Talphera, Inc. (TLPH) Earnings Call Transcript & Summary

Good afternoon, and welcome to the AcelRx KOL Panel Discussion. [Operator Instructions] As a reminder, this event is being recorded, and a replay will be made available on the AcelRx website following the conclusion of the event. I would now like to turn the call over to your host, Dr. Pamela Palmer, Chief Medical Officer and Co-Founder of AcelRx. Please go ahead, doctor.

Thank you, Sara. We're super excited today for our KOL panel discussion. The topic is the anticoagulation market for dialysis and update on our Niyad registrational study. And we may be making forward-looking statements, and please refer to our SEC filings regarding those. Our agenda for today is an introduction to our panelists and to the product, Niyad. And then we'll be talking about our quantitative market research study on the current U.S. CRRT anticoagulation practices. And we'll then be discussing the NEPHRO CRRT Study, which is our registrational trial of Niyad, and then we'll be opening it up to Q&A. So Sara, could you go ahead and advance the slide? So with us are Dr. Busse, who -- and Dr. Boldt. Both are esteemed, nationally recognized experts in acute intensive care treatment of patients, including dialysis. And I will have them introduce themselves. They'll speak more eloquently about their accomplishments than I will. Dr. Busse, would you like to start?

I'm happy to. My name is Larry Busse. I am an intensivist. I boarded in internal medicine and critical care medicine, and I practice at Emory University. I'm the Medical Director of the Medical ICU at Emory Johns Creek Hospital and the Site Director for the Emory Johns Creek Hospital location of the Emory Critical Care Center. I am a trialist, and have done years of clinical bedside research, including a number of research projects within the kidney injury space. My patients in my intensive care unit are a mixed set of patients, including medical, surgical, neurosurgical, neuro and cardiac patients. So I see a wide breadth of patients, any number of which can suffer from kidney injury. We deploy, very frequently, dialysis and renal replacement therapy modalities, and I am happy to be here to contribute today.

Wonderful, and we're glad to have you. Dr. Boldt?

My name is David Boldt. I'm a critical care intensivist as well as an anesthesiologist at UCLA Medical Center in Los Angeles. I spend most of my time or about 1/2 of my time in the ICU doing intensive care medicine and the other 1/2 of my time in the operating room, where I'm the Division Chief of trauma anesthesia as well as just multi-specialty anesthesiology. In the ICU, I work in primarily a cardiothoracic intensive care unit as well as a trauma and surgical intensive care unit. So as such, I take care of patients after heart and lung surgery, patients who require ECMO, which is a form of a full body heart and lung bypass in renal patients. I also take care of patients in the ICU after significant traumas. We're a Level 1 trauma center at UCLA, as well as just general surgical patients who are very ill after very big surgeries. And so as such, I take care of patients regularly on dialysis, both continuous dialysis and as well as intermittent dialysis, which will be sort of -- I hope you guys understand the differences of. But -- so we -- also in my role, I'm a clinical trialist as well. So I've done many clinical trials, both industry-sponsored as well as grant-funded research trials here at UCLA, mostly in the ICU space but also in the operating room as well. So I'm happy to be here with you guys today.

Terrific. And both of these experts are authors on the paper we'll be discussing coming up as well as Emory and UCLA, our clinical sites for our study. Sara, go ahead and advance that slide, please? The next slide. We'll be talking briefly. Many of you on the call may already know about nafamostat from earlier talks we've had. However, for those of you who are new to the story, nafamostat is an exciting molecule. It's a broad-spectrum serine protease inhibitor. And serine proteases are enzymes that are involved in a lot of cascade systems in our body. So inflammation cascade, immune cascade, the clotting cascade. And specifically, the first indication that we are at AcelRx working it up for is -- or developing for is an anticoagulant specifically for dialysis circuit. What's interesting about this molecule as opposed to other anticoagulants such as heparin, which is commonly used hospitals is an ultra-short half-life of 8 minutes. That allows us to titrate very finely to get the anticoagulation you like, but you don't dip into side effects. It does have multiple other potential indications. It's been approved in Japan and South Korea for over 30 years specifically to anticoagulate the extracorporeal circuit such as the dialysis circuit, but also for disseminated intravascular coagulation treatment, acute pancreatitis. And it's also been studied throughout the U.S. and other countries for COVID, ARDS, Dengue and numerous other diseases it could certainly possibly benefit. The next slide, please. So acute kidney injury, 3 million patients a year suffer from acute kidney injury and 500,000 of those require some sort of dialysis. What we'll be talking about today is the subsection of the dialysis that's called CRRT or continuous renal replacement therapy. 165,000 patients suffer from that or have to undergo that. And that's what Dr. Busse and Dr. Boldt are, in fact, experts in. And specifically, these patients are so sick in the ICU that they can't undergo intermittent renal dialysis. That sort of results in intermittent rapid shifts and human dynamic changes in the body. They have to be on dialysis at a slow rate continuously because they don't -- they can't really undergo those hemodynamic shifts. So that's specifically what we're talking about today. Next slide, please. So why is anticoagulation important in the dialysis circuit? Dr. Boldt, would you like to sort of tell us about what you see in your ICU?

Yes, I'd be happy to. Thank you, Pam. So -- and just to kind of highlight what Pam just said about Niyad in terms of the very important pharmacology-related aspects of its uniqueness is the ultra-short half-life. So this is extremely important to us in the ICU because we constantly have patients that are at high risk for bleeding from various sources. Myself, working in a trauma ICU, we often have patients who have concurrent head injuries, they could have spinal injuries. And so if we are giving them an anticoagulant for CRRT, then we would love to be able to have that go away very quickly if we do run into some like life-threatening bleeding. And so that ultra-short half-life is -- I can't underscore how important that is. And if you -- just so you understand the sort of basic need for anticoagulation here is that as Pam was saying, these patients are extremely sick. So they can't tolerate going through a normal dialysis session like you would take a renal failure patient through where, in those sessions, you have a lot of blood flowing quicker through the machine, you're able to do the dialysis much more efficiently. So you could be done in a number of hours instead of being continuously on dialysis. The problem is that when blood is moving very slowly, it's at risk for clotting. And so when you're moving the blood through the renal -- the CRRT circuits, it is very prone to clotting. And so that's why anticoagulation is needed. Now clotting is a very, very serious problem for these patients because not only is it laborious in terms of more frequent filter changes as well as expensive in terms of those filter changes, but these patients get a lots of time off of dialysis where you have to change those filters. And that can result in significant changes to their treatments for the day. Because if you have a patient where you're trying to remove liters of fluid in a day and they're off dialysis for 8 hours of that day or 1/3 of the day because you're changing filters, that's a significant problem, which is going to result in delays of care. To them, it's going to result in a prolongation of their time in the ICU, possibly prolongation of their time on dialysis. It's going to result in lots of downstream consequences, which are major. In addition to the increased blood loss, which results in more transfusions. And for a lot of these patients, it's -- can be difficult to get blood for them, especially platelets. We often have platelet shortages at our hospital in our blood bank. And so that is a big problem as well. So -- so it's not just about, well, the filter clotted, so we have to change it, and that's time consuming. It's a lot more in terms of downstream consequences towards the patients, potentially significant complications.

Yes. And the anticoagulant is, in fact, injected in all these situations into the circuit. And the whole goal is to not have it, in fact, affect the patient. You don't want to anticoagulate the patient, you just want to anticoagulate the circuit. And so that is one of the reasons we're really excited about that 8-minute half-life. Dr. Busse, what are your thoughts, if you want to add any to Dr. Boldt's statements regarding anticoagulation of the CRRT circuit?

Yes, sure. So I think one of the biggest issues that we see in a medical ICU is that when our CRRT circuit clots, we are unable to return blood back to the patients. So a lot of the blood that is out of the body circulating through the CRRT circuit, the tubing, the filter and then the return tubing, if there's a clot, that can't be washed back to the patient. And so every time we have a filter that clots, it's a non-insignificant amount of blood that we lose. My patients are typically medically ill. I think this is a little bit of a difference between David's patients, a lot of the trauma patients who might come in healthy off the street and have suffered a trauma. My patients oftentimes have a profound anemia due to their critical illness. They can't afford to lose any blood. So one of the things that we look for and try to avoid in the extreme is any filter clotting. So we take very seriously the ability to anticoagulate the CRRT circuit. Likewise, from David's comments, we also worry that our patients would -- are over-anticoagulated. So we want the circuit to be anticoagulated, but not our patients. Oftentimes, our patients, again, are critically ill with low platelets or bleeding risk. And so we want to find that sweet spot where the circuit is anticoagulated, but not the patient.

All righty. Next slide, please. So currently FDA-approved for anticoagulation of dialysis circuits is heparin, and another drug called citrate has an emergency use authorization to be used in that manner. Heparin, everyone's heard of. The problem with it is it can have a prolonged half-life of 2 to 3 hours. So even though, again, it's injected into the circuit, as you see there in the diagram, it will sort of float back into the patient after it goes through the filter. So it's doing a great job of anticoagulating the circuit, but unfortunately, it's now going to start anticoagulating the patient. That's a concern. There's also other risks with heparin, which our experts will talk about. So folks have started using citrate, which works by binding calcium out of the blood. So you're injecting citrate, right through the filter, it binds up the calcium. You need calcium to clot, so the blood goes to the filter without clotting. However, calcium is critical to maintain at a normal level in the patient. Therefore, these folks have to now run a calcium infusion on the other end of the filter, such that the patient's calcium remains normal. And that is a dance that's sometimes difficult to do. And what we're going to go through this slide pretty quickly, but Dr. Busse, what do you see is your biggest concerns with heparin and citrate?

Using citrate as a systemic anticoagulant or as an anticoagulant for the CRRT circuit exposes the patient to heparin. Oftentimes, this is not a problem. In fact, a lot of patients, we want them to be systemically anticoagulated, but there is a subset of patients that we don't want, those that have a high bleeding risk, those that have underwent recent surgery. And so the exposure of a patient to heparin, when really, you just want the heparin to make sure that the CRRT circuit is anticoagulated and flowing well, is a big risk. The other risk that we see with heparin is unique to heparin, and that is in a subset of patients that are exposed to heparin, they could experience heparin-induced thrombocytopenia, which is a severe side effect of heparin which causes a dramatic reduction in platelets and ironically, a dramatic increase in the body's -- and clotting. And so you have a life-threatening situation where the body basically clots off and every limb and it could lead to significant morbidity and mortality. With citrate, our big fear, and my ICU at Emory uses citrate with some frequency, with citrate, our fear is that when citrate flows systemically into the body, it can chelate calcium and you can get life-threatening hypocalcemia. It's pretty challenging to manage, in that you have to sample and replete calcium with a rigorous, time-consuming protocol. When the CRRT circuit or the citrate pump is held and the calcium infusion is not held, you can get a mismatch in terms of the citrate and calcium needs, and that can be life-threating. So it's very cumbersome to monitor and manage your calcium levels with the citrate infusion. The other concern we have with citrate is that when folks have liver failure, it's -- there's some clearance issues. And so we do not like to use or basically do not use citrate in anyone with any liver dysfunction, which is again, not a small subset of RSE patients.

Right. Dr. Boldt, do you have anything to add to that?

Yes. Just quickly regarding citrate, I will echo Larry's concerns about the challenges. Citrate's toxicity and hypocalcemia can be very life-threatening, as you mentioned on your slide here, which can result in cardiac arrest. So this is definitely a very serious complication. And a good portion of our patients also have liver dysfunction, which makes citrates relatively contraindicated to use in those patients because of the increased risk for them. Heparin, yes, the main disadvantage here is that heparin is getting to the patients when you try to anticoagulate them. And so as I was explaining earlier, in my subset of patients, where you have significant trauma, we are often not able to use heparin either. So we are oftentimes using nothing, which is very a big problem because then we have lots of circuit clotting. Because the heparin that you're giving to the circuit ends up going systemically. And that's a big problem. And then you have that -- also that prolonged pathway. So heparin, in a lot of my patients, is also relatively contraindicated, meaning I can't really use it safely because of the fear of bleeding. But in addition, even in those patients where, as Larry said, you are able to use the heparin and you're okay with a little bit of systemic anticoagulation, heparin has significant problems, the least of which is not -- as Dr. Busse mentioned, heparin-induced thrombocytopenia, which is a life and limb threatening complication that is very, very, very hard to manage because then, you are forced to anticoagulate that patient with a much more potent systemic anticoagulant. And so you have significant -- meaning the patients have significant bleeding and clotting issues. It's a terrible disease with a very high mortality. So when patients do develop it, it can be very serious. And heparin is also very difficult to titrate. Many patients have -- it's called heparin resistance. And so it can take hours and sometimes even days to get to a therapeutic level of heparin anticoagulation. And during that period, where you're waiting for them to get therapeutic, you're having circuit clotting and all of those issues. So if it takes you a couple of days to get therapeutic on your heparin, you're dealing with that 48 hours and just constantly changing the circuit and all of the other side effects that go with that.

Yes. So in talking to CRRT experts around the country, we hear over and over that they're stuck with kind of 2 bad options. And I think you both have summarized the problems with what is currently used in the U.S. today and why there is this unmet need for more choice in this particular market. Next slide, please. So the whole potential benefits that we see of nafamostat or Niyad is, again, with its ultra-short half-life of 8 minutes, you can inject it into the circuit. It can work in the circuit. And the small amount that does make it past the filter -- because the interesting thing about nafamostat is it's very sticky to the filter. And so much of it is actually pulled out of the circuit at the site of the filter. So the small amount that does start to get into that efferent limb going back into the patient will be metabolized by plasma esterases very quickly, such that your anticoagulant, the goal is to anticoagulate the circuit and not anticoagulate the patient. Another advantage is -- so hopefully, less bleeding than heparin would -- you'd see with that. Another advantage is that you can use it, hopefully, in liver failure patients because there should not be a contraindication such as there is with citrate in those liver failure patients. And of course, compared to no anticoagulation, we're hoping to see in our study, because that's what we'll be using as the other limb of that study, is a potential for fewer filter changes, better dialysis, fewer transfusions and an overall lower cost doctor and nursing time. Next slide, please.

And Pam, so I just wanted to echo what you were saying, if we could just go back to the last slide just for one second. Like you said at the beginning of this slide, that -- we are basically left with 2 terrible options, which is heparin and citrate. And so for a lot of my patients, I end up using nothing because I can't use citrate if they have liver dysfunction. It's very cumbersome to use. The heparin, we don't want them systemically anticoagulated. So that's a big problem because they have significant bleeding risk. When it comes to Niyad, you have this -- a couple of great advantages. One is that most of the Niyad is removed. Whereas like with heparin, you're getting systemically heparinized by the heparin. So you have a full-body anticoagulation, along with the circuit, which is not desirable. Most of the Niyad would be removed by the filter. And the small portion that we get to the patient is going to be gone in 8 minutes. And that metabolism, that ultra-short half-life is independent of liver function, renal function. So you can have patients that have liver dysfunction as a lot of my patients do and still use Niyad safely because you know that even the little bit that gets to the patients that's not removed by the filter is going to be metabolized quickly, independent of end organ function.

Absolutely. And that's -- I mean, again, it's been used for 30 years in Japan and South Korea. So I think giving our U.S. physicians the chance to use this is what we're really, here at AcelRx, excited about. Next slide, please. So one thing we wanted to quickly bring up, and we're going to move through this again fairly quickly so we get to the actual quantitative market research data and the study protocol. This is a meta-analysis, and it's -- there's many studies that were published on nafamostat over the past 3 decades, specifically for CRRT anticoagulation. But last August, Lin et al. actually did a meta-analysis that they published in the journal, Renal Failure, that evaluated all of these studies together. And I just thought it was interesting to point out, 11 studies qualified for their rigorous analysis. And what they found overall was lower mortality with the circuits that -- and the patients attached to the circuits that were anticoagulated with nafamostat compared to conventional anticoagulation and compared to using no anticoagulant. They saw lower bleeding risk compared to conventional anticoagulants. And then they had a longer filter life than for use of no anticoagulant. I mean, to both of you, how important are these 3 major endpoints that they evaluated in the study?

So these are far and away, the important endpoints that we look at in patient care. Obviously, if a patient doesn't live, it doesn't matter what we do. If they -- so getting them to live, getting them discharged home out of the ICU is the #1 task. That's the #1 job we have. And so when I look at a study like this, and I see that there's meaningful patient-centered endpoints, this catches my attention. Bleeding risk, same thing. This is an actual patient-centered endpoint, which has associated with it significant morbidity and mortality. And then lastly, what do we do when we are providing renal replacement therapy? And that is we are cycling blood through a filter. And so if our filters are lasting longer, it's evidence of improved ability to perform renal replacement therapy. I think these are meaningful patient-centered outcomes, and I'll just leave it there. I think this is an important study. David?

Yes. No, I agree with everything you said 100%. I think mortality is the holy grail of clinical endpoints, right, when it comes to benefits that we're looking for from medications or procedures, treatments. So I mean, that's huge. Bleeding risk, I think I've spoken to that quite a bit, that this is very significant in these patients, very serious. And filter life, as I mentioned a few slides back, is that this is big. I mean 10.5 hours longer is huge because all that time off of dialysis when you're changing filters, all the blood loss associated with clotting filters, a lot of that stuff can be mitigated by having a longer filter life.

Right. So I mean, seeing that nafamostat actually sort of won out against both standard of care anticoagulation as well as using no anticoagulant, it's really -- I think it was impressive to see this study. Next slide, please. So we've performed, here at AcelRx, a quantitative market research study on U.S. physicians and how they're currently using anticoagulation for their CRRT patients. And we're excited to announce that it has actually been accepted for publication in press in the journal Renal Failure. And we'll just talk on the next few slides about some of the data that we found from that study that was conducted last year. Next slide, please. So we used a company called Objective Insights, and they conducted an Internet-based quantitative study among 150 nephrologists and critical medicine specialists who practice in ICU and are involved with CRRTs. And this was conducted in November, December of last year. And you can see from physician type, it was almost evenly split between critical care medicine docs and nephrologists. And it was slightly weighted towards larger academic centers compared to community and general hospital. And I'd like to say that both of these authors are -- both of these KOLs here today are authors on this manuscript. Next slide, please. So one of the key questions we asked was what are you using in your patients currently? And you can see overall, 43% of patients are getting heparin to anticoagulate the CRRT circuit, 28% citrate, and no anticoagulation is used in 29% of the patients. There is a bit of a difference between critical care specialists and nephrologists. You see here that critical care specialists in general tend to use more anticoagulation in the circuit. More use of both heparin and citrate versus no anticoagulation. Dr. Busse, what -- when you see this pie chart, what are your thoughts on the current U.S. use of anticoagulation?

So the -- what struck me when we found this result and this analysis was really the difference between critical care medicine and nephrology with regard to no anticoagulation. And what I interpreted this to mean is that we in critical care medicine oftentimes are -- well, 100%, we are more at the bedside than nephrologists. Nephrologists tend to have a consult-based service. They start dialysis, they write an order and then they kind of leave the ICU. But what they, I don't think, have as much exposure to is when patients get sicker and when patients are failing the circuit and really the higher acuity of critical care patients versus patients under the care of a nephrologist. And so I was -- it's a striking difference in terms of anticoagulation versus no anticoagulation, but I think it's really well explained by the acuity we see in the ICU as critical care medicine specialists. And by the way, I was not a participant on this study. So this was just an observation that I saw, and I am opining as a critical care medicine specialist.

Dr. Boldt?

Yes, I agree with Larry, 100%. I think that as a critical care medicine specialist, you are looking at the patient as a whole. And so most patients in the ICU that do not have a significant risk of bleeding are usually at a very significant risk for clotting, for developing DVTs, pulmonary embolisms because of their acute illness. And so those -- most critical care medicine specialists recognize that and would move towards anticoagulating the patient to prevent some of those complications. Because critical illness in general, promotes people to clotting. And it's not just clotting of their circuits, like the CRRT circuit, it's clotting of their body, developing these DVTs and PEs. Many of my patients have immediate bleeding risks. But once that bleeding risk has subsided, I always move to anticoagulate them once I think the bleeding risk has minimized because of their tendency to clot because of their critical illness.

Yes. And I think it just goes to show with 29% overall not receiving any anticoagulation, I guess that's not that surprising after hearing about the complexities of both heparin and citrate that many places just choose to use no anticoagulation and just change out a filter more frequently. So definitely, it seems as though there's room for a new product in this market, for sure. Next slide, please. So another question that was asked in this particular study was on a scale of 1 to 5, how challenging is heparin as it relates to the heparin-induced thrombocytopenia that was mentioned earlier and the systemic bleeding risk? And you can see here overall, it rated pretty high for -- 3.4 and 3.5 on that scale of 1 to 5 regarding how challenging it is to sort of deal with those 2 issues. Anything to add to that that we haven't already mentioned regarding the risks of heparin?

Yes. So I think this is reflective of what we sort of -- how we perceive heparin. This is a dangerous drug. Bleeding can be minor. It can be major. It can be life-threatening. And heparin, the 1 role of heparin that we have is really to prevent clot. And the 1 big risk that heparin has is that it causes bleeding. So this is a drug that we are very careful with. It gives us a lot of anxiety when we use it in the ICU because oftentimes, this could be quite risky and things could go bad.

Yes. I think -- I mean, just from this slide alone, you can see what a double-edged sword using heparin can be, right? You have, on the 1 hand, significant bleeding risk in most patients. And then you have a subset of patients that can develop heparin-induced thrombocytopenia, which is an antibody-mediated condition that develops in a smaller subset of patients. But those patients that do develop it, as we've said, this is a life and limb threatening complication. And so you have a drug that clots sometimes and promotes bleeding most of the time. And when it does clot, it can be deadly. So heparin is a very dirty drug. It's incredibly difficult to use.

Yes. All right. Well, next slide, please. So also in this study, what we asked the physicians was if you didn't feel the patient could tolerate heparin, but then you chose not to use citrate, why? Why did you then choose no anticoagulation? And the #1 reason was the fear of hypocalcemia, followed by overall citrate safety, alkalosis, nursing time, calcium shortage, it just goes on and on. I'll start with you, Dr. Boldt. Do you have the same fears about citrate in the same order?

Yes. Yes, we do. And so for these exact reasons, as I mentioned, we often have to use nothing because we -- heparin has too many risks, and then citrate with the hypocalcemia, the extreme safety risks, a lot of our patients having some form of hepatic dysfunction, liver dysfunction, we're just forced to not use anything.

Right. And Dr. Busse, I know that you use a fair amount of citrate there at Emory, but it is still complicated?

Yes, it is. And this slide does not surprise me. I mean, the roadblocks or the obstacles to using citrate really have to do with safety. And so there's a lot of anxiety about this because it's so complicated to use. And obviously, with something more complicated, you can have missteps or accidents or poor titrations. And you can -- and you could be doing everything right and still have the risk of hypocalcemia or citrate toxicity. The other thing that I observed really in this slide is that a lot of the complications have to do with the administration, the fact that it's cumbersome to -- to run calcium. There are shortages. There's frequent changing of the bags. There's the cost of it. And so it's cumbersome from a health administration point of view, which really is, I think, 1 reason why a lot of centers avoid it.

Right. Right. Next slide, please.

Yes. And one -- sorry, one last thing I want to say, for calcium, just from a heart function standpoint. So another reason that we can't use it a lot in my unit is because a lot of our patients already have cardiac dysfunction and heart dysfunction. And when calcium -- the role of calcium is integral to heart function. And so even if you have relatively low levels of calcium, you can have worsening heart dysfunction just in the setting of low calcium. I mean, before you get to toxic levels of low calcium, you can have just some cardiac dysfunction. And so that's very important in my patients as well.

Right. I mean, calcium is sort of -- homeostasis is critical in these patients. And I think infusing a drug that chelates the calcium and then trying to perfectly replace that calcium back again is -- again, it's a dance that's difficult to do in these very sick patients. Next slide, please. So the next question was those -- the previous question was why do you not use citrate? Then we asked the doctors who do use citrate what proportion of their patients develop hypocalcemia. And you can see the overall was 37%. So it is not a trivial -- there's a reason why it's the #1 concern with citrate is that it is not a trivial percentage of patients who, in fact, develop this. So next slide, please. Now when not using anticoagulation, and we've talked a little bit about this earlier, of what did they see as the incidence of more frequent filter clogging. And overall, it was 84%. The increased transfusions, because again, when you clot a filter, you got all that red blood cells and platelets that are now getting caught up and the filter gets thrown away, the patient loses those, they now require transfusions. They saw that in 23% of the patients. And then regarding folks who felt that the issues were minimal or manageable when not using anticoagulation, you see the big discrepancy between nephrologists and the critical care docs who are really living in the ICU 24/7 and seeing these patients. Dr. Busse, what are your thoughts about this data that we saw?

I think this is just reflective of, I think, what we have already mentioned that no anticoagulation is the filter -- loss of a filter is a big risk with no anticoagulation. This is almost kind of a given if we're not using anticoagulation, that at some point, the filter is going to -- we're going to lose the filter prior to the natural end of life of a filter. And so we're sort of at the ready to change these filters. And I think this is reflective of that. Our patients, as I mentioned early on, are anemic at baseline, and we are really oftentimes chasing that number with transfusion. So this is not trivial either. And by the way, we treat blood transfusion just like any other medication. It's got risks and benefits as well. So if we can avoid transfusion, we like to. Now obviously, the body doesn't operate when it's really low on blood, so we transfuse if we have to. But there's a therapeutic window for transfusion as well. So if we don't have to transfuse, we don't want to. And then the difference between critical care medicine and nephrology when asked if issues are minimal and manageable, this is, I think, reflective of what I said a couple of slides ago that we, at the bedside, really see what goes wrong 24/7. And I think it's less perceived by nephrologists. It doesn't mean that the same issues don't exist there. But I think those of us at the bedside in the ICU really see a lot of stuff that goes wrong with the CRRT circuit, probably more so than gets filtered up to the nephrologist.

Right. Dr. Boldt, any additional comments?

I think Larry said it perfectly, and I agree 100%. And I think we see the downstream consequences of these filter clotting issues, like I said, like prolonged ICU length of stay, just not being able to get these patients to where we want to get them on a daily basis.

Right. Next slide, please. So now we're going to talk about the CRRT study called NEPHRO, stands for Nafamostat Efficacy in Phase III Registrational CRRT Study. Next slide. So just a general overall diagram. It's up to 10 clinical sites, and we mentioned before, Emory and UCLA are involved in this study. 166 adult patients who are requiring CRRT and who cannot tolerate heparin or at higher risk for bleeding. They will be divided equally between the Niyad arm and the placebo arm. And they only have to complete 3 days to be a completer in this study. They can use the products up to 7 days, and we will allow an extension of 10 days, in fact, if they're doing well. These are very critically ill patients, and you don't necessarily want to remove a therapy if they're doing well. The primary endpoint is actually the mean post-filter activated clotting time of the first 24 hours versus placebo. And we're using -- looking some of the clinically relevant endpoints we mentioned earlier, filter lifespan, number of filter changes, transfusions, et cetera, as secondary endpoints. Next slide, please. So the inclusion criteria, this is just some of the key ones here, for the study is 18 to 80 years of age. They need -- patients need to require CRRT or, in fact, have been started on CRRT within the past 48 hours. They can then be enrolled into this study. They can either not tolerate heparin, let's say they have a previous history of heparin-induced thrombocytopenia, for example, or they have to be at a high risk of bleeding due to any of the following. And that's any abnormal clotting time, thrombocytopenia, intracranial hemorrhage history, major surgery, poly trauma, history of gastrointestinal bleeding, history of pulmonary hemorrhage, and their baseline activated clotting time has to be below 150 seconds. Dr. Boldt, how do you feel about this inclusion criteria in our study and how many of your CRRT patients would, in fact, qualify with this inclusion criteria?

I think I'm actually very happy with this inclusion criteria. I think it's quite broad. I think that there are going to be many of my patients who qualify for this trial based off of these inclusion criteria.

Dr. Busse?

Yes, I think that this is -- this is an easily doable inclusion -- sort of inclusion criteria. In particular, a lot of my patients in the ICU have a history of GI bleeding. And so I think that inclusion right there really brings a lot of patients into this study if we can. And so I think this is a very doable set of inclusion.

Yes. We tried to cast a broad net there for our inclusion criteria. Next slide, please. And regarding the exclusion criteria, as long as they meet the inclusion criteria, we want to make sure no single one of these was onerous: patients weighing less than 50 kilos; patients can't be on systemic anticoagulation; or have a very recent intracranial hemorrhage in the past 7 days. There's a number of others here as well, severe thrombocytopenia, less than 25,000/?L; life expectancy less than a month; patients with active bleeding. Are any of these -- Dr. Busse, do you feel like any of these are real sort of limiting exclusion criteria for this trial at all? Do you see any of these really making -- being a stumbling block for enrollment?

No, I don't. And in fact, a lot of these are very common in clinical trials. So when I look at a set of exclusion criteria, you automatically -- you want to exclude folks that you're not going to learn from if you include them in the study. So folks that are going to die regardless, they're not -- that doesn't -- you're unable to differentiate endpoints. In folks that are actively bleeding or profoundly thrombocytopenic, those are folks that I think have an excessive risk of any anticoagulation. So this is a reasonable set of exclusion criteria, and nothing pops out as especially onerous.

All right. Dr. Boldt?

I would agree with Larry. I think this is a very reasonable set of exclusion criteria.

Okay. Next slide, please. So the endpoints here, these are all agreed upon with the FDA. And post-filter -- and you can see from that diagram here, we talked about all of the anticoagulants for use in CRRT are injected, in fact, into the circuit. That's why this product is actually being evaluated by the FDA as a device and not a drug. It's odd, because it is a drug, but it's being evaluated as a device because its mechanism of action is outside the patient's body and in the circuit. So we are injecting Niyad in. It goes in and anticoagulates the filter. We mentioned before, the filter filters out a lot of the Niyad, it's very sticky to the filter membrane. And then what isn't is degraded by plasma esterases in the blood with a very short half-life. We'll be measuring the post-filter activated clotting time, and that is a bedside measurement that comes back within a few minutes. So it's easy for physicians to, in fact, measure the ACT in the post-filter line, make sure it meets the target that we would like. And adjust, and we'll talk about that in a minute, the infusion rate if it is not on goal. We evaluate the ACT at 1, 4, 16 and 24 hours after the CRRT has started and compare those post-filter ACT clotting times to the placebo group. Secondary endpoints are, in fact, looking at not just the first 24 hours but the first 72 hours to make sure there's a durable effect of nafamostat on the circuit; looking at the number of filter changes due to clotting in the first 72 hours; the average filter life span in the first 72 hours; the average number of transfusions; and then the actual dialysis efficacy, which is looking at the average concentration over the first 24 hours of the blood urea nitrogen. So how do you feel about nafamostat versus placebo for this primary endpoint, Dr. Boldt?

Well, I think, like you said, I think the key here is that most of the Niyad is removed by the filter. And so what is, I think, going to be very wonderful about this drug, and this is going to be shown through these endpoints, is that Niyad does a great job of anticoagulating the CRRT circuit, but does not systemically anticoagulate the patient to any appreciable degree, thus negating the risks of having patient systemic anticoagulator with heparin or citrate, but also being able to result in higher filter lifespans and sort of avoiding a lot of those problems related with frequent filter changes. So that's what I think this will show.

Yes. And we'll be measuring ACT systemically in the patient as well as the post-filter. And hopefully, the study will show that while the filter ACT is elevated, that the patient's ACT remains at baseline. And, Dr. Busse, the primary secondary endpoints here, any additional comments?

Yes. So I think this is a good blend of endpoints, which comprise of endpoints related to the mechanistic function of nafamostat. And so we're looking at what we think it does, which is anticoagulate the filter, but we're also looking at more holistically and more patient-centered outcomes, which really obviously drive what Dr. Boldt and I do for a living. And so I think this is a nice combination of endpoints that answers the scientific question, but also I think would potentially get to some of the more meaningful endpoints that really revolve around patient care.

Yes. Yes. Next slide, please. We just have a few more slides here on the trial, and then we'll open it up to Q&A. So we have a number of exploratory endpoints in the study. And you look at the bottom, proportion of patients who died at day 14, 28. So we're definitely evaluating mortality. In the middle there, you can see proportion of subjects who are converted to intermittent hemodialysis or can discontinue the CRRT if they're doing well. So do any of these jump out at either of you as being particularly interesting for you all for this study?

Well, again, these are things that we look at as part of our routine care of a patient on CRRT, what do the platelets look like? What does the hemoglobin look like? How many filters are we changing? We look at the metrics on the CRRT machine themselves, including transmembrane pressure, and that's how we guide whether or not we are at risk of losing a filter. We obviously pay very much attention to how long our patients are in the ICU, how long they're in the hospital and those who die. So these are patient-centered relevant endpoints that we would be looking for anyway. And so I think this is a meaningful set of endpoints that are -- would, I think, will shed light on whether or not nafamostat makes a difference.

Next slide, please. Just quickly get to the -- and I'll briefly mention this. Very simple to use, Niyad versus placebo. The drug is infused into the pre-filter circuit. You measure the post-filtrate ACT. You titrate up or down based on whether it's in the range. The sweet spot we want is between 175 and 225 seconds. And anything outside of that range will either raise or decrease infusions. You're not worried about calcium infusions, you're not worried about ionized calcium drugs, and all of those hypocalcemia issues, very straightforward to infuse this drug. And so we'll move to the next slide in the interest of time. And as Dr. Busse mentioned earlier, we are evaluating the filter life, and so filter clotting, we have very specific parameters that they're supposed to evaluate to know that the filter is beginning to clot; transmembrane pressure, greater than 200 millimeters of mercury there you can see is one of the key ones; and they can continue for at least 3 days to be a completer and up to 7 to 10 days, if, in fact, they're doing well in the study. Next slide. I believe we're -- with that one, there we go, Sara, we're opening up to Q&A.

Excellent. Thank you, Dr. Palmer. [Operator Instructions] We'll kick it off with our analysts first. So the first question is going to come from Ed Arce. Apologies. The first question will come from Jim Molloy at AGP.

This is Jim Molloy from Alliance Global Partners. Doctors, thank you very much for your opinions today. I very much appreciate it. I'd love to get your thoughts on an option like Niyad coming into your treatment algorithm. Can you walk through where you anticipate a Niyad would be mostly used? I think clearly, the no anticoagulant seems to jump out in the citrate. But could you walk through potential for using it with the heparin patients as well, please?

So should Niyad become a choice for us in terms of CRRT, managing the CRRT circuit, I would foresee Niyad probably being used in lieu of citrate, just by virtue of citrate's complicated titration algorithm and complicated administration algorithm. If it were to be proven that Niyad is a regional anticoagulant like citrate is and the safety was better than citrate, I would sort of foresee Niyad really taking the place of citrate in a lot of centers. We would use heparin. We would not use Niyad and heparin together. We would use heparin in patients in whom we also want systemic anticoagulation. And there are a lot of those. I mean, a lot of patients with pulmonary embolism or clots somewhere else. And so we like to systemically anticoagulate patients who need it. And those who are on CRRT circuit that also need systemic anticoagulation, heparin is a great choice. But for those that we don't want to systemically anticoagulate or for those that there is a risk of nonregional anticoagulation, I would foresee Niyad, if it were proven to be as efficacious or more efficacious and safer than citrate, to really replace a lot of the citrate use that we see.

Well maybe I'll follow-up. Dr. Boldt, you had mentioned, I think, during your remarks -- and what Dr. Busse was just referencing, I mean, it was you, Dr. Busse, mentioned, my apologies, that there were a percentage of patients that you want heparin in the body versus percentage you don't want heparin in the body, just -- you said what percentage of patients are there that -- is it 50%, is it 10% where you want the heparin versus you absolutely don't want it, but you're using it because you have to?

That's a great question. So I think that when it comes to heparin -- so I think, as Larry mentioned to your previous question, I do think that citrate would be mostly replaced by Niyad. And certainly using Niyad versus no anticoagulants, Niyad would be 100% better because you're not having to deal with the constant filter clotting. In terms of the heparin piece of the pie, I think that there are -- of the patients that I use heparin in, I would say, 2/3 of them are patients where, if I had the choice of anticoagulating just the CRRT circuit regionally with citrates and then using something a little more gentle for the systemic anticoagulation piece as far as like what we call prophylaxis from clotting. So we can do with [ code ] clotting for prophylaxis patients that are prone to systemic clotting with much lower doses of heparin, that's not necessarily systemic. And so that level of heparin would not be considered systemic anticoagulation and doesn't do anything to help with the CRRT circuit. So a lot of times, I'm forced to use heparin systemically in patients who are both clotting the circuit and at risk of clotting, where, if they were not on CRRT, I would be using a much, much lower dose of heparin just to prevent blood clots in the patient without having to address the circuit. So I think, as I said, probably about 2/3 of the patients that I use heparin in to be managed with a Niyad regionally for the CRRT and then just a very, very low dose of heparin, which is not necessarily prone to all the other side effects that we worry about with heparin.

So Jim, I'll also add on that this is a very real scenario. I mean, last week, I had 2 patients that are still there in my ICU, both of which were on CRRT, both of which were getting systemic heparin and both of which developed GI bleed. And so we ended up having to stop heparin use and continue CRRT with no anticoagulation. So not only is it a real scenario, but it also changes throughout a patient's stay with us. So they can certainly need or we may desire a heparin drip at the beginning of their stay, but then something happens or vice versa. And just to sort of give a little bit more data to David's comments, I would say probably about 1/2 of my patients want some sort of systemic anticoagulation. And this is 1/2 of my CRRT patients. And then the other 1/2, I'll want something regional or no anticoagulation.

Great. And maybe a follow-up. How sort of price-sensitive are -- do you see your colleagues in the space if branded Niyad comes in versus these generic drugs have been there for a while? How quickly do you see an adoption in this space, given what -- again, I assume the benefits hold out in the trial, the clear benefits you seem to see in Niyad?

So that's a what-if question. And I will say, if this study shows that Niyad is safer and more efficacious, hands down, than citrate, I think we will be very price insensitive. I think at least at my center, we adopt something if it shows a better safety profile or a better efficacy profile. If the data is equivocal, we are much more price sensitive. So I mean, that's the best way I can answer that is that we are driven primarily by safety and efficacy at my center, I think most centers. And so if the data shows that it's better in all respects, then we would probably adopt it without any roadblocks.

Yes. I want to -- I agree with Larry. I think at UCLA, we are also very safety and efficacy-driven. And so if those things are clearly demonstrated, then price becomes much less of a concern.

Okay. Maybe my last question for me, then I'll pass it over, I'll get back in the queue. Can you walk through sort of the biggest -- what are the potential concerns you see with the Niyad that you're keeping an eye on, you're waiting to see how the data looks? And then are there any other anticoagulants in development that -- do you see that look interesting as well?

No, I'm not aware of any anticoagulants that are currently being studied that would have the efficacy and safety profile that we're looking for here in terms of a regional anticoagulant for the CRRT circuit. I don't know if you're aware of anything, but I'm certainly not.

I don't know of any other regional anticoagulants that are being looked at. There are other systemic anticoagulants. But they would have the same issues as heparin with some nuanced differences. Excuse me, I have a little bit of a chest cold. In terms of what I'd be looking for in terms of safety, I've never used the product. I know that they've used it in Japan and Korea. And the safety profile is what I know from that extensive use, which is that it's pretty safe. There are some risks that are highlighted in the literature that are very low. Probably the one thing that I'd look for that I'd be most sensitive about would be a hypersensitivity reaction, which looks like in the literature, it occurs at around 0.25 of 1%. So pretty low risk but of all the risks, that's probably the one that's most important.

Yes, I agree. And I think with any new medication, you're looking at potential allergic reactions or sort of hypersensitivity reactions as a potential side effect, but something that has less than 1% of that is quite low. And I think that Larry said, as I said, the very encouraging thing about this medication as far as from a safety profile is that you have 30 years of experience in Asia using this medication. And so you've got what I see as a pretty well established safety profile from an international standpoint already going into this trial, which is pretty big.

Thank you for the questions, Jim. I think we have a question now from Ed Arce from H.C. Wainwright.

Great. Okay. Sorry about before, we got a bit of an unstable Internet connection here. So a few questions for me. I wanted to start with just getting a baseline for the administration of Niyad. How often -- and I guess this is more likely a question for Dr. Palmer, how often would you put a new Niyad 2, I guess, in a typical day, over treatment? And during the changes, is that a very short period of no anticoagulation every time you change that?

Yes. So it's a continuous infusion. So in the study, we're using a 250-milliliter bag of nafamostat. When it's used clinically after approval, they could use a larger bag. It depends on the rate and how sensitive the patient is and what their ACT is. So a bag could last 5 to 10 hours, but they would not stop the infusion until the new bag was there. So it's really a continuous -- there's no time when they're off anticoagulation. They just turn off one bag and pop the other one right on.

Okay. Understood. And then there was reference in some of the discussion earlier about sort of the standard or perhaps expected life of a CRRT filter. I'm just wondering, how much shorter is it than that life when you're using heparin or citrate?

So our standard filter life is 72 hours. The shorter filter lives really depend on the clotting risk. And it can be as short as, you start the [ thin ], and 20 minutes later, it's clotted. And so it could really be anywhere from a life of 0 up to a life of 72 hours. And so it's hard to sort of say what the average -- how much shorter on average a filter is, it really is a patient-specific thing. With anticoagulation, we can typically get to our filter life. It's not a guarantee, and we can certainly clot and lose a filter even with heparin, even with citrate. But I would say, usually, with anticoagulation, we can get to the end of the filter life. And without anticoagulation, it could be, as I mentioned, anywhere from 0 to the filter life. It's quite variable without anticoagulation.

Yes. And I think that the meta analysis paper that was presented or the data which was presented that showed one of the things that was seen was about, on average, about 10.5 hours longer filter life with the use of Niyad. And so that 10.5 hours, I mean, it's almost 1/2 a day. That's -- that can be very significant in a critically ill patient. With each filter change is subject to some of the sort of downstream consequences of that, which is time off of dialysis, which can be very significant for these patients in terms of fluid retention, in terms of electrolyte abnormalities or acid-based abnormalities, which in these patients, they can be very sensitive to because they're already critically ill. So just alterations in electrolytes and acid base can have a huge difference in their clinical picture as well as the risks associated with transfusions like what was alluded to as well as some of the difficulties with sometimes obtaining blood products. Blood products are a scarce resource and are treated as such. And so I think, 10.5 hours, if you look at that data from that large meta-analysis, is pretty significant.

That's helpful. And then perhaps one last question and then set it up with a statement just for management to confirm here with regard to the NEPHRO CRRT study. As I understand it, for those patients that are on for the 4 or 5 days or perhaps the full 7 days, the goal is to titrate or maintain their ACT between 175 and 225. And then the primary endpoint post-filter measured at 1, 4, 16 and 24 hours. That mean, is that expected to be significantly higher? And I guess the more important question I had was, if we have -- given all the prior studies and the real-world data in both Asia and Europe, do we have any sort of benchmarks or analogs that could help us predict what that might be?

Well, I will say that the clinical studies that have used nafamostat over in Japan and Korea and evaluated ACT show that the drug ranges that we're infusing absolutely result in a post-filter ACT that is in the 200-plus range. Remember, they can only get into the study if their baseline ACT, their systemic baseline ACT is less than 150. So the group that's getting placebo, there's no reason for their ACT to change. So what we're hoping to see is 1/2 the patients continue their ACT at less than 150. And then the group that's actually on the nafamostat will have elevated ACTs, as they've seen historically in the literature that get into the 200 range. And so the 166 patients is definitely powered to see that effect size in this primary endpoint.

Thank you for the questions, Ed. I'll now turn the call over to Raffi Asadorian for some questions that came in over the webcast. Please go ahead, Raffi.

Thank you, Sara. Yes, we've got a lot of questions, but I think in the interest of time, we've already run over about 15 minutes, but we'll take one here for our guests. The question is, what would the process at your hospital be to bring nafamostat onto formulary? Meaning, would you need a full P&T committee? And do you see any major hurdles, assuming the endpoints are achieved, to getting the product on formulary?

Yes, it would have to go through P&T formally. At Emory, that's not a particularly onerous process, especially if the drug is shown to be safe and efficacious. That's usually not an issue. Where my hospital system tends to push back is in drugs that are pricey without really demonstrable benefit over the current standard. And so I think if the endpoints are met on this study, I think that will have shown a demonstrable benefit over alternatives. So I would not envision an obstacle there. But yes, full P&T approval.

Yes. I would say exactly the same goes for our hospital here at UCLA, I think exactly the same as Larry said. It definitely would have to go through P&T. But if safety and efficacy of the drug are clearly shown in the trial, I don't think there'll be any hurdles getting it through.

Okay. Thank you. We've got to -- we're already over time.

Yes, I think we're over. And you know what? It's 9:18, but I -- this has been an incredible session, Dr. Boldt, Dr. Busse. Thank you so much, very educational. I know I learned a lot just hearing from your particular experiences, and I'm sure the analysts appreciate your time as well. So we'll wrap it up now Sarah. Again, thanks both of you.

Thank you, Dr. Palmer.

Thank you.

This concludes…

Thank you. My pleasure.

Thanks, everyone. You may go ahead and disconnect your lines.