Thank you, Tara. Good morning, everyone, and thank you for joining our event today.

I'm excited to be joined by Dr. Shakil Aslam, Talphera's Chief Medical Officer, and two key experts in continuous renal replacement therapy who are also principal investigators in our NEPHRO CRRT registrational study.

Through their experience and expertise, we hope to provide you with a better understanding of CRRT, the anticoagulants currently being used during CRRT, and how these experts see nafamostat potentially filling an unmet need for anticoagulation of the CRRT circuit. Our agenda will specifically include, first, a very brief business update so we can move quickly to our key expert discussion, followed by Q&A and closing remarks.

Before we begin, I want to remind listeners that during this call, we'll likely make forward-looking statements within the meaning of the federal securities laws. These forward-looking statements involve risks and uncertainties regarding the operations and future results of Talphera.

Please refer to our press release, in addition to the company's periodic, current, and annual reports filed with the SEC, for a discussion of the risks associated with such forward-looking statements. These documents can also be found on our website within the investor section.

Now for the business update, earlier today, we announced our Q4 and full year financial results. The NEPHRO CRRT study is progressing nicely, and as announced a few weeks ago, we reached the 50% enrollment milestone.

This achievement, along with the achievement of some other conditions, triggered the closing of the third tranche of our March 2025 financing, generating gross proceeds to the company of $4.1 million, in addition to the funds received back in October 2025 when two investors waived all their conditions and closed on the second and third tranches of this investment. As of December 31st, we had cash and investments of $20.4 million, which, along with the remaining tranches, if closed, should provide runway through a potential FDA approval of Niyad next year.

We expect to complete enrollment of the NEPHRO CRRT study later this year and file the PMA within about 3 months after study completion. As a reminder, the primary endpoint of the study is measured at 24 hours, a quick turnaround of data is expected once patients have been enrolled.

I'd now like to move on to why we're all here today. As a reminder, continuous renal replacement therapy, or CRRT, is a specific type of dialysis that runs for 24 hours on a slow flow and continues, on average, between 5 and 7 days while the patient is in the intensive care unit, the ICU.

Because the blood clots when it comes in contact with an outside material, the filters used in CRRT machines frequently clog. Therefore, to make sure the patient is receiving continuous therapy that is not interrupted by clotting, international guidelines specify using an anticoagulant to make sure the filters remain functional for as long as possible.

As you'll hear today, each hospital currently has a different protocol to achieve the best uninterrupted therapy for the patient, sometimes not using an anticoagulant at all because many physicians don't trust the current options being heparin or citrate. Other times, physicians select one of the two available options despite their limitations.

I'll now hand the call over to Dr. Aslam to introduce our key experts so you can hear directly from them how each of their institutions manage CRRT for their patients and their broad experience with CRRT and currently available anticoagulants.

Dr. Aslam?

Yes. Thanks, Vince.

Good morning and welcome to an exciting session with our two experts in acute kidney injury and continuous renal replacement therapies. My name is Shakil Aslam.

I'm the Chief Medical Officer at Talphera. As a nephrologist, I have had special interest in acute kidney injury, dialysis, continuous renal replacement therapy for over 30 years, first as a clinician and then as a device and drug developer in these areas.

It's my privilege to have Drs. McMahon and Teixeira join us on this call.

In addition to being key thought leaders in AKI and CRRT, Dr. McMahon and Teixeira are also principal investigators on our Niyad registrational trial.

In fact, their sites are the highest-enrolling sites for our study. We are very excited to have them.

I would like to briefly introduce them. However, I would not be going through their entire list of accomplishment and contributions to these fields for the sake of time.

First, Dr. McMahon.

Dr. McMahon is an associate professor of medicine at the Medical University of South Carolina in Charleston.

Her key interests are in the areas of acute kidney injury and renal replacement therapies in intensive care setting. She has published over 50 papers in leading peer-reviewed journals and has written numerous expert opinions, review papers, and book chapters.

She is director of nephrology clinical trials at MUSC and is involved in several ongoing studies in acute kidney injury and continuous kidney replacement therapy. Dr.

McMahon is also the director of CRRT program at MUSC and is responsible for managing prescription protocols for CRRT and dialysis in the intensive care unit. She has won multiple teaching awards at Johns Hopkins, MUSC, and University College Dublin.

Dr. Teixeira is an associate professor in the divisions of nephrology, pulmonary critical care, and sleep medicine at the University of New Mexico in Albuquerque.

In addition to other clinical responsibilities, Dr. Teixeira serves as the director of acute dialysis and continuous renal replacement therapy programs at UNMH.

As a critical care nephrologist, his research interests lie in acute kidney injury, CRRT, and septic shock, among others. He has enrolled over 300 critically ill or hospitalized patients into more than a dozen clinical trials.

He has co-authored over 100 peer-reviewed publications, book chapters, and conference abstracts. He's on the editorial boards of three journals.

As a director of the CRRT program at UNM, Dr. Teixeira is responsible for overseeing the development of CRRT protocols and quality assurance programs.

Welcome to our call, Dr. McMahon and Teixeira.

Nice to have you.

Thank you. Good morning.

Thank you for having us.

Absolutely. Let's just start off with some basics.

As I'm sure you have the same experience, there're just so many different names, acronyms, when it comes to acute kidney injury and different modes of dialysis. For our audience, could you just break it down to—Dr.

McMahon, this question is for you—what exactly are the key differences between CRRT, which I recognize increasingly is referred to as CKRT, continuous kidney replacement therapy, although they mean the same thing, we use this CRRT and CKRT interchangeably, and then you have regular intermittent hemodialysis, which most people are aware of. What are the key technical difference between these two modalities?

Yeah. When we consider—

Tara, if you have that slide, I think that will highlight—

The difference, yeah.

Sure, yeah. Got it.

Perfect, yeah.

When you think of outpatient dialysis, these are chronic dialysis patients. Yes, they have organ failure, and they're attending an outpatient facility in the community.

These are usually relatively health-stable patients. Most of them are relatively healthy other than the organ failure, and they often walk into the unit and attend 3 days a week for their dialysis therapy, either Monday, Wednesday, Friday for 3 to 4 hours or a Tuesday, Thursday, Saturday.

Then when you compare that to the chronic renal replacement therapy, dialysis in the intensive care unit, most often these are critically ill patients. Most of these patients will have more than one organ failure in the ICU.

Some of them are mechanically intubated and they're really sick. Some of them are unstable.

In other words, they're hemodynamically unstable and require medications to keep their blood pressure up. The big difference between the two modes of dialysis is one is, it's a higher dose of dialysis for stable patients, but the CRRT dialysis is a more gentle form of continuous dialysis run 24/7 in the ICU at the bedside.

Okay? It's a more gentle form, a lower blood flow, and you can see the setup here in this picture where you can actually see the filter on this continuous renal replacement therapy setup, the machine on the left-hand side.

I don't think this picture reflects sometimes you go into a room, there's a lot more machinery like a mechanical ventilator, and you can see at the bottom of the machine, you have these bags, these replacement fluids, and often the citrate anticoagulation is contained within those bags, and they require infusions of calcium to run to maintain that filter lifespan. The filter is really everything.

It's really important these patients get really good quality dialysis in the ICU. You do not want to interrupt their dialysis.

It's really important for the patient.

Right. To summarize, intermittent hemodialysis is done mostly outpatient, though can be done inpatient as well.

Patients are typically more stable, walk in to dialysis, very high speed, quick 3-4 hours dialysis and they go home, whereas CRRT is patients with life-threatening disease, many of them on ventilators, multiple comorbidities, they are in medical ICUs, critically ill, multiple machineries and interventions, and the dialysis is very gentle and slow, but since it's not as quick, it has to be done over extended period of time, 24 hours a day and can go up to 5-7 days, as long as the patient needs it. Thank you.

That was very helpful.

That's it, yeah.

Yeah. Dr.

Teixeira, you work as director of an outpatient unit as well as you're the director of the ICU. Are you seeing any interesting epidemiological trends in the incident rates of end-stage kidney disease, which is what most these patients get dialysis for as an outpatient, versus acute kidney injury, which you see in ICU in a patient like that shown in this picture?

Absolutely. The chronic dialysis adult population in the United States is kind of historically over the first 20 years of this century has gone up and up, and that's been kind of a big topic in nephrology.

It's starting to level off. If anything, during the pandemic, although these are somewhat more stable patients, they are vulnerable to things like infection, locally with our dialysis population, and I think this reflects national data, too, dropped somewhat.

To some degree, the chronic dialysis population may be stabilizing. In theory, with some of the treatments that we've developed to help sort of prevent progression of chronic kidney disease to end-stage kidney disease, that will continue, I think, that trend that chronic dialysis may become a smaller part of our practice.

The opposite is true of the acute kidney injury. ICU populations in general are just growing across the United States.

There are some kidney-specific things that can happen to land someone in ICU, but most of the time, this is a complication of some other severe illness, like septic shock, for example, being a very very obvious one. The incidence rates of septic shock and acute kidney injury and acute kidney injury severe enough to require a dialysis, often continuous renal replacement therapy, has only continued to go up and up and up.

This is becoming a bigger problem, a more frequent problem, and over time, I think it's going to be dominating the practice of your average nephrologist, not to mention someone like myself who's kind of a dedicated critical care nephrologist. I think the patient population that this issue is relevant to is only going to continue to grow.

Dr. Teixeira, as fewer patients are progressing to end-stage kidney disease and going on dialysis, that means that the proportion of patients who have chronic kidney disease, but not on dialysis, that portion of patient is going to expand, I presume.

Those patients are very high risk of acute kidney injury. Is that what you're seeing as well, that there's actually more patients to develop acute kidney injury?

Yeah. To some degree, these things relate.

That's absolutely fair. The patients with chronic kidney disease not yet requiring dialysis, that population's not going anywhere, and they are more at risk of acute kidney injury.

To some degree, the proportion of patients with what we call end-stage kidney disease or chronic kidney failure that requiring maintenance continuous dialysis outside the hospital, the proportion of those patients that originally developed their kidney failure due to acute kidney injury that usually gets better, but sometimes does not, especially in those with underlying chronic kidney disease, in other words, those who previously had kidney disease and have a superimposed kidney injury, the portion of those patients that account for the total chronic dialysis patient population in the United States is going up over time, slowly starting to compete with things like diabetes and hypertension that are thought to be the most common causes of end-stage kidney disease in the United States. Yes, absolutely.

The patient population, just as the United States population is aging and developing more chronic kidney disease, the patients at risk of acute kidney injury are increasing, which I think is part of the reason why we're seeing more of it, along with, to be fair, I think just the gradual, I think I was going to say gradual explosion, it seems slightly to me an explosion over the course of my 20 years since I was a med student, messing around in ICUs long ago, the expansion of critical care in the United States is only going up and up and up. The complexity of the patients that we're supporting, the amount of devices that we are using to keep people with impaired circulation, whether it's mechanical circulatory support, and ECMO, extracorporeal membrane oxygenation.

These complex life support devices are being used more and more, and not just in academic medical centers, spreading to sort of community hospitals, and more and more to sort of somewhat less subspecialized centers. The complexity of I think the life support that we're offering across the United States is only increasing.

As a result of that, acute kidney injury to some degree is kind of the collateral damage that can happen with some of these really high levels of life support. Patients to be blunt, may not have survived 10, 15, 20 years ago are being supported by some of this more complex level of critical care that we can provide.

A lot of them along the way, unfortunately, are suffering some degree of kidney injury, which is often a consequence of this underlying severe illness.

Right. I presume that you're seeing similar trends in utilization of CRRT for management of these patients seems to be growing pretty rapidly.

Absolutely. I think the use of CRRT is only going to continue to rise over time, which we're seeing it locally and across the country.

Right. Dr.

McMahon, tell us about the risk of clotting in two totally different modalities of treatment. You have very fast, high-flow acute dialysis and obviously filter can clot, and then you have slow dialysis for long period of time, low flow and patients who probably are much more sick and inflamed.

How do you compare the risk of clotting between these two?

Yeah. It's a good question.

The risk of clotting, by far, is a lot higher in the intensive care unit patient. I think we can say that for sure.

These are a different cohort of patient. The majority of the time, we're starting CRRT, for example, for septic shock, and that means patients are really inflamed.

They have these inflammatory markers. A lot of those markers will stick and adhere to the filter, reducing the efficiency of the filter, predisposing them to clotting.

It's not just with sepsis or septic shock. We're a big liver center.

Our liver patients have bilirubin, these other proteins floating around that can affect the filter. There's a lot of risk factors that exist in the ICU patient that makes them vulnerable to clotting in the ICU on CRRT.

Preventing that clotting is paramount, and delivering good dialysis is really important. We do use some anticoagulation, typically heparin, a very low-dose heparin, in a small proportion of outpatient chronic dialysis patients for some patients, but we don't see that level of clotting in the outpatient compared to the ICU,

yeah.

Yeah.

Dr. Teixeira, I've seen you even on national holidays, running off to the ICU and putting those fires out.

What happens? General, I think many people take a very simplistic view, well, okay, the filter clots, you pop the filter out and put a new filter in and keep going.

Could you just walk us through what exactly are the implications when a filter clots? Implications for you as a clinician, for support staff that's taking care of those patients, and the patients themselves.

What is life like when you get a call in the middle of the night, "Hey, gee, Dr. Teixeira, this filter has clotted off"?

There's implications kind of in many levels and affects sort of both the patients as well as the healthcare system, I would say. Very simply, if you are not on the machine, you're not getting the therapy that's sort of life-saving kidney replacement therapy.

Whatever you're trying to fix with the machine, whether it's a buildup of potassium in the blood, which can be directly life-threatening, acid buildup in the blood, excess salt and water that you're trying to remove to say, let's get someone off of mechanical ventilation because they have too much fluid in their body, none of that happens when the machine is down. It takes at least, and I say at least, because sure, if the nurse has absolutely nothing else to do, and this patient's on multiple forms of life support, and they drop everything that they do, it maybe takes just an hour, but takes at least an hour.

I think on a practical level, it's often an hour or two, sometimes three, before the nurse has the kind of bandwidth and time to sort of reconnect everything and get everything going again. That's valuable sort of time that the patient's not receiving the therapy.

That ends up reducing the effective delivered dose, which is not the goal of this sort of life support modality that is indeed meant to be continuous. Then, like I already alluded to, the nursing time is extremely valuable that we're sort of kind of cutting into here.

There's all sorts of costs as well. Each of these hemofilter sets, as we call them, cost hundreds of dollars, just thinking from an equipment perspective.

That's obviously extremely sort of counterproductive for kind of efficient patient care. Then, occasionally, usually not, the nurses are able to often identify that the filter is about to go down before it completely clots off, and rinse back the blood, as we say, to prevent as much blood loss that would typically occur with one of these filter sets.

Occasionally they don't, and the net result of that is they lose all the blood in that tubing in that filter. These filters are pretty slick, but they still have about 150 mL or perhaps a more kind of intuitive way to think about it, basically about a half a unit of blood is in these circuits at any given time to allow this therapy that cleans the blood to be going on continuously.

It's not infrequent. It's the minority, but still a substantial number of times, the issue, the clotting or whatever issue that causes it to stop all of a sudden is sudden enough, and catches the nurse by surprise that they actually lose half a unit of blood, which is obviously the exact opposite of what you want to do for a critically ill patient, many of which already have active bleeding or because of their sepsis or some other disease process, they're already very anemic.

The implications of that are definitely not helpful to the patient or to the healthcare system.

Briefly, what exactly are you doing to prevent the clotting? What is your anticoagulation of choice right now to prevent this filter plottings?

If for me, I can answer. I've been at the University of New Mexico now about 7 years, and when I came in, we didn't have a specific protocol about how to approach it, and we haven't really evolved beyond that.

In part, to some degree, I think the guidelines suggest that we should, but there is no hard data suggesting that these other options available improves outcomes, and sort of none of them are free of major issues or complications. In other words, heparin, we can talk about a lot, but, in short, I'm not a huge fan of heparin.

I've definitely never had the thought that becoming a heparin-first center made sense. We haven't done that.

Then citrate can work well if I'm sitting at the bedside managing it. I joked that I love citrate because it gives me job security, cuz I'm perhaps the only nephrologist in the state who understands it well.

It's a little bit perhaps arrogant of me to say, but it's complicated. The reality is that it's complicated.

Citrate nominally has been recommended as first line for CRT worldwide for over a decade, and it still accounts for only a fraction of practice as a, in other words, only less than 50% of centers across the United States are citrate first because of the complexities and issues related to that. We are a nothing-first center, which is, arguably, not

adhering

to the guidelines. That's because the options available are basically neither of them are fully satisfactory.

Right. Okay.

Dr. McMahon, what is your strategy for anticoagulation?

Yeah. We're the same.

If you clot more than once in 24 hours, you automatically start citrate anticoagulation. We have ACD-A, 2.2% citrate in our bags.

My last institution, they didn't have citrate because the director of CRT there just didn't want to take it on board because, like mentioned before, it's the complexity and the burden. It's quite fascinating when you talk to your colleagues in the division, some of them still aren't 100% familiar with the protocols, and we see these events occurring.

Safety is an issue, especially as

a

director of CRT. Your job is to keep things safe for the patient while delivering good dialysis and modifying these protocols as we go,

but so

yes, we do use ACD-A, and it is a job security.

Right. Life expectancy of these or useful life of these filters is about 72 hours.

When you're not using an anticoagulation, what kind of lifespan do you get for these filters?

Yeah. If you actually look at the data, the data has been published on this, a third of filters that start go down in the first 12 hours.

Then

another third will last 12 to 24. Most institutions are therefore not getting 24 hours with their filters.

Remember, these filters are expensive. Dialysis is expensive.

A connection fee at our institution is about $2,300, plus the nursing fee. It's not cheap.

Then the cost of anticoagulation, the cost of the connection, the cost of blood, should it go down, and then the implications obviously for the patient.

Yeah.

It's not cheap. Yeah.

Dr. Teixeira, what kind of filter life do you get at UNM?

You're on mute.

Yeah. No, I just pulled up some of our most recent data.

This is actually skewed by pediatrics, which is a little bit different situation. Their filter life tends to be better than ours.

Our median is 13 hours. I'm just looking at some data.

This is a few months ago. We have some that extend a little bit longer, our mean is a little bit longer than that, but still less than 24 hours.

That is suboptimal. Again, I think part of the issue with that is that the options available to us to improve that are limited.

We haven't sort of implemented any major changes based on that, other than trying to remind people to consider heparin or citrate upon premature filter loss. Our data locally match the sort of more global data that Dr.

McMahon just cited.

Heparin has been used forever, and it's FDA-approved. There is a lot of, I would say, disagreement on when to use it, if to use it at all.

Does it really offer a favorable benefit to the risk profile to the patients? Dr.

McMahon, you tend to, looks like, avoid heparin altogether. What is the your beef against heparin?

Yeah. I used that at my last institution for 7 years, and I can tell you, it just is not as efficacious as citrate.

Okay? The data on it is about 26 hours with heparin.

That's not these filters are supposed to last 72 hours,

and

if you're getting 26 hours with heparin, it's just that's just not really good enough. More importantly, it's not regional.

It doesn't stay in the circuit. You're affecting the systemic thinning of the blood, and your bleeding risk goes up with heparin.

If you've got someone in with a brain bleed post-op, the surgeons don't want you to start it, and it's a huge problem. It's lack of efficacy, well, reduced efficacy, and then the risk of bleeding with it.

Yes, it's cheaper, but the cost doesn't come into it at that point. Even though it is approved, we actually don't have a heparin protocol at our institution for that reason, and we actually did bring one in for research because it was a requirement for a protocol, but we don't use it.

We don't use it at all.

Right. Do you see any issues with, at least I felt that titration with the heparin was never a straightforward thing?

No. You see this with regular patients, too, right?

They get supratherapeutic, and you have to hold it, and, oh, it's a mess.

Shakil, I can add to that, too, just more globally, thinking about my practice as an intensivist, just use of heparin is no longer It is the only thing that's FDA approved for CRRT. I hope that that changes soon for obvious reasons.

It's no longer

considered

first line for anything. Unfractionated heparin is no longer considered first line for acute

PE. It's no longer

for clotting in the lungs. It's no longer considered first line for heart attacks.

It's because, in addition to the fact that, like Dr. McMahon just pointed out nicely, doesn't really work that well, like the benefit you get in terms of prolonging the filter, it's pretty marginal.

You have the risk of bleeding that comes with it, but also it has to try to phrase this in a nonmedical term, it both overshoots a lot in terms of its blood-thinning effect, and then sometimes doesn't work. It doesn't adequately thin the blood when it's supposed to.

The technical term, it's got unpredictable pharmacokinetics. Basically, it's hard to get it on and off, and then some patients, it's hard to prevent it from overshooting.

It's just a pain in the ass. It's like a drug that I think even outside, if you set aside CRT, I think is eventually going to fall away to newer agents that are just kind of easier to use.

Is not either very good at doing what it's supposed to do, which is get the blood thin quickly, nor is it good at preventing overshoots and bleeding risk associated with thinning the blood too much. It's really just like an inferior agent.

Even you overshoot, it's not like you just turn it off and it just goes away in many patients. It can linger on for hours, and sometimes you have to reverse it, which using fresh plasma and all that.

It's dirt cheap, at the do your hospitals incentivize you to "Hey, use it. It's cost us pennies, and why not?"

You don't buy into that incentivization? No.

Great. You talk to other people, and this is obviously is your experience with heparin, and is that the general consensus you get?

I know you guys goes to all these meetings, as we are going to the one at the end of this month, you meet all the main people in CRRT world. When you talk to them, is this experience with heparin universal across all or you have some real strong supporters of heparin out there?

No. It's not.

Citrate still is superior, is a higher incidence of use across the United States. Compared to heparin, it's definitely not used despite the cost advantage.

Cuz you wouldn't sacrifice patient safety or efficacy over it's just not used. It's not used as much.

Okay.

I've never met anyone who's a strong proponent of heparin. Heparin hasn't been recommended as first line for the last 10 to 15 years, right, despite the fact that it's the only thing that's approved technically for this use.

Nobody's pushing for heparin to be first line.

Dr. McMahon, you do use citrate in select patients.

Tell us, what is life like? Oh,

well, how long have you got? Because I can tell you, As the director of CRT at MUSC, it is an absolute pain in the ass for me, because it's constant.

I'm not going to bash citrate, okay? It does its job, but there's issues with its use.

These

we talked about complex protocols, and it has a huge burden on nursing staff and also on the medical staff.

These

monitoring of labs, the iCals, the post-filter calciums, the lactates, the CMPs, and then these titration of this calcium infusion that you have to give the patient. There's certain cohorts of patients that you can't even use citrate in.

You've got to watch them really closely: the liver patients, for example.

Right,

they can accumulate it and get some degree of toxicity related to it, and then you're stopping the citrate.

Then,

because you're starting a calcium infusion, my protocol starts at 60 ccs an hour, and if you have a decompensated heart failure, you can't even pull off that 60 ccs, you're going in there with your machine and then you're overloading them with this infusion.

Then

don't even mention now because the Regiocit, the 0.5%, got pulled by the FDA because they didn't have an emergency use authorization, and then we moved to ACD-A, this higher percentage. I'm seeing a lot more metabolic disturbances with it while they're not therapeutic.

Dr. McMahon, for some of us who may not know, what exactly is ACD?

It's a higher percentage of citrate that we use.

It's a highly concentrated citrate solution. Highly

concentrated citrate, 2.2%. It's like this alkalotic drug, and it changes the pH of the blood,

and

you have to monitor for that. We see a lot, I get a lot of the safety events that come back with its use, and it's all the time, to the point now that I actually have to do We have to do citrate rounds when we start citrate.

I have highly skilled nurses who actually do their round do one nurse that actually does her rounds on anyone who starts so that we can start monitoring it,

cuz

what we're seeing is a lot of these metabolic disturbances, and then at the same time, we're not getting therapeutic. We have our methods of monitoring events, and sometimes they're still clotting.

It's been a thorn in my side since we moved to ACD-A, and there just has to be better option.

Right. What kind of other logistical challenges that you face?

ACD is now, you have it injected into your substitution dialysis fluid

and

so that offers that

causes

some challenges for you. Then

storage, right? We live in Charleston, and the pharmacy are screaming at me going, "We don't have room," because every time you order another bag with this citrate, it's another pallet.

You can, Tara, you can see on the next slide. You can see the fluids that we have in storage.

We had to actually store it at a warehouse in North Charleston,

and

every 2 days, they send a pallet of this stuff down for use. There's a storage problem with this as well, and that's a big deal for my We had to pull back on other bags to allow for the citrate anticoagulation.

We had to drop one of the phosphate-containing bags, cuz they're just saying

we've

too many bags, you need to find options for storage, and that's not my job as a physician. I want a simpler option.

I want a smaller bag.

Yeah. I'm sure that you win some popularity points from your nurses every time you prescribe citrate.

How does that

look? It's a heart sinker.

The nurses go, "Oh, really? Are you kidding me?"

Then they just sit there and they're like, "Yeah." You can see here with this slide, on the right-hand side, these are the citrate bags.

These are the CRRT bags, but to order citrate, you need another shipment of citrate bags. They're big, these are 5 L bags.

Patient might go through, it's probably six of these, six to nine depending on the blood flow, per day. It's a lot,

and

if a patient's on CRRT from 2 days to a month, you're going to turn over these bags.

Yeah. Yeah.

In comparison to the nafamostat on the left-hand side, this is the See where the circle is? That's the bag.

It's just like a saline bag.

It's

just a 1 L bag. They're actually this is a 500 cc bag or 250 cc, much smaller.

Right.

Easy storage. That's what we want.

Yep. Dr.

Teixeira, you actually train at one of the premier citrate-using institutions, but you have not been able to implement citrate program at UNM. Tell us about what are the challenges our pushbacks that you experienced?

I think Dr. McMahon sort of kind of hit upon it.

It's a drag on kind of nursing time, bandwidth. It's complex.

It's hard enough for me. I'm involved with the nephrology fellowship quite intimately here.

I think most of the fellows graduate from our program understanding how to use it well.

Then

we did have citrate available where I trained at the University of Colorado, but to be honest, actually, I wouldn't have actually probably call it a center of CRRT excellence.

All right,

I kind of know that a little bit better now in retrospect, to be honest. Surely I had faculty there, these are world-famous nephrologists in their field, but who didn't understand citrate.

I only started to learn it somewhat after training, cuz it's hard to sort of learn. When I was a fellow, there was a disruption in the supply of calcium infusions related to one of the hurricanes in Puerto Rico.

We lost our ability to prescribe citrate, for a year of my training, to be honest. At UNM, and again, I think we've already hit this up, it is complicated.

We'll just say, I won't name him, a brilliant nephrologist, who sometimes even within my own field, even though he's not specifically a critical care nephrologist, I'll ask him questions cuz he knows so much about everything. Even some of the most experienced nephrologists in my group who are brilliant, kind of general nephrologists who know everything about everything to some degree, don't know how to manage citrate properly.

The fellows sometimes text me on a Saturday afternoon being like, "Dr. Teixeira, I can't understand what's going on with this patient.

Why are we doing this?" I'm like, "I don't know, either."

What ends up happening half the time is that we end up stopping just because people are confused, they don't understand what's going on. Sometimes they develop real accumulation of citrate or toxicity, like Dr.

McMahon alluded to, that can occasionally be life-threatening. Most of the time, the nurses, the intensivists, even the nephrologists are just confused and we end up stopping it anyway.

It ends up being kind of this dance that burns up sort of my bandwidth, to be honest. I'm not there at the bedside all the time, able to manage things, and that's the difference between sort of a clinical trial that shows citrate's better than heparin than real life.

If you're running a clinical trial where everything is sort of carefully controlled with a complex therapy like citrate, it's going to look great. It's going to look great.

There's actually good data from the United Kingdom that it doesn't actually perform that much better than heparin. We've already talked about how much I think heparin is basically garbage.

Citrate in real-life settings, when it was implemented on a national basis in the United Kingdom, had no benefits basically. I think I see that on a day-to-day basis when I try to sort of provide this therapy to my patients, and so that's part of the reason why we have citrate available, but we're not a citrate-first center.

It's very clear that two options that we have, they have their own unique challenges. Heparin, yes, easy to administer, and far less complicated, but very unpredictable, doesn't always work the way it should, and then causes systemic anticoagulation and adds too much risk to the patient safety.

Then you have citrate with no uniform protocol, intensive monitoring, extremely high workload, and a benefit which could be there to some degree, could not be there based on where you use it, what setting you use it in, and how experienced your staff is, and also the nurses that are well trained in it, they are always there, they're not really rotating through other jobs, and you're not always having to find new staff to train. What would be the profile of an ideal anticoagulant that you would feel comfortable using?

Obviously, it has to be safe and— It has to work.

We want a drug that works and is safe even in our high-risk patients, like our liver patients who are vulnerable to clotting, and they have these clotting disorders. We want to be able to use it in our surgical patients, and I want that drug to remain in the circuit and not to overflow into the patient's blood.

Having a drug that remains in the circuit is important. Having a drug that does not require these complex protocols that we talked about, that I don't have to send half a dozen labs to monitor.

I'll do the one one lab or the two labs to monitor its safety, but it's really straightforward and simple.

Simple

in the ICU is really important for the nursing, you don't want to overwhelm the nurses,

and then

also not requiring these calcium infusions and titrations of calcium.

Right, right.

Also, the storage thing, you might not think it's important, but it is. For me, it is, and so yeah, I want it to tick all of the boxes.

Right, right. Both of you have been involved with Niyad trial, and I recognize this is a blinded trial, but their administration of the placebo and the active drug are very similar, exactly same.

They have to be by trial design and the titration. What is your nursing experience so far who've been exposed to citrate and they say, "Okay, we don't know what it is, but, gee, it is very simple to use," or is it serious?

Actually, it's quite fascinating. The nurses are really excited.

They're coming down and going, "Is this the new drug? Is this the—" and they're popping their heads in and they're going, "Is that it?"

They're excited at this. They're even like, "Oh, please, come on, hurry up, finish the trial, make our lives easier."

It's all over. We get a lot of excitement when we set

up. Good to know, good to know.

Yeah.

Your titration, again, as we mentioned, that one of the challenges that at least I felt, titration with the heparin to hit your target window of aPTT is always challenged, and many times you had to give a bolus of heparin in the beginning, which many of these patients don't get because of the high risk of bleeding. Do you find this easier to kind of get into your therapeutic range when you want it, the steps to get there are easier and more convenient than you would say with the heparin?

Dr. Teixeira,

yeah.

You're on mute.

Yep. Oh,

you're good now, yeah.

There you go. No, it's straightforward.

It's

straightforward.

Within a few titration steps, it levels out. The amount of adjustments is a fraction that's required for heparin, which is the easier thing to, in general, titrate.

Usually within the first hour of therapy, we have a steady rate, and then maybe we need to be adjusted once more over the next 24 hours,

and

even then, not always. It's been very very straightforward.

I think, just like Dr. McMahon described, the nurses are like, "That's it?

That's all we have to do?" It's been pretty straightforward.

It's definitely easier than heparin and citrate, in my experience, that the titration not only once you get to titration, you constantly have to move back and forth and with all the other things that change in patient or the dialysate. I'll start with Dr.

Teixeira, how do you see if Niyad is approved, becomes available to you, and how do you see it fit in your anticoagulation regimen? Right now, that you don't have one, occasional citrate.

Where would nafamostat fit?

I think, would, move to the front of the line of our options available, for anticoagulation, for sure. Like, there there'd be no I I could never foresee a situation in which, I would use heparin in- instead of nafamostat, like like like like that wouldn't wouldn't wouldn't exist.

Uh, and then, occasionally, maybe rarely, we would use citrate in a in a especially complicated patient, in which the risk of bleeding is like extremely high, or or the risk of worsening bleeding is extremely high. I think that would be, few and far between, like to be honest.

Um,

I think, nafamostat would would, become sort of our first option, whether we would nafam- nafamostat, up front on all patients versus, having it be the first option if we clot, like again, that's sort of kind of a cultural thing like at our institution. We're a nothing-first center,

and so, I

I would think that, that might be something we should consider, honestly, cuz it would probably improve our outcomes overall in terms of, filter life. At the very minimum, I would think that, if we encounter anything that requires initiation of anticoagulation, I think this would be our our first option because, it's just, straightforward and effective.

Yeah. Same here.

As having had experience in the trial, and as a CRRT director, I would move it to front line. I would actually replace my current protocol with it.

Also because MUSC has bought up all these other community hospitals in South Carolina,

and

some of those programs don't have anticoagulation, and they're not getting the filter lifespan, and talking to some of the ICU staff there, they want simple. They won't take on the citrate protocol, because it's too complex and they just don't have the bandwidth to deal with it.

This is really simple. It's really simple.

You just hang it in the pre-filter and it runs, and you might do a couple of titrations,

and then

the nephrologist will monitor a couple of labs,

but

that's it. It stays in the circuit, allegedly.

It's nice. We're looking forward to finishing out the study.

This is where we are.

We are frequently asked, and we have seen ups and downs in enrollment in this trial, and some of this really had to do with the sites that we originally had, which were not the right sites for this study, but we made those changes, we had sites like yours brought on, and study enrollment picked up and we are way past the half point. Does that reflect any challenges in acceptance of nafamostat?

I think the people always ask us, "Gee, if you cannot enroll this trial, how you going to find patients who are going to need this?" What are your thoughts on that?

I can answer this one, we've talked about this, Shakil. The study was designed to be extremely cautious, right?

They exclude anyone basically with increased risk of bleeding, including, to be blunt, a bunch of patients who I think would be ideal candidates for nafamostat, because the whole concept of nafamostat is that it produces regional anticoagulation. There's a bunch of patients end up being excluded that I think would be perfect candidates for this therapy.

CRRT studies are hard.

CRRT studies are hard. These are sick sick patients.

You mentioned I've enrolled 300 patients in trials and prospective studies, to be honest, not all trials. Nonetheless, most of them are not CRRT patients.

This is my one area of most interest, to be honest, is CRRT. Enrolling patients who are requiring CRT into clinical trials, it's extremely hard in any setting.

Then this case, the way the protocol is designed, which I understand. I don't think it's reasonable to criticize per se.

Anyone with any sort of issue related to possible increased risk of bleeding can't be in the study. They have to have very specific dose of DVT prophylaxis, if their ACT is 151.

Again, a patient who has a slightly high ACT that's excluded from the study, those patients would all be completely reasonable candidates for this actual therapy in real life. The study protocol, the way it's designed, assuming, basically erring on the side of assuming that the bleeding risk associated with this drug is much higher than it actually is, in my opinion, the study protocol excludes a whole bunch of patients who would be very reasonable if not even ideal preferential candidates for this therapy.

I think that's the challenge of the studies, finding patients who meet all the criteria, including that baseline ACT. That's been a major issue for our center.

We've identified more people who have had a baseline ACT out of range than in the range that the FDA asked for,

and

that's not something that we've been able to sort of negotiate to change the protocol. I understand that.

I don't think that's going to reflect the real-world use of this whatsoever. These are six sick patients.

Just getting consent for any CRRT study to do anything is complicated. The stars kind of all have to align to get someone into the study.

We're making progress. We're doing the work.

All that said, I think the limitations of the study or the challenges in rolling the study will not translate whatsoever to the use outside of the study.

It's good to know.

Yeah. No, I enrolled three patients last week.

I

don't have an issue with it.

Then

a lot of patients are coming in bleeding, actively bleeding,

and

then we've still managed to wait safely, wait 24 hours, 48 hours,

and then

re-enroll them later once the bleeding had stabilized and they were treated and they were still on CRRT. Even in high-risk patients, we're still able to get them in,

and,

yeah, no, I don't think it doesn't reflect it at all,

and

drug will sell itself, to be honest with you. It's not

going

to change it at all.

That's great to know. Coming to selling itself, how much challenge do you foresee selling it to your hospital formulary?

Yeah. I don't think it's going to be an issue, because we're the ones that request the purchase order on the drug as the director of the CRRT in the hospital, and then we just have to go to a P&T committee and say, "Look, these are the adverse events I've had.

These are the challenges." They already know the challenges with citrate.

It's not going to be an issue for me,

and

I can see that the other peripheral hospitals, they will probably end up starting the drug at the time of initiation, it's just set up and then they walk away from it, and use it.

Then

they will gain money, because these filters are expensive. If you're getting longer lifespan of the filter, the drug will pay for itself.

Right, and citrate is not cheap. There's a human personnel cost to it, with their components and multiple testing and all that, nafamostat is not going to be more expensive than citrate actually,

in a setting like that. No, and it's actually quite shocking.

Those bags expire with the drugs really quickly, those big bags. I got an audit last year back from the hospital, $45,000 of expired drug.

It's massive money. It's huge money on the hospital, we have to do better.

Absolutely. That brings me to the end of my questions for you, and we have some little time left for any questions from the audience, from other people who are listening in.

Tara, I'll hand it back to you. Before I do that, I really want to thank both Dr.

Teixeira and Dr. McMahon for very exciting and enlightening discussion today.

Thank you for joining.

Thank you for letting us be part of the study. It was great.

Absolutely. Tara, back to you.

Hi, everyone. Thanks for the discussion and the education on nafamostat and just CRRT in general.

One thing that was mentioned, or I guess a couple points that were mentioned, is that the rates of chronic kidney disease is increasing over time, and citrate is very labor-intensive, and I guess there's also the nurse shortage going on. I guess with these factors combined, do you have any data on whether or not all of this is changing or increasing mortality risks for patients over time just due to how labor-intensive citrate is to use?

Does this create a backlog, or is there a backlog of patients that are being affected, and how does this all sort of fit in with nafamostat?

I could try to answer that. I don't think it's affected mortality rates.

I guess I would start by saying that this patient population, like Dr. McMahon was saying, is extremely ill.

The typical survival rate of a patient who is sick enough to be in the ICU, particularly in acute kidney injury, requiring continuous renal replacement therapy, is 50, 60% depending on the study. In other words, half these patients won't survive because of their underlying severe illness.

I don't think that's improved a lot over the last 20 years, which is actually in the context of critical care, where to some degree, all these devices have improved survival rates in many populations, slowly but surely, improved overall, let's say, survival rates from septic shock, one of the most common reasons to be in the ICU. I don't think the issues that we described have led to increase in mortality.

I think to some degree, this is hard to prove, I suppose, but it may be part of the reason why we've made minimal impact on that survival rate in patients with acute kidney injury severe enough to require renal replacement therapy, is that we haven't seen improvements in mortality for the last 10, 15, 20-plus years. I think some of these challenges maybe part of that.

I don't know, Dr. McMahon, if you have other thoughts.

If you look at how medicine is going now, dialysis isn't just the only form of extracorporeal treatment. They're developing new membranes, new devices for new indications.

We were part of another clinical trial for another device that requires anticoagulation. The application of nafamostat into extracorporeal treatments, in patients with AKI and other illnesses, non-AKI, you're going to see it exploding.

You can tell, because these trials are listed on ClinicalTrials.gov, and they're all requiring anticoagulation. I think we're going to take ownership of those devices in our ICUs as well as for dialysis, and these devices, once they get FDA approved, will bring down the mortality rate and have shown in one previous study to reduce mortality.

I think you're going to see the application of nafamostat outside of AKI as these devices come in.

Got it. That was helpful.

One more question, if I may. Seeing how this study has an extremely strict criterion for excluding patients with bleeding risk, do you think that could create a regulatory headwind in terms of getting potential approval or potential adoption risk by other institutions based on your conversations with other experts?

I think it's unethical to enroll a patient who's bleeding, because you just couldn't get away with doing that clinically. I've enrolled several patients who came in bleeding and then were stabilized and then enrolled them.

They're high-risk patients, but they also need good dialysis, and we still managed to get them in. No, I don't think it's going to have any implications.

It's just for the sake of the study, and once the pharmacokinetic data that comes out about the nature of the drug, we'll have a better idea, but it's certainly not an issue in my experience. Obviously, we don't give the drug to someone who's actively bleeding.

You couldn't find a trial to do that.

I agree. This issue of dealing with patients who are at risk of bleeding, clotting, it's just a daily issue in the ICU.

Again, the only sort of kind of major issue here is that the bleeding risk associated with nafamostat, it's going to be so much less than any other traditional anticoagulant that if anything, that balance is going to be easier to strike in real-life clinical practice in the ICU with nafamostat than certainly heparin or anything else that we routinely use as an anticoagulant.

Thanks for taking my questions.

Thanks, Naz.

Thank you for taking our questions. Maybe first to the company, to Vince or Dr.

Aslam, for the trial, you have an anticipated enrollment completion in first half 2026, and we have a 28 days safety follow-up. I wonder, what's the timeline for the top-line readouts?

Should we anticipate in 3Q 2026?

I can answer that, Shakil, and you can add any additional color. Yeah.

Right now, we anticipate, again, second half 2026, and our operating plan includes a PMA submission in the second half of 2026, as well. The data is being cleansed all along.

It's because it's the 24-hour endpoint. We're doing everything we can to have that PMA submission ready as quickly as possible.

The reason it slipped, honestly, past first half of year was because two sites that we were planning on having just continued to delay. It wasn't anything to do with us or the contracts.

It was their own internal issues, and one in particular had all research studies on hold as they were revamping their research protocols throughout their facility. They just recently released the ability to initiate studies again, and we were one of the first couple that was reinitiated, and they lifted their hold and immediately activated the study with a training refresh.

Outside of that, we felt like we were on track for the midyear, except for those two institutions that caused the slip, and we believe we'll be in a strong position to have this completed and ready for submission before the close of the year. Shakil, did you have any additional commentary?

No, Vince, I think you covered it all. Those were unexpected delays, but I think we are way past that and will continue to execute quite nicely, actually, from this on.

You heard from Dr. McMahon, that she enrolled three patients last week, I think the pace is good now.

Got it. Thanks for the helpful color.

To the two doctors, when a new nurse is onboard, how long does it take for them to get used to citrate for this ICU setting, versus how long does it take for them to get used to Niyad if it's approved?

I can take that one. The nurses go through certain levels of experience when it comes to CRRT.

They have to go through their basic CRRT training, and they can do another more advanced training, and it's the advanced training nurses that actually have to do the citrate training. Not all of the ICU nurses do CRRT training, and of those who do the initial CRRT training, they don't deal with citrate.

It's actually the superusers that deal with the citrate protocol. It's the cream of the crop of the CRRT nurses that do it, because it is complex, they don't overwhelm them initially when they're getting trained on CRRT, and they reserve that for a more skilled CRRT nurse.

With this, if we managed to bring this on board, we would actually train everyone up front because it's so simple. You hang a bag, you run a pre-filter, you're checking a lab, and you're titrating based on a simple box, and that's it.

It's so easy to use compared to our current protocols. I can see the nurses changing that for the initial all-comers up front, yeah.

Dr. McMahon, in the citrate training, what would you consider typically it takes to train nurses?

Do you kind of

check— You have to take them through the protocol, you have to talk to them about where to draw the calciums from the different circuits, it's two different lines, you have to draw the calciums from there, the timing of it, the interpretation of it, how do you titrate your calcium in response to that, how do you look for citrate accumulation, what you do with alarming, because you're dropping the blood flow, you get increased alarming with the citrate, how do you handle that? It's a cluster, and so you can't just put the nurses on that straight away.

They'll get too overwhelmed. It's our superusers that use the citrate protocol.

Niyad would be just like hanging a bag of heparin, except that it's—

You just hang it up, you let it run, and then you set it at a rate, and then you check your ACT level within 15 minutes, and then you titrate based on that. It's simple.

It's easy. It's uncomplicated.

No, it's good.

I could second some of that. I'm not sure exactly how long it takes, probably ends up being months before they're comfortable, I would say.

Like Dr. McMahon saying, first of all, only a fraction of our ICU nurses are trained to do any CRRT.

I think in our institution, they all get some initial training on citrate, but only the most experienced nurses are comfortable with it. To some degree, again, one more reason why we are reluctant to just throw people onto citrate willy-nilly is because, certainly in the middle of the night, the expertise from the nursing side in delivering this therapy may be limited.

Just like Dr. McMahon described, nafamostat is going to be far more equivalent to just like any other drug administration that the nurses are capable of doing.

I don't think there'd be any sort of restriction, basically. If you run CRRT, you would be able to run nafamostat without issue.

Yeah. Got it.

Maybe one last question to Vince. Since the Niyad is approved and used in Japan and South Korea for over 30 years, how should we think about the market exclusivity in the US, and for this drug-device combination?

Would any new patent application in this setting help to extend the market exclusivity here?

Good question. Put patents aside for a moment, just on data exclusivity from a regulatory standpoint, we would get 6 years post-approval.

Then beyond that, we've already filed international and domestic patents that are citing different mechanisms of use. It'll be on method of use in the United States, the titration schedule, the supply, etc.

We feel comfortable right now that we'll get those patents awarded, and that would take us into the 2040s. Correct me if I'm wrong, Ralph.

We feel confident in that moving forward and have been working on that really since the day we got the asset.

Got it. That's all from my end.

Thanks.

Great. Thank you for taking my questions, and thank you to both of the physicians who have joined here as KOLs, very, very helpful and insightful.

Just a couple questions for me. I think Dr.

Teixeira earlier on mentioned how, despite citrate being the nominal recommended first line, at least in his facility, and I would imagine similar situations at others, it's used maybe 2% of the time, I think he said. In other words, the protocol is basically don't do anything at first.

As you think about all of the benefits and advantages over the two options today, I'm wondering if you would expect to see a significant increase in the use of this versus the two other options today. In other words, could the market, as it is today, actually grow because of the use of Niyad as the first-line therapy going forward?

I I yeah, I can try to address that. Let me back up.

The the recommendation to to that citrate is nominally first line is actually not specific to my institution. It's from what we call our KDIGO, or Kidney Disease: Improving Global Outcomes recommendations in 2012.

Th- They, recommended citrate as the first-line anticoagulant, in patients who don't have a contraindication, which is a little bit vague, but basically suggested that should be first line. That's been like a global recommendation for almost 15 years.

I I would say, like across the US, it it's more than 2%, but, a substantial minority of centers It's definitely less than 50%, though, of substantial minority of centers are citrate first right now and kind of follow that recommendation. I I guess the point is that like more than 50%, 2/3, 3/4 of of of of centers in the US don't follow that recommendation to be citrate first, in patients who don't have an obvious, contraindication.

That, kind of paradox or or seeming contradiction, I think just underlines the challenges in actually effectively delivering citrate. In our institution, maybe it's 2%, probably a little bit higher than that.

It is the minority of patients who can end up getting started, on on citrate. It maybe is like 1/4 of the patients end up getting citrate, and, often that's because they're clotting a lot and they're not a candidate for heparin, or they're clotting despite heparin, which, we've talked about how heparin's kind of a, basically, in my opinion, a inferior drug overall.

One of the issues with it is that it doesn't do that great of a job of preserving the filters, like it doesn't even do what it's supposed to do. It's kind of, certainly if you had to compare citrate versus heparin, heparin is simpler, but citrate's a more effective anticoagulant.

Sometimes, we'll try heparin first and they'll fail that, to speak, and and then go to citrate. So, the the second part of your statement or the question I think you're saying, "Will will CRRT use overall increase because of nafamostat?"

Hey, Dr. Teixeira, I think when we're talking about the market, it's more the anticoagulation market.

Correct me if I'm wrong, Ed. The question would be, if you're hesitant today to use anticoagulation, because there's a large segment that uses no anticoagulation as a first line and might not even use the therapy for all the aforementioned reasons that Dr.

McMahon and you have mentioned, do you think that a simpler agent would compel them to maybe start introducing it into the protocol where historically they haven't? The overall market of anticoagulation in this area would start to increase.

Yes,

that's exactly my question. Sure, that makes total sense.

Would CRT use increase? CRT use is going to increase regardless.

Actually, I don't think that nafamostat's going to change that. The answer is yes, overwhelmingly, will a larger proportion of the nothing-first centers like my own switch to using nafamostat first?

I think absolutely. Those would be centers in which a therapy like this will be attractive, because I think nothing first is going to become a second-line approach or newer guidelines are going to sort of continue to sort of emphasize what's already been emphasized is that something is almost certainly better than nothing, and with all the issues with heparin and citrate, having a therapy that is both effective, but less complicated and less risk of severe complications like citrate gone wrong, which is unusual, but can happen and can be severe, I think, overwhelmingly, the global use of anticoagulation with CRT, it's going to go up, yeah.

Yeah, 100%, it will go up. I I I agree with that statement.

The, the only reason we don't start with citrate is because of the issues that we're having with citrate. If I had a friendlier drug, better drug with less complications, I would absolutely use it, because I want to push those filter lifespans out to 72 hours, like the FDA says they should get.

We're not reaching that. 67% of people across the United States are not getting 24 hours, getting up to 24 hours.

That's not good enough. We're not getting the quality dialysis we should be getting, and I think, nafamostat has the potential to change that.

Okay. Thank you.

My next question is sort of the flip side to this where the first one is thinking about the potential for a substantially better option to actually grow the market overall for CRRT. The second question is, more related to what limitations can you see?

What patient populations or specific protocol situations do you envision where Niyad perhaps would not be thought of as first line and you'd prefer just to do nothing?

The only thing that comes to mind is a drug allergy. Someone has an established allergy with the drug.

Outside of that, I can't see another reason why. Can you, Pedro?

I think we need to sort of, we need some data, and this study's going to help clarify that. The the question is is, is nafamostat, 100% regional?

In other words, is the effect on systemic anticoagulation 0%? I I it's possible, but I think there may be some slight slight slight bleeding risk associated with it.

We already talked about how part of the challenge of the study is that a whole bunch of patients who have like a little bit higher risk of bleeding, that are to be blunt, like in average ICU patient is at higher risk of bleeding. There's a whole bunch of kind of relatively average ICU patients that are excluded from this protocol because they're like, have slightly thin blood to begin with, based on their ACT.

Those are all a bunch of patients who I think would be extremely well served by nafamostat. It's possible that like the the highest-risk scenario, which I would think like, someone comes in with a large intracranial hemorrhage, which is like, not a common scenario where where CRT is needed, but can occur, and this would be like a fraction of our CRT population, like I would think 5% or less, some of those patients with a large intracranial hemorrhage, any, anticoagulant may be prohibitive risk.

In that situation, even one that wears off within 5 to 8 minutes, may still not be a first-line approach. Maybe a situation where, you wouldn't necessarily, start them on, on nafamostat at first.

In that situation, you would do nothing at first, or or if you still have citrate Like again, like I wonder if if if citrate protocols are going to, slowly go away over time, because the the the the effort required to maintain them is so high. If it becomes like rare that they're used, less than 5% of patients, maybe it's not worth, maintaining them.

Nonetheless, the one maybe option is like the the patients who are bleeding, which the bleeding is, in of itself, extremely sort of life-threatening, the most kind of extreme of extreme, like a fraction of the bleeding patients that we deal with would be those with intracranial hemorrhage, that any additional drop of blood, to speak, could be prohibitive risk, to speak. Those might be a patient population in which, nafamostat, wouldn't be a good idea to to start up front.

You would only consider introducing it, 3 or 4 days later around the time when they would be starting, standard what we call, preventative therapy or prophylactic therapy against clotting in the legs, which develops a lot in ICU patients. These these patients with head bleeds eventually actually end up getting started on low doses of of of heparin injections to prevent clots in the legs, like most ICU patients.

I wouldn't necessarily do that on day zero, like, ICU admission for someone who, let's say, is a chronic dialysis patient but develops a head bleed. Again, not super, large chunk of of our CRT population, like again, maybe 5% or less, but, those might be one population in which nothing maybe the most safe thing, up front.

I don't know, that's that's about it. Like, I think most other situations, certainly like, bleeding into your gut, that's a big deal, but it's not nearly as as, directly lethal, to speak, as bleeding into your brain.

Great. Thank you very much.

That's quite helpful.

Oh, hey, guys. Sorry, I missed a couple of the Q&A here.

Sorry if it's already been asked. I was over on another call.

When will the trial expect to now finally enroll and the PMA will be filed? Then, actually, the $4.1 million you guys got in, I thought it was 4.9 when you hit 50%.

Was that explained earlier in the call and I missed it?

I can help answer that. That tranche was larger than $4.1 million in totality, but because an early investor waived and yielded some of those conditions, $1.6 million in proceeds had already been received of that tranche.

Separate from that, then another 4.1 came in when we achieved the 50%. Does that make sense on that portion?

It does. Is that and cash on hand get you through to the PMA?

Yeah. With the cash on hand in the expected activation of the other tranches, we expect this to get through approval from our cash position.

Yes. Beyond that, I think your question was guidance on the study completion.

We mentioned it earlier in the Q&A. It slipped a little bit.

The last two sites came on later due to their own internal processes. One of them in particular had a hold on all research studies at their facility, had nothing to do with the Talphera study in particular.

They just recently released that. With those two sites built into the forecast to complete by midyear, it'll slip a little bit past that.

Enrollment seems to be performing nicely. We'll have this study completed in the second half of the year.

Our goal is to also have the submission of the PMA in the second half of the year.

All right. Great.

Then, quick follow-up. Could you walk through what an ideal candidate would look like?

I know there's some talk on the with the KOLs about how there's exclusive criteria for the trial is a little more demanding than you might find in real life. What would be sort of the ideal candidate you'd be looking at?

Then also, the two trials are driving 90% of the enrollment to date? Is this effectively sort of a two-site trial at this point?

No. The over 90% of the enrollment is coming from the new target sites, of which there are nine, since we inherited the study.

Just to give you a quick background on that, if you recall, when we bought the company, La Jolla Therapeutics, that had the asset, they had already engaged a number of institutions, good institutions, that had been used for a previous study affiliated with that company, slash La Jolla Pharmaceuticals as they were a subsidiary and prior to that. The change to the new profile sites incorporated not just critical care physicians, but Dr.

Aslam came in and moved it towards nephrology leads, and he moved the study towards the MICU, the medical intensive care unit, instead of some of the other ICUs involved. With that two-element profile of institutions, he engaged nine new institutions into the study.

Those nine new institutions are the ones that are enrolling more than 90%. It's not just the two trial sites.

Refresh me. I think the question prior to that was the ideal profile for the patient to be used on nafamostat as an anticoagulant in CRRT.

I think we've kind of mentioned it, but Dr. McMahon or Dr.

Teixeira, can you just quickly again It didn't sound like there was a lot of restrictions to patients that are going on CRRT, but maybe reiterate who you feel is ideal for the profile.

It's almost

It's

Yeah, I I can or Sharon, you go ahead. Trying to give you a shot.

Again, I think, Vince, you're basically taking the words out of my mouth. I think it's easier to think of who this would be inappropriate for and list a very few number of patients.

Again, the day of admission for a head bleed, perhaps not, obviously, we have need to do no harm. I think this will serve the average ICU patient that needs CRT extremely well, including most of the patients that are excluded from this study due to kind of the extremely conservative inclusion criteria that we have for the study.

I think it's harder to think of patients in whom we wouldn't use this therapy. I don't know, Dr.

McMahon, if you have any other thoughts.

Yeah. Septic shock is the most common indication in cause of AKI in hospitalized patients, and including those in the ICU, and so they're relatively straightforward.

I can even see use for this in liver patients, because they clot all the time, because citrate is You got to be really careful with citrate use, and we use half the dose of citrate in our liver patients, and they clot all the time. They're so vulnerable to clotting, and we obviously have to wait and see what the data shows from the trial, but I can envisage it being used even in those patients.

They're currently a cohort that we're not using in the study, but we have used a couple of patients with out-and-out liver failure. I can see the use of this drug expanding across the entire cohort of patients.

I agree with that. Liver patients would be pretty routinely excluded from this study based on the current inclusion criteria.

Those are patients in whom this therapy, I think, would be perfectly appropriate for, absolutely.

Yeah.

Did that answer your question, Jim?

It did. Thank you very much for taking the questions.

Rich discussion. I can't thank enough our experts, Dr.

McMahon and Dr. Teixeira, two very busy professionals in patient care, in particular, ICU patient care, you can imagine what their days and nights are like, for their time today.

I really hope that gave you an appreciation for the opportunity for Niyad in CRRT and our excitement, once the study is completed, assuming all is as expected, to get this in the hands of the physicians dealing with these complicated ICU patients. We'll keep you updated on the progress of the trial and the FDA PMA submission planned for later this year.

Thank you all for joining the call and listening. Dr.

Aslam, thank you for conducting the questions and the engagement with the key experts, and that concludes our call for the day.

Thank you, Vince, and thank you again to Dr. Teixeira and Dr.

McMahon.

Thank you. Have a good day.

Bye-bye.

Thank you, guys.