Humacyte, Inc. ($HUMA)

Good morning, and welcome to the Humacyte Virtual Webinar. [Operator Instructions] . As a reminder, this call is being recorded, and a replay will be made available on the Humacyte website following the conclusion of the event. I'd like to turn the call over to Dr. Laura Niklason, Founder, President and Chief Executive Officer of Humacyte. Please go ahead, Laura.

Thank you, Tara, and welcome, everyone, to Humacyte's virtual webinar describing the current unmet needs in dialysis access for patients who have kidney failure. As many of you know, we have been engaged in a Phase III program looking at the safety and the efficacy of Humacyte's acellular tissue engineered vessel or AAV, in its function as an access for hemodialysis and specifically comparing this access to patients who receive the current gold standard, which is fistula. Next slide, please. These are just our disclaimers. Next slide. As you'll see from this program, you're going to hear from 2 important key opinion leaders discussing about the current unmet medical need and the current shortcomings of hemodialysis access and how humacytes ATEV may be able to benefit some patients. The first speaker will be Dr. Prabir Roy Choudhary, who is the Co-Director of the UNC Kidney Center and who is an eminent Professor of Nephrology at University of North Carolina. Importantly, Dr. Roy Choudhary is also the immediate past President of the American Society of Nephrology and has a broad view on the current challenges that are presented to many dialysis patients in the United States. After that, you'll hear from Dr. Mohammad Hussain. He's an associate professor, I believe, at the Brigham Women's Hospital in Boston, and he is a vascular and endovascular surgeon and has participated in several of Humacyte's clinical trials studying the safety and efficacy of ATEV compared to fistula in patients with kidney failure. After the presentation from these 2 speakers, you'll then hear from our Chief Medical Officer, Dr. Shamik Parikh, who will give you a little preview of the current Phase III trial that we're running comparing the ATEV to fistula, particularly in women who suffer kidney failure and who are on hemodialysis. After that, we'll have time for questions. And with that, I'm going to turn it over to Dr. Roy Chaudhury.

Great. Thanks so much. So I'm going to start off by saying that I'm a nephrologist, as Laura said, which means that for the last 25 years of my professional life, I have taken care of patients on hemodialysis. My charge, as I see it over the next 10 to 15 minutes, is to speak to you about the why, why we need the ATEV, why we need to do better as a kidney community and why I believe that the ATEV could actually make a difference in the quality of lives of patients. So with that, let's talk a little bit about vascular access. There are 3 -- so we have 550,000 patients currently in the United States who are on dialysis. And if you're on, I should say, hemodialysis, you need to have some form of dialysis vascular access, so that the nurses and the physicians get access to the blood, purified in the [indiscernible] back. So vascular access is truly for these 0.5 million-plus patients on hemodialysis. But it is also unfortunate [ Achilles ] heel of hemodialysis. And this slide tells you why. Main forms of dialysis vascular access, the arteriovenous fistula, the tunnodialysis catheter and then synthetic grafts. The gold standard, although it isn't really a gold standard at the moment, is the arteriovenous fistula. In 2025, if you place 100 or if Dr. Hussain, I should say, 100 new a fistula in dialysis patients about 45 without a problem.

Dr. Roy Chaudhary, I'm so sorry to interrupt. But at least for me, the audio is a little choppy. I'm wondering if you can go off camera and that me help the bandwidth.

Okay. How about now? Is that better?

It's better.

My apologies. Okay. So if we were saying that if Dr. Hussain puts in 100 arterial venous fistulate, about 40 will actually function without a problem, which I think is actually in 2025 for a vascular access procedure. And remember, gold standard, although it's actually been unchanged, if you will, for the last 50 years. Now the problem that happens when a fistula doesn't mature is that in our current process of care, 80% of new hemodialysis patients actually start with the hemodialysis catheter and we then place fistula, which means that it's going -- that if the fistula does mature quickly or fistula fails, you're going to have a long time you're going to have a long time with a catheter. You're going to have a prolonged catheter contact time. And to me, that is one of the worst things that can happen in the world because if you have a prolonged catheter time, you have the complication of catheters, infection thrombosis, central vein stenosis, but most importantly, I would say, infection, infection infection, which results in ICUs, hospitalizations and a huge increase in cost, which is why, particularly in older patients, if you dialyze for a year with a dialysis catheter, the cost is almost $100,000 a year. If you can dialyze that same patient through then that is down to about $120,000 in older patients. So huge savings. And these savings, again, in my mind, particularly through the work that we've done in the American Society of Nephrology, could actually be very, very important in global payment systems such as the comprehensive kidney care contracting models and other such patients, where you reduce initial costs, you're going to end up with a significant cost savings. So let's move on a little bit more. Who are the people who actually end up with a catheter and who are the people who actually have complicated -- so this is data from the United States renal data. And what it shows is that if 100 patients starting dialysis with a tunnel dialysis catheter. And remember, I said earlier that if you have 100 starting dialysis, 80 of them will start with a catheter. So this is the vast majority of patients start with a catheter -- sorry, pardon, so which means that the vast majority of patients starting hemodialysis catheter. So even at 6 months, if you're a male, 50% of patients still have a catheter. But if you are a women, that is actually a lot more. We have 54%, and that number continues to be high as you go down to 9 to 12 months. So the next question, of course, is why do women have an increased incidence of catheters. And the answer comes back to the fact that women are the phenotype where your arteriovenous fistula is actually not to mature well. And the reason for that is that these fistula, these connections between the artery and vein, actually fail because you have arteries and smaller women, of course, do have smaller arteries and smaller veins compared to men. So if you take it further, what I've spoken about till now are the people or the patients on hemodialysis. 100 patients who've been on dialysis for a long period of time have more women in a catheter about 30% as compared to 24%. So both for incident hemodialysis patients and for prevalent hemodialysis patients, you have more women on catheters, you have fewer women with, which is the goal of preventing complications and for reducing. And then finally, if I go on to my penultimate slide, I believe, I just want to, as a physician say that catheters are in a way evil. I think catheters are often described as the white cube of death. I just want to emphasize that, yes, you can say that they cause infection thrombosis and venous access dysfunction. You can say that they cause a lot of money. But I would say that most importantly, catheters destroy the quality of our patients. So in summary, what I want to emphasize is that 80% of our dialysis patients start with a catheter. When intravenous fistula are placed, it takes many months for the fistula to work. And the people, the patients who suffer the brunt more than anything else of failed fistillate or fistillate mature are actually women, which results, as you can see on this slide, in a higher and all the in terms of infection, stenosis and thrombosis that I spoke about. And that's why I'm so excited about the potential of the ATEV to be placed in women instead of an ATEV fistula so that we can target all of these complications and problems. I want to end just as I started, clinical nephrologist. And this is a patient story that is absolutely true. It was about 15 years ago. I do a lot of transplant work. And I remember seeing this 28-year-old black female stall and she came. They had just got married. She had end-stage kidney disease and she had catheter in place. And as a transplant nephrologist, I remember spending a lot talking to her that we can give you a normal life if we can get you to a transplant, you can work, you can have children really positive about it because she had a living donor. But what I had not taken into consideration at this point in time is that she had a tunnel dialysis catheter and that she was a woman. And that combination changed everything for the worst. The next time I saw at the vascular access clinic, she was paraplegic, so she couldn't move her lower and she was in [indiscernible] . And what had happened was that she had a fistula placed, it didn't work. She had a prolonged duration of catheter exposure. The catheter got infected. The bacteria from that seeded her heart and she had an embolus that went off to her spine that resulted in spinal cord compression. And the tragedy is that my 25 years as a nephrologist, these problems the same. And I'm going to end really I really hope that we can do better. And I do believe, depending on the results, of course, but I'm excited about Mohammed's presentation and Shamik's presentation that the actually allow us to improve our patients' quality of life at a reduced cost by reducing catheter time. So with that, thank you for your attention, and I will hand to you, Mohammed.

Good morning, everybody. Thank you so much. It's really a pleasure being here, and thank you, Dr. Roy-Chaudhury, for setting it up so nicely. So I'm a vascular surgeon at the Brigham and Women’s Hospital and Harvard Medical School in Boston. I've had good experience using the ATEV as we've been participating in Humacytes randomized controlled trials because like Dr. Chaudhury said, we feel that there's a big unmet need for these patients. So today, I'll specifically talking to you about results from the V007 randomized controlled trial focusing on the female subgroup. So as we heard, AV fistulas are generally the preferred initial access for hemodialysis according to our national guidelines. But there's a big problem. These fistulas do not mature well, especially for women with small blood vessels. ATEV is a promising alternative vascular access, as we've heard about, and it has shown durability and low infection risk, which is very important to me as a surgeon as well as for our patients. So the analysis I'm presenting to you today is a 2-year outcome analysis from the V007 randomized controlled trial that compared ATEV with autologous AV fistulas in hemodialysis patients in the subgroup of women who are enrolled in this trial. So here's the study design. This was a prospective multicenter randomized controlled trial across 31 centers in the U.S. with broad representation. 242 patients were enrolled in the trial. All of these patients had end-stage kidney disease. They were on hemodialysis with a tunnel catheter, and they were eligible for both an AV fistula creation or an AV graft creation. And they were randomized 1:1 to receive either the ATV or AV fistula. And all of these patients were followed for 2 years. The key inclusion criteria were as follows: These were adults with ESKD on dialysis who were eligible for either AV fistula or AV graft and were expected to live longer than 2 years. And the key exclusion criteria were that patients who were candidates for the perfect optimal fistula in the hand of distal arm were excluded, which is not every women. Patients who had uncontrolled diabetes were also excluded. And importantly, patients who would need a 2-stage access were also excluded. And let me put that in context. Many patients, if they have small blood vessels, we often need to do 2 surgeries to give them a usable fistula, which could take several more months to mature and get ready for use. Often, these are women and these particular high-risk subgroup were excluded who would otherwise get a fistula. The key primary endpoints. The primary endpoints was a combination of functional patency at 6 months, which is defined as true needle tenuation in the dialysis unit for 4 weeks and secondary patency at 12 months, which is a measure of durability. Key secondary outcomes included duration of usability of the access over 1 year and 2 years as well as interventions over the first 2 years and safety outcomes included infection and other adverse events. This is a subgroup of patients in the overall trial. You can see mean age was around 57 to 60 in both groups and about 1/3 were over the age of 65. Female subgroup, which we will focus on in the next slide, was about 30% in both groups. About 40% were obese in the ATEV group and 35% were obese in the AV fistula group. 2/3 of the patients were diabetic, which is in line with our expectations. And you can see patients already had the catheters in for 3 to 4 months by the time they even enrolled in the study. Here is the primary outcome in the overall trial, so all patients. You can see the trial was positive with functional patency 81% in ATEV and only 66% in AV fistula and secondary patency 67% in ATEV and 62% in AV fistula. And this is a number I'd like for you to remember the secondary patency as we move on to the women subgroup. Overall, the p-value was 0.009 with a joint relative patency of 1.17 in favor of ATEV over AV fistula for all patients in the trial. But this benefit of ATEV was really amplified in the women subgroup. So you can see the functional potency in women was 89% for the ATEV group and 54% in the AV fistula group. And the secondary potency was also not dramatically different, 81% in the ATEV group and 48% in the AV fistula group with a p-value of less than 0.0001 or joint relative patency of 1.65 or 65% improvement in outcomes in the female subgroup with ATEV compared with AV fistulas. There was a larger ATEV benefit for females with respect to usability of the access over the first 2 years. So you can see the first bar graph represents all randomized patients. Purple is AV fistula and dark blue is ATEV. You can see AV fistula was used about 12 months of the first 2 years, whereas ATEV was used about 13 months from the first 2 years. But the difference was significant when you look at that female subgroup. So in the female subgroup because of high-risk anatomy and patients, AV fistula was only used about 10 months, whereas ATEV was used about 15 months with a p-value of 0.0137, a significant difference. Patients who received the ATEV also matured earlier at a higher rate. So the first graph on the left shows median time to maturation. And you can see in all randomized patients, fistulas take about 3 to 4 months to mature, which is in line with our expectations, whereas ATEV can be used much quicker between 5 to 6 weeks. And again, the difference is amplified in the female subgroup. Females it takes much longer for their fistulas to mature. In the trial took about 4.5 months, whereas ATAV recipients, the access was usable within 5 to 6 weeks. The maturation rate was also higher in the ATEV group. All randomized patients, about 69% used their fistula that matured, whereas this number was 84% in the ATEV group. And when you look at the female subgroup, again, the difference is amplified with only 55% of females who received fistulas had their fistula mature, whereas the ATEV was 94%. Take a look at the safety outcomes over 24 months, and there's a lot of numbers here, but I'll break this down for you. One of the most important things to me as a surgeon and again, for the patients is infection, especially when it comes to testing new techonderitis and new technology in patients. And importantly, graft infections were 0 in the ATEV group and 0 in the AV fistula group, which is very reassuring and very exciting that this infection rate is very low, similar to AV fistulas in the ATEV group. The rates of thrombosis, stenosis and pseudoaneurysm were higher with ATEV as they generally are with non-autogenous conduits. Aneurysms and steel syndromes were very low in both groups, either 0 or 1. And the second very important thing, again, to me as a surgeon and for patients is the rate of rupture when testing these conduits in patients. And the rate of rupture was 0 in the ATEV group. And this is important because you can imagine these patients have their access cannulated with 2 needles 3 times a week for years. So it was very reassuring to see despite all that cannulation and [ aogenic ] trauma that we purposely caused, there were 0 rates of rupture in the ATEV group. AV Fistula, there was only one rupture. Now of the thrombosis that did occur in the ATEV group, the vast majority were successfully treated. You can see 83% of females who had a thrombotic event was successfully treated with standard vascular techniques. So in summary, in this clinical trial, ATEV outperformed AV fistula in patients who were female and had ESKD. There was superior 6-month functional patency, which is usability as well as durability, which is 12-month secondary patency. In addition, we observed longer duration of successful dialysis over the first 2 years in the female patients who received the ATEV. When we look at the safety profile in the trial, there were no infections in the ATEV and AV Kistula group. There were fewer maturation and surgical revision procedures required with ATEV compared with AV Kistula, but higher rates of thrombosis and stenosis with ATEV, which were successfully treated with most endovascular or open surgical techniques. The key takeaways for ATEV in this trial, it demonstrated meaningful improvements in usability and durability. The access use was faster and more reliable, particularly in the high-risk groups such as females. And there was anticipated decreased prolonged exposure to catheter dependence. Thank you. And I'll turn it over to Dr. Parikh for his slides.

Thank you, Dr. Hussain. Thank you, Dr. Prabir Roy-Chaudhury. I'm going to talk to you a little bit about our V12 study. This is a Phase III study. I'll introduce this study to you. As you have heard from our experts, the reason for doing this study should be quite clear. And it is our way of calling to action and shifting the paradigm by testing if deploying the right access, in this case, the ATF for the first time in the right patient, in this case, women helps them in terms of a durable AV access and decreasing catheter exposure. We want to see if this helps shift the fistula first ideology to a more individualized life plan for choosing the correct AV access for the right patient. And in this study, we directly will be testing the catheter dependence because we believe that women are, as you have heard, at a higher risk of catheter dependence, and this is a fixable problem. So V12 study is AEF versus AVS in women with end-stage kidney disease. It is a prospective randomized multicenter study with over 25 centers within the United States enrolling patients. It's a 1:1 randomization. The clinical trial started in 2023. The goal was to randomize 150 patients, of which we have randomized 126 patients. The key inclusion criteria was women with end-stage kidney disease requiring hemodialysis on a dialysis catheter and requiring an AV access and then being randomized to either ATEP or AF. This is an inclusive study. We are allowing patients who might be candidates for even 2-stage AVF to enroll and the study is stratified based on whether they get an upper arm access or a 4-arm access and also based on whether it's a 1-stage or 2-stage AVF patient in the opinion of the investigator to balance the 2 treatment arms. The endpoints we are directly testing is the freedom from catheter over 12 months, catheter-free days over a 12-month period, which is a way of testing the durability of the AV access that they get. The primary safety endpoint would be infections through 12 months post implant. And we have a number of secondary endpoints for efficacy and safety, including testing the potency and durability as well as other safety endpoints that Dr. Hussain just went over in the V007 study. This is a protocol that we have discussed in great detail with the FDA. And the protocol is designed with an interim analysis when the first 80 patients complete 1 year of treatment, we are able to pause and analyze the data. We have reached that milestone recently where the first 80 patients have completed 1 year of analysis. Our clinical research organization is now cleaning the data. We'll be sending this data. Once cleaned, we'll be sending it to the independent adjudication committee, who will adjudicate for our key endpoints like catetrophy days, patency, infections and abandonment of the access. We currently expect results in the second week of June, and we do have plans to present the results at the SVS meeting. This is the Vascular Access meeting in Boston this year on June 11 at a women's forum section. So if we have results earlier, we'll be announcing them earlier, of course, but we do plan on presenting the results at this SVS session. I think with that, I would like to end the formal presentation and would like to see if there are any questions from the audience. Thank you so much.

[Operator Instructions]. So our first question comes from Matt Miksic at Barclays.

Great. I appreciate the update. Wondering if maybe you could talk about to both of you or all 3 of you, I guess, what do you think the process looks like for the clinical community and for centers to start to uptake these new devices and new approach for AV fistulas, assuming, obviously, data comes through, the product is available, what does that process look like? If you could lay that out for us?

Dr. Hussain or Dr. Chaudhury?

Yes. So I can speak to the surgeon's part and then maybe others can comment on sort of the process part. I think from a surgeon's point of view, there's not much difference in terms of -- we are already used to creating accesses with prosthetic conduit. So the technical aspects of the ATE really are not that unique to a surgeon's usual skill. Usually, an initial conversation to go over any nuances or questions I found and have had a chance to speak with other surgeons in the trial is adequate for them to be comfortable using the access and describing it to their patients. I think there might be some additional nuances from the patient or the DOS unit point of view. Maybe Dr. Roy-Chaudhury have some comments on that.

Yes. Thank you, Mohammed. I just want to make sure that you can hear me and see me because I know there were some problems with my audio.

You sound much better.

Okay. I'm sorry. All right. So yes. So from a nephrologist and I would say, larger kidney community point of view, the most important thing clinically is trying to get rid of the catheters. And both Mohammed and I sort of spoke about at a morbidity level, at a mortality level and at a quality of life level, the huge impact that prolonged catheter contact time has on our patients. Now that vision or that mission has really, I think, translated into our organizational system. So every month as a medical director, you get a print out of the percentage of your patients that are on a fistula, on a graft and a catheter. And the one that we focus on is the catheter. And we focus on that. We focus on trying to reduce the numbers of catheters. And we focus on that because of all the negatives that we've spoken about, but we also focus on that because catheter prevalence is a metric that is increasingly being linked to payment, both in prevalent patients and also in incident patients. So to me, what excited me most about Mohammed's presentation and about what Shamik said was that the endpoints that the study is looking at are catheter-free days. And I just cannot emphasize how important that is to the kidney community in terms of quality of life, complications and payment. Shamik, do you want to -- or Laura?

I just want to add one thing. We've already seen the analysis of the 007 study. Dr. Hussain presented it. That's one clinical trial in women's subgroup. This would be the second clinical trial that we are doing exclusively in women. So we do anticipate that with 2 clinical trials, we will -- showing good results should have an impact on clinical guidelines because it's very much data-driven. And so we do expect guidelines, which are already talking about individualized access options to look for different access options and to choose the right access option for the right patients. So that's another thing that we should be able to...

That's great. Could I ask just one follow-up, if I could, on just the -- it's great -- the metric that you've described is important. And obviously, the clinical benefit is exciting for these patients. Is there anything from a purchasing or a cost adoption that you anticipate will meet some resistance? Or do you think that the benefit to the center in terms of improving outcomes, improving metrics is a sufficient motivation to begin adoption generally?

I think Dale or Laura probably is going to respond to this.

Yes, I can speak to this a little bit, but then I'd ask Dr. Roy Choudhury to also chip in. So certainly, for patients who are at high risk to be stuck on a catheter to remain on catheter for 6 or 12 or 18 months, we know that the costs associated with caring for those patients on an annual basis can be $200, $30,000, $40,000, $50,000 more than if the catheter were removed. So just from a very simplistic cost analysis, the cost of keeping the catheter in even during the first year well exceeds the cost of placing an ATEV. So I think what these studies are designed to show is that for particular high-risk patients, women who have a very -- who, in some cases, have a very low chance of having their fistula mature, there are better clinical outcomes, but also savings to the system. Dr. Roy Chaudhury may be able to speak about newer payment models that are being implemented now by Medicare.

Yes. Yes. No, thank you, Laura. Thank you, Shamik. So I'm going to start off by emphasizing one of the things that Shamik said, which is that the kidney community really is excited about moving towards a more individualized and more precision medicine-based approach to vascular access, and that's what our guidelines say. I also want to say that the kidney community as a whole is moving because of the huge costs of care is moving towards a more global payment system. And one of the things that I personally, and I'm wearing my American Society of Nephrology hat here, I'm excited about is that the person who pretty much wrote the kidney executive order, Aid Sutton, is currently the Director of CMMI and the Deputy Administrator for CMS as a whole. And many organizations in the kidney space, including the American Society of Nephrology, and you can blame them actually for the bad connection because I'm sitting in their office in D.C., have really worked hard and have created connections and pathways to move towards a system where we reduce complications in patients. And again, as Laura said, if you have a global payment system where you get a certain amount of money for taking care of, let's say, 5,000 dialysis patients. And if you can spend x amount of dollars upstream, in order to save 3x dollars downstream, preventing the angioplasties when your fistula fails, preventing the ICU admissions, preventing all the things that happen to my patient, right? That woman went through a $1 million admission between the time that I saw her with a catheter and when I saw her about 3 months later in the vascular access clinic. So I really do believe we're moving towards that sort of payment system. And remember, end-stage kidney disease patients comprise 1% of the Medicare population, but they use up 7% of Medicare resources. And just recently, for the first time, and we're very proud of that, 4 people from the kidney community, including somebody from ASN testified before the Chairman of the House Ways and Means Committee. And that, I think, is is a congressional testimony just about 2 weeks ago that I think is really important for the community.

Our next question comes from Iseult McMahon at BTIG.

So I just wanted to start out, as we think longer term about adoption of the ATEV in these populations, do you think it will primarily be within these high-risk populations that were highlighted today? Or could we see broader applicability across the dialysis population?

Could I take that, Laura and Shamik?

Yes. Go ahead.

So absolutely, good question. We are always looking for new therapies that can initially target a high-risk population. But as the kidney community gets more experience with these new devices. And in a way, it's not so new, as Mohamad said. This is like a graph that has been used for many, many years. I am very positive about this sort of device, in particular, sort of moving out into other patients. And I think a key issue is going to be both the ease of placing the device and then how -- and then the ease of cannulation. And I don't see that any of those are different from normal standard of care. And I just want to emphasize again what Mohamad said in that there were very few infections. And I think that, that's really key when compared to other therapies. So when compared to the standard of care, which is a draft. So I am really positive actually about the potential of this happening.

Yes. And let me just add a couple of points to this. As Dr. Han showed, ATEV worked well in across the patients. 07 was all comers, males and females. The mean duration use was actually slightly more in ATEV versus AVF in all patients. A lot of significance came from the women's side and women represent 45% of the population. And then we look at other high-risk categories. We look at obese males or diabetic males or even elderly patients. Together, this comprises more than 2/3 of all patients who get dialysis. So the so-called high-risk group is the majority of dialysis population.

And if I could add one other thing, and maybe this is more of a philosophical or personal point. And that is that in many different areas, we are moving not only towards sort of individualization of care, but also trying to see whether women are different. And to me, one of the things that is exciting is that this would really be the first intervention in the vascular access dialysis area that's actually targeting a very large minority of patients where there is actually a biological rationale for doing so, which is small arteries, small veins, poor fistula maturation, increased incidence of catheters. And then at a disparity health equity level, there are -- there is a lot of evidence about the fact that women get short changed in that they are not assessed for fistula rightly or wrongly -- and an intervention like this, I think, could actually have a big -- make a big difference in vulnerable populations, not just women, but women in deprived areas, in a city areas, other situations.

I think it's a great question, and I'll add one more thought. We're only talking about access creation. But from a surgical perspective, there's a lot of patients who have dysfunctional accesses that are fistulos grafts. And they're high risk because maybe they've had a previous infection or a focal infection. Maybe they are large and they have diabetes and all the risk factors. So there is a whole population that the surgeon when they get comfortable using this vessel would definitely, I know I would, utilize this for revision or revising accesses that are dysfunctional. So I think that will be a natural progression of an additional area that surgeons would consider using this vessel.

That's all really helpful. And actually, Dr. Hussain, if I could follow up with you for one question here. You specifically called out the advantages of ATEV for the earlier usability relative to AF. I was curious in your practice, how meaningful is the faster time accumulation in terms of both the quality of clinical outcomes, but also quality of life for the patients? And does this play a major factor in your decision-making on what to use for these patients?

Yes, that's a fantastic question. So I think we obviously want to minimize catheter time because of all the things we discussed with the catheter issues. But also, there's an element of what the patient wants. We focus on the ESKD life plan, which is guiding our therapy that lines with patients' needs and wants. And there are patients who come to us and say, I want this thing out as quickly as possible. And even though they may have a vein and he said we can create a fistula, take 2 surgeries in a few months, they're like, no, I just want this out. And in those particular patients, I think using a vessel that matures faster and usable quicker definitely is in line with their ESKD life plan. So I do think the timing does play a large part. It's not the only factor. But it does play a large part in our conversations with the patients to see what's meaningful to them and what we achieve their best outcome consistent with their goals.

Our next question comes from RK at H.C. Wainwright.

Thank you, doctors, for spending the hour with us this morning and helping us understand the ATEV. I'm trying to -- I'm focusing just on a couple of slides from Dr. Hussain's presentation on the VNOT7 study. So if you're looking into the slide that talks about the safety outcomes over 24 months in the females, I know you called out the infections and rupture. But then when I look at this, there is stenosis and thrombosis also, which shows up at a higher number compared to the AVF. My question is, was there anything specific about these patients, either smoking or some other therapies that they're on that's causing this increased number? And also, would you characterize that certain patients may not be real candidates for A, especially when you have these issues?

Thank you. It's a great question. And maybe Shamik, you want to chime in after too. I think I'll answer with 2 points. One is, yes, it's a great question. Are there specific factors that are contributing to axis thrombosis? And my initial response is the sample size was too low in the subgroup and probably with the larger V012 and combining data, one could do some subgroup analysis to try to pick up any specific signals to see if there's any particular things that are unique to this population. My second point would be that we know that thrombosis and stenosis is a common issue with any non-autologous access in a patient, whether it's PTFE that we've been around or other conduits. The most common area of stenosis happens at the venous connection. So the connection between the conduit and the vein, not with the artery, but the vein. And that's because there's a change in high pressure to low pressure and there's more sheer stress and turbulent flow, and that's a common area of stenosis, which leads to thrombosis and leads to often intervention. So that is a problem that is present just like it has been present in other accesses. But it was reassuring to see with standard minimally invasive techniques, which usually involves the day procedures where we do endovascular thrombectomy that the access is revived and the patient can carry on with their use. So I don't think there's -- certainly, this has not solved the problem, which is present in non-vein conduits. But it's reassuring to see that even though the problem is present, it can be treated successfully with standard maneuvers. And sort of final point, are there particular patients that would not be candidates. So there was a requirement to get in a trial that you have to get antiplatelet therapy. So if there are patients who are not candidates for any antiplatelet therapy because of certain medical history or contraindications, which we know reduces the rate of stenosis and thrombosis. I think those -- that particular population, which is probably not that much, is one to consider not implanting it.

I think the only thing I would add is that the V007 study went on for about 6 years and 4 of those years overlapped with COVID. And there was a major disruption, especially in hemodialysis access of care during that period of time. And simple things like antiplatelet treatment or even the training that they have been given to the staff was disrupted at that time for ATEV like not using balloon catheters and things. Those are not the issues we have in V012. So it will be interesting to see how that incidence pans out in V012 study. And I think the results will help us understand better what is the difference between the 2 treatments when it comes to thrombosis and stenosis.

Yes. And if I could just very quickly add, I would say that in general, in the kidney community, getting rid of a catheter and preventing ICU admissions, multiple other complications, in general, trumps the need for an intervention, which, as Mohamad said, is almost always successful.

If I may, I can ask a quick second question. Just the following slide where you have shown, Dr. Hussain, that about 83% of these females when they experienced a thrombosis were taken care of successfully. So I'm thinking about the other 17%, which did not go through successfully. So what -- are there additional things that you as in the physician community can do so that you can increase this number so that you get more of these females back to using the ATEV?

I think that's a great question. And again, I think the sample sizes were low. So there's only very few patients in which it was not successful. But I think the key things to think about are as surgeons get more comfortable implanting it, surgeons get more comfortable picking the right patient, making sure they're an on [ ATEV ] therapy. And I think also acknowledging that even if you're not successful in 17% with thrombectomy, there might be another option that was offered and maybe it was leveraged. For example, you can create now a new access around the vein that's developed and the artery that's developed with AAV being there for several months. So I think there's a lot to learn, and I think there is an opportunity to, yes, get that number from 82% hopefully to 100% at some point. That's what we want to do. We want to do better for our patients. But I think those things will learn as we get the new data from the women trial.

Our next question comes from Bruce Jackson at Benchmark.

I'd like to know a little bit more about how you think about the decision to use the ATV. So do you feel there are clear patient selection criteria? Are they similar to the criteria for the clinical trial? Do they -- do you need to have guidelines in order for physicians to start using the ATV? And then where does it fit in the sequelae of like which different treatments you select? Could it potentially be the first thing you select? Dr. Hussain mentioned this about the timing could be a factor. So that's kind of generally what I'm trying to get my arms around here. Any one of you can start with that question, that would be great.

Sure. I'm happy to take that first. So I currently have a patient scheduled next week, which will be out of the clinical trial, but I'm doing an ATA because she's a high-risk patient. She had an infection in the contralateral arm for non-ATEV conduit that needed explantation. And now she needs a new access in the other arm. And I'll be planting an ATEV because being a woman already had a history of infection on the other side. So I think as a surgeon, when you start off, you really want to include people that were included in the trial because you want to see if you can produce consistent results with the trial. So I would -- patient who would not include if you have that perfect snuff box vein in the hand and that type of vein might do really well, especially in a patient who's a male and nondiabetic. But if I do have a patient like the one I described to you next week, a woman diabetic and has a high-risk features, I would definitely consider an ATEV because it performs well. And I think surgeons -- we would want to be consistent with the inclusion criteria for the trial starting off. But at the same time, people will use it for accesses that are dysfunctional and may need some revision and maybe it's a little -- have had an infection in the past, a large arm. So maturation will take a while. So I think it will be a combination of using that objective inclusion criteria and a bit of clinical judgment to see the new and the revision access cases that I think will particularly benefit from this vessel.

I would just add, it's important to be holistic. It's important to look at the whole patient. And I think all of the things that Dr. Jose spoke about come into play. I do think that as there is more and more experience, the earlier question was about expanding indications potentially. But I think as we get more and more experience with the ATI, I think we're going to find more patients who could benefit from them.

Okay. And then if I could do one more follow-up question. Dr. Roy Chaudhury shared some data from the U.S. renal data system database. There's a subpopulation in there with grafts, 21%, I believe. And I just wanted to know what kind of grafts are you using today? And how would you approach that particular subpopulation if you have the ATF available?

Yes. So the grafts that are generally being used today are standard PTFE grafts. We've used the same grafts, I think, for the last 40 years. And what I am particularly looking forward to is data that shows that if you use the ATV in a female population who almost by definition, are at high risk for problems with all sorts of vascular access, fistula and grafts, if we find that the ATEV performs well, I think that is -- I think that's hard data that to me would be very, very important.

Our next question comes from Charles Wallace at H.C. Wainwright.

So when comparing the V007 and the V12 study, the study populations are a little bit different and maybe potentially there's room for the ATEV gap to widen. So I just wanted to maybe get a better understanding on how you think the benefit will be for the number of catheter days between the ATEV and the A.fistula patients compared from the V12 study to the V007 study.

I think it's a very good question, and I can go over one nuance that's important to me. So as I mentioned, in the V007 study, 2-stage fistulas were excluded. So many patients, they need 2 surgeries, one to prepare the vein, do a little connection. And then a second surgery, usually about 2 to 3 months after when the vein has developed, matured and to bring it closer to the skin, either because it's too deep or it's not accessible because it's a [indiscernible] vein that's developed away and deep in the arm. So those patients were excluded from the first trial. The second trial, the VE012 is more pragmatic in that those are fistula patients. So those patients are included. And I think the more representation of the real world, like some high-risk patients will need 6 months and 2 surgeries to get the fistula usable. So I think there will be a more direct comparison between what's actually happening in the real world in women versus ATEV. And we don't know the results yet, but my expectation is that the time to using an AV fistula in the control arm would be longer in the control arm in V012. -- but that's my hypothesis, and we'll see.

Yes. I think I would only add that RTL is a very inclusive study for women. In one way, it's a study for women, but it's quite inclusive compared to tell them. And the thinking was, well, of course, it's good to have a big gap from a product perspective, but the thinking was more to see to conduct a very balanced clinical trial, which was in all its facets discussed with the FDA, and they were quite conservative in a number of instructions they provided, which we incorporated. So our goal was to make sure that this truly represents the clinical population, especially in women and be inclusive and we'll look at both maturation time and eventual success rate as 2 big factors that can perhaps help differentiate and lower catheter dependence on ATEV versus ABF.

Great. Thanks for the question, Charles. So it looks like that concludes our Q&A session. I'll turn it back over to Laura for quick closing remarks.

Well, I just want to give a huge shout out to our speakers and Dr. Parikh for really describing the landscape in kidney care, especially for women, patients with kidney failure who rely on hemodialysis in order to survive. This is a very complex population. And it's a population that has seen very little genuine innovation as our speakers said, for decades. So I personally am very excited to see the results that we've already generated in the Phase III trial, and I'm really excited to see what's going to come in June. So I appreciate all of your attention, and I appreciate all of the participants, and I wish you a nice day.