Talphera, Inc. ($TLPH)

Good morning, everyone, and welcome to the Talphera Virtual Analyst and Investor event. [Operator Instructions]. As a reminder, this call is being recorded, and a replay will be made available on the Talphera website following the conclusion of the event. I'd now like to turn the call over to Vince Angotti, Chief Executive Officer at Talphera. Please go ahead.

Thank you, Tara. And 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 2 key experts in continuous renal replacement therapy who are also principal investigators in our NEPHRO CRRT registrational study. To their experience and expertise, we hope to provide you with a better understanding of CRRT, the anticoagulants currently being used during [ DRRT ] 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 will 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 Investors 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 2 investors waived all their conditions and closed on the second and third tranches of this investment. As of December 31, 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. So a quick turnaround of data is expected once patients have been enrolled. I'd now like to move on to why we're 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 CRR 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 [ City ]. Other times, physicians select 1 of the 2 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 in currently available anticoagulants. Dr. Aslam?

Yes. Thanks, Vince. So good morning, and welcome to an exciting session with our 2 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 dialysis, continuous renal replacement therapy for over 30 years. First as a [indiscernible] and then as a device and drug developer in these areas. It's my privilege to have Dr. McMahon and Dr. 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. So 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 accomplishments and contribution to this field for the sake of time. So first, Dr. McMahon. Dr. McMahon is an Associate Professor of Medicine at the Medical University of South Carolina in Charleston. Our key interests are in the areas of acute kidney injury and renal replacement therapies and intensive care setting. She has published over 50 papers in leading peer-reviewed journals and has returned numerous expert opinions, review papers and book chapters. She is Director of [ Neuro nephrology ] clinical trials at MSU 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 MSU 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 [ MSC ] and [ University College ]. Dr. Teixeira is an associate professor in the Divisions of nephrology primary Critical Care and Sleep Medicine at the industry of Mexico and Turkey. 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 [indiscernible] in acute kidney injury, CRRT and septic shock, among others. He has enrolled over 300 critical or hospitalized patients into more than a dozen clinical trials. He has coauthored over 100 peer-reviewed publications, book chapters and conference abstracts. He's on the editorial board of 3 journals as a Director of the CRRT program and [ U&M ] Teixeira Taser is responsible for overseeing the development of CRRT protocols and quality assurance programs. So welcome to our call, Dr. McMahon and Joao Teixeira. So nice to have you.

Thank you. Good morning.

Thank you. Thank you for having us.

Absolutely. So let's just start off with some basics. So as I'm sure you have the same experience, there are just so many different names, acronyms when it comes to acute kidney injury and the different modes of dialysis. 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 as referred to as [ CKT], which continuous kidney replacement therapy above the same thing. So we use the CRRT and [ CPR ] interchangeably. And then you have regular intermittent hemodialysis, which most people are aware of. So what are the key technical difference between these 2 modalities?

Yes. So when we consider --

[indiscernible] if you have that slide, I think that will highlight the end.

So when I -- when you think of outpatient dialysis. These are chronically chronic dialysis patients. Yes, they have organ failure and are attending an outpatient facility in the community. These are usually relatively stable patients. Most of them are relatively healthy other than the organ failure, and they often walk into the unit and a 10, 3 days a week for their dialysis therapy either Monday, Wednesday, Friday for 3 to 4 hours or a Tuesday, Thursday, Saturday. And 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. So the big difference between the 2 modes of dialysis is, one is it's a higher dose of dialysis for stable patients, but the [ CORT ] dialysis is a more gentle form of continuous dialysis on 24/7 in the ICU at the bed side, okay? So it's a more gentle form, 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 set up the machine on the left-hand side. And I don't think this picture reflects -- sometimes you go into a room, there's a lot more machinery like the mechanical ventilator. And you can see at the bottom of the machine, you have these bags, these replacement fluids and often the [ sitra ] anticoagulation is contained within those banks and acquire infusions of calcium to run to maintain that filter life span. So 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.

Great. So to summarize, intermediate hemodialysis is done mostly outpatient though can be done in patients as well. Patients are typically more stable, [indiscernible], very high speed. quick 3, 4 hours doses and they go home, whereas CRRT is patients with live tracking disease, many of them on ventilators, multiple comorbidities. They are medical ICUs, critically, multiple machineries and interventions. And the dialysis is very gentle and slow, but it has -- since it's not as quick, it has to be done over an 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. And Dr. Teixeira, you work as a director of an outpatient unit as well as you're the Director of the ICU. Are you seeing any interesting epidemiological trends and the incident rates of end-stage kidney disease, which is what most of these patients get down as far as an outpatient versus acute kidney injury, which you see in ICU in a patient like that shown in this picture?

Yes, absolutely. So the chronic dialysis population United States is kind of historically over the first 20 years of this entry has gone up and up and that's been kind of a big topic in nephrology. But it's starting to level off. If anything, during the pandemic, all those -- these are somewhat more stable patients, they are vulnerable to things like infection like with our dialysis population locally, and I think this reflects national data, too, dropped somewhat. So 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 [indiscernible] kidney disease that will continue. I think that trend, that chronic dialysis maybe become a smaller part of our practice. The opposite is true of the acute kidney injury. [indiscernible] populations in general are just growing across the United States. And 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 obvious one. And the incidence rates of septic shock and acute in injury and acute in injury is severe enough to require dialysis often continuous renal replacement therapy has only continued to go up and up and up. And so this is becoming a bigger problem, a more frequent problem. And over time, I think, is 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. And so I think the patient population that this issue is relevant to is only going to continue to grow.

And 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 owned houses that portion of patient is going to expand, I presume. And those patients are very high risk of acute kidney injury. And so is that what you're seeing as well that there's actually more patient to develop acute kidneys?

Yes. And so to some degree, I mean, these things relate. That's absolutely fair. So the patients with chronic kidney disease that not yet requiring dialysis that population is not going anywhere, and they are more at risk of acute kidney injury. And to some degree, the proportion of patients with what we call end-stage kidney disease or chronic kidney failure, they're requiring maintenance continuous outside the hospital. The portion of those patients that originally developed their kidney failure due to acute kidney injury that usually gets better, but sometimes it does not, especially in those with underlying chronic kidney disease. In other words, those who previously had a kidney disease and have a superimposed kidney injruy portion of those patients that account for the total chronic pain population 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 [indiscernible] kidney disease in the United States. But yes, absolutely. So the patient population, just like the United States population is aging and developing more chronic kidney disease to patients at risk of acute kindey injury increasing, which I think is part of the reason why we're seeing more of it along with, to be fair, I think just a gradual -- that I'm going to say gradual explosion, it seems like to be an explosion. Over the course of my 20 years since I was a med student messing around in ICUs use long ago, the expansion of critical care in the United States, it's 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 [indiscernible]. So these complex life support devices are being used more and more and not just an academic micro center 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. And as a result of that, acute kidney injury to some degree 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. We got 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.

So I presume that you're seeing similar trends in utilization of CRRT for management of these patients seem to be growing pretty rapidly?

Yes Absolutely. Look, I think the use of CRT is only going to continue to rise over time. We think it locally and across the country.

But Dr. McMahon tell us about the risk of clotting into totally different modalities of treatment. So you have very fast, high flow acute dialysis and obviously, filter and clot. And then you have slow dialysis for a long period of time, low flow and patients who probably are much more sick and inflamed. So how do you compare the risk of clotting between these?

Yes. It's a good question. The risk of [indiscernible] 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 patients. The majority of the time we're starting CRT, 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. And it's not just with sepsis or septic shock. We're a big liver center. Our liver patients have bribing these other proteins flow around that can affect the filter. There's a lot of risk factors that exist in the ICU patient that makes them vulnerable to plan in the ICU on CRT. So 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. We don't see that level of clotting in the outpatient compared to the ICU.

And Dr. Teixeira, I've seen you even on [indiscernible] holidays running off to the ICU and putting those fires out. So what happens? So in 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. So could you just walk us through what exactly are the implications when a filter clots, implications for you as a clinician for staff that's taking care of those patients and the patient themselves. What is life like when you get a call in middle of the night, day, Dr. Teixeira, this filter has clotted off?

Yes. I mean there's implications kind of in many levels and affect sort of both the patients as well as the health care 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 to much fluid in their body. None of that happens when the machine is down, takes at least and I say at least because sure if the nurse has absolutely nothing else to do in this patient on multiple forms of life support, they drop everything that they do. It maybe takes just an hour but takes at least an hour, like I think on a practical level, it's often an hour or 2, often before they get -- the nurse has the kind of bandwidth and time to sort of reconnect everything and get everything going again. And so that's valuable sort of time that the patient is not receiving the therapy. And 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. And then like I already alluded to, the nursing time is extremely valuable that we're sort of kind of cutting into here. And there's all sorts of cost as well like each of these [ hemophilter ] 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. And then occasionally, it's usually not the nurses are able to often identify that the filter is about to go down before it completely clots off, and [indiscernible] back the blood as we say, to prevent as much blood loss that would typically occur with one of these their sets. But occasionally, they don't. And the net result of that is they lose all the blood and that too being in that filter. And the filters are pretty [ slick ], but they still have about 150 milliliters or perhaps a more kind of intuitive way to think about it, basically, about half unit of blood is in these circuits at any given time to allow this therapy that cleans the boot to be going on continuously. And so it's not infrequent. It's a minority, but still a substantial number of times they're unable, 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 of unit blood, which is obviously the exact opposite of what you want to do 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. And so the implications of that are definitely not helpful to the patient or to the health care system.

So briefly, what exactly are you doing to prevent the clotting? So what is your anticoagulation of choice right now to prevent those virtual clients?

For me, I can answer. So I've been at the University of 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. And in part, like 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 none of them have sort of none them are free of major issues or complications. So in other words, Heparin we can talk about a lot, in short, I'm not a huge fan of heparin. And so as a -- definitely never had the thought that becoming a [ heparin first center ] made sense. So we haven't done that. And then [ Citrate ] can work well if I'm sitting at the bedside, managing it. I joke that I love [ Ctrip ] because it gives me job security because I'm perhaps the only nephrologist in the state who understands it well. It's a little bit perhaps, [indiscernible] me to say, but it's complicated. The reality is that it's complicated. [ Citrate ] nominally has been recommended as first-line for CRT in the United States for -- or worldwide, I should say, for over a decade, and it still accounts for only a fraction of practice as in other words, only less than 5% centers across the United States are [ citrate ] first because of the complexities and issues related to that. So we are nothing first center, which is like arguably not adhering to the guidelines just because the options available are basically neither of them are fully satisfactory.

Okay. And Dr. McMahon, what is your strategy for anticoagulation?

Yes. So we're the same. We -- if you clot more than once in 24 hours, you automatically start [ citrate ] to coagulate. We have [ ACA, 2.2% Sitran]. But like my last institution, they didn't have [indiscernible] because the Director of CRT there just didn't want to take it on board. Because like I mentioned before, it's the complexity and the burden. It's quite fascinating to -- when you talk to your colleagues in the division, some of them still aren't familiar with the protocols, and we've seen these events occurring. Safety is an issue, especially as the Director of CRT. Your job is to keeping safe for the patient while delivering good dialysis and modifying these protocols as we go. But -- so yes, we do use [ ACDA ] and then it is -- it is a job security.

Right. Right. So life expectancy of these or use full life of these filters is [indiscernible] hours. So when you are not using anticoagulation, what kind of life span do you get for these filters?

Yes. So if you actually look at the data, the data has been published on this, 1/3 of filters that start to go down in the first 12 hours. And then other 1/3 will last 12 to 24. Most institutions are, therefore, not getting 24 hours with their filters. Remember, these filters are expensive. Dialysis is expensive. The filter alone is a connection via our institution is about $2,300 plus the nursing fee. So not cheap and then the cost of coagulation the cost at the connection, the cost of blood, should it go down? And then the implications, obviously, for -- but yes, so it's not cheap.

And Dr. Teixeira what kind of filter life do you get at [indiscernible]?

Yes, I'd just like to pull up some of our most recent data. This is actually skewed by pediatrics, which is a little bit different situation and [indiscernible] will be better than ours. But our filter life tends to be our meeting is 13 hours. I was living out some data, this is a few months ago. And we have some that extend a little bit longer. So I mean is a little bit longer than that, but still less than 24 hours. And so that is suboptimal. But again, I think part of the issue with that is that the options available to us to improve that are limited. And so we haven't sort of implemented any major changes based on that other than trying to remind people to like consider [ heparin or citrate ] upon a premature filter loss. But yes, our data locally match the sort of more global data that Dr. McMahon just said.

And heparin has been used forever and it's FDA approved. And -- but 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. So Dr. McMahon, what is you tend to -- looks like a world [indiscernible] altogether. So [indiscernible] beef against heparin.

Well, I used at my last institution for 7 years, and I can tell you, it just is not as efficacious as citrate, okay? So the data on it is about 26 hours will happen. It's not significant -- like these filters are supposed to last 72 hours. And if you're getting 26 hours will happen, 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 pinning of the blood and your bleeding risk goes up for heparin. So if you've got someone in with a bit brain bleed, post-op, the surgeons don't want to -- need to start it. And it's a huge problem. So it's lack of efficacy, it will reduce efficacy and then the risk of bleeding with it. And yes, it's cheaper, but that the cost doesn't come into it at that point. So yes, even though it is approved, we actually don't have a heparin protocol our institution for that reason. And we actually did bring a [indiscernible] for research because it was a requirement for a protocol, but we don't use it. We don't use that at all.

And do you see any issues with -- at least I felt that titration the heparin was never a straightforward thing.

[indiscernible] too, right? We get super therapeutic, and you have to hold it and it's a mess.

Yes, Shakil, I can add to that, too. Like just more globally, taking my practices as a [indiscernible], just use of heparin is no longer -- it is the only thing that's FDA approved for CRT. I hope that to change soon for obvious reasons. It's no longer consider a first line for anything. It's no longer regular in [indiscernible], longer consider first line for [indiscernible], no longer for clotting in the lung. 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, it 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 like both overshoots a lot in terms of its blood thinning effect. And then sometimes don't work, it doesn't adequately in the blood when it's supposed to. The technical term has got unpredictable pharmokinetic. So basically, like, it's hard to get it on and off, and then some patients, it's hard to get prevented 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 it's eventually going to fall away to newer agents that are just kind of easier to use, but it's 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 doing too much. So it's really just like an inferior agent.

Yes. And if a new overshot, so it's not like you just turn it off and it just goes away in many patients at [indiscernible] it all for hours. And sometimes you have to reverse it with using fresh plasma and all that. But it's very cheap. So do your hospitals incentivize you to, hey, use it is causes [indiscernible] and what -- so you don't buy into that incentivization?

No.

Right. Okay, right. So -- and you talk to other people, and this obviously is your experience with heparin and is that the general consensus you can -- 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 do you have some real strong supporters of heparin out there?

No, it's not -- I mean, citrate still is superior as a higher incidence of use across the United States. So compared to heparin, it's definitely not used despite the cost advantage. You wouldn't sacrifice patient safety or efficacy over -- it's just not used. It's not used as much.

I've never met anyone who is a strong proponent of heparin. It hasn't been recommended as first-line for the last 10 to 15 years. Despite the fact that one thing that's approved technically for this use, nobody is pushing for heparin to be -- in first line.

And Dr. McMahon, you do use citrate in select patients. And so tell us what is life like?

Well, how long [indiscernible] because I can -- if I can tell you it and absolutely as the Director of CRT at [ MUSC], it is an absolute pain in the [ arse ] because it's constant. I mean I'm not going to bash citrate, okay. It does the job, but there's issues with its use. We talked about complex protocols and it has a huge burning on nursing staff and also on the medical staff. These monitoring of labs, the ICOs, the post-build or calcium, the lactates the CMPs and then these titration of this calcium infusion that you have to give the patient -- there are certain cohorts of patients that you can't even use citrate in. Well, you've got to watch them really closely. Deliver patients, for example, they can accumulate and get some degree of toxicity related to and then you're stopping the citrate. And then because you're starting a calcium infusion, my protocol starts at 60 ccs and hours, and if you have decompensated heart failure, you can't even pull off that 60 ccs. So you're going in there with your machine and then you're overloading them with this infusion. And then don't even mention now because -- because the [ Rego ] sit, the 0.5% got pulled by the FDA because they didn't have an emergency use authorization. And then we moved to ACDA, this higher percentage, I'm seeing a lot more metabolic disturbances with it while they're not [indiscernible].

For some of us who may not know what exactly is ACD.

It's just -- it's just a higher -- it's a higher percentage of citrate.

Highly concentrated citrate.

Highly concentrated citrate 2.2%. So it's like this [ alkolotic ] drug, and it changes the PH of the of the blood and you have to monitor for that. So we see a lot -- I get a lot of the safety events that come back when it's used 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 -- do one nurse to actually does our rounds on anyone who starts so that week and we can start monitoring it because what we're seeing is a lot of these metabolic disturbances and then at the same time, we're not getting therapeutic. So we have methods of monitoring events and sometimes they're still clotting. So it's been a torn on my side since we moved to ACDA, and that just has to be better option.

Right, right, right. And what kind of other logistical challenges that you face? So ACD is now you have it injected into your substitution, dialysis fluid and so that offers that see -- some challenges for you.

And then [indiscernible], right? So we live in Charleston and then the pharmacy are screaming up [indiscernible], we don't have room because every time you order and know the bag with the citrate, it's another [indiscernible]. You can [ target]. You can see on the next slide, you can see the fluids that we have in storage. We had to actually store out of warehouse in North Charleston, and every 2 days, they send a [ palette ] of this stuff down for us. So there's a storage problem with this as well. And that's a big deal for my -- we have to pull back on other bags to allow for the citrate anticoagulation. We had to drop one of the phosphate containing banks because they're just saying you have 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.

Yes. And I'm sure that you win some popularity points from your nurses every time you prescribe citrate. How does that [indiscernible].

It's a [indiscernible] sinker. Are you kidding me? We just sit there and they're like yes. So you can see here with this slide on the right-hand side, these are the citrate bags. Well, these are the CRT bags, but to order citrate, you need another shipment of citrate. So they're big -- these are 5-liter bags. Patient might go through probably 6 of the -- 6 to 9 depending on the blood flow per day. So -- and the patients on CRT from 2 days to a month, you're going to turn over these bags. In comparison to the Nafamostat on the left-hand side, this is the -- see where the [indiscernible] is, that's the bag. It's just like a salient bag. So this is a 1 liter bag, -- sorry, this is a 500 cc bag or 250 cc, much smaller. Yes, easy storage. That's what we want.

And you actually train at one of the premier [ Citrix ] using institutions, but you have not been able to implement a citrate program at [indiscernible] so tell us about what are the challenges or pushbacks that you experienced?

I think Dr. McMahon sort of hit upon it. Like it's a drag on kind of nursing kind of bandwidth, it's complex. The -- it's hard enough for me. I think most of the fellows I'm involved with the nephrology fellowship quite intimately here. I think most of the fellows graduate from our program and understanding how to use it well. And 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 CRT excellence. I know that a little bit better now in retrospect to be honest. But like you certainly had faculty there. And these are like world famous nephrologists in their field, but who don't -- didn't understand citrate -- and I only started to learn it somewhat after trading because it's hard to sort of learn. We actually went [indiscernible] felt there was a disruption in the supply of calcium infusions related to one of the hurricanes in Puerto Rico and we lost our building to prescribe citrate, like for year by training, to be honest. At [ U&M]. And again, I think we've already hit this offline. It is complicated. One of this -- we'll just say, I won't name him, I'm brilliant nephrologists who sometimes even within my own field, even though he's not specifically a critical care [indiscernible]. I'll ask them questions because you know so much about everything. Like even some of the most experienced nephrologists in my group who are brilliant kind of general nephrologist, everything about everything, to some degree, don't know how to manage citrate properly, like the fellows sometimes texts me on a Saturday afternoon [indiscernible] like, Dr. Teixeira, I can't understand what's going on with this patient like why are we doing this? I'm like I don't know either. But what ends up happening half the time is that we end up stopping 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. But most of the time, the nurses, the intensivist, even the nephrologist is confused and we end up stopping it anyway. And so it ends up being kind of this like dance that like burns up sort of my bandwidth to be honest. And I'm not there at the bedside all the time, able to manage things and that's a difference between sort of a clinical trial that shows citrate is better than heparin than real life. Like 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, but we know it. There's actually good data from the United Kingdom that like it doesn't actually perform that much better than heparin. We've already talked about how much I think heparin's basically garbage, citrate in dual life settings, when it was implemented on a national basis in the United Kingdom had no benefit basically. And so I think I see that on a day-to-day basis when I try to provide this therapy to my patients. And so that's part of the reason why we have to trade available, but it's -- we're not a citrate for a sector.

Yes. So it's very clear that 2 options that we have, they have their own unique challenges. So happening, yes, easy to administer and far less complicated, but very unpredictable doesn't always work the way it should and then cause systemic anticoagulation and adds too much risk to the patient safety. And then you have citrate with no uniform protocol, intensive, intensive monitoring, extremely high workloads and a benefit, which could be there to some degree, it could not be there based on where you use it, what setting you use it in and how experienced your staff is. And also then [indiscernible] that are [ we train ] and always there. They're not really rotating through other jobs, and you're not always having find new staff to train. What would be your ideal -- the profile of an ideal anticoagulant that you would see -- feel comfortable using? Obviously, it has to be safe and --

It has to work.

It has to work.

We want to [indiscernible] that work and that's works and is safe even in our high-risk patients like [indiscernible] or vulnerable to line [indiscernible] can disorders. We want to be able to use it in our surgical patients. And I want that drug to remain in this circuit and not to overflow into the patient's blood. So 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, okay, I'll do the 1 lab or the 2 labs to monitor its safety but it's really straightforward and simple. Simple in the ICU was really important for the nursing especially with the nursing shortly, like you don't want to overwhelm the nurses and then also having not requiring these calcium infusions and titrations of [indiscernible]. And also like the storage thing, I mean, you might not think it's important, but it is, for me, it is -- and so yes, I wanted to tick all of the boxes.

Right, right. Yes. So I think -- and both of you have been involved with Niyad trial, and I recognize this is a blinded trial, but there administration of the placebo and the active drug are very similar, exactly the same. They have to be in trial design and the titration. What is your and 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 like --

Actually, it's quite fascinating and the nurses are really excited. They're coming down the ones. Is this the new drug? Is this -- and they pop in their heads in we going to state, and they're excited at this like, please come on hurry. Finish the trial, make our lives easier. It's all over. We get a lot of excitement when we set --

And your titration, again, as we mentioned that one of the challenges that actually [indiscernible] titration with the heparin to hit the -- your target window of [ APTT ] is always challenged. And many times, you have to give a bolus of happening at the beginning, which many of these patients don't get because of the high risk of bleeding. So 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 what happened?

So no, it's straightforward. It's straightforward. Within a few titration steps, it levels out like the amount of adjustments is a fraction that's required for heparin, which is like the easier thing to in general [indiscernible]. And so usually within the first hour of therapy, we have a steady rate and then maybe it will be -- need to be adjusted once more over the next 24 hours, even then not always. And so and it's been very straightforward. I think just like Dr. McMahon described like the nurses are like that's it. That's all we have to do. And it's been pretty straightforward.

Yes, 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 [indiscernible]. So how -- 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 into your anticoagulation regimen, but right now, you don't have one, you occasionally trade the [indiscernible].

8 Yes. I mean I think it moved to the front of the line of our options available for anticoagulation for sure. Like there'd be no -- I could never foresee a situation in which I would use heparin and instead of Nafamostat if it like wouldn't exist. And then occasionally, maybe rarely we would use citrate in an especially complicated patient enrich the risk of bleeding is like extremely high or the risk of worsening bleeding is extremely high, but I think that would be few and far between. I like to be honest. I think nafamostat would become sort of our first option. Whether we were nafamostat upfront on all patients versus having been the first option if we [indiscernible] again, that's sort of kind of a cultural thing like our institution, we're a nothing first center. And so I would think that, that might be something we should consider honestly because it would probably improve our outcomes overall in terms of filter life. But at the very minimum, I would think that if we encounter anything that requires initiation of anticoagulation, I think this would be our first option because it's just straightforward and effective.

Same here, haven't had experience in the trial and as a CRT Director, I would move it to front line, I would actually replace my current protocol with it. And also because [ MOC ] has bought up all these other community hospitals in [indiscernible], 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 don't have to invest. You just don't have the bandwidth to deal with it. This is a -- it's really [indiscernible]. You're just hanging in the pre-filter and it runs and you might do a couple of titrations and then the nephrologists will monitor a couple of labs, but that's it. And it stays in the circuit allegedly. So it's nice. We're looking forward to finishing out the study where we are.

We are frequently asked, and we have been -- have seen ups and downs in enrollment in this trial. And some of this was 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 have sites like yours brought on and the study enrollment picked up, and we are way past the half point. And does that reflect any challenging challenges in acceptance of nafamostat? I think the people always ask us, gee, if you cannot enroll this trial, are you going to find patients who need this? What are your thoughts on that?

I can answer this one. We've talked about this, Shakil. So the study was designed to be extremely cautious, right, like the [indiscernible] basically with increased risk of bleeding, including to be blunt, a bunch of patients who I think would be ideal candidates for nafamostat like because the whole concept of the nafamostat is that it produces regional coagulation there's a bunch of patients end up being excluded, I think would be perfect candidates for this therapy. And CRT studies are hard. CRT studies are hard. These are sick, sick patients. You mentioned ever enrolled 300 patients in trials and prospective studies to be honest, not all trials. But nonetheless, like most of them are not CRT patients -- this is my one area of like most interest, to be honest with CRT, but enrolling patients who are requiring CRT into clinical trials, it's extremely hard in any setting. And in this case, like the way the protocol is designed, which is like -- I understand, I don't I think it's reasonable to criticize per se, but like anyone with any sort of issue related to like possible increased risk of bleeding can't be in the study, they have to have like very specific dose of [ DVT ] prophylaxis, if they're [ ACT ] is 151. And 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. So the study protocol, the way it's designed, assuming basically airing 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 would be very reasonable, if not even like ideal or preferential candidates for this therapy. And so 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 identified more people who have had a baseline in [ ACT ] out of range than in the range that the FDA asked for. And that's not the thing that we've been able to sort of negotiate to change the protocol. I understand that. But I don't think that's going to reflect the real view on the real-world use of this whatsoever. These are sick, sick patients just getting consent for any CRT study to do anything is complicated. And so like the stars kind of all have to align to get someone into the study. We're making progress. We're doing the work. But all that said, I think the limitations of the study or the challenges enrolling a study will not translate whatsoever to the uses outside of [indiscernible].

Dr. McMahon, if you have any comment on that?

Yes. No, I mean I enrolled 3 patients last week. Like I don't have an issue with it. And a lot of patients are coming in bleeding, actively bleeding and then we still manage to wait -- safety wait 24 hours, 48 hours and then we enroll them later once the meeting has stabilized and they were treated and they were still on CRT. So even in high-risk patients, we're still able to get them in. Yes. No, I don't think it doesn't reflect it at all and drug will sell itself, to be honest with -- it's not going to change at all.

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

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 CRT 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 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. So it's just set up and then they walk away from it and use it and then see those longer -- like they will gain money because these filters are expensive. So if you're getting a longer lifespan of the filter, the drug will pay for itself.

And citrate is not cheap. I mean, there's -- there's a few cost to it, but there are components and multiple testing and all that. So citrate -- nafamostat is not going to be more expensive than citrate actually.

And so like 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, like -- I mean, it's massive money. It's huge money on the hospital. So we have to do better pattern.

So 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.

Yes. Thank you for letting us be part of the study.

Absolutely. Tara, back to you.

Great. Thanks, Shakil. [Operator Instructions]. So our first question comes from Naz Rahman at Maxim Group.

Hi, everyone. Thanks for the discussion and the application on nafamostat and to CRRT in general. So one thing I was mentioning or I guess a couple of points we 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 [indiscernible] 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 per patients over time just due to how labor-intensive citrate is to use like, does this create out the backlog? Or is there like a backlog of patients that are being affected? And how does this all sort of fit in on with nafamostat?

I can 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 we started off saying that Dr. McMahon was saying like is extremely help. So the typical survival rate of a patient who is sick enough to be an ICU with, particularly in acute kidney injury requiring continuous renal replacement therapies like 50%, 60%, depending on the study. So in other words, half of these patients won't survive because of their underlying severity of illness. I don't think that's improved a lot over the last 20 years, which is like actually in the context of critical care, where to some degree, our supportive care, all these devices have improved survival rates in many populations like slowly but surely improved overall, let's say, survival rates from septic shock, one of the most common reasons to be to be in the ICU. But I don't think the issues that we described have led to increase in mortality. But I think to some degree, it may -- 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 [indiscernible], severe enough to require renal replacement therapy. It's not like we haven't seen improvements in mortality for the last 10, 15, 20-plus years. And I think some of these challenges may be part of that. But yes, I don't know, Dr. McMahon if you have other thoughts.

Yes. And if you look at how medicine has gone now, dialysis isn't just the only form of extraoral treatment. They're developing new membranes, new devices for new indications, we were part of another clinical trial for another device that requires anticoagulation. So the application of Nafamostat into extra oral treatments in patients with AKI and other illnesses on AKI, you're going to see it exploding. And we can tell you because these trials are listed on clinical [indiscernible]. And they're all requiring anticoagulation. So I think and we're going to take ownership of those devices in our ICs 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. So I think you're going to see the application of Novama outside of AI as these devices come in.

Got it. That was helpful. And 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 like regulatory headwind in terms of getting potential approval or potential adoption risk by other institutions based on your conversations with other our experts?

I think it's unethical to enroll a patient who's bleeding because you just couldn't get away with doing that clinically. And 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 manage to get them in. So no, I don't think it's going to have any implications. You just got to -- it's just for the sake of the study, and it really depends on -- 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 just -- you couldn't find a trial to do that.

Yes. I agree. I mean, like this issue of like dealing with patients who are at risk of bleeding, clotting is just like a daily issue in the ICU. And again, like the only sort of kind of like major issue here is that the bleed risk associated in the [indiscernible] 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 and ICU with Nafamostat and [indiscernible] then certainly happen or anything else that we routinely use as a net [indiscernible].

Our next question comes from [ Yan Zi ] at [ B. Riley ]

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-day safety follow-up. So I wonder what's the time line for the top line readout should we anticipate in 3Q 2026.

I can answer that, Shakil, and you're going to add any additional color. So right now, we anticipate again second half 2026, and our operating plan includes a PMA submission in the second half of 2026 as well. So the data is being cleansed all along. It's because it's the 24-hour end points that 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 the year was because 2 sites that we're planning on having just continued delay. It was anything to do with us or the contracts and 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 throughout their facility. And they just recently released the ability to initiate studies again, and we were one of the first couple that was reinitiated and they lifted the hold immediately activated the study with a training refresh. So outside of that, we felt like we were on track for the midyear, except for those 2 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, do you have any additional commentary?

No, Vince. I think you've covered it all. those were unexpected delays, but I think we are way past that and we'll continue to execute quite nicely actually potion as [indiscernible]. You heard from Dr. McMahon, as you know, 3 patients last week. So I think the pace is good now.

Got it. To the 2 doctors, when a new nurse is on board, how long does it take for them to get used to citrate for this SU segment versus how long does it take for them to get used to Niyad if it's approved.

So yes, I can take that one. The nurses go through certain levels of experience when it comes to CRT, they have to go through their basic CRT training and they can do another more advanced training and it's the advanced training nurses that actually have to do the citrate training. So we have our basic nurses that not all of the ICU nurses do CRT training. And of those who do the initial CRT training, they don't deal with citrate. It's actually the super users that deal with the Citrate protocol it's like the cream of the crop of the CRT nurses that do it because it is complex. So they don't overwhelm them initially when they're getting trained on CRT and they reserve that for a more skilled CRT nurse with this -- if we manage to bring this on board, we will actually train everyone upfront 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. So yes, I can see the nurses change in changing that for the initial all-comers upfront.

So the -- in the citrate training, what would you consider typically, it takes to train nurses do you kind of --

Well, you have to take them through the protocol, you have to talk to them about where to draw the calcium from the different circuit, just 2 different lines. You have to draw the calciums from there, the timing of it, the interpret [ station ] of it? How do you interpret 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 this in [indiscernible]. How do you handle that? Like, I mean, it's a cluster -- and so and you can't just put the nurses on that straight away. They'll get too overwhelmed. It's our super users that use the citrate protocol.

And Niyad would be just like hanging it bag of heparin except that it's --

Yes. It's a high -- it's a small [indiscernible], you let it on and then you set out a rate and then you check your ACT level within 15 minutes, and then you titrate based on that. It's a simple -- it's easy. It's uncomplicated. And yes, no, it's good. It's good.

I mean I could second some of that. I'm not sure exactly how long it takes, probably like ends up being months before they're comfortable, I would say. But like Dr. McMahon saying, first of all, look, only a fraction of our ICU nurses are trained to do any CRT. I think in our institution, they all get some initial training on citrate, but like only the most experienced nurses are comfortable with it. And so to some degree, again, one more reason why like we are reluctant to just throw people on [indiscernible] willy-nilly is because certainly in the middle of the night, expertise from the nursing side in delivering this therapy may be limited. And just like Dr. McMahon described like nafamostat is going to be far more equivalent to just like any other drug administration at the nurses are able -- capable doing. So I don't [indiscernible] there'd be any sort of restriction. Basically, if you run CRT, you would be able to run Nafamostat without issue.

Yes. Got it. Got it. Maybe one last question to Vince. Since Niyad is approved and used in Japan and South Korea for over 30 years, how should we think about the market exclusivity in the U.S. for this drug device combination. And would any new patent application in this setting help to extend the market exclusivity here?

Yes. Good question. So put patents aside for a moment, just on data exclusivity from a regulatory standpoint, we will get 6 years post approval. And then beyond that, we've already filed international and domestic patents that are citing different mechanisms of use. It will be on method of use in the United States, the titration schedule, supply, et cetera. And 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, Rob. So we feel confident in that moving forward and have been working on that really since the day we got the asset.

Our next question comes from Ed Arce at Westpark Capital.

Great.. And thank you to both of the physicians who have joined here as [indiscernible] very helpful and insightful. Just a couple of 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 than others. It's used maybe 2% of the time, I think he said. In other words, the protocol is basically won't do anything at first. So as you think about all of the benefits and advantages over the 2 options today, I'm wondering if you would expect to see a significant increase in the use of this versus the 2 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?

Yes. So I can try to address that. So let me back up. The recommendation citrate nominally in first line is actually not specific to my institution. It's from what we call [indiscernible] or Kidney disease improving global outcomes recommendations in 2012, they recommended citrate as the first-line anticoagulants in patients who don't have a contraindication, which is a little bit vague, but basically suggested that should be first line. So that's been like a global recommendation for almost 15 years and I would say like across the U.S., 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. So I guess the point is that like more than 50%, 2/3, 3/4 of centers in the U.S. don't follow that recommendation to be citrate first in patients who don't have an obvious contradiction. And that kind of paradox or seeming contradiction I think just underlines the challenges and actually effectively delivering citrate. In our institution, maybe it's 2%, it's probably a little bit higher than that. So -- but it is a minority of patients who get up getting started on citrate. It -- maybe it's 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 is kind of basically, in my opinion, inferior drug overall. But one of the issues with it is that it doesn't do that great of a job of preserving the filters. 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 is a more effective anticoagulant. So sometimes we'll try heparin first, and they'll fail that, so to speak, and then go to citrate. The second part of your statement or the question, I think you're saying is it will -- will CRT use overall increase because nafamostat --

Dr. Teixeira, I think it's -- I think when we're talking about the market is more the anticoagulation market, correct me if I'm wrong, and the question will be, if you're hesitant today, to use anti-coagulation because there's a large segment that uses no anticoagulation as a first line and might not have been used this 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 to the protocol, whereas historically they haven't. So the overall market of [indiscernible] in this area would start to increase.

Yes, that's exactly my question.

[indiscernible]. So actually, I don't think that a that's going to change that. But the answer is yes. So we're [indiscernible], like will more centers will a larger proportion of the nothing first centers like my own switch to using nafamostat first. I think absolutely. Those will be like centers in which a therapy like this will be attractive because like I think nothing first is going to become 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't ] happen and can be severe. I think overwhelmingly, like the global use of anticoagulation with CRT is going to go up.

Yes, 100%, it will go up I agree with that statement. 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, a better drug, with less complications. I would absolutely use it because I want to push those filter life spans out to 72 hours, like the FDA says they should get and 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 begin. And I think a nafamostat has the potential to change that.

Okay. So 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 or CRRT. The second question is more related to what line patients can see? What patient populations or specific protocol situations do you envision where Niyad perhaps would not be thought it was first time and you prefer just to do nothing?

Well, I mean, the only thing that comes to mind is the drug allergy. Someone has an established allergy with the drug. Outside of that I can't see another reason why. Can you, [indiscernible]?

Yes. I mean -- so I think we need to sort of -- we need some data and the study is going to help clarify that. And the question is, is nafamostat 100% regional? In other words, is the effect on systemic [indiscernible]. it's possible, but I think there may be some 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 an average ICU patient, is that higher risk of bleeding. There's a whole bunch of kind of relatively average [indiscernible] patients that excluded from this protocol because they're like have slightly thin blood to begin with, based on their ACT. So those are all a bunch of patients who I think would be extremely well served by nafamostat. It's possible that like 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 CRT is needed but can occur, this would be like a fraction of our CRT population, like I would think 5% or less. Some of those patients with a large [ intraprenal ] 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 or maybe a situation where you wouldn't necessarily I'll start them on nafamostat at first in that situation you would do [indiscernible] first or if you still have citrate, like again, like I wonder if citrate protocols are going to slowly go away over time because the effort required to maintain them is so high. And if it becomes like rare that they're used, less than 5% of patients, maybe it's not worth maintaining them. But nonetheless, the one maybe option is like the patients who are bleeding, which the bleeding is in and of itself extremely sort of life-threatening the most kind of extreme of the extreme, like a fraction of the bleeding patients that we deal with would be those with intrapreneal hemorrhage that any additional drop of blood, so to speak can be prohibitive risk, so to speak. Those might be a patient population in which nafamostat wouldn't be a good idea 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 the legs, which develops a lot in ICU patients. So these patients with [ head leads ] eventually actually end up getting started on low doses of heparin injections to prevent clot [indiscernible] like most 2 patients. But I wouldn't necessarily do that on day 0, 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 our CRT population, again, maybe 5% or less. But those might be 1 population, which nothing may be the most safe thing upfront. But I don't know. 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 directly lethal, so to speak, as bleeding into your brain.

So our final question comes from Jim Molloy at AGP.

Sorry, I missed a couple of the Q&A here. What would -- do you want to get a confirm on the -- sorry if it's already been asked. I was over in another call. When will the trial expect to now finally enroll in the [ PMA ] will be filed? And then actually, the $4.1 million you guys got I thought it was $4.9 million when you hit 50%. Was that explained earlier in the I missed it?

Yes. So I can help answer that. So 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. So separate from that, then another $4.1 million came in when we achieved the 50%. Does that make sense on that portion?

It does. Is that in cash on hand, get you through to the [indiscernible]?

Yes. So with the cash on hand and the expected activation of the other tranches, we expect this to get through approval from our cash position. So 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 last 2 sites came on later due to their own internal processes. One of them in particular to hold on all research studies at their facility had nothing to do with the Talphera study in particular. They just recently released that. And so with those 2 sites, built into the forecast to complete by midyear. It will slip a little bit past that, but enrollment seems to be performing nicely. We'll have the 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.

Great. And then a 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 demand than you might find in real life. What sort of the ideal candidate you'd be looking at? And then also, is the 2 trials are driving 90% of the enrollment to date, is this effectively sort of a 2-site trial at this point?

No. So the over 90% of the enrollment is coming from the new target sites, of which there are 9 since we inherited the study. Just to give you a quick background on that. If you recall, when we bought the company [ Law Therapeutics ] that had the asset. They had already engaged a number of institutions, good institutions that have been used for the previous study affiliated with that company. [indiscernible] Pharmaceutic because as they were a subsidiary them prior to that. And 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 MCU, the medical intensive care unit instead of some of the other ICUs involved. And with that, to element profile of institutions. He engaged by new institutions into the study. So those 9 new institutions are the ones that are enrolling more than 90%. It's not just a 2 trial site. 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 CRT. 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 CRT, but maybe reiterate who you feel is ideal for the profile.

Again, like I think you're sort of Vince, you're basically like taking the words out of your mouth. I think it's easier to think of who this would be inappropriate for and list like a very few number of patients like again, they have admission for a head bleed, perhaps not. Like obviously, we have to -- need to do no harm. But I think this will serve the average ICU patient needs CRT extremely well. Like including some -- not something most of the patients that are excluded from the study due to kind of the extremely conservative inclusion criteria that we have for the study. And so I think it's harder to think of patients in whom we wouldn't use this therapy. But I don't know, Dr. McMahon if you have any other --

I mean septic shock is the most common indication cause of [ AKI ] in hospitalized patients and glutens in the ICU. And so they're relatively straightforward. And I can even see use for this in liver patients because they call all the time because citrate is -- you've 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 and they're currently a cohort that we're not using in the study. But actually, we have used a couple of patients with [indiscernible] liver failure, but yes, I can see the inclusion 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, but those are patients in whom this therapy, I think, would be perfectly appropriate for it absolutely.

So we've run a bit over. So we're out of time for questions. I'll turn it back to you, Vince, for closing remarks.

Rich discussion, I can't thank enough our experts, Dr. McMahon and Dr. Teixeira, 2 very busy professionals in patient care, in particular, ICU patient care. So you can imagine what their days and nights are like. For their time today, and I really hope that gave you an appreciation for the opportunity for Niyad and CRT and our excitement once the study is completed, assuming all is as expected to get this in the hands of the physicians doing 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 in 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. Thank you.