CorMedix Inc. (CRMD) Earnings Call Transcript & Summary

Greetings, and welcome to antimicrobial resistance, catheter-related blood stream infections and the potential for Neutrolin, hosted by CorMedix conference call. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Dr. Paul Chew, Chief Medical Officer from CorMedix. Mr. Chew, you may begin.

Good morning, and good afternoon, everyone. Welcome to the CorMedix webinar antimicrobial resistance, catheter-related bloodstream infections and the potential for Neutrolin. Please read the forward-looking statement slide when you have a chance. COVID-19 is a global pandemic that's focusing everyone on the need for disease prevention, but there's a group, a vulnerable group, that faces life-threatening infection every day. Patients with chronic hemodialysis catheters face the risk of catheter infection, hospitalization and even premature death from sepsis and its complications. On this slide, the National Health Safety Network at CDC conducts a monthly surveillance of U.S. hemodialysis clinics. As you can see that the bloodstream infections, or BSIs, are essentially an issue of patients with CVC, or central venous catheters, who have rates that are 5 to 7x higher than arteriovenous fistulas, or AV grafts, in this very lopsided bar graph. This is all the more surprising given that catheter patients represent only 20% of hemodialysis patients. The NHSN has also published on the fact that hemodialysis bloodstream infections are significantly underreported by nearly 40% to 50%. In other words, we know that the unreported cases would make it even worse. Today, we'll be talking about antimicrobial resistance, catheter-related bloodstream infections and the potential for Neutrolin to help these hemodialysis patients with central venous catheters. And to do it, we have a group of distinguished experts in the field. I want to note that FDA has granted conditional approval for the brand name that the CorMedix catheter lock solution will have in the U.S., DEFENCATH, D as in David, E-F-E-N-C-A-T-H. This is in contrast to the Neutrolin brand name, which will be retained outside the U.S. where the product has been CE-marked as a medical device. For this webinar, however, we will still refer to the product as Neutrolin since this brand name is most closely associated with the LOCK-IT-100 trial. The webinar agenda is shown in figure 4. Our first speaker, Dr. Bruce Polsky, is Associate Dean of Faculty, Professor and Chairman of Medicine at the NYU Long Island School of Medicine and NYU Winthrop Hospital. Dr. Polsky is a consultant to CorMedix. Our second speaker, Dr. Nelson Kopyt, is Chief of Nephrology at the Lehigh Valley Health Network, which has 15 dialysis clinics. He's also Director of Research at the Northeast Clinical Research Center. Dr. Kopyt was an investigator in the LOCK-IT-100 trial. Our third and final speaker, Dr. Reidenberg, is adjunct Assistant Professor of Medicine and Pharmacology at Weill Cornell Medicine and Assistant Clinical Professor of Pediatrics at Mount Sinai's Icahn School of Medicine. Dr. Reidenberg is a consultant to CorMedix. Today's agenda will feature the 3 presentations, as shown. Q&A on these medical topics will follow the last presentation. Dr. Polsky?

Thank you very much, Dr. Chew, and it's a pleasure to have been invited to join this session. I'm going to talk about antimicrobial resistance, biofilm and the relation to catheter-related bloodstream infections. I think it's no secret to those who follow the news, let alone follow closely the space, that antimicrobial resistance has increased the number and severity of infections and also has had a significant impact on health care costs. We know that with use, and even with use shortly after introduction, that all of the antimicrobial agents we have, have generated resistance at some level or another. And this leaves patients with fewer options and, in many cases, more expensive treatment options and increased morbidity and mortality. The economic impact is significant. 2 million patients in the United States become ill with these resistant infections, resulting in over 20,000 deaths with a cost that is in the many thousands of dollars. For example, methicillin-resistant staph aureus, which is the most garden-variety resistant organism you can get, costs more than $18,000 a case. So this is a big imperative for us in medicine. The drivers have been improper human use. I think a lot has been publicized about the use of antibiotics in -- just because, in other words, without a good justification, using broad-spectrum agents when more focused agents would do. And then, of course, the people who have multiple exposures to antibiotics over time may increase the risk of antimicrobial resistance. Also, the use of antibiotics in feed, in animal feed, they're often the same antibiotics used in humans, particularly tetracyclines and fluoroquinolones, in order to promote growth in these animals and rapid growth so that the farmers can bring these animals to market more rapidly. However, once these antibiotics are in the food chain, they have an impact then on humans. And the more antibiotic resistance you get, you have the more antibiotic resistance you're going to get. So poor hospital infection control allows this spread to other patients, not in my hospital, though. Even last-resort antibiotics have lost a lot of their power, a lot of their umph. And antibiotic microbial-resistant genes may move, maybe transferred from bacteria to bacteria even across species, which is another particular problem. And this has been recognized by the World Health Organization and by other international agencies, and it's imperative that action be taken. Antimicrobial resistance and nightmare bacteria, so super bugs, nightmare bacteria, whatever you want to call them, this has been well recognized by public health agencies around the world, and this comes from the CDC. You see here, it's basically a vicious cycle of individuals being colonized or being infected with these bacteria that can be transmitted then in the health care setting. Animals, I already mentioned, can then become colonized with these organisms through the means I said. And then these organisms may spread in the environment. So the cycle just perpetuates in this way. This is a cartoon showing several mechanisms that confer antimicrobial resistance in bacteria, for instance. And as you can see, I'm not going to go through this in great detail, but the point is that there are different multiple mechanisms through which bacteria may become resistant to antibiotics. And you -- a particular bacteria can possess 1 or several of these mechanisms in 1 organism, which makes them even more resistant. So extreme resistance can occur over time. And I should say that makes resistance even more difficult to fight because you may think you have a new agent that is resistant, if you will, to the effects of one of these mechanisms, but then another one of these mechanisms may come into play. Now moving on to biofilm. What are biofilms? So biofilms are a complex community of bacteria that live within a matrix of exopolysaccharides, sometimes referred to inelegantly as slime, which adhere to surfaces, particularly to prosthetic surfaces or artificial surfaces. And well, a hemodialysis catheter would be such an item where you have -- it's a foreign body with a synthetic surface to which this biofilm can adhere. And this results in a barrier to antibiotic penetration, this biofilm, and it increases bacterial tolerance and resistance to eradication. So you can imagine these bacteria live within this biofilm, which makes them very difficult to get to. So then you have a catheter that's then colonized, if you will, virtually permanently with these microorganisms. And this is a representation of one of the early microbiologists, the inventor of the microscope, van Leeuwenhoek, who, among other things, scrapped his teeth in the plaque that he got off, was able to observe bacteria in this plaque, biofilm, whatever you want to call it, and made drawings of it. And here it is now in more modern day representation, even electron microscopy. So how does this link in to catheter-related bloodstream infections? So you can see in this cartoon, you have the catheter surface, and you have the normally free-floating bacteria, which will be cleared by antibiotics, white cells, antibodies in the blood, but now bring in biofilm, if you will, in the second panel from the bottom, and you can see then how bacteria can be attracted then to these biofilms that are adherent to the catheter surface, and then they resist antibiotics, antibodies and even white blood cells. So you can never fully penetrate the biofilm, and you will always have then a colonized situation. In other words, bacteria will be present, and these bacteria then can come off of this biofilm as they increase in number and result in bacteremia, and that's what we would call a catheter-related blood stream infection, which then can become systemic, go through the bloodstream and seed distant organs, such as the heart, bone, brain and lung, which is quite serious. So about 80% of these -- of the microbial infections we see are biofilm associated, and typically due to implanted devices. So catheters aren't the only thing. We're talking about catheters today. But if you think of total joint replacements, for example, they are also subject to this kind of biofilm situation. And all of these conditions are found in the end-stage kidney disease patient, so they're kind of the mean common pathway for a lot of these types of infections that you -- that are biofilm-associated that you want to avoid. Biofilms, as I've said before, protect the microbes. They form a sanctuary, if you will, for the microbes, and you virtually can never get rid of them. And in fact, the antibiotics are eliminated or kicked out. The antibiotics -- the bacteria develop these methods to kick the antibiotic out when it sees the antibiotics, so increasing resistance even more. And then we know that biofilm bacteria, because they are constantly exposed to antibiotics when these patients get infection, even though they stay in the biofilm, they may even become many fold, 500 to 5,000x more antibiotic-tolerant. So you can see here, this is from a paper in science 27 years ago, which is basically showing the types of human infections involving biofilms. There's van Leeuwenhoek's dental situation right at the top. And then in the nosocomial setting toward the bottom, and you see we have Hickman catheters and central venous catheters boxed out. And so these have been appreciated for some time as a source of biofilm-associated infections and staphylococci, fungi, a variety of microorganisms are implicated. And this is what I was talking about before. This is a very nice representation by electron microscopy of these bacteria that are in this biofilm, adherent. And if you will, it's almost like a -- so they're in there like glue. So this shows bacteria introduced from the catheter -- in the catheter, attached, adherent. And then as the number of organisms increase and the biofilm matures, there is the opportunity for detachment of bacteria from the lumen of the catheter, from this biofilm, and some of these bacteria will then go out from their sanctuary. And then you have a bacteremia, and if you have a catheter, we call it a catheter-related bloodstream infection. The patients in hemodialysis with the catheter are 7x more likely to develop a vascular access-related infection than those with an AV fistula, and that's very important. The symptoms may be severe and life-threatening. The majority of the patients have fever and chills. And you can see here that a not insignificant number, 25%, will have hemodynamic instability, even shock in some cases, with end organ dysfunction, mental status, GI, et cetera, and much higher than with the exit-site/tunnel infection. Here are the dire consequences, 2 of them, in patients who develop a bacteremia related to a catheter. And you can see on the left is septic cerebral emboli. This is an MRI representation of emboli causing these abscesses in the brain. So these are infection within the brain. And then bacterial endocarditis. So this depicts the heart valve with bacteria on it. And from there, not only is bacterial endocarditis is bad enough, but you may get bacterial emboli shooting off and affecting other organs. So this is really a big deal. Well, catheter lock solutions have been attempted in the past. And one that was used and was citrate as a catheter lock solution seemed effective at very high concentrations, but there were adverse events, such as hypocalcemia at dangerous levels and causing ventricular arrhythmias and even death in some cases. So the FDA recommended against the use of this methodology now 20 years ago. So -- and then others such as aminoglycoside antibiotics within a catheter lock solution is -- these are not routinely recommended. And most experts would certainly not recommend them because we're here today talking about antimicrobial resistance, and what better way to have a catheter lock solution that is a -- one of your major classes of antibiotics. So at the end of the day, at the moment, we have no approved catheter lock solution in the United States to prevent catheter-related bloodstream infections. And that's where Dr. Nelson Kopyt comes in to talk about this condition from the nephrologist's perspective.

Let me initiate this discussion with a description and a review of what end-stage kidney disease, which I will term as ESKD. ESKD story actually started in the 1960s when we started to have the advent and availability of dialysis as a mode of therapy for this disease, which prior to that was fatal. Resources and the cost of this therapy was quite high, and at that time, actually, ESKD was felt to be an orphan disease and, with the direction of the government, came under the auspices of Medicare. As you can see in this slide on the left-hand graph, we have the incidence of new starts of dialysis in the blue bars, and the prevalent population of dialysis in the red bars from 1980 to 2014. And we can see that by 1980, there was already approximately 70,000 prevalent patients on dialysis, which increased exponentially over the next 20 years and continue to increase, so that in 2016, on the right-hand side of this graph, we now have around 700,000 prevalent patients, of which 500,000 are on dialysis. You have to understand that now we have a population of 500,000 patients on dialysis that are under the care of the Medicare system, which accounts for about 1% of the Medicare population that is actually utilizing 7% of the Medicare dollars, which is to the tune of approximately $35 billion to $45 billion a year. On average, a typical cost of a dialysis patient per year is about $80,000 to $100,000 per year. The right-hand side of this graph depicts the 4 most common etiologies of patients developing end-stage kidney disease, with the top 2 being diabetes as the primary cause and hypertension; followed by glomerulonephritis in purple; and then cystic disease of, which autosomal-dominant polycystic kidney disease is the most common cause. In our next slide, we can see that in the 1960s, as dialysis became prevalent, we now had a modality of therapy for those patients with progressive chronic kidney disease, once -- of which, there are 5 stages. Once they progress to stage 4, which is considered when a kidney function, or GFR, is less than 30%, there is an inexorable progression of loss of function of the kidney with a progressive problem with maintaining electrolyte balance, fluid balance and then, eventually, the removal of toxins that accumulate that the kidney is responsible for removing to the point when the kidney function falls below 10%, we start to manifest signs and symptoms of kidney poisoning called uremia. If nothing is done to circumvent those issues, these patients will then have a mortal event from their progressive uremia. Fortunately, we have this therapy called dialysis in which we require an access to the blood compartment. Typically, 80% of the patients starting dialysis even today are started with a catheter that's inserted into one of the central veins, primarily the internal jugular venous -- internal jugular vein with a pump then circulating the blood out of the catheter through a filter, which then filters out the excess toxin, maintains electrolyte balance and returns the blood volume to its normal state. And then the good, clean blood leaves this filter or dialyzer and then returns to the patient typically through the same catheter or through a fistula or graft that's in the arm of these patients in which 2 needles are inserted for the blood to be taken out of the body through the dialyzer and then return to the body. This catheter has been a godsend with regard to the ability for us to access this system, and I'll talk more about that in detail in the next slide. Dialysis -- could we go back? Dialysis performed optimally, which is 3 times a week in a 4- to 5-hour session, typically in clinics with 15 to up to 30, 35 patients or even 50 patients in the setting, may be 3 shifts a day on a Monday, Wednesday, Friday or Tuesday, Thursday, Saturday shift, and only restore the equivalent of 10% of normal kidney function. That's it. Hemodialysis is a very resource-intensive procedure requiring a significant team, including a nephrologist, a nurse, technicians, engineers, case managers and dietitians that are constantly monitoring these patients and adjusting the parameters in order to provide optimal therapy for these patients. As I mentioned, the catheter, which was basically developed by Dr. Hickman in the '60s was a godsend for us. Prior to that, we had no real good way to access the blood compartment other than an external shunt that was called the Scribner shunt between the radial artery and the vein. The catheters can be inserted percutaneously through the skin and then through a tunnel, entering into the internal jugular vein in the neck and going into the main vein coming out of the heart through the superior vena cava, and the tip of the catheter commonly lies within superior vena cava or in the right atrium of the heart, literally centimeters away from one of the valves, the mitral valve. There are 2 types of catheters. There's a temporary catheter, which we insert in acute settings or in settings where we can't have a tunneled catheter. These catheters can only be maintained for about 7 to 14 days because of the tremendous increase in risk of infection. In order to circumvent that, the cuff was developed as part of the catheter system, and it creates a barrier through a fibrotic inflammatory reaction underneath the skin that then prevents the migration of bacteria from the skin through the tunnel and into the vascular system, creating these infections. These catheters were godsend. However, they also have major problems associated with them. As I mentioned, 80% of our new starts start with a hemodialysis catheter. And after 90 days, still, about 2/3 of them have a catheter; and after a year, still, about 18% of them have a catheter. These catheters, as Dr. Polsky has mentioned, are associated with a significant increased risk, roughly a 53% increased risk of all-cause mortality due to threefold increased risk for fatal and nonfatal infections and a 68% risk of hospitalization compared to patients with a fistula. These risks are real. And even though the numbers may seem small with regard to the incidence of these infections and the CDC typically reports them as number of events per 100 patient months on hemodialysis, on average, roughly we see 2 bloodstream infections per 100 patient months on dialysis. And for example, in our population, we would have about 150 patients with catheters, so that we would then see roughly 2 of these infections per month as well as -- equivalent to 24 infections per year, which is quite costly, both from a morbidity, mortality as well as a cost standpoint in the care of these patients. CDC was very concerned about that and developed a core intervention program for the circumvention of bloodstream infections in our hemodialysis facilities. As you can see here, this is a rather comprehensive list of hygienic factors that are -- come into play with regard to the interventions. But also with regard to significant education of the staff and continuous monitoring of their competency to make sure that they are following these procedures. And also a significant component with regard to patient education and engagement in order to try to encourage these patients to participate in reducing the burden of these catheters as much as possible and limiting the risk of the -- that is associated with this problem such that -- but roughly 28% of nearly all the infections affecting our end-stage kidney disease population as -- related to these vascular access infections. Just to review again, the potential routes of these catheter infections are basically twofold. On the left-hand 2 upper rectangles, we can see what we call the acute infections, which are predominantly related to either a contaminated device, which is quite rare, or due to skin organisms that traverse through the entry of the catheter into the subcutaneous tissue through the skin, which then goes through the skin and then in to the vascular system in the vein. This occurs typically within the first 2 weeks to 3 weeks of insertion of the catheter. And that is why in those patients who can -- start therapy for the first time with a temporary catheter or, for some reason, cannot get a long-term chronic catheter have to then have their temporary catheters exchanged every 7 to 14 days. In order to circumvent this initial problem, we then developed a catheter with a cuff, this white rectangle that appears here underneath the skin, which results in the creation of a fibrotic reaction and inflammatory process that causes a barrier to the entrance of bacteria through the skin into the tunnel and then eventually infecting the glycocalyx and the bloodstream so that after 2 weeks of this catheter being started with the cuff, we don't see these acute infections and we end up with the chronic infections, which are the right-sided 2 upper rectangles. These are also related to either extrinsic sources for the infection, which is from the health care workers. And utilizing the steps that were outlined by the CDC, we've tried to minimize that. Also, the major culprit remains the endogenous flora from the skin. And very rarely, it could be through contaminated infusion of fluid medication through the catheter. Remember that these catheters are accessed 3 times a week every week for years that these patients are on dialysis and have a catheter so that there is a significant exposure to the possibility of an infection. And besides this increased risk that you've heard Dr. Polsky mention and the terrible metastatic complications with metastatic infections from these -- primarily the biofilm becoming infected, you have to understand that once that biofilm becomes infected and these patients are hooked up to the dialysis machine, the blood is traversing these catheters at a rate of about 350 to 450 milliliters per minute. That tremendous amount of blood going through the catheter, not uncommonly, will then cause some of these bacteria from the biofilm to then break free. And it's -- I've seen it happen where patients come into the clinic, into my clinic, completely fine, normal, looking terrific, sit down, start their treatment, within an hour to 1.5 hours into the treatment, within the blink of an eye, they develop tremendous chills, teeth-chattering rigors. They look very toxic, become diaphoretic, spike temperatures to 102, 103, 104, and very quickly look very sick. They then get cultured, we give them antibiotics. And as soon as they come off dialysis, a number of these patients improve and go home with the understanding and the instructions that they must go to the emergency room if they become febrile again. A number of these patients, however, do not get better, remain toxic, emergency medical services have to be called, and they end up going to the emergency room. So those unfortunate few that do develop metastatic infections, such as an endocarditis, then end up having to go to surgery, have a valve replaced, end up on rehab for 2 to 3 months, become severely debilitated, and finally, come back out of the hospital, unless they've had a mortal event, and end up coming back to dialysis. So from my perspective, this is a real issue. As you've heard from Dr. Polsky, problem is that despite the efforts made by CDC and what we've been doing in the clinics, we still have this incidence, and we don't have any catheter lock devices that have become successful. So when I heard about the catheter LOCK-IT-100 study and the possible impact this could have, I became quite excited about it and the opportunity for my patients. So that is the major reason why I participated in this study. So with that introduction and review, I'll then turn it back over to Dr. Chew.

Yes. Thank you. Thank you, Nelson. That was quite an overview.

You have obviously lots of experience with hemodialysis patients, tell us about the Lehigh Valley Health Network. How big is it?

So we're located in Southeast Pennsylvania. Our network encompasses about a 30-mile radius with a catchment area, believe it or not, of about 2 million patients. We're in the third largest populated area of Pennsylvania. Our network has 15 hemodialysis clinics. We're with one of the large LDOs, the Fresenius system. Our practice, which is 26 nephrologists, has 1,000 hemodialysis patients, with about 25 home hemodialysis patients and 130 peritoneal dialysis patients. I am the Chief of Nephrology of the Network as well as the Medical Director of 2 of our clinics.

Well, after hearing Dr. Polsky and yourself, why in the world would patients get a catheter or keep a catheter? Why wouldn't they all have AV fistulas?

We would love everyone to have an AV fistula or an AV graft, preferably an AV fistula. However, that is not possible. Even though we've had the advent of the fistula-first initiative, USRDS data has demonstrated that there is still a large number of hemodialysis patients who start dialysis with a -- with a tunnel hemodialysis catheter. Actually, 1/3 of our patients with a fistula in place, when starting hemodialysis, still require a tunnel hemodialysis catheter for a number of reasons, including an immature fistula, the fistula is too fragile, other technical problems. And despite this, we still have 80% of our patients initiating dialysis with a tunneled catheter. And as I mentioned, 2/3 are still having a catheter at 90 days and 18% at 1 year. Also, believe it or not, despite our education and our best efforts, some patients still refuse catheter removal, even though they have a functioning fistula. Other reasons include -- for chronic catheters include patient preference, elderly patients with inadequate anatomy, failed attempts at fistulas or grafts, the fact that they may have heart failure or cardiac valvular disease that is common in our elderly population. The estimated catheter population in our clinic still [ remains ] 15% of the prevalent population.

Well, this is such a big problem. What efforts does your hospital have in terms of surveillance? You've told us about the CDC. How do you track it on a hospital or health network level?

Well, obviously, this is a very important problem, and what we do is we utilize 2 things. Number one, our network does monitor and track and surveil these infections and resistance on a monthly basis and send out an antibiogram, which we, as clinicians, then utilize to optimize our treatment of these infections when they occur. Second thing is that at the clinic standpoint, as a medical director, we have a monthly Quality Assurance Committee meeting at which time we look at all of our infections that occur in the clinic, which are then basically divided into those that are vascular access and nonvascular access related and those that are catheter-related. And we then report them as a events per 100 patient months, and we then report them to our network, who then reports them to the -- to Medicare and CMS. And this also is utilized for SWOT analysis when we see an uptick above 2 events per 100 patient months in order to try to circumvent this and improve it. So this is a quality issue that's ongoing all the time. It also has an impact from the Medicare standpoint and from the payment standpoint for the clinics in that this also can be taken into consideration with the percentage at which we receive reimbursement at the clinic.

Thanks, Nelson. I mean, clearly, there's a huge patient impact, there's a huge impact on the quality metrics and on the system as a whole.

So with this, we're going to move on to Bruce Reidenberg. Bruce?

Thank you. I get the pleasure of talking about taurolidine, and I want to start with the laboratory studies. Taurolidine is the active ingredient in DEFENCATH, also known as Neutrolin, and it may add to a novel mechanism where its breakdown product methylol causes irreversible injury to microbial cell walls, and it also injures the membrane protein responsible for bacterial adhesion. Taurolidine has had no evidence of resistance when tested in the laboratory across a broad range of bacteria, both gram-negative and gram-positive, as well as fungi, which is extremely unusual. Most of the antimicrobials we're used to are very specific to bacteria or fungi, taurolidine has microbicidal activity against each of the ones listed. Very interesting from the point of view of dialysis, the vancomycin-resistant enterococci and oxacillin-resistant staphylococci are a horrific problem with high mortality, and both of those are inhibited by taurolidine. And the candida albicans a fungus, which is not inhibited by any antibacterial, is killed by taurolidine. And candida auris, which is genetically not susceptible to fluconazole and several other antifungals, is killed by taurolidine. In addition, taurolidine inhibits biofilm formation in hemodialysis catheters. And I want to show you a picture of that. On the left is the surface of a catheter taken from a patient, and that catheter was maintained with a heparin lock solution so that it did not clot, and it did not clot. But as you can see, it is covered with microcolonies of bacteria encased in biofilm. If you look at the catheter that was in place in a different person that was maintained with taurolidine citrate for 5 months, you can see that there isn't the biofilm with microcolonies of bacteria in it. So what about Neutrolin, or as it will be known in the U.S. DEFENCATH? It's a proprietary solution, and it contains heparin, which is the current standard of care; it contains taurolidine, which is the antimicrobial with broad spectrum of activity; and it contains citrate, in this particular case as a PH buffer, not as a calcium calculator. And this is the catheter lock solution, and it's used to fill the catheter lumens when they're not in use in between dialysis sessions. And it is not approved in the United States yet. So what study has CorMedix done to look for approval? It's the Phase III LOCK-IT-100 study, and this was an elegantly designed study. It's a Phase III multicenter, double-blind, randomized, active control study using the standard-of-care heparin as the active control. It was an event-driven study. It was designed to go until 56 catheter-related bloodstream infections were observed. At 28th catheter-related bloodstream infection, an interim analysis was done, and I'll talk about those results in a moment. The objective was to demonstrate the efficacy and safety of Neutrolin as a catheter lock solution for the prevention of catheter-related bloodstream infections and to look at the incidence of treatment-emergent adverse events compared to heparin, which was, as I said, the standard of care. The end point was the time to occurrence of a catheter-related blood stream infection, and the treatment effect is the minimum of 55% versus the control arm, which is what we were guessing was going to happen. Key adverse events looking -- that we were looking for were catheter patency and the need for catheter removal. Now interestingly, what happened is at the interim observations of 28 infections, the Data Safety and Monitoring Board determined that the data was so competitive that the study should not continue because the significance had been demonstrated that Neutrolin decreased the rate of infection, and therefore, the placebo arm, the standard care arm was no longer appropriate. So we achieved the goal to reduce -- produce a significant reduction in infection compared to standard care of heparin. Then the final analysis was when all the data was brought in, since the previous one was just the interim. And I'll show you that in detail. So the top line efficacy, the left column is the interim analysis. The total number of catheter-related bloodstream infections was the prespecified 28; the total number of subjects, 673; and Neutrolin reduced the rate of infection by 72%. For those who follow the literature, the infection rate of the heparin was 0.491 events per 1,000 patient -- catheter days, which is about 2.7 years, and the standard in the literature is about 0.5. So that was right on what standard care is. And compared to that, Neutrolin produced 0.136 infections per 1,000 catheter days, and that was statistically significantly different. This is not an effort by chance. The full study had a total data of 41 catheter-related bloodstream infections among 795 patients. The Neutrolin reduction was 71%. So you can see with the full data, there's no difference. And the event rate was 0.133, and it was statistically significantly different from heparin, as previously seen in the interim analysis. What about the secondary endpoints, loss of catheter patency? The event rate was 0.99 for Neutrolin and 0.74 for the heparin, but that was not statistically significantly different and most likely due to chance. That's what the p equals 0.12 means. Similarly, for catheter removal, the event rate in Neutrolin was 3.48 and for the control arm is 3.23, but that also was not statistically significantly different. The serious adverse events and the mortality on the 2 arms was not different, and I'll move along with that. Dr. Chew, do you want to give the takeaway?

Yes. Thank you. Thank you, Bruce. Well, as you've heard this morning, the key takeaways are that AMR is a significant public health problem. A lot of it stems from overuse and inappropriate use. Taurolidine has in vitro efficacy against a wide range of microbes and no reported resistance in vitro probably because of its mechanism of action through the methylol derivatives directly on the cell wall. Well, to help reduce antimicrobial resistance, we should prevent infections and the use of antibiotics and the need for antibiotics. So hemodialysis catheters patients are highly vulnerable and would benefit from a catheter lock solution that prevents CRBSI, as would society as a whole, by preventing the inappropriate use of antibiotics. But the bacteria have a secret weapon, which is catheter biofilm. Biofilm is impervious to antibiotics. It increases the risk of CRBSI because of resident bacteria. Taurolidine has been shown to greatly reduce biofilm formation. So now we have no in vitro resistance, wide efficacy and a reduced biofilm formation in these catheters. As you've heard, CRBSI may lead to significant hospitalization, sepsis, ICU, metastatic infection and death, and we briefly touched on the high points of the LOCK-IT-100 trial. It's a landmark study in end-stage renal disease, reduced CRBSIs in a double-blind, randomized trial, the gold standard of trials, with a 71% reduction with comparable safety and comparable rates of serious adverse events. And I should say, we haven't mentioned it, but these potential CRBSIs were reviewed independently by an external group that was blinded to treatment. So it's the highest standard you can have for the conduct of a clinical trial. So finally, Neutrolin is an investigational catheter lock solution in the U.S. that contains taurolidine, heparin and citrate buffer designed to prevent CRBSI and have antithrombotic activity. So with that, operator, I think we have some time for some questions.

[Operator Instructions] Our first question comes from the line of Raghuram Selvaraju from H.C. Wainwright.

This is Blair Cohen on for Ram. Just a couple of questions for you. What do you consider to be the most troublesome and recalcitrant pathogens associated with CRBSIs?

Well, there are a wide range of bacteria, they're all listed by the CDC. They include gram-positive and gram-negative organisms, staph aureus, staph epidermidis, pseudomonas, klebsiella. There's a long list, and a lot of these are biofilm producing. Nelson, you've seen CRBSIs in your clinic. Do you have any comment on that?

By far, the most prevalent is going to be the gram-positive staph being the primary culprit. The one that -- especially with regard to the resistance, staphs are the ones that give us a lot of concern. The gram-negative pseudomonas is something that we do see. It's one of the ones we kind of start to shiver and raises the hair the back of our neck. But -- and then there's a myriad of other organisms, which come into play. Primarily, as I mentioned, a lot of these come from the skin flora, especially since the CDC procedures have come into effect within all the clinics. Those are the main organisms that probably are the main prevalent ones.

Okay. Thanks, Nelson. Next question?

Sure. Do you think the LOCK-IT-100 data was impressive enough to drive potential off-label application as well beyond hemodialysis?

Well, this webinar is based on the medical topics, so we won't be commenting on any regulatory or use since the product is still unapproved. So if you have any medical questions on what was discussed, we'd love to talk about that.

Our next question comes from the line of Andrew D'Silva with B. Riley.

Really comprehensive, and I believe you touched on this, but as it relates to the secondary endpoints with -- especially as it relates to catheter removal, do you have any insight into how many of those were due to adverse events taking place versus just progressing on to alternative treatments or catheters or anything of that nature? I believe there just might be some overlap there.

Yes. Thanks for the question. Well, the goal of every nephrologist is to get that catheter out when the mature fistula is ready, right? So there are very good reasons to take a catheter out if you can because of the risk of infection. So there are good reasons for that. And the goal is to keep that catheter in until your fistula is mature, when you have a more permanent, less prone to infection access. What we saw in this trial was that more Neutrolin treated patients were able to get to that point where if they wanted the catheter out, the fistula was ready. It was a good reason, and they -- many more catheters survive to that point. Not surprisingly, since there were many more infections and catheters on the heparin arm, those catheters had to be changed out, either switched out or taken out when the fistula was not ready. So there were more bad reasons for taking out a catheter on the heparin side, and more good reasons for the Neutrolin side.

And is there -- happen to be any data or statistics that you could share related to that? Or do you expect to release that in a follow-up data readout?

Yes. When we have that ready for the total analysis, we will, but I'm telling you what we've already seen, and it's not surprising. So that's already been discussed.

There are no more questions. Ladies and gentlemen, we have reached the end of the question-and-answer session over the phone. I would now like to turn the call over to Mr. Dan Ferry, who will be discussing the questions submitted over the webcast.

Thank you, operator. So Paul Chew, I have some questions that we've received over e-mail here. The first question is quite general here. Is the use of antimicrobial catheter lock solutions considered the ideal way to address CRBSIs?

Well, I'll let Bruce Polsky address that. But before that, let me say that the best way to address this problem is to prevent it because once you start using an antibiotic, you will start having side effects, including antimicrobial resistance. So a catheter lock solution, which can prevent biofilm and the seating of an infection is, I think, a very specific way to protect the catheter and protect the patient. Bruce Polsky, any other comments on the use of antimicrobials to prevent catheter infection?

So the -- I mean prevention is key. And you would not want to use a true antibiotic for some of the reasons that I said in my remarks relating to the development of antimicrobial resistance through that pathway and potentially losing that antibiotic. So aminoglycosides as a lock solution was an example from real life. And I mean -- and that is, in many ways, the -- an advantage of using a product like this one, like Neutrolin, and is that you would not be using this for treatment of a catheter-related bloodstream infection. Therefore, you're going to -- and it has a barrier for resistance apparently as well. So it makes it a suitable agent to be used in a catheter lock solution for prevention.

Thanks. Thanks Bruce. Dan, any follow-up questions?

Yes. I think you've already answered this, but I'll just read it again here. Do you find the LOCK-IT-100 data highly convincing and potentially practice-changing?

The answer is yes. It's the longest, the largest trial of its kind in this patient population, very difficult trial to do. It has all the attributes of a standard practice-changing trial. If approved, Neutrolin or DEFENCATH, will be the first and only catheter lock solution to prevent catheter-related bloodstream infections in this vulnerable population in time of spiraling health care costs and increased morbidity from catheter use.

Okay. Excellent. That is all I have from the written questions here at this point, Dr. Chew. So I'll turn it over to you for final -- yes.

Yes. Thank you, operator, and thank you to you, Dan. First of all, I'd like to thank the speakers for taking the time to share with us their experience and their expertise in this very difficult area. It's still an unmet medical need. I'd also like to thank the audience for participating today, and I hope it was helpful and informative. So thank you all very much. We're all very optimistic and hopeful that Neutrolin will be a game-changing, practice-changing medication for patients. So thank you. Stay safe, and be well. Thank you, operator.

This concludes today's conference. You may now all disconnect your lines at this time. Thank you for your participation, and have a great day.