Talphera, Inc.

Good morning, everyone, and welcome to the Telfair Virtual Analyst and Investor event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. As a reminder, this call is being recorded and a replay will be made available on the Telfair website following the conclusion of the event. I'd now like to turn the call over to Vince Angotti, Chief Executive Officer at Telfair. 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. Shaquille Aslam, Telfer's chief medical officer, and two key experts in continuous renal replacement therapy, who are also principal investigators in our NEFRO 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 Nifamistat 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 Taufera. Please refer to our press release in addition to the company's periodic, current, and annual reports filed with the SEC for 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 NEFRO CRRT study is progressing nicely and as announced a few weeks ago, we reached the 50% enrollment milestones. 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 in investments of $20.4 million, which, along with the remaining tranches, if closed, should provide runway through a potential FDA approval of NIAID next year. We expect to complete enrollment of the NEFRO CRRT study later this year and file the PMA within about three 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. And I'd 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 five and seven 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. So good morning and welcome to an exciting session with our two experts in acute kidney injury and continuous renal replacement therapies. My name is Shakeel Aslam. I'm the Chief Medical Officer at Telfarum. 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 NIAD 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 will not be going through their entire list of accomplishments and contributions 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. 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 the Director of Neurofnephrology 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, 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. So welcome to our call, Dr. McMahon and 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, you know, 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, which you continuous kidney replacement therapy, although they mean the same thing. So we use the CRRT and CKRT interchangeably. And then you have regular intermittent hemodialysis, which most people are aware of. So what are the key technical difference between these two modalities?

Yeah, so...

When we consider... And Dara, if you have that slide, I think that will highlight the difference. Okay, got it. Perfect.

So when you think of outpatient dialysis, these are 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 attend three days a week for their dialysis therapy, either Monday, Wednesday, Friday for three to four hours or 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 two modes of dialysis is one is it's a higher dose of dialysis for stable patients, but the C or T dialysis is a more gentle form of continuous dialysis run 24 seven in the ICU at the bedside. Okay. So 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 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 citrate anticoagulation is contained within those bags and they require infusions of calcium, to run, to maintain that filter lifespan. 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, intermittent hemodialysis is done mostly outpatient, though it can be done inpatient as well. Patients are typically more stable walking the dialysis, very high speed. quick three, four 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 an extended period of time, 24 hours a day. and can go up to five, seven days as long as the patient needs it. Thank you. That was very helpful. That's it. Yeah. 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 in the incident rates of End stage kidney disease, which is what most of 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.

Yeah, absolutely. So the chronic dialysis population United States is kind of historically over the first 20 years of the century has gone up and up and that's been a kind of a big topic in nephrology, but 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, like 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. And 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 obvious one. And the incidence rates of septic shock and acute kidney injury and acute kidney injury 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, you know, 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 the patient population that this issue is relevant to is only going to continue to grow.

And Dr. Shera, 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. 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 patients to develop acute kidney injury?

Yeah. And so to some degree, I mean, these things relate. That's absolutely fair. So the patients with chronic kidney disease that, you know, not yet requiring dialysis, that population is not going anywhere and they are more at risk. acute kidney injury, and 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 proportion of those patients that account for the total chronic dialysis population is going up over time, slowly starting to compete with things like diabetes and hypertension that are thought to be the the most common causes of NCH kidney disease in the United States. But yes, absolutely. So 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 was going to say gradual explosion. It seems like 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 just, 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, ECMO, extracorporeal membrane oxygenation. So 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 sub-specialized centers. And 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 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. But 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. Yeah, absolutely.

I think the use of CRT is only going to continue to rise over time. We're seeing it locally and across the country.

Dr. Mukband, 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 can clot and then you have slow you know, 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?

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 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 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 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, but we don't see that level of clotting in the outpatient compared to the ICU. Yeah.

Yeah. And Dr. Shen, I've seen you even on national holidays, you know, running off to the ICU and, you know, putting those fires out. So what happens? So general, I think many people take a very simplistic view. Well, OK, the filter clots, you pop the filter out and put a new filter in and, you know, keep going. So could you just walk us through what exactly are the implications when a filter clots, you know, implications for you as a clinician, for the support staff that's taking care of those patients and the patients themselves? What happens, you know, what is, you know, lifelike when you get a call in the middle of the night, hey, Dr. Shera, this filter has clotted off?

Yeah, I mean, there's implications kind of, you know, in many levels and it affects sort of both the patients as well as the healthcare system, I would say. You know, very simply, if you are not on the machine, you're not getting the therapy that sort of, you know, life-saving kidney replacement therapy, whatever you're trying to fix with the machine, whether it's a buildup of, you know, 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 on multiple forms of life support, they drop everything that they do. It maybe takes just an hour, but it 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. And so that's valuable sort of time that the patient's 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, the, the nursing time is extremely valuable that we're sort of kind of cutting into here. And there's all sorts of costs as well. Like, each of these, um, uh, hemo filter sets as we call them cost hundreds of dollars. Um, you know, just thinking from an equipment perspective. That's obviously extremely sort of counterproductive for kind of efficient patient care. And 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, but occasionally they don't and the net results of that is they lose all the blood and that tubing in that filter and these 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 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. 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 a unit of blood, which is obviously the exact opposite what you want to do for a critically ill patient many of which you know already have active bleeding or because of their sepsis or some other disease process they're already very anemic and so um the implications of that you know are you know definitely you know not helpful to the patient or to the healthcare system so so briefly what exactly are you doing to prevent the clotting so what is your anti-regulation of choice right now to prevent those filter clottings Um, is that for me? I can, I can answer. So, um, you know, I've been at the University of Mexico now about 7 years and, um, when I came in, we didn't have a specific protocol about how to approach and we haven't really evolved beyond that. And in part, like, I. 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. 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. And so I 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 citrate 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 arrogant of me to say, but it's complicated. The reality is that it's complicated. you know, 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 a, you know, in other words, only, you know, less than 50% of centers across the United States are citrate first because of the complexities and issues related to that. So we are a nothing first center, which is like arguably not adhering to the guidelines, but it's because the options available are basically neither of them are fully satisfactory.

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

Yeah. So we're the same. If you clot more than once in 24 hours, you automatically start citrate anticoagulant. We have ACDA 2.2% citrate in our institution.

Okay.

But, you know, like my last institution, they didn't have Citric 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 to, you know, when you talk to your colleagues in the division, some of them still aren't 100% familiar with the protocols. And we've seen 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 ACDA and it is. It is a job security.

Right, right. So life expectancy of these or useful life of these filters is around 72 hours. So when you are not using anticoagulations, you know, what kind of lifespan do you get for these filters?

Yeah. So 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. And 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. The filter alone is a connection fee. Our institution is about $2,300 plus the nursing fee. So it's not cheap. And then the cost of anticoagulation, the cost of the connection, the cost of blood should it go down. And then the implications, obviously.

Yeah, sure, sure.

But yeah, so it's not cheap.

Yeah, yeah. And Dr. Teixeira, what kind of filter life do you get at UNM? You're on mute.

Yeah, I just pulled up some of our most recent data. This is actually skewed by pediatrics, which is a little bit different situation. And their filter life tends to be better than ours. But our filter life tends to be, our median is 13 hours. I'm just looking at some data. This is a few months ago. And we have some that extend a little bit longer. So our 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 consider heparin or citrate upon premature filter loss. But yeah, our data locally match the sort of more global data that Dr. McMahon just said.

And hapten has been used forever and it's FDA approved. 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, you know, to the risk profile to the patients. So, Dr. McMahon, what is, you tend to, looks like a word, heparin altogether. So what's your beef against heparin?

Well, I used that at my last institution for seven years, and I can tell you it just, is not as efficacious as citrate. So the data on it is about 26 hours with heparin. It's not significant. These filters are supposed to last 72 hours. And if you're getting 26 hours with heparin, 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. So if you've got someone in with a brain bleed post-op, The surgeons don't want you to start it, you know, and it's a huge problem. So it's lack of efficacy will reduce efficacy and then the risk of bleeding with it. And yes, it's cheaper, but that, you know, the cost doesn't come into it at that point, you know. And so, yeah, 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.

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

We see this with regular patients too, right? They get super therapeutic and you have to hold it.

It's amazing. Yeah, Shaquille, I can add to that, too. Like, you know, just more globally, you know, thinking of my practice as intensivist, just use of heparin is no longer, it is the only thing that's FDA approved for CRT. I hope that changes soon, for obvious reasons. It's no longer considered first line for anything. It's no longer, you know, regular infractionated heparin is no longer considered first line for QPE. It's 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 non-medical term, it like both overshoots a lot in terms of its blood thinning effect. And then sometimes it doesn't work. It doesn't adequately thin the blood when it's supposed to. You know, the technical term has got unpredictable pharmacokinetics. So basically, like, it's hard to get it on enough. 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, but 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 eating too much. So it's really just like an inferior agent.

Yeah. And when you overshoot, so it's not like you just turn it off and it just goes away. You know, in many patients it can linger on for hours and sometimes you have to reverse it with using, you know, fresh plasma and all that but it's dirt cheap so do your hospitals incentivize you to you know hey use it it's cost us pennies and why not so you don't you don't buy into that uh no incentivization right okay great um So, and you talk to other people and this obviously is your experience with the happening. And is that the general consensus you get? I know, you know, you got goes to all these meetings as we are going to the one at the end of this month, you meet all the, you know, main people in CRRT world. When you talk to them, is this a experience with happening universal across all, or you have some, you know, real strong supporters of happening out there?

No. 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, you know, it's just not used. It's not used as much.

OK, OK.

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. 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?

Well, how long have you got? Because I can tell you it's an absolute, as the director of CRT at MUSC, it is an absolute pain in the arse for me. because it's constant. I mean, I'm not going to bash citrate, okay? It does its job, but there's issues with its use. 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 titrating of this calcium infusion that you have to give the patients. 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 they can accumulate it and get some degree of toxicity related to it and then you're stopping the citrate and then because you're starting a calcium infusion my protocol starts at 60 cc's and hours and if you have a decompensated heart failure you can't even pull off that 60 cc. 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 the regiocid, 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 therapeutic.

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

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

It's a highly concentrated citrate.

Concentrated citrate, 2.2%. So it's like this alkalotic drug and it changes the pH of the blood and you have to monitor for that. So we see... a lot you know 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 one nurse actually does her rounds on anyone who starts so that 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 our methods of monitoring events and sometimes they're still clotting. So it's been a thorn in my side since we moved to ACDA and that just has to be a 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 some challenges for you.

And then storage, right? So, you know, 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 the citrate, it's another pallet. Tara, you can see on the next slide. You can see the fluids that we have in storage. We had to actually store at a warehouse in North Charleston. And every two days they send a pallet of this stuff down for use. So there's a storage problem with this as well. And that's a big deal for my family. We have to pull back on other bags to allow for the citrate anticoagulation. We had to drop one of the phosphate-containing bags because there were just too many bags. You need to find options for storage. And that's not my job as a physician. You know, I want a simpler option. I want a smaller bag.

Yeah, yeah. And I'm sure that, you know, you win some popularity points from your nurses every time you prescribe citrate. How does that?

It's a heart sinker. The nurses go, really? Are you kidding me? And then they just sit there and they're like, yeah. 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 bags. So they're big, but these are five liter bags. The patient might go through It's probably six of these, six to nine, depending on the blood flow per day. So it's a lot. And if a patient's on CRT from two days to a month, you're going to turn over these bags.

Yeah, yeah, yeah.

And I think in comparison to the nifamistat 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 one liter bag. No, sorry, this is a 500cc bag or 250cc, much smaller. Yeah, easy, easy storage. That's what we want.

And Dr. Teixeira, you actually trained at one of the premier citrate-using institutions, but you have not been able to implement a citrate program at UNM. So tell us about what are the challenges or pushbacks that you experienced?

I think Dr. McMahon sort of kind of hit upon it. Like, it's a drag on kind of nursing kind of bandwidth. It's complex. It's hard enough for me. I think most of the fellows, you know, 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. 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 called it a center of CRT excellence. I know that a little bit better now in retrospect to be honest. But like certainly I had faculty there. These are like world famous nephrologists in their field but um uh who don't didn't understand citrate and i only started to learn it you know somewhat after trading because it's hard to sort of learn um we actually when i was a felt um there was a disruption in the supply of of calcium infusions um related to one of the hurricanes in puerto rico um and we lost our ability to prescribe citrate like for like a year of my training to be honest At UNM, and again, I think we've already hit this up, it is complicated. One of the, we'll just say, I won't name him, brilliant nephrologist who sometimes even within my own field, even though he's not specifically a critical care nephrologist, I'll ask him questions because he knows so much about everything. Even some of the most experienced nephrologists in my group who are brilliant 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. Descher, I can't understand what's going on with this patient. 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 just because people are confused. They don't understand what's going on. um sometimes they you know develop real accumulation of citrate or toxicity like dr mcmahon alluded to um that can occasionally be life-threatening but most of the time the nurses the intensivists even the nephrologists are just confused and we end up stopping it anyway and so it ends up being kind of this like uh um you know dance that like you know burns up sort of my bandwidth to be honest um and uh um you know i'm not there at the bedside all the time you know able to to manage things And that's the difference between sort of a clinical trial that shows citrate's 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 gonna look great. It's gonna 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 is basically garbage. Citrate in real life settings, when it was implemented on a national basis in the United Kingdom, had no benefits, basically. And so 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's safety. And then you have citrate with no uniform protocol, you know, intensive, intensive monitoring, extremely high workload, and a benefit which, you know, 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 rotate. through other jobs and you're not always having to find new staff to train. What would be, you know, if your ideal, the profile of an ideal, you know, anticoagulant, you know, that you would see, feel comfortable using? Obviously, it has to be safe and, you know.

Yeah, it has to work.

Yeah, 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 have clotting. vulnerable coag disorder like these clon disorders uh 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 um is 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 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, especially with the nursing shortage. Like you don't want to overwhelm the nurses. And then also having, not requiring these calcium infusions and titrations of calcium.

Right, right.

uh and also like the the storage thing i mean you might not think it's important but it is uh for me it is and uh so yeah i wanted i wanted to tick all of the boxes yeah right right yeah um so i think and both of you have been involved with the naya trial and i recognize this as a blinded trial but you know their administration of the placebo and the active drug are very similar exactly the same. They have to be by 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 you know gee it is very simple to use or is it like you know they actually it's quite fascinating the nurses are really excited they're coming down they're going is this though is this the new drug is this the and they're popping their heads in and they're going is that it and you know they're excited at this

set up and they're like, oh, please, come on, hurry up, you know, finish the trial, make our lives easier. It's all over. We, you know, we get a lot of excitement when we set up.

Okay. Good to know. Good to know. Yeah. And your titration, again, as we mentioned that, you know, one of the challenges that at least I felt when titration with the heparin to hit the, you know, your target window of APTT is always challenged. And many times, you know, you have to give a bolus of heparin 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, you know, kind of get into your therapeutic range when you want it? And, you know, the steps to get there are easier and more convenient than, you know, you would say with the heparin? Dr. Shera, you're on mute. You're good now.

There you go. So, no, it's straightforward. It's straightforward. Okay, good. Within a few titration steps, it levels out. Like, the amount of adjustment is a fraction that's required for heparin, which is, like, the easier thing to, in general, titrate. Okay. And so, you know, usually within the 1st hour of therapy, we have a steady rate and then maybe it'll be need to be adjusted once more over the next 24 hours. And even then, not always. And so it's been very, very straightforward. I think, you know, 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.

Yeah, it's definitely easier than haptrine and citrate, you know, in my experience that, you know, 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 dialysis. So I'll start with Dr. Pichetta. How do you see if NIAT is approved, becomes available to you, and how do you see it fit in your anticoagulation regimen? But right now, you don't have one, but you occasionally see a trade. Where would the FAMUS stat fit?

Yeah, I mean, I think, you know, it would move to the front of the line of our options available for anticoagulation, you know, for sure. Like, you know, there'd be no, I could never foresee a situation in which Uh, I would use heparin instead of, like, wouldn't wouldn't wouldn't exist. Um, and then, you know, occasionally, maybe rarely we would use citrate in a, in a, especially complicated patients. Uh, in which the risk of bleeding is, like, extremely high, or the risk of worsening bleeding. It's extremely high, but I think that would be few and far between, like, to be honest, I think, you know, would would become sort of our 1st option, you know, whether we were in the front, you know, upfront on all patients versus having to be the 1st option. If we clot, like, again, that's sort of kind of a cultural thing. Like, our institution, we're nothing 1st center. And so. I would think that, you know, 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, you know, if we encounter anything that requires initiation of anticoagulation, I think this would be our first option because it's just, you know, straightforward and effective.

Yeah, same here. You know, as having had experience in the trial and as a CRT director, I would say move it to frontline, I would actually replace my current protocol with it. And 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 you don't have the nurse. You 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. And it stays in the circuit, allegedly. So it's nice. We're looking forward to finishing out the study. We'll see 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 the We are way past the half point. And does that reflect any challenging challenges in acceptance of nifamistat? I think the people always ask us, gee, if you cannot enroll this trial, how are you going to find patients who are going to need this? What are your thoughts on that?

Uh, I can answer this 1. um, we've talked about this, um, um, so, um, the study was designed to be extremely cautious, right? Like, they exclude anyone basically with, you know, increased risk of bleeding, including to be blunt a bunch of patients where I think would be ideal candidates for the family stat. Like, because the whole whole concept of the family status that it produces regional act regulation. you know, there's a bunch of patients that end up being excluded that I think would be perfect candidates for this therapy. And CRT studies are hard. CRT studies are hard. These are sick, sick patients. You know, you mentioned I've 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, you know, most interest, to be honest, is CRT. But enrolling patients, you know, who are requiring CRT into clinical trials, it's extremely hard. in any setting and in this case like the the way the protocol is designed which like you know I understand I don't um I think it's you know reasonable to criticize per se but like anyone with any sort of you know uh issue you know 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 um if their ACT is 151 and again a patient who has a slightly high ACT that's excluded from the study Um, you know, those patients would all be completely reasonable candidates for this, uh, actual therapy in real life. So, so the study protocol, the way it's designed, assuming, you know, basically area on the side of assuming that the bleeding risk associated with this drug is much higher than it actually is in my opinion. Um. 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 study is 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. But I don't think that's going to reflect 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 we're making progress we're doing the work uh um but all that said um i i think this the the the limitations of the study or the challenges in rolling a study will not you know translate whatsoever to the use um outside it's good to know and i think man you feel you have any comments on that

Yeah, no, and I mean, I enrolled three patients last week. Like I don't have an issue with it. And then, you know, a lot of patients are coming in bleeding, actively bleeding. And then, you know, 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 CRT. So, you know, 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 the drug will sell itself, to be honest with you. It's not going to change it at all.

That's great to know. That's great 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, you know, 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 challenge. 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. 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 longer lifespan of the filter, the drug will pay for itself.

Okay. And citrate is not cheap. I mean, there's a human cost to it, you know, but there are components and multiple testing and all that. So citrate is not going to be more expensive than citrate.

Like it's, it's actually quite shocking. Those bags expire with the drugs really quickly. Those big bags. I got, I got a, an audit last year back from the hospital, $45,000. of expired drug. I mean, it's massive money. It's huge money on the hospital. So we have to do better.

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 a very exciting and enlightening discussion today. Thank you for joining.

Yeah, thank you for letting us be part of the study.

It was great. Absolutely. Dara, back to you.

Great. Thanks, Shaquille. So at this time, we'll be conducting a question and answer session with our speakers. Please hold for a brief moment while we pull for questions. So our first question comes from Naz Rahman at Maxim Group. Please go ahead, Naz.

Hi, everyone. Thanks for the discussion and the application on the FAMISTAT and just CRRT in general. So one thing that was mentioned, or I guess a couple of 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 NERDS, NERDS shirts 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 citrates is to use? Like, does this create like a backlog or is there like a backlog of patients that are being affected? And how does this all sort of fit in with the FAMSTAT?

I could try to answer that. I don't think it's affected mortality rates. You know, I guess I would start by saying that this patient population, like we started off saying, like Dr. Maman was saying, like is extremely ill. So the typical survival rate of a patient who is sick enough to be in the ICU with particularly an acute kidney injury requiring continuous renal replacement therapy is like 50, 60% depending on the study. So in other words, Half 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 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, you know, 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, you know, AKIs, acute kidney injury, severe enough to require renal replacement therapy. It's like, like, we haven't seen improvements in mortality for the last, you know, 10, 15, 20 plus years. And I think some of these challenges, you know, maybe, maybe, maybe, maybe part of that. But, but yeah, I don't know, Dr. McMahon, if you have other thoughts.

Yeah. And, you know, if you look at how medicine has gone now, there's actually dialysis isn't just the only form of extracorporeal treatment. They're developing new membranes, new devices for new indications and, we were part of another clinical trial for another device that requires anticoagulation. So the application of nifamistat into extracorporeal treatments in patients with AKI and other illnesses, non-AKI, you're going to see it exploding. And you can tell because these trials are listed on clinical govs and they're all requiring anticoagulation. So I think And 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. So I think you're going to see the application of Nafamasa outside of AKI as these devices come in.

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 a regulatory headwind in terms of getting potential approval or potential adoption risks 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. And I've enrolled several patients who came in bleeding and then we're stabilized and then enrolled them. They're high risk patients, but they also need good dialysis and we still managed to get them in. So no, I don't think it's going to have any implications. You just got to, you know, it's just for the sake of the study. And it really depends on, you know, once the pharmacokinetic data comes out about the nature of the drug, we'll have a better idea. But 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.

Yeah, I agree. I mean, like this issue of like dealing with, you know, patients who are at risk of bleeding and clotting is just like a daily issue in the ICU. And again, like the only sort of kind of like, you know, major issue here is that the bleeding risk associated with nifamistat is going to be so much less than the other traditional anticoagulant that if anything, that balance is going to be easier to strike in real life clinical practice in ICU with nifamistat than certainly Heparin or anything else that we routinely use as an anticoagulant.

Thanks for taking my questions.

Yeah, thanks, Naz. Thanks for the questions, Naz. Our next question comes from Yuan Z at B Reilly. Please go ahead, Yuan.

Thank you for taking our questions. Maybe first to the company, to Wayne or Dr. Aslam. For the trial, you have an anticipated enrollment completion in first half of 2026. and we have a 28-day safety follow-up. So I wonder what's the timeline for the top line readout? Should we anticipate in 3Q2026?

I can answer that, Shaquille, and you can 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 endpoint, so 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 two sites that we were planning on having just continued to delay. It wasn't 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 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 the study with the training refresh so outside of that we felt like we were on track for the mid year 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 she killed did you have any additional commentary i know i

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 from this on. As you heard from Dr. McMahon that she enrolled three patients last week. So I think the pace is good now.

Got it. Thanks for the helpful color. To the two doctors, when a new nurse is on board, how long does it take for them to get used to citrate for this ICU setting versus, you know, how long does it take for them to get used to niad if it's approved?

So, yeah, I can take that one. You know, the nurses go through certain levels of experience when it comes to CRT. They have to go through the 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. So 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 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. So yeah, I can see the nurses changing that. for the initial all comers up front.

Yeah. In the CITRE 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 calciums from the different circuit, just two different lines. You have to draw the calciums from there, the timing of it, the interpretation of it. How do you interpret? How do you 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? Like, I mean, it's a cluster, you know, and so you can't just put people, 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 I would be just like, you know, hanging a bag of heparin except that it's.

Yeah, it's a high, it's a small, you just hang it up, you let it run and then you set out a rate and then you check your ACT level. Within 15 minutes. And then based on that, it's a simple, it's easy. It's uncomplicated. And yeah, 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, 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 Oh, you know, only the most experienced nurses are comfortable with it. And so, to some degree, you know, again, 1, more reason why, like, you know, we are reluctant to just throw people on to trade willy nilly is because, you know, certainly in the middle of the night, you know, expertise from the nursing side in delivering this therapy may be may be limited. And, you know, just like, um, um, Dr described, like, Nifamistat is going to be far more equivalent to just like any other drug administration that the nurses are able capable of doing. So I don't think there'd be any sort of restriction. Basically, if you run CRT, you would be able to be able to run Nifamistat without issue.

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

Yeah, good question. So put patents aside for a moment. Just on data exclusivity from a regulatory standpoint, we would get six years post-approval. And 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, 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, Ralph. So 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.

Okay. Thanks.

Yes. Thanks for the question, Jan. Our next question comes from Ed Ars at West Park Capital. Please go ahead, Ed.

Great. Thank you for taking my questions. And thank you to both of the physicians who have joined here as KOLs. Very helpful and insightful. Just a couple questions for me. I think... Dr. Texeda 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. So 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 NIAID as the first line therapy going forward.

Yeah, so I can try to address that. So let me back up. The recommendation that citrate is nominally first line is actually not specific to my institution. It's from what we call our or kidney disease improving global outcomes recommendations in 2012. They, you know, 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. So that's been like a global recommendation for almost 15 years. And I would say like across the US, it's more than 2%. But, you know, substantial minority of centers, it's definitely less than 50%, though, a 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%, you know, two-thirds, three-quarters 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, you know, kind of paradox or seeming contradiction I think just underlines the challenges in actually effectively delivering citrate. In our institution, maybe it's 2%, it's probably a little bit higher than that. But it is the minority of patients who can end up getting started on citrate. It maybe is like a quarter 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, an inferior drug overall. But 1 of the issues with it is that 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, you know, certainly if you have to compare citrate versus heparin. Um, um, heparin is simpler, but citrates are more effective anticoagulants. So sometimes we'll try heparin 1st, and they'll fail that, so to speak and then go to citrate. And so, um. The second part of your statement or the question I think you're saying is, will CRT use overall increase because of Nefamistat?

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. And 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 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 into the protocol, whereas historically they haven't? So the overall market of anticoagulation in this area would start to increase.

Yes, that's exactly my question. would Cot use increase? Cot use is going to increase regardless. So I actually don't think that's going to change that. But the answer is yes, overwhelmingly. Like will more centers, you know, will a larger proportion of the nothing first centers like my own switch to using Nefamistat first? I think absolutely. Those will be like, you know, centers in which a therapy like this will be attractive because like I think nothing first is going to become you know, a second line approach or newer guidelines are going to sort of continue to sort of, you know, emphasize what's already been emphasized is that something is almost certainly better than nothing. And, you know, with all the issues with heparin and citrate, um um having a a therapy that uh uh um is both effective but you know less complicated and and less risk of uh of you know severe complications like citric gone wrong which which is unusual but can happen it can be severe um I think overwhelmingly like the the the the global use of anticoagulation with CRT is going to go up yeah yeah 100 it will go up I I agree with that statement the

You know, the only reason we don't start with citrate is because of the issues that we're having with citrate. And if I had a friendlier drug, a 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. And we're not reaching that. 67% of people across the United States are not getting 24 hours of getting up to 24 hours. That's not good enough. We're not getting the quality dialysis we should be getting. And I think Nafamasa has the potential to change that.

OK. Thank you. 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 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 NIAID perhaps would not be thought of as first time and you prefer just to do nothing?

Uh, well, I mean, the only thing that comes to mind is a drug allergy. Someone has an established allergy with the drug outside of that. Um, I can't see another reason why. Can you, Pedro?

Yeah, I mean, you know, so I think we need to sort of, you know, we need some data, and this study is going to help clarify that. And, you know, the question is, you know, in the FAMISAT, you know, 100% regional, in other words, is the effect on systemic human anticoagulation 0%. You know, 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 this 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 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, you know, 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 Nefamistat. It's possible that, like, the highest risk scenario, which I would think, like, you know, someone comes in with a large intracranial hemorrhage, which is, like, you know, 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. You know, some of those patients with a large intracranial hemorrhage, any anticoagulant, May be prohibitive risk, and then that situation, even 1 that wears off within 5 to 8 minutes may still not be a 1st line approach. There may be a situation where you wouldn't necessarily start them on the family stat at 1st. And that situation, you would do nothing at 1st, or or if you still have to train, like, again, like, I wonder if if. Citric protocols are going to slowly go away over time because the, the, the, 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 1, maybe option is like, 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, you know. Any additional drop of blood, so to speak, could be prohibitive risk. So, to speak, those might be a patient population, which, you know, wouldn't be a good idea to start up front. You would only consider introducing it, you know, 3 or 4 days later on the time when they would be starting. you know, standard what we call preventative therapy or prophylactic therapy against clotting in the legs, which develops a lot in ICU patients. So these patients with head bleeds eventually actually end up getting started on low doses of heparin injections to prevent clots in the legs like most ICU patients. But I wouldn't necessarily do that on day zero, like, you know, ICU admission for someone who, let's say, is a chronic dialysis patient but develops a head bleed, you know, again, not super large chunk of our CRT population, again, maybe 5% or less, but those might be one population in which nothing may be the most safe thing upfront. But I don't know, that's about it. I think most other situations, certainly 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.

Great. Thank you very much. That's quite helpful.

Thanks for the questions, Ed. So our final question comes from Jim Malloy at AGP. Please go ahead, Jim.

Hey, guys. Sorry, I missed a couple of the questions, Q&A here. What would... Do you want to get a confirm on the... Sorry, if it's already been asked, I was over on another call. When will the trial expected now finally enroll and the PMA will be filed? And then actually the... 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?

Yeah, 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 shares, conditions, 1.6 million in proceeds had already been received of that tranche. So separate from that, then another 4.1 came in when we achieved the 50%. Does that make sense on that portion?

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

Yeah. 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. 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. It had nothing to do with The TAFERA study in particular, they just recently released that. So with those two sites built into the forecast to complete by mid-year, it'll 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.

All right, great. 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 demanding than you might find in real life. What would be sort of the ideal candidate you'd be looking at? And then also, is the two trials driving 90% of the enrollment to date? Is this effectively sort of a two-site trial at this point?

No. So 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, Law Therapeutics, that had the asset, they had already engaged a number of institutions, good institutions that had been used with a previous study affiliated with that company, slash La Jolla Pharmaceuticals, as they were a subsidiary then prior to that. And The change to the new profile sites incorporated not just critical care physicians, but Dr. Aslan 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. And with that two-element profile of institutions, he engaged nine new institutions into the study. So 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 nifamistat 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?

Yeah, I mean, it's almost, yeah, I mean, I can, or give it a shot. Like, again, like, I think that, you know, you're sort of, Vince, you're basically like, you know, taking the words out of my mouth. I think it's easier to think of who this would be inappropriate for and list like, you know, a very few number of patients. Like, again, the day of admission for a head bleed, perhaps not. Like, you know, obviously, we have to need to do no harm. But I think this will serve the average ICU patient in ECRT extremely well, like including some, not some, like most of the patients that are excluded from this study due to kind of the extremely conservative inclusion criteria that we have for this 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

Yeah, I mean, you know, septic shock is the most common indication cause of AKI in hospitalized patients and including those in the ICU. And so they're relatively straightforward. And, you know, I can even see use for this in liver patients because they clot all the time because citrate. is you gotta 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 uh, without Florida liver failure, but, um, yeah, I can see the inclusion, uh, use of this drug expanding across the entire cohort of, of patients.

Yeah, I, I, I agree with that liver patients would be, you know, pretty routinely excluded from this study based on the current inclusion criteria, but those are patients in whom, um, um, this therapy I think would be perfectly appropriate for, absolutely.

Yeah.

Did that not answer your question, Jim? It did. Thank you very much for taking the questions.

Great. Thanks for the questions, Jim. 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.

Yeah, 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. 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 NIAID and 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. Asim, 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. Tashara and Dr. O'Brien. Thank you. Bye-bye. Thank you, guys.