup where that effectively if you've got preeclampsia in Cape Town, you filter into her clinic. So she gets four to five patients a day, which is allowing her to dose a lot of patients. So the first thing we wanted to know about this drug is safety, its most critical aspect.
And so the study was designed is that these patients come in, they'll get, so these would be mothers that have been, you've got preeclampsia, they've got systolic over 150, they've been on maximum tolerable meds and we start them off at a very low dose. We give them first dose IV and then two hours later they get a subcutaneous dose and we really wanted to figure out what dose can we see a significant drop in both systolic and diastolic blood pressure. We have 10 cohorts. We've gone up to cohort nine. We're currently in cohort 10.
We're going to push the dosing a little bit higher, but really want to see what dose significant drops in blood pressure and then importantly, we want to determine whether or our drug crossed the placental barrier. The only way to do that is to deliver the baby within the placenta, get the cord blood and determine is there any DM199 detected in the cord blood, first and foremost. And so we did that and we had some very encouraging results and then the other measurement we wanted be looking at the pulsatility index, which is basically a resistant index, which is a strong indicator of placental perfusion.
And then maybe discuss what you showed on blood pressure and the uterine artery dilation.
Sure. So, we really saw in particular as we got into cohort six to cohort nine, that's where we saw very clear effects. For those three cohorts, there's three patients per cohorts. Combined we saw a 25 millimeters drop in systolic blood pressure, p value of point zero zero three. On the diastolic we saw a 13 millimeters drop with a p value of point zero zero seven.
I mean, pretty much every patient saw an immediate drop as soon as that IV infusion started. So very clear effect there. Importantly, from a safety perspective, the drug was well tolerated, there was no increase in fetal heart rates and importantly, there was no DM199 detected in the placenta. So there's no DM199 across the placenta barrier, which was really encouraging. And then the other piece, potential sign of a future disease modifying effect is that when we look at the pulsatility index, there was a 13% overall reduction in this cohort six to nine p value of 0.0007.
So although that measurement was conducted at two hours, a very clear signal and maybe an early sign of disease modifying.
How do we interpret that kind of a drop in terms of its clinical utility?
So as we talk to our collaborators and some of the experts, it's I mean, really what they've told us, they haven't seen this effect. So, you know, if we see a thirteen percent reduction in the pulsatility index, I mean, could correlate to fifteen percent, twenty five percent in placental perfusion. And as Dave mentioned earlier, I mean, the root cause of this disease is a hypoxic placenta. And so if we are actually getting more blood flow to the placenta and in particular on future studies where we're going to be dosing earlier, so at the first diagnosis of preeclampsia, get drug on board and over a few days, maybe and hopefully even a few weeks, we could be potentially targeting the root cause of the disease. If there's more blood flow getting to the placenta, we should have fewer of these noxious factors that are released, like the S FLT1, S, E, and Ds and a number of these inflammatory markers that very noxious.
It sounds like the blood pressure drop is very rapid. For the pulsatility index, you only measured it at two hours. Would you expect that two hours to kind of see the full effect in the same way that you see the blood pressure drop quickly or is there reason to think that longer exposure may further improve the pulsatility index?
Yes, we mentioned it at two hours. We also did measure at twenty four hours where we did see a similar effect. The caveat there is that most of many of these patients had delivered at the twenty four hour time point. The other perspective here is that the fact we see that, drop in the pulsatility after just two hours is encouraging because most of these patients were late were more late term, so they're more in that thirty five to thirty seven week window. We actually think where the real value in this drug will be when we start dosing these patients in that twenty four to thirty two week and then dosing them over days to weeks, that's where we could really see we're hoping to see a really profound impact, even greater than what we've seen in this from this current study. My expectation would be
it would happen fairly rapidly, too, because what we're looking at is the uterine artery. We cause vasorelaxation. Blood pressure is measuring systemically, but I would expect that it would happen. We just didn't measure it. Two hours was the time point we measured.
So the key opinion leader you had on the call when you reviewed the data observed at least one patient who she thought had very rapid resolution of edema, which was seemingly a very notable observation. How do you interpret that? And is that something that was seen in any other patient?
So she was like, overall, she was incredibly excited about, you know, just how the mothers and all the babies in terms of how they turned out. She did talk about, you know, edema being resolved very rapidly after dosing. It's an N of one, so we'll be very cautious in terms of reading too much into it. But if we are improving endothelial health and that can happen quite rapidly, the fact that that occurred concurrently with, you know, a drop in the pulsatility index and blood pressure drops is, I'd say, very encouraging and we'll definitely be looking for that in future trials.
Have you been able to discern whether that patient with rapid edema resolution also had rapid increase in urinary output? Because that would be a pretty compelling pairing observation.
Yeah, we haven't, we didn't, we haven't measured the biomarkers yet and so we'll do that in the future, but that'll be one of the things we'll be looking at.
All right. So what are the next steps for this program, recognizing that you've done a great job enrolling a novel agent in a preeclampsia setting where it can be very difficult to get enrollment? So you've kind of found at least one center that you can tap into. But as we evolve from here, tell us about the development plan and ultimate path to a registration study.
Sure. So, I'll start off with the ongoing study that's happening in South Africa. So, there's three more cohorts that I'll be starting. So first off, we are moving to in the Part 1a, we just we announced the interim data, we will be doing the we're currently in cohort 10. And then as soon as that's completed, then the Part 1b of the study will be taking the optimal dose from the Part 1a that we've completed and we'll be doing 30 more patients.
So that will more safety, more efficacy data. And then Part two, we'll be moving into is the expected management. So this will be then our patients that when they get initially diagnosed with preeclampsia, they'll get that first dose IV, a couple hours later they'll get the subcutaneous and they'll get subcutaneous delivery until dosing until delivery. So that'll be 30 patients and then because in the study we completed we did see very encouraging drops in the pulsatility index, we're also moving into a 30 patient cohort for fetal growth restriction. Related, but these are, you know, these babies are typically born in the tenth percentile in terms of size And again, the root cause of that disease is not enough blood flow.
So those three cohorts will all be moving along concurrently. While that's happening, we're preparing to filing a U. S. IND to run a Phase II trial in The U. S.
We'll have more as we kind of finalize the protocol, but right now we're looking at about a 30 patient trial and a lot of that's going to be multiple U. S./Canadian sites to confirm the data that we've already seen in The U. S. And North American patient population. And then very rapidly, we're also working here now on the pivotal trial in terms of what that will ultimately look like.
And we're hoping we can move very quickly from the Phase II to the pivotal trial.
Any thoughts preliminary thoughts of a Phase III trial design? Do you need a placebo control? What might the primary endpoint be? And how large a trial might it be?
Sure. Really good question. So, we actually got feedback, some encouraging feedback from the FDA recently on from a Type C meeting and basically from the feedback is that if we can prolong gestational days by seven, which we think will be kind of the minimum that we'd hope to see with this drug, we believe that we can do some powering analysis that a seven day extension should be looking at about a two forty patient trial at a ninety percent powering. And we'll be looking at for primary endpoints there would be neonatal events based upon outcome. Importantly, we've been able to actually we actually got access to a, repository of neonatal events, three four thousand patients over several years.
So we can basically build a map out that a five, seven, ten day extension of gestational days directly correlates into the reduction in neonatal events.
Is it possible that that plan changes depending on how compelling the Phase II data look? I mean, at some point, your signal may be so strong that you might, in theory, need a placebo comparator.
Yes, so we'd look at doing this as compared to a placebo. So we'd be looking at right now, if you look at one of the more recent studies that were done for preeclampsia, PRESERVE-one trial, looking at basically twenty three to thirty week of gestational days, what they saw in the placebo and actually drug on, the drug didn't work, but they saw a basically a six days of extension of gestational days. So if we can take that six days and add another five to seven days, that would have a profound impact in terms of reducing neonatal events.
If you're if you are disease modifying cure, that added six days could prove quite conservative now?
That we think as as a base case just just from an empowering perspective. Okay. But ultimately, if we are, you know, if we are controlling blood pressure, so delaying the increase in blood pressure increasing, by this mechanism improving endothelial health, which we probably don't talk enough about, but then also by also dilating the intrusion arteries, the combination of these three factors. I mean, there's no reason to be surprised if we could get a few extra weeks and that would have a profound impact and would also impact the study size for the pivotal trial.
Every week. Every day matters.
Every day literally matters. I mean, if you've got, you know, a baby born at twenty eight weeks, I mean, if you can get an extra week, I mean, it could drop mortality in half. And so as doctors say, there'll be doctors every day, you know, it really does impact the outcomes for these babies.
How are you thinking about pricing in this environment?
Yeah. So, I mean, initially what we're looking at for the early onset setting, it's orphan like population, so less than thirty thousand patients in The United States annually. The pharmacoeconomics are quite compelling in the sense that if you can avoid NICU costs and then just the long term costs of special education and the complications associated with premature birth are very compelling. So we would certainly expect orphan like pricing in this. It's premature until we get some more data, but hopefully, we can present, especially for the value that we think we're going to provide, strong orphan like pricing.
Yes. And I'm sure willingness to pay in this context is as high as you'll ever find for
Agreed. Agreed.
Maybe very quickly cover stroke because we do have an update coming up there. What are we looking for? Maybe take us through a quick overview of the clinical program.
Sure. Really quickly here, I'll just mention a high level in terms of how we think our drug works. I think it's important. So, the key thing here is that following a stroke, you've got this area at risk, the penumbra area is at risk of dying. What happens in response to the stroke, you've got these bradykin-two receptors that are upregulated 40 fold in the endothelium in that area at risk of dying.
What's missing is the ligand. So DM199, the production of basically increasing levels of tissue caliprine, increases levels of bradykinin, attaches to bradykinin-two receptor, and then locally focally vasodilates in the penumbra area pulling in blood flow. That's how we think our drug works. So we're at right now, we're currently in a pivotal trial. Our recent guidance was that we'll have the interim analysis on the first 200 patients, Q2 of next year.
At that point in time, we should be pretty close to two eighty patients at the time of the interim analysis. And so we believe base case, we'll be looking at three to three forty patients and if that's what the interim analysis says, we'll be looking at completing the trial next year. How interim analysis is designed is that there's a futility. So if we're not seeing a drug effect, so let's say we're seeing five six percent, full recovery MRS score of zero to one versus placebo, the study will be terminated. Otherwise, there will be a resample size and that resample size will range from 300 to 700 in total.
Can you come up with a price point to reconcile stroke and preeclampsia if both are viable?
We can. And it's really just due to the amount of drug. So, so, we have pretty good pricing analysis done for stroke that suggests $30,000 for the patient through its treatment. But in preeclampsia, we're going to be giving a lot more. We're going be dosing at much, much higher levels than stroke.
So. Right. Well, thank you so much for joining. Appreciate your efforts in two very high unmet medical needs and very keen to see some of the updates ahead. Thanks for joining. Thanks, everyone.