Good morning, and Welcome to the CytoSorbents virtual KOL and Analyst Investor Day. At this time, all attendees are in a listen-only mode. A question and answer session will follow each formal presentation section. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded, and a replay will be made available on the CytoSorbents website following the conclusion of the event. I'd now like to turn the call over to Dr. Deliargyris, Chief Medical Officer of CytoSorbents. Please go ahead.
Welcome, everyone, to the CytoSorbents virtual Key Opinion Leader and Analyst Investor Day. Good morning to those participating in the Americas, and good afternoon and good evening to our international participants. My name is Efthymios Deliargyris . I'm the Chief Medical Officer of CytoSorbents and will also be the moderator for today's event. Approximately four years ago, we held a similar event to introduce you to the application of antithrombotic removal and to show you how this novel therapeutic intervention can be made possible by our unique polymer bead technology. We also reviewed at the time the rationale as to why this application was the right one to lead our efforts in opening the North American markets.
Well, a lot has happened since then, including completion of our pivotal trial, and today is the perfect opportunity to bring you up to date on all the great progress that we have made. We are privileged to be joined today by an esteemed faculty panel, including the three STAR-T principal investigators, Doctors Michael Mack, Mike Gibson, and Richard Whitlock, and also by Professor Michael Schmoeckel, who's a true pioneer in the field of antithrombotic removal and also serves as the principal investigator of the International STAR Registry. Let's now review the agenda for today's call. Leading off is Dr. Gibson, who will discuss how the antithrombotic landscape is evolving and how both the unmet medical need, but also the need for innovation, is greater today than ever before. Unfortunately, Dr. Gibson is not able to join us live today but was kind enough to record his presentations.
Any questions relating to his presentation will be covered by the rest of the panel. Next will be Dr. Michael Mack, who will be reviewing the top-line results of the pivotal STAR-T trial that were presented approximately a week ago at the 104th annual American Association for Thoracic Surgery meeting in Toronto, Canada. I suspect that for our callers who were not present in Toronto, there is a lot of excitement to learn about this data. Following the first two presentations, there will be a 10-15-minute Q&A session. Please enter questions to your chat room. The third lecture will be by Dr. Richard Whitlock, who will review the key issues faced by cardiac surgeons today when managing patients on antithrombotics, the serious consequences of severe bleeding after surgery, and who will also discuss the Canadian experience in the STAR-T trial.
Our final lecture will be given by Professor Schmoeckel, who will review how antithrombotic removal is changing European practice in cardiac surgery. Also, the growing evidence base that supports its use and will provide an update on the great progress of the International STAR Registry. Following the completion of these lectures, I will then take a few minutes to review our plans going forward by outlining both the regulatory strategy and the associated timelines. The event will conclude with another 10-15-minute Q&A session. However, prior to turning it over to Dr. Gibson, let's review the regulatory status of the technologies that will be discussed today. First, for DrugSorb-ATR, this is an investigational device. That means that it's limited in the U.S. by federal law to investigational use only. This investigational device has not been evaluated by the FDA, Health Canada, or by any other global regulatory agency.
This investigational device is not yet cleared or approved by FDA, Health Canada, or by any other global regulatory agency, and it is not commercially available for sale. The proposed indication for its use is to reduce the severity of perioperative bleeding in patients undergoing coronary artery bypass grafting within two days of ticagrelor discontinuation. In relation to CytoSorb, please note that it is CE Mark approved in Europe for the following approved indications: cytokine removal, bilirubin and myoglobin removal, and also ticagrelor and rivaroxaban removal during cardiothoracic surgery. CytoSorb is not yet cleared or approved by the FDA or Health Canada. Thank you for participating, and welcome once again. Now, let's listen to the first lecture by Dr. Michael Gibson.
Hi, I'm Mike Gibson, an interventional cardiologist, clinical trialist, and professor of medicine here at Harvard Medical School. Thanks for having me join today. I've had the honor of being involved in the development of numerous anticoagulants and antiplatelets over the past 40 years. We've built better and better drugs over time. Think of it as successive cars. We've gone from Fords to BMWs to Ferraris. They're better and better, and they're faster and faster, but everyone always wants to know is: how do you put the brakes on when anticoagulation or antiplatelet therapy goes awry? So what we're here to talk about today is putting the brakes on when we need to put the brakes on, when antiplatelets and antithrombotics are in there and lead to delays in care. My disclosures are shown here.
I do have research grant support from CytoSorbents, the sponsor of today's call. Well, this is the anticoagulation and antiplatelet pathways. Very complicated, lots of arrows here. Drug companies have targeted all these different arrows with drugs to prevent clotting, and then they've targeted these different arrows to, again, reverse that risk. We have risk when people come in to the hospital and need surgery, and we may need to prevent bleeding as well as reverse bleeding. There are a lot of patients out there nowadays on antiplatelets and anticoagulants. Back in 2019, it was estimated that about 6 million people were on anticoagulants and about 4 million were on antiplatelets. Now, that gets rid of aspirin use. The number's much higher, probably double that if you include aspirin use.
That number is probably much higher now, and it's expected to be closer to 12 million by 2030. It just keeps going up because our population is aging. And as the population ages, they have more and more of the diseases that we're treating, things like acute coronary syndromes, things like stable disease in their coronaries, their carotids, their peripheral vessels. After you put a stent in, you're gonna need to be on one of these drugs, and after bypass surgery, you're off these—on these drugs. Atrial fibrillation, irregular beating of the heart, is going up as the population ages, and they're on anticoagulants as well. More strokes out there as the population ages. They're on antiplatelets or anticoagulants. And finally, we have more and more patients in the hospital, and we're going to need to prevent and treat deep vein thrombosis or clotting in the legs.
Now, the good news is we have better therapies. The bad news is, as we introduce more and more of these therapies, there's a greater and greater risk in the population as a whole for bleeding or a need to stop bleeding or prevent bleeding in surgery. Well, over on the left-hand side, you see some of the numbers we've been talking about. The antiplatelet numbers have been stable at about 10 million patients on antiplatelets. About half of those are on aspirin. On the right-hand side, you see how the field is changing with respect to which of the super aspirins or thienopyridines people are on. What is happening is ticagrelor, in blue, continues to gain market share. It's up to 60% now. Some of the other drugs in this class, like clopidogrel and prasugrel, are going down.
Some of this is because clopidogrel has resistance, as many of you know. Ticagrelor does not. And, you see that this is before, before ticagrelor comes off patent, and once it does later this year, I expect those numbers to grow. So expanding use of thienopyridines, there's more and more data out there comparing aspirin monotherapy to ticagrelor monotherapy, showing that ticagrelor monotherapy is probably superior to aspirin monotherapy. So I think you're gonna see a reduction in aspirin use in the future because it causes GI bleeding and a continued growth in, say, ticagrelor therapy over time. That's the antiplatelet side. This is the anticoagulant side, and what you see is that warfarin use is going down over time, and it's being replaced more and more by the novel oral anticoagulants like rivaroxaban and apixaban.
When you look over on the right-hand graph, you see that there is expanded use of anticoagulants. The whole market itself is expanding when you lump together warfarin plus the DOACs. So antiplatelet therapy, kinda constant, a lot of people on it. Anticoagulant market growing, largely driven by apixaban and rivaroxaban. The good news is we have better thrombotic outcomes. The bad news is we have more and more patients on these drugs who are at risk of bleeding or who do bleed. The two big issues are sometimes someone comes in on these drugs, and we're worried that they're going to go to surgery or have an intervention while on the drugs, and that may cause bleeding, and that gives us a lot of hesitation, as you'll see.
The other problem, which is less frequent, is that they come into the hospital bleeding, and we've got to reverse that bleeding. Bleeding is not just painful for patients and frightening to them. What it does is it also causes them, in many cases, to back off on the medicines that they're on. They say, "Well, I don't know whether it was the blue pill, the yellow pill, or the red pill. Something's causing me to bleed. I'm gonna stop all those different pills to prevent bleeding." And what it does is it causes them to fall off the pathway of evidence-based medicine. So aside from just the bleeding complication itself, there's also a withdrawal of a lot of good evidence-based therapies when you bleed.
Now, aside from overt bleeding, we also have the problem of people coming in, for example, with a broken hip, and they're on an anticoagulant and the surgeon is scared to operate, and rightfully so, because they're worried about bleeding complications, so they delay care. And those delays in care, as we're going to see, can be very, very costly. So our unmet need is this: We need to reduce the high cost associated with bleeding, we'll look at some of those, and we also need to make care more efficient. Hospitals are at 100% capacity. We need to keep people out of the hospital to make room for other patients. So we really need to improve the efficacy or efficiency of our hospital care.
Last time we were together, I showed this slide, and it showed that as the use of anticoagulants goes up, the number of adverse drug effects related to anticoagulants has gone up tremendously. Likewise, for antiplatelets, you can see over the years, those numbers have climbed as well. When you put together anticoagulants and antiplatelets, they account for the most adverse drug effects that cause someone to come to the emergency room. Well, let's fast-forward now to 2016 to 2020. As the use of these drugs goes up, the number of ED visits in patients on these drugs go up. Here you can see the numbers in red, going up to almost 200,000 ED visits in people on anticoagulants at this point, and about 100,000 of those, or about half of them, will be hospitalized.
So they're in the hospital, and they may need surgery or an intervention, or they're bleeding, and this is a big, big management issue for us clinicians. Let's look at one kind of bleeding, in particular, that's bypass surgery bleeding. I'm an interventional cardiologist, and I'm highly focused on this as a clinician. Here is the usual rate of bleeding when someone has, probably most often an elective surgery. You see, most of the surgeries are coronary artery bypass grafting surgeries, about half or more than half of them. And the risk of bleeding with bypass surgery is about a 5% risk of major bleeding, or a rate of reoperation for bleeding for 1 out of 300 patients. Now, that's the uncomplicated elective case. What happens when you throw antiplatelets and antithrombotics into the mix? And this is current data.
It comes from an E-CABG registry. Being on Brilinta, or clopidogrel, triples the risk of bleeding. What you see over on the right-hand side is that the risk of bleeding is time-dependent. So if you go to the OR within the first two days after having ingested one of these two drugs, you have about a 15% or greater risk of bleeding. So that is very high, and it gives the surgeons a lotta, lotta hesitancy to take someone to the OR if they have taken clopidogrel or ticagrelor within the past two days. And this is a conversation I have all the time with my surgeon friends when we have a sick patient, and I want them to take them to the OR urgently. They cite this data, and they cite their concern about bleeding.
Well, this is a snapshot of my life as an interventional cardiologist. People come in, they're having a heart attack or an acute coronary syndrome, bring them to the cath lab, and then we find a problem that needs to be fixed, not by me putting a stent in, but needs to be fixed by the bypass surgery. And the tension is always this: They have an acute problem, needs to be treated acutely, and on the other hand, they're now on an antiplatelet or an anticoagulant, and the surgical team is hesitant, and rightly so, because of the risk of bleeding. So this is a tension. There's an acute problem that needs acute treatment, but there's an acute risk, an acute risk of bleeding.
What we need is a strategy that can get them to the OR quicker to minimize that risk of acute thrombotic complications, but at the same time, allow us to do it safely. Well, let me tell you about a case I saw recently. A gentleman came in. He was clutching his chest, having chest pain, came into our emergency room, was seen, was diagnosed as having a heart attack. As usual, got put on aspirin and ticagrelor in the emergency room immediately, was brought upstairs to the cath lab, where I did a cath. The person was found to have a totally blocked right coronary artery and a severe blockage over on the other side of the heart, of the left main artery that supplies most of the blood flow to the heart.
Now, ordinarily, we would do what you see on the right-hand side of the screen here, we would put a stent in. But given the extent of disease in this patient, we called our surgical colleagues to come evaluate the patient. This happens in 5%-10% of our cases, but in this case, it was really an urgency. Now, what would have been optimal would be to stent the patient, but again, they needed bypass surgery. Our surgeons are very concerned about bleeding, and frequently, what we have to do is we have to take a detour. We have to send that patient to an area of the hospital where they can let the drug wash out over the next 4 or 5 days, whether it's ticagrelor or clopidogrel.
They sit in the hospital bed for four or five days, waiting for the ticagrelor or clopidogrel to wash out. Then we bring them over to the operating room for their bypass surgery, which can be done with less bleeding at that time. So we need innovation. We need innovation because in many of these patients, we don't have the luxury of waiting. Time is muscle. In this case, it was a heart attack, and the patient really needed to go to the operating room sooner than later. That's why we need innovation, and the innovation we need is shown here, which is antithrombotic removal strategies. Now, let me talk to you about the focus of today's discussion, and that's polymer bead chemoabsorption. The technology consists of a cartridge filled with these biocompatible polymer beads that have a very, very large surface area.
The beads are small, but they have a very large surface area, and they were put into the bypass circuit itself. These beads absorb to molecules that are under 60 kilodaltons and absorb drugs like the antiplatelets and the antithrombotics, in particular, ticagrelor. Now, the beads have a CE Mark for approval for removal of cytokines, myoglobin, bilirubin, ticagrelor, and rivaroxaban. The beads are also emergency authorized for COVID-19 for cytokine removal in both the U.S. and Canada. There had been 230,000 treatments to date without any unanticipated adverse device effects. Well, let's talk about the P value. There's the P value that applies to the statistics in a trial. The most important P value is the patient value. Really, I think patients want the safest route possible that minimizes their pain and suffering.
There's also the P value for the payer, and that is, you know, very important in 2024. What we looked at in the START-T trial that you'll hear from, Dr. Mack about, was we looked at big drivers of cost. Two of those big drivers are transfusion, and probably one of the bigger ones is ICU length of stay. Now, as you'll note, we looked at bleeding very, very carefully in this trial. The greater the bleeding, in particular, the greater the severe bleeding, the greater the need and volume of transfusions, which can be costly. Also, you'll see that the greater the bleeding, the greater the ICU length of stay. Now, you'll see we broke it down into hours here because the ICU isn't like a hotel room.
You know, we don't say, "You know, tomorrow morning at 11, you're gonna be discharged." We try and get people out of the ICU as quick as possible because it is a big, big driver of cost. It's also kind of a bad place to be in because there's a lot of sick people in there, a lot of competing needs, and we try and get people out of the ICU as quickly as possible. Big driver of cost. Now, one of the endpoints you'll see today is chest tube drainage. Chest tube drainage, the greater the chest tube drainage, the greater the length of stay. Again, a potential major driver of costs. We also did a survey in STAR-T to see how long were people waiting and where were they waiting during that washout period. In the U.S., they're waiting about four days for washout.
In Canada, waiting 3.7 days for washout. Where were they waiting? They were waiting in some pretty costly areas, like in the ICU or the step-down unit, which is a transitional care unit, but with a lot of labor-intensive care. And over on the right-hand side, you see that if you implemented the STAR-T strategy, there was a cost savings of about $8,800 in the US, about $6,300 in Canada. And if you just look at the daily implementation of the strategy, $3,700 dollar cost saving in US, and $3,000 of cost savings in Canada. Well, it's been really invigorating over the past 40 years to be involved in the development of more and more potent antithrombotics and antiplatelets. That's the good news.
The bad news is sometimes we need to put the brakes on, and this is a big problem for me as a clinician. We have to balance the need for getting someone to the OR or intervention quickly with the risk of bleeding. This is a dilemma I face multiple times a week. I'm so excited to be involved in a trial where we're evaluating a technology that may allow us to bridge this gap. Now, I'm gonna turn things over to the other investigators to talk about the results of the STAR-T trial, particularly Dr. Michael Mack. Thanks for allowing me to speak today. Well, just as a reminder, Dr. Gibson is not live with us today, so any questions related to his presentation, the panel will try to address during the Q&A. But next is Dr. Mack, discussing the STAR-T trial, pivotal trial top line results. Dr. Mack?
Thank you, Makis, and I think that you heard very well from Dr. Gibson, the clinical conundrum that we face, not rarely, but frequently, and maybe not on a daily basis, but at least weekly, in terms of caring for patients who have recently been admitted with a heart attack. So the trial we conducted was the STAR-T trial, which is a pivotal randomized sham control trial examining the safety and efficacy of intraoperative removal of ticagrelor in patients undergoing urgent cardiac surgery.
This is my conflict of interest disclosure. I have been in the leadership of a number of trials, involving cardiac surgery. My background, as you've heard from Dr. Gibson, ticagrelor is a potent P2Y12 inhibitor, which is used as first-line therapy in the management of patients who are admitted with a heart attack, and are potential candidates for stents. There was a trial called the PLATO trial that showed that patients undergoing a heart attack on ticagrelor and required bypass surgery have a high risk of severe bleeding complications if operated within the first three days after the dose. Because of the results of this trial, the guidelines that we all follow in clinical practice recommend that we wait three days before proceeding with surgery so that the drug can be washed out naturally by the body's own systems.
However, this three-day benign period - this three-day period is not benign because there are complications associated with just waiting on an unstable patient. Until now, there were no available solutions that allow more timely surgery without excessive bleeding occurring. So you heard about the DrugSorb-ATR bead technology from Dr. Gibson, and it can remove ticagrelor. Early evidence, specifically from Europe, that you're going to hear subsequently, suggests that reduced perioperative bleeding with intraoperative use occurs before the three-day washout. Now, the FDA recognized the unmet need here and granted breakthrough device designation for this, and that resulted in the STAR-T trial, as you're going to hear the results from now. So again, this is the device. I'm not gonna go through again what Dr.
Gibson did, about how it works, but what you see on the lower right is the diagram of how this is set up into the circuit of the heart-lung machine, which is used in all of these operations. It's important to note that this is one of the few sham control trials that I've had the opportunity to participate in. What that means is, this device that you see on the right, the DrugSorb device, is either an active device or a sham control. Nobody in the operating room, including surgeon, perfusionist, anesthesiologist, knew whether the patient was actually getting the device treatment, or a fake or dummy one, nor did anybody recording the results after surgery know whether the patient had received the active device or not. Truly an objective, evidence-based trial.
Now, there's a couple of ways that we define bleeding after surgery. The first is the Universal Definition of Perioperative Bleeding, or UDPB. There's five criteria, as you can see on the left side of this slide. Zero is no bleeding, one is mild, two is moderate, three is severe, and four is massive. These categories are based on two separate factors. One is the amount of chest tube drainage, and chest tube drainage means how much blood comes out of a chest tube that we place around the heart during time of surgery. Some amount of bleeding is expected. However, the more bleeding you have, the more it's associated with complications, as you can see on the right side of the slide here.
It goes from zero to 500 cc's of blood in 24 hours on the left, to over two liters of blood on the right. Now, another component of this definition is the blood products that the patient actually receives, or transfusions. There's a number of different components of transfusions, as you can see listed on the slide. For purposes of this trial, we're gonna focus on UDPB2, which is moderate bleeding, and level three, which is severe or massive bleeding. Those were part of the endpoints that we used for the trial. So this is the design of the trial. The objectives were to evaluate the safety and the intraoperative use, and then re-evaluate the efficacy in terms of reducing postoperative bleeding.
There were 140 patients randomized. The total trial duration was 30 days. The safety endpoint was adverse event rates assessed by an independent data safety monitoring board, and there were 2 efficacy endpoints. The primary one was a composite of fatal bleeding, moderate to severe bleeding, and 24-hour chest tube drainage. Composite number 2 was any fatal bleeding, severe bleeding only, and 24-hour chest tube drainage. We used a statistical method called the hierarchical win ratio of these 3 components. There were a number of pre-specified populations. The results for safety and efficacy were analyzed in 3 study populations. The safety population was all patients who actually received the device, which was 132 patients out of the 140 patients. Efficacy was analyzed in 2 populations.
One is overall population of patients that received all surgery, inclusive of protocol deviations, which was 132 patients, and the second was patients who underwent isolated CABG without protocol deviations, which represented about 92% of the patients in the whole study. This is the baseline characteristics between patients that received the device and those that received the sham control, and there is no difference in any of the parameters on this slide. Now, as I mentioned, about 92% of the patients were isolated CABG, and there were a number of other surgeries that were included. Now, we did not know at the beginning of this trial what the exact composition of this was going to be and what patients would be randomized, and as I said, it turned out that 92% were CABG.
But there were a number of other operations performed, including, aortic valve replacement, aortic root replacement, and more complex surgeries. And as you can see by the P values highlighted on the right side here, all were associated with greater duration of surgery, greater duration of the heart-lung machine, higher risk ahead of time. And all this is important because of these sicker patients that had more bleeding, I think, partially obscured, an efficacy signal here. So this is the safety results. This was determined by the Data Safety Monitoring Board, which reviewed, all patients that were enrolled, at predefined intervals of 40 patients, 80 patients, and the complete 140 patients, and found that there were no safety concerns present, and that the study met its primary endpoint.
There you can see, on the bottom left, the adverse events, in the population, and there was no difference between drug and control, and these are typical adverse events that we see after cardiac surgery. There were three deaths in the population in the study, as shown in the graph on the lower right. One patient underwent CABG and died at five days afterwards, and that was a patient that was randomized to the control device. A second patient underwent a complicated aortic root and aortic valve replacement, did receive the device, but died of complications on day 17. This was adjudicated as a cardiac death, but not device-related. The third one was a patient that underwent coronary bypass and double valve replacement, and did not receive either device.
This is the pre-specified efficacy endpoints analyzed by the win ratio, and on the top is the overall population, and the first composite is moderate- includes moderate to severe bleeding. And there was no difference between treatment group and control group, nor was there any difference in terms of severe bleeding, with a win ratio that was not statistically significant. However, if we look at the isolated CABG per protocol population, for patients that had moderate or severe bleeding, the win ratio was 1.33, which again, is not statistically significant. But if we look at only those patients that had severe bleeding, there was a statistically significant win ratio of 1.59, and we'll go into this in some detail as we look at this isolated population.
This is the hierarchical win ratio, which looks at every patient and pairs them with every other patient in the trial, resulting in 3,060 pairs. The most important complication, of course, is death or fatal bleeding, and there was no incidence of this in either population. The next most important in the hierarchy is UDPB3 bleeding, and that was in favor of DrugSorb, which won 14% of the time, versus only 5% of the time in the control group. Then if we look at the amount of blood coming out of chest tube over the first 24 hours, again, that was favorable for the device compared to the control of 46.9% versus 33.5%.
So it ended up in 61% of wins for the device, and 38.5% of the control, which ends up at a win ratio of 1.59, which is statistically significant. Now, if we look at these specific events and look at the component of those, and you in the CABG population, you can see that there were 6 UDPB2 or greater. There's about an equal number in both. If you went to UDPB3, there were 15% of events in control, and I'm sorry, 9%- 9 events in the control and 3 in the DrugSorb.
If we look down at the bottom left of the components of severe bleeding, there were four patients in the control that had excessive bleeding in the first 12 hours, four compared to two that underwent reoperation for bleeding, and 1 patient that had to have their chest left open in the control group because of excessive bleeding. If we look at moderate bleeding, there was no real difference between the two, except there was less bleeding, one patient less bleeding in the device group, and seven patients received no blood transfusion, but still were characterized as moderate bleeding. If we look at the transfusions per se, so packed red blood cells are, is basically concentrated blood, and that was down 51% with device compared to control.
The platelets, which help prevent bleeding, or down use, was down 24%. Fresh frozen plasma and cryoprecipitate, which are other factors in the blood, that help prevent bleeding, was down 70% and 55%, so that overall, there was a 50% reduction of blood usage with the device compared to control. There was also and this was statistically significant at a p-value of 0.25. If we look at a sensitivity analysis, there are actually some patients that received blood transfusions but had no or minimal evidence of bleeding by their chest tube, yet they met the standard definition.
So the three principal investigators underwent a blinding review of these patients and found that there were nine patients that actually, by the classification, had bleeding events, but we couldn't find any evidence of bleeding. If we then look at this population, you can see that the win ratios for both moderate to severe and severe bleeding were statistically significant. If we look at just 24-hour chest tube drainage alone, you can see that, again, there is a benefit in favor of the DrugSorb device, with low amounts of bleeding, less than 800, being 75% of patients receiving the device, versus 53% with the control, which is statistically significant.
On the right side here, if we look at the highest quartile of bleeding, again, there were much fewer patients in the DrugSorb group compared to the control. Looking at it one other way, as what's categorized as major bleeding, we found that there was a 73% decrease in the number of patients undergoing severe bleeding events, with an absolute risk reduction of from 22% to 6%, 16%. So the number of patients needed to be treated to prevent a major bleeding event was 6.3 patients. So I know that this is a lot of data, because we analyzed this many different ways. But we concluded from all this that the primary safety endpoint was met. The primary efficacy endpoint was not met in the all-comer population.
The severe bleeding efficacy endpoint, which was pre-specified, was met in the isolated CABG population, which represented about 92% of the patients. In this isolated CABG population, the use of the device was associated with reduced bleeding severity by either grade or chest tube volume. The number of patients needed to be treated was six to prevent a major bleeding event, and there was an overall favorable benefit-risk profile. So on the basis of these trial results, the sponsor is planning a regulatory submission to the FDA under the breakthrough device designation and to Health Canada for the use of the DrugSorb-ATR in patients undergoing isolated CABG within two days of ticagrelor discontinuation. And, this is the study leadership and oversight of the trial at top sites.
As Makis mentioned, myself, Dr. Gibson, and Dr. Whitlock were the co-principal investigators of the trial. A number of luminaries in cardiology, blood experts and surgery comprised the executive committee. You can see the Data Safety Monitoring Board and Clinical Events Committee. And then the top enrolling sites was London Health Sciences Centre in Canada, Maryland, New York University in the United States, and you can see the rest of them there. And with that, I will stop the presentation and turn it over to Makis for Q&A.
Thank you, Dr. Mack. Actually, I'm gonna turn it over to Tara. Tara, do we have any questions coming in?
Yes, we do. So please hold for a brief moment. So we're gonna begin the Q&A session with some verbal questions from research analysts, and then I'll turn it back over to you, Dr. Deliargyris, for any written questions. So the first question comes from Brandon Carney at B. Riley. Please go ahead, Brandon. Brandon, you might be on mute.
Yeah, Tara, we're not getting a question in. Is there anyone else waiting for a question?
Yes, so we'll just go to the next analyst, Sean Lee at H.C. Wainwright. Please go ahead, Sean.
Hi, good afternoon. This is Sean. My first question is on the differences that we see between the I-CABG group and as well as versus the other surgeries group. What do you think explains the discrepancies we see in the bleeding results between the two patient populations?
So perhaps I can take this first, and then have Richard weigh in here. I think that there was so much bleeding that occurred in the higher risk, more complicated population, that it obscured any benefit that may have been seen when you look at just the isolated CABG only. I think that there's too much background noise associated with these higher risk patients to detect the signal benefit in the overall population. Richard?
Yeah, I agree, Michael. So bleeding in other cardiac surgery, that being non-CABG surgery, is quite complex. So you have surgeries like aortic surgery, aortic dissections, where you have prolonged cardiopulmonary bypass time. You often will lower the patient's temperature in order to safely perform surgery on vessels going to the head and other parts of the body. That it really is a heterogeneous population with multifactorial cause of bleeding. Whereas the CABG patients, which is the predominant population that the drug ticagrelor is used in, it's either you have a surgical problem that is rapidly fixed, or you have a some type of inhibitor, specifically a drug, that's causing bleeding. And I think that's why, you know, it's a more homogenous group. It's less multifactorial, and really, I think focusing on that, the CABG population really focuses on the cause of bleeding, in this case, which was predominantly drug.
Great. Thanks for that. My last question is on the clinical benefit of what we see in these results. So, maybe correct me if I'm wrong, but based on what I'm seeing is, DrugSorb-ATR seems to have the most effect on the severe bleeding patients. So for these patients, how much of a clinical relevance is there for, you know, to improve them from severe to moderate bleeding, for example?
I think there's two answers to that. One is, the less bleeding and the less transfusion you have, there's benefit to it. It's a continuum. It isn't a, an off/on switch, or a dichotomous variable. It's, suffice it to say, the less bleeding you have, the better. But I think the biggest clinical benefit here will be in not waiting, in clinicians feeling comfortable not having to wait three days in the hospital, and being able to know that if they have this device, they can feel more comfortable moving ahead earlier and not delaying the patient, taking up beds, taking the risk of complications happen by waiting. Richard, your thoughts?
Yeah, you know, I share those two same thoughts, but I would even say there's a third component here. You know, there's a patient-centered, and I will show in the slides coming up that as Michael said, this is not a binary thing. This is a somewhat, almost a linear relationship between bleeding and bad outcomes, and bleeding by any definition. Secondly, you know, healthcare resource focused, you know, blood is a limited resource. The less we use, the better, because we have limited number of donors. You know, and this is not just red blood cells, but this is plasma, these are platelets, so if we can shift people from severe to moderate or to mild, it's great for the healthcare systems.
And lastly, as Michael alluded to, is not only getting the patients to the operating room sooner, but also once that patient has a bleeding event, it tends to cause a longer length of stay postoperative. Now, this, the STAR-T was not powered to look at this. That is also a very complex variable that is fairly difficult to study, but I, I can assure you, when I have patients who bleed excessively, they have increased rates of atrial fibrillation, they have increased length of ICU stay, hospital stay, respiratory complications. So again, they occupy healthcare resource, hospital resource for longer.
Right, uh
I see, oh.
Oh, Sean, are you finished, Sean? We can move on to the next one.
Yes, I am done. Thanks for taking my questions.
Thank you, Sean. Tara, looks like Brandon is ready to ask his question.
Yes. Brandon, you may now unmute your line.
Thanks, and sorry about that. And thanks for taking our question. Can I just ask about the. It looks like there was 10 I-CABG patients that were not included in the per protocol analysis. Can I just ask about why those patients weren't included?
Sure. I believe, Makis can correct me if I'm wrong here, there is a technique that is used in cardiac surgery to help prevent what's called hemodilution or patients becoming anemic during surgery. And what's happened is an amount of the patient's blood is drawn off before they go on the heart-lung machine and saved. It's a procedure called ANH. And at the end of that procedure, that blood is then transfused back into the patient, and this is a technique that we use to help prevent what's called hemodilution and the need for blood transfusion. However, it was not allowed in this trial because of the fact that that blood that you remove has active ticagrelor drug in it.
It's not exposed to the device, and then it's transfused back into the patient afterwards. So any potential benefit you would receive from removing ticagrelor would be offset by infusing blood with active drug back in it at the end of the procedure. Despite this being a protocol violation, we realized partway through the trial that there were actually some patients that had this, and they were not included in the analysis for that reason. Makis, anything to add?
Nope, that was, that was perfect. That was the vast majority of protocol, major protocol deviations were related to ANH.
Okay, thanks for that clarification. And then I wanted to also ask about those nine patients that you were talking about, that were classified as bleeding events on the protocol analysis, but then you did the reanalysis and didn't find any evidence of bleeding. Can you give us some more details about those nine patients, what the differences were between those two analyses?
Yes, absolutely. So what we did was, it was a blinded review, so we had no idea whether these patients had received the device or not, and looked at the amount of chest tube drainage they had, the number of transfusions they received, what happened to their hemoglobin and hematocrit afterwards, as well as their platelet count. We also looked at the time that they received the blood transfusions. Some of the patients actually received the transfusions before they ever left the operating room. So in other words, they didn't have a chance to bleed, but the surgeon or anesthesiologist was concerned enough on the front end that they just went ahead and gave the patient platelets.
In two of the patients, it looked like it was standard protocol within with this particular surgeon or institution to go ahead and give platelets afterwards. I think all of these patients had less than 800 ccs of chest tube bleeding, or a couple of patients looked like they had it just because they had no chest tube drainage, but their blood count, and these were women that started anemic, went quite low afterwards, and the clinical care team felt it was the best in interest of the patient to give a blood transfusion. And again, this probably occurred due to fluid they received around the time of surgery that caused dilution of the blood, but was not due to bleeding per se. Richard, other thoughts?
Yeah, so this is quite a complex issue. You know, I'll highlight my talk. I run a lot of clinical trials with tens of thousands of patients in cardiac surgery. Right now, in another trial, we're facing a very similar issue, dealing with appropriately defining bleeding after cardiac surgery. And pigeonholing it into a definition can be complex. As Michael alluded to, some patients get transfusion because they already have some a baseline anemia. The hemodilution, by putting them on the heart-lung machine with a prime or a crystalloid solution, a non-blood solution that occupies all the tubing and filters, it dilutes them, and suddenly get a transfusion, and then they get a protocolized platelet administration, and suddenly they need a definition.
What we really wanted to do is to ensure that we were capturing the spirit of the trial in trying to prevent bleeding that was visible and obvious, meaning the actual visualization of blood loss, along with those definitions of transfusions. And when we did that in a blinded way, some of the events that, you know, if one was just solely focused on purely a purest approach, they met the definition, really was not what we were trying to capture. Though that was the sensitivity analysis that we did in a blinded fashion, that demonstrated some of these events were not true bleeding events, but rather dilutional or protocolized care.
Thank you both. We're running a little behind, so we're gonna move on to the next. That's perfect for you, Rich, to start with your lecture here. Some of the questions in the chat are just we've been reviewing them. They will be answered as part of the sponsor's remarks at the end in relation to the regulatory path forward and the timelines. And then we'll use whatever time we have left for a Q&A. Rich, please.
Great. Thanks, you know, thanks so much for the invitation. It was my pleasure to participate in the STAR-T trial. Canada and myself came in a little bit later. As I was discussing with the leadership team, the proportion of Canadian patients that are exposed to ticagrelor is significant, and we are having a significant problem with this. So I'm gonna talk to this, you know, from the Canadian perspective. You know, just. Sorry about that. Just so you're aware, so I am a lead investigator at McMaster University, Population Health Research Institute. I have a lot of experience with clinical trials.
The clinical trials that I have led out of PHRI, I've randomized probably the most number of cardiac surgery patients in the world through trials that I've led, so a lot of experience. I was very pleased to see the sponsor take up this, this blinded randomized trial to generate robust evidence in a field that has previously been dominated by single-armed or studies or observational studies indeed. I do have these disclosures. I am a co-principal investigator of this trial. I also have grants from other industry partners that I feel are trying to better outcomes for patients. I'm gonna breeze through these slides again to allow further discussion. The gist is that there are several categories of antiplatelet agents.
The ones that we are focused on here is one of the P2Y12 inhibitors that works on the ADP receptor, and that is ticagrelor, and it basically prevents activation of platelets. This came, and Michael Mack earlier, and I believe also Michael Gibson, alluded to the PLATO trial, where that trial compared ticagrelor to the more common drug that was added on top of aspirin at the time, clopidogrel. And what was very powerful about this trial is this shows a forest plot. The smaller inset here is time from procedure in months, and the Y-axis is the cumulative endpoint, includes death.
But there was a significant reduction of death in cardiovascular events compared to Plavix, and therefore, ticagrelor is- has been supported in the Canadian guidelines as basically the go-to drug when you have a stent or an acute coronary syndrome, such as a heart attack, to add on top of aspirin. So we see this used a lot. And then we get into, it's a great drug for preventing events, just as Michael Gibson's alluded to. But what happens when suddenly that patient, who is loaded with this drug, needs to have surgery urgently, or they start bleeding? So, you know, again, commonly used in Canada, we're not sure what to do with it, and it certainly delayed care. And this is the recruitment graph from STAR-T.
The reason I highlight this is, you know, I discussed probably at the end of 2022 with the team about bringing Canada on board, said that, you know, Canada will be a major contributor of patients in this. You can see that when we activated Canada in February 2023, there was a sudden increase or uptick in terms of the recruitment rate. Proportionally, you know, Canada did extremely well in this trial, not only because we have centralized care, a lot of patients taken care of at a single institution, but because our cardiologists particularly are very evidence-based, and they follow the guidelines very closely. Many of our patients with coronary artery disease or signs that they're having a heart attack or myocardial infarction get loaded with this drug.
So let's speak specifically to the P2Y12 inhibitors, of which ticagrelor is, and the perioperative management. You know, we know clopidogrel. We have a lot of experience in that. Generally, you wait about 5-7 days, ideally 10. However, Plavix or clopidogrel responds very well to platelet transfusions because it basically is permanently bound to the platelet, and you can just overwhelm the drug by the administration of additional platelets. Same with prasugrel. We do not see prasugrel use in Canada anymore. However, ticagrelor, a very potent drug, ideally you wait 3-5 days, postponing surgery, but if you need to go sooner, platelets transfusions do not work well with this drug because this drug is irreversibly bound, and it just bounces on and off platelets, messing platelets up. So you give platelet transfusions, and that drug's floating between platelets and messing each of these platelets up.
It's very hard to overwhelm this drug. When we first started seeing this drug used in our center, all of a sudden I got a call from one of our head hematologists and say, "Hey, what is going on? We're seeing these massive bleeding events with you guys, and you know, I, I'm really, really worried about this drug." That was Theodore Warkentin. I remember that call extremely well. You know, he's one of the world-renowned hematologists, one of the most published hematologists around heparin-induced thrombocytopenia and transfusions around cardiac surgery, and to get that call was a bit shocking. So indeed, this is a real problem. The second thing is that not only do we start delaying surgeries, but you know, speaking earlier, the comment about shifting patients from severe to moderate, moderate to mild.
If you look at any definition of bleeding, so the Universal Definition of Perioperative Bleeding, chest tube outputs on the right here, over 24 hours. If you look at a number of packed red blood cells administered, platelets administered, there is a continuous relationship, an almost linear relationship with very bad outcomes. The more bleeding, the more transfusions, the worse patients do in terms of morbidities and mortality. And this is highlighted again in this graph from Karkouti, who's a very experienced and well-known researcher at the University of Toronto, who looked at the number of red blood cells transfused and mortality, and you can see this almost linear relationship. When you look at liberal transfusion in this forest plot, liberal to the left, restrictive to the right.
If you are restrictive in your transfusions, you tend to save patients, and indeed, we proved that in a trial that I led with David Mazer out of Toronto, called TRICS-3. So this is why I really believe these results were important, and when we look at the spirit of the trial, as I mentioned, and I, I'm not gonna go back and review all of the, the trial results, but those patients that had significant bleeding and those patients who are isolated CABG, which is truly the focused population or the population that this drug is intended to, we have a win ratio of 1.59, a p-value of 0.04. The data suggests that you have better outcomes with, with the treatment group as opposed to control group.
And again, this is the per protocol CABG population, the sensitivity analysis, and when you look at moderate to severe bleeding, the worst type of bleeding, the one that is associated with the greatest morbidity and mortality, you have a win ratio of 1.65, a p-value of 0.02. If you look at severe bleeding alone, again, similar win ratio of around rounds off to 1.6, a p-value of 0.04. So these results from the STAR-T trial suggest that the group that received treatment was favorable as compared to the control group. So thank you so much.
Thank you, Rich.
I'll pass it over to Dr. Schmoeckel.
Thank you, Rich, and then we look forward to the Q&A session. Potentially some questions in the Canadian perspective will be very interesting. Now, on to Professor Michael Schmoeckel, joining us this evening from Munich, Germany. Michael, take it away.
Hello. Can you hear me?
Yes.
Okay, great. Next slide, please. Unfortunately, I can't move it at the moment, so if you could move it for me, that would be nice, actually. Okay, so this is my disclosures. I've actually- I'm actually together with Rob Storey from Sheffield, one of the PIs of the European STAR Registry, which I'm going to present to you in the upcoming slides. Next, please. How did it start? Actually, about 10 years ago, we were facing more and more patients that were on rivaroxaban or apixaban, so one of the DOACs, when they underwent cardiac surgery. And the manufacturers of these two drugs recommended that we should stop these drugs 48-72 hours before surgery.
However, we realized that there's still more bleeding, even if we discontinue the drugs for 48-72 hours, and actually, our recommendation after our own data was that we should actually wait for up to 10 days before you are down to the normal bleeding rates that you would expect without these two drugs. So this comes especially true in patients that have a reduced kidney function, and that's actually not a rare event in cardiac surgery patients. Next slide, please. Then we read a paper on, in 2017 of Angheloiu, who did a mock circulation, where he was actually able to remove both ticagrelor and rivaroxaban from a mock circulation with the help of the CytoSorb adsorber, and that was actually quite effective in this experimental setting.
So we decided at that time that since the CytoSorb adsorber was actually already CE marked for cytokine removal in Germany and in Europe in general, that we should use this CytoSorb adsorber for the removal of these two drugs, both ticagrelor and rivaroxaban. And in fact, next slide, please. The first experience was quite promising. On the left-hand side, you see the ticagrelor group. There was 43 patients, was published in 2019, actually, where we had a significant reduction of operation time since we had less time for hemostasis necessary. We had less chest tube drainage and actually no re-thoracotomy at all. And in the rivaroxaban group, that was only 12 patients, we could even show that we had a reduction in time on the ICU and in total hospital stay.
Next slide, please. This shows you again, the reduction of the chest tube drainage in these two groups. So they came down from 600 mL to 390 mL in the rivaroxaban group, and from 890 mL to 350 mL in the ticagrelor group. So next, please. We actually then, expanded our experience, to remove apixaban in a clinical setting, and we also used it not only in isolated CABG, but also in acute aortic dissection, which is the middle paper.
Last not least, I was able to present at the AATS meeting in Los Angeles last year, that if you run the blood of the patient through the CytoSorb adsorber for about 1.5 hours in a study, and you measure the levels of ticagrelor, you are able to reduce these ticagrelor levels by 67% in these patient groups, and thereby reducing bleeding. So next, please. In Europe, we then decided that we should even expand our small, little local experience in Hamburg to a more generalized European experience, and we started a registry together with Rob Storey from Sheffield. The objective was to generate high-quality data, both on the clinical outcome and on health economics. We were actually able to include quite a substantial amount of centers. If you look at the next slide, please.
We are now, as of today, up to five countries, Germany, the U.K., Austria, Belgium, and Sweden, with twenty-three participating sites. And we have now enrolled 453 patients since April 2022, and this is steadily increasing, as you can see on the right-hand side of the slide. Actually, if you press the button again, then you see all the countries. Next, next, next, and next. And on the right side here, you can see the enrollment of the registry, which is quite steadily growing, and I am actually quite optimistic that we will reach about 500 patients quite soon. Next slide, please. Last year, on the European Association of Cardiothoracic Surgery meeting, I was able to present some of the data, preliminary data of this registry.
And actually, as of today, they've just been published in the Journal of Thrombosis and Thrombolysis. So if you're interested in detail, you can read it up there. Just briefly, at that time, when I presented this data, we had included 165 patients. Two-thirds of them had a P2Y12 inhibitor, mostly in 77% ticagrelor, and some of them together with others, and some also clopidogrel and prasugrel. Although I myself, I'm not really a believer that it will help in this subgroup of patients, because clopidogrel usually binds irreversibly to the platelets. And we had one-third of patients, namely 51, who were on DOACs, mainly apixaban, the yellow group, 47%, and 27% on rivaroxaban, and the others are dabigatran and edoxaban.
If you look at the next slide, please, you can see that actually the bleeding was what you would expect, like a moderate bleeding, not a severe bleeding. It was again, kind of a difference between two groups. Those on ticagrelor underwent mainly isolated CABG, and those who were under DOACs had more complex surgery, which is reflected by the yellow or orange bar on the bottom, on the right side, because you had more bleeding due to these more complex procedures in the DOAC group. But still, it was actually quite moderate, and all the centers actually I've spoken to, they were very enthusiastic about continuing with this form of therapy. Next slide. In parallel to the START-T trial that has just been referred to by
Dr. Mack, Rob Storey from our registry will present the data, isolated CABG, just with ticagrelor in this registry on the EuroPCR meeting in Paris, just in about 10 days' time. And so you will hear about, I think, more or less a similar data set in this registry if compared to the STAR-T randomized trial. The next slide, please. There have been also some newer applications of the device. So it's not only used during cardiopulmonary bypass, during surgery, but also in patients that are operated by CABG, but off pump, so without the use of a heart-lung machine. And in this case, my colleague here in, at the Artemed Klinikum in Munich, he used the device using an apheresis pump before surgery, and he actually put this patient on an apheresis pump via a veno-venous return access.
He could actually remove successfully, again, ticagrelor and DOACs to reduce bleeding events in this specific patient group. The next, please. So just to sum up, what we know so far about the antithrombotic removal is that it's a significant unmet need, and this was referred to in the very first talk, and this is now also validated in the STAR Registry. We can perform our surgery timely, which means the patient doesn't have to wait until there is the usual washout period of about at least 72 hours. We have, therefore, a significant saving in health day resource costs and utilization of hospital costs.
And even we think that we can reduce operation times and ICU times, which is actually a kind of a bottleneck in our health system because we don't have enough ICU beds and not enough operation capacity because of personnel resources problems. So all this drives actually quite an enthusiasm to introduce the CytoSorb adsorber and this indication as a standard of care. The next slide shows you that even the guidelines have now incorporated this into their. Is this the next slide, actually? Yeah. Yes. Okay. Into their recommendations. So in patients on ticagrelor or rivaroxaban, the European Society of Anaesthesiology and Intensive Care has given it a 2C recommendation to use the CytoSorb adsorber as an adjuvant therapy to reduce bleeding complications.
On the very last slide, I would like to leave you with some of these testimonials of, most of them actually, are participants in our registry, who are quite enthusiastic about continuing to use this kind of therapy, which has already been CE marked in Europe for the indication of removal of rivaroxaban and ticagrelor from blood of the patients who are who undergo a cardiac surgery. This is a more and more common feature that it's actually used in more and more centers, and the interest is still high to include more patients into this registry. Thank you very much for your attention.
Thank you very much, Professor Schmoeckel. So to the audience, hopefully, the four lectures that you already listened to today provide you with a detailed update as to where we stand today in relation to the unmet need we're trying to serve, the clinical data on safety and efficacy from our pivotal randomized double-blind STAR-T trial, and the growing experience and evidence with the increasing adoption of antithrombotic removal in the European Union. But as many of you are thinking now, what happens next? Well, what happens next are the regulatory submissions, and we're moving full steam ahead with submissions both to FDA and Health Canada. In the next few minutes, I'd like to give you a little bit more visibility around our strategy and the timelines related to that. So first off, let's remember that DrugSorb-ATR is a breakthrough device.
The FDA has actually granted 2 breakthrough device designations for DrugSorb-ATR. In 2020, for the removal of ticagrelor during emergent urgent cardiothoracic surgery, and in 2021, a second breakthrough designation for the removal of apixaban and rivaroxaban. The Breakthrough Device Designation Program provides timely access to medical devices by speeding up development, assessment, and review for pre-market approval of 510 and De Novo marketing authorization. The devices need to meet 2 criteria. The first criterion: device needs to provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or condition.
The second criteria, where the device must meet at least one of the four listed below, either to represent a breakthrough technology or to be indicated for use where no other approved or cleared alternatives exist, to offer significant advantages over existing approved or cleared alternatives, and device availability to be in the best interest of patients. Obviously, DrugSorb-ATR has met those criteria, and that's why we were granted those two breakthrough device designations. Since 2015, the FDA has granted 192 such designations to cardiovascular devices, which is our population of interest, as you saw from the STAR-T trial, and to 83 GI, uro- or urology devices and diagnostics. The reason that number is important, because that's the review branch that was gonna be reviewing the DrugSorb-ATR submissions.
The breakthrough devices must meet the FDA's rigorous standards for device safety and effectiveness to be authorized for marketing, and breakthrough device marketing submissions receive priority review. So that's an important backdrop to consider as we discuss the next steps. This is one of our external regulatory experts that we've been working with and is advising us on how to proceed, Mr. Mark DuVal, President and CEO of DuVal & Associates. Here's his quote: "We have been working with CytoSorbents on the development of the regulatory strategy for the DrugSorb-ATR device based on the data the company has shared with us and the extensive experience we have in the preparation of De Novo submission, it is our opinion this device is appropriate for the De Novo pathway.
The De Novo pathway is for low to moderate-risk devices for which special controls, in our case, our clinical trial data, provide reasonable assurance of safety and effectiveness, but there is no approved predicate device. There's a heavy emphasis during these reviews on the probable benefit and risk of the device in the intended population. Breakthrough devices receive priority review on device marketing submission, and in the recent analysis, led to a more rapid review of De Novo applications by 25%. So having a breakthrough designation is important. Accordingly, we are targeting parallel De Novo submission to FDA and also regulatory submission to Health Canada in Q3 of this year. The timelines by the FDA for the De Novo reviews are listed as 150 days. However, post-COVID, review times have been closer to about a year.
So to summarize, ticagrelor is an FDA-approved drug, widely used as standard of care, both in the United States and Canada, but does confer serious risk of perioperative bleeding for patients requiring urgent surgical treatment. DrugSorb-ATR has FDA breakthrough status for this application, highlighting the large unmet medical need and the lack of available alternatives. We believe that the STAR-T data support a favorable benefit to risk profile for DrugSorb-ATR in reducing the risk of severe perioperative bleeding in patients undergoing CABG surgery. Based on the favorable benefit to risk profile observed in STAR-T, our regulatory experts recommend that we submit to the FDA for DrugSorb-ATR use in CABG surgery under the De Novo pathway.
Therefore, we plan on parallel FDA and Health Canada submissions to occur in Q3 2024 under the combined Mutual eSTAR program. Pending FDA agreement of the De Novo pathway submission, breakthrough designation is expected to facilitate a priority review, with a potential FDA decision between 6-12 months following submission. So that concludes our prepared remarks for today. Thank you again for participating to the CytoSorbents virtual KOL and Analyst Investor event. Now we're gonna turn it over for a second Q&A session. Let's see if we have any live questions, and then we'll turn to the questions that have been entered in the chat. Tara, do we have anyone calling in?
Yes. So our first question of our second Q&A session will come from Brandon Carney at B. Riley. Please go ahead, Brandon.
Hey, thanks for taking our questions again. I guess my first one is for Dr. Whitlock. Do you expect any difference in how the Canadian regulatory agency will interpret the data and the application, compared to the US agency, just based on the differential usage of ticagrelor in Canada versus US?
Yeah, I don't think so. I mean, I certainly don't have a crystal ball, but I think there certainly is a strong backstory here in terms of the problem and the magnitude. You know, again, this is geographic, you know, we're a country of just over 35 million, so, slightly more concentrated in terms of our centers, but there are also areas within the States that where there is heavy use. So, I don't think that will lead to any sort of differential decisions between the two agencies.
Okay, thanks for that. And then for Dr. Schmoeckel, what is the data like in the EU for the ticagrelor iCABG patients versus those with the more complicated surgeries? Do you see a difference like we have in the STAR-T trial? And how has that affected usage? Are physicians there still using the device for more complicated surgeries?
Actually, we do. I think that we don't get this significant because, as it was already mentioned, in these complicated cases, you have a mixture of coagulation bleedings due to coagulation disorders, and you have due to the very wound a lot of wound problems and bleeding for surgical reasons. So it's difficult to differentiate where it's coming from. But however, if you can get rid of the coagulation disorder bleeding, and you are just left with the surgical bleeding, it still makes a difference. And so that's the reason we would still continue to use that also in the complicated case, although it's not significant in this specific study, because sometimes it's just an effect of the small numbers. You have some singular patients that bleed a lot, and that will kill your whole statistics then.
Under
But we think we believe that it works because we have shown that it reduces both the levels of ticagrelor and the DOACs, and so it's a mechanistic thing. If you can get rid of maybe 70%-80% of the ticagrelor or the DOACs, it should have an effect.
Great, thanks for that. And, basically, I guess the question would be, in the US and Canada case, would anybody using that expect basically off-label usage for these more complicated surgeries based on what Dr. Schmoeckel was just saying? Even if we get approval just for the isolated CABG, would you expect usage for the more complicated surgeries?
That's obviously a different. So, but, you know, people do try to practice within label. You know, there's different approaches, compassionate release, et cetera. But, you know, will we see creep? We usually do.
Dr. Mack, any thoughts on that question?
No, I, I agree with that. The FDA and Health Canada do not regulate the practice of medicine, and that is left to the discretion of the clinicians, which does lead to off-label use of devices, when it is felt to be in a patient's best interest. And, you know, we see this, you know, very frequently. So I can. You know, again, no crystal ball, but I would see that if available, and there are some other potential uses, then off-label use is not unrealistic.
Okay. Thanks for the responses, and thanks for the detailed presentations.
Great. Thank you, Brandon. Tara, do we have any more live questions, or should we turn to the chat?
Doesn't look like any other live questions, so I think we can go to the questions in the chat now.
Okay, great. So, here's a question. If FDA approval is granted, how long will it take for DrugSorb-ATR to expand from cardiac surgery to other fields, for example, trauma, neuro, et cetera? So, maybe I'll take a swing at this one, and then we'll see if any of our panelists want to weigh in. I think there's gonna be additional evidence required. I think the mechanistic evidence and the clinical evidence that we have for now, it's related to STAR-TA
And it's about to have to go in cardiac surgery, it's about to undergo review by the FDA. However, we do agree with the question that there is unmet need that extends beyond cardiac surgery, and we hope to be able to generate the evidence required to make, you know, a, a potential important treatment available in those additional areas. But, well, I don't know if any of our panelists have any thoughts about use beyond cardiac surgery.
Well, perhaps if I can just add that in, the results of our colleagues here in Munich, they used the device without using cardiopulmonary bypass, and this can be used in any patient who has got a bleeding problem. I think it's a very easy thing. You can use a dialysis or an apheresis machine and just include the CytoSorb over into this machine, which is on the market, which is already approved, and this could be then extended to any patient who is in need.
Great. Okay, let's move on to the next question. So we have, actually, there's a few questions about when do we expect to receive FDA approval? When do we plan to submit to the FDA? Hopefully, this last session provided the necessary answers. So let's see. Please explain the potential of DOAC removal since DOACs will be anticipated to reach a market share of more than $50 billion in the next few years. So as you know, the same investigators that we have on the call today were also co-leading the STAR-D trial, which was a very similar study design, similar patient population, but looking to the removal of apixaban and rivaroxaban.
However, the sponsor decided for, to allocate all our resources to accelerate, the completion of the STAR-D trial, initiate our discussions with the regulators, and then move forward subsequently to this very, very large, addressable market and unmet need with the DOACs. Hopefully, you all, you agree when you saw the, the enrollment curve, and that was right around the time where actually Canada also joined us, that Rich and, and his group up in Canada did an outstanding job, and, and I think that decision helped us cross the finish line
actually ahead of our own expectations and with 20 more patients than we initially planned. So yes, DOACs are on the horizon, but we do need to wait for our regulatory interactions and discussions with the FDA to decide what kind of evidence base will be required to expand to DOACs. I don't know if the group wants to talk about how frequently they see ticagrelor versus DOACs in their practice.
Yeah. So, Mack, as you said, you know, it is a slightly different patient population. And the o ften, I find the emergent patients with DOACs really need to go quickly. So, it's certainly we do not have currently, besides dabigatran, at least in Canada, we do not have an effective reversal agent for the direct oral anticoagulants, and particularly the anti-Xa's and andexanet alfa. It's not available to us and also has significant limitations in the cardiac surgery population. So, it's gonna be an important thing.
As has mentioned, the drug use, you know, atrial fibrillation, the most common reason for its prescription, is yet undertreated in terms of use of these anticoagulants. And I expect with. you know, as, as we've shown, increased knowledge translation of the safety of these drugs and the efficacy, that we'll continue to see uptake, of these drugs, and we'll be seeing more and more DOAC patients coming for surgery. So, an important area to, understand what the requirements in the future will be, in terms of, getting indication, for, this technology within that population.
You know, I would just add that, I think that it is a different population than the CABG population a lot of times. Acute aortic dissection would be one instance in which you really don't have a choice other than go ahead and operate, and if the device were available, this might be where you would see off-label use of the device. Whereas in clinical practice, if you have the availability of the device, and there's evidence from Europe that it's beneficial in the DOAC population, you know, I could see it being used there. Regarding the regulatory question of what it would take, you know, whether it would be another randomized trial or whether there would be a performance goal that would need to be met, I think all pending discussions with regulatory agencies once we get through this first bar with ticagrelor.
Yeah. Yeah.
Okay, let's move on to one more question. So, since everyone knew the results of the CABG data would be very good, why did management decide to overshoot and have the original trial results not meet expectations? So if, if I can interpret this question was that if you had designed this trial for only CABG patients from the beginning, you would have had results that were positive in the overall population. So, did any, our PIs here, any thoughts?
Hindsight's 2020.
Rich?
Yeah, same. You know, yes, exactly. So, you know, again, you know, we're doing research. It's continual learning, and you know, hindsight is 2020, certainly.
Well, I think it's to the credit to the executive committee, and I know we don't have the rest of the members with us today, but Dr. Mack did list them on the slide, that the pre-specification to look at the CABG population was placed in the protocol. I think that makes it important because it navigates around any concern that the data that you presented today, Dr. Mack, may be just the result of any post hoc data dredging, but rather, you guys have thought about this, you thought there might be hybrid heterogeneous groups involved, and you wanted to look at the main case individually, in isolation. That was the CABG population. Is that about right?
Yeah. Yeah, yeah. I mean, the thoughts at the time, again, as was highlighted earlier, that predominantly that is the population that this drug is targeted at, is, is the coronary artery disease with, stents or acute coronary syndrome, so it really made sense. And also the fact that it- we, we had a sense it would be a more homogeneous population in terms of the factors that feed into their bleeding.
Okay, on to the next one. When is adoption in the US market expected to be attained? I suspect the person asking is already considering that the device may be approved, and therefore, how do you see adoption playing out in the US and Canadian markets should this device be approved by regulators? Either of you is fine. Dr. Mack first, maybe, for the US?
Yeah, I would see adoption first would be within the trial sites that have experience with it and have a positive experience with it. And then I think it would grow organically from there. You know, I think a lot of our enthusiasm for this came from hearing about Dr. Schmoeckel's experience in Germany at the beginning of this. So I would see that clinical adoption would happen at trial sites to begin with, that already have the experience and the training to be able to use this and the initial enthusiasm, and then it would grow organically from there. Rich?
Yeah, I agree. Yeah, I agree. I, I've had some of the high enrolling sites contact me chomping at the bit, saying, "Our experience was very positive." You know, it was- it's always interesting. The surgeons were contacting me before saying, "Ugh, you know, there, there seemed to be a clear difference in some patients," and they, they were attributing it to, to the intervention. So, looking at the CABG patients, which they agreed is kind of the homogenous population that would be the one to show signal
They are very interested in getting this into their hospital. And, it, it's such a horrible thing to have these patients with these inhibitors on board, and you finish a technically nice surgery, and you sit there packing and unpacking, often leaving chests open. It's such a nice thing not to have that for everybody, including the surgeon at midnight. So, they really want to see access to this device.
Actually, that was the reason I didn't want to have a randomized study in Germany because I didn't want to have the control arm and standing there overnight, waiting for the bleedings to stop.
Michael, I think we have one for you. It says, "What needs to happen for the use of CytoSorb in CABG surgeries to become standard of care in Germany for patients on ticagrelor or DOACs? It seems like there's been an awareness of clear clinical benefits for many years." Hold on, there's the final part, "But the results of CytoSorbents indicate that it's not yet standard of care.
I think it has more to do with the reduced use of ticagrelor at the moment. I don't encounter that much ticagrelor anymore here in Germany. They have changed to prasugrel for some study results, so maybe it's more due to the fact that this problem with the ticagrelor is not so much at the forefront at the moment. I encounter more patients on the DOACs, and that's, I think, for me, it's the next frontier we will have to see that we will use it more and more in the DOAC population.
Great. Yeah, it's our understanding, speaking to our teams in Germany, that the vast majority of the German heart centers do indeed have CytoSorb available for antithrombotic removal as part of their protocols. Is that an accurate statement in your view and your experience?
Well, in my experience, definitely. I'm not so sure about all these 70, 80 centers in Germany. It's not everywhere, and there are some non-believers everywhere, of course, but it's growing, and we can see it in our registry. I mean, the registry is growing all the time, and so it's convincing, and that's why more and more people will use it.
Okay, and then the final question for the panel, I think this is maybe more to the STAR Team investigators. What would the total economic advantage be to the hospitals combining both less ICU, fewer ICU days and fewer infusions, I suspect they mean transfusions, required?
And that's dependent somewhat on a couple things. One, obviously price point of device. Second thing is, who pays for the blood? So, in the Canadian healthcare system, it's actually not the hospital pays for the blood. That may change. It's actually, it's higher up in the healthcare system. But it's still the same pie. So, but, you know, if you reduce transfusions, length of stay, this would be an easy economic win, particularly if you're reducing the morbidities caused by bleeding. The easy win economically.
Yeah, and I would just add to that, that the biggest bottleneck in the system right now is the ICU, and that's not due to a lack of beds, it's due to a lack of staffed beds. Because you just can't find ICU nurses, and everybody is, everybody is suffering from this lack and paying premiums for them. So anything we can do to free up ICU beds, both before, in other words, not waiting for drug to wear off, as well as after, as Richard alluded to before, from dealing with the complications of excessive bleeding, is a significant economic benefit, to any healthcare system.
And, uh
And then
We did the calculation actually, and the saving of the time in the OR and on the ICU sums up to about EUR 3,000-EUR 5,000 per patient bleeding. So it covers probably the cost of the device by far.
Great. I don't know if there are any more closing remarks from the panel, but that was the last of the questions we received in the chat. So we're approaching the end of our event today. I'd like to remind everybody calling in that this Thursday, May 9th, after market close, CytoSorbents will be presenting financial results for Q1 of 2024. Please join us there. And to thank everyone for participating today, both our callers and of course, our faculty. Any closing remarks or should we call it?
Makis, again, it was great. Again, I just wanna call out for the sponsor. You know, doing this kind of research is what we need to better outcomes for patients, clearly answering questions. So, just congratulations again.
Thank you. Thank you on behalf of the whole CytoSorbents team, and thank you, too, for the leadership in the trial. Thank you, Dr. Schmoeckel, for leading the field in Europe, and thank you for all you do for these patients every day. And with that, that is the close of the CytoSorbents KOL, virtual KOL and investor analyst event. Thank you so much for joining, and have a nice afternoon.