CareDx, Inc. (CDNA) Earnings Call Transcript & Summary

Hi. Welcome to CareDx's Innovation Day. My name is Reg Seeto, President and CEO of CareDx. Really proud to be hosting Xenotransplantation Innovation Day. This is our fourth in a series. And what an incredible series it's going to be. As we look at today, we really have an incredible host and panel, which I think is going to be really the sort of luminaries and the experts of this entire space. And as we think of xenotransplant, it's always been on the cusp of victory, right? Always on the cusp of excitement. And what we see here today is two of the leading pioneers in the space, Dr. Bob Montgomery, Dr. Muhammad Mohiuddin will be talking about their experiences. And I think we're all super excited to what they're going to tell us about. We've also seen an incredible number of companies now emerging in this space. And so we have presentations today both from Miromatrix, and also eGenesis. And as we think of this incredible day, we're going to open off with some opening comments from some of the different patient and physician advocate groups that we have. We're going to start with Dr. Osama Gaber, who is the President of ASTS. We're also going to have Dr. Andreas Zuckermann, who is the President-Elect of ISHLT. We also have Dr. Palevsky, who is also President of the NKF. And also, last but not least, we always have patients which are core and center on what we do at CareDx, which is Jim Gleason, who's the President of TRIO. So before we go to first introduction, I just want to say CareDx has been around for more than 2 decades, if I think of the hard work and sweat and tears we've put into building this company driven by innovation, I think of the work of xeno. Xeno has been such an incredible space and one which has, I think, going to transform what we can do in the field of transplantation. And it really takes a grit and really takes a lot of passion, but also a lot of hard work. And I think what you'll see today is although it's a 1-hour presentation, it has taken decades in the making, and these are the leaders in the space. So now I'm going over to the first introduction.

Hello, everyone. I'm Dr. Osama Gaber, the President of the American Society of Transplant Surgeons and a transplant surgeon at Houston Methodist Hospital. Really excited for being here today to say a few words at the start of this very exciting meeting. The whole concept of xenotransplantation has been a dream of the transplant field and the patients for many years. And it's really important for me to salute the pioneers, the researchers and the people who worked very hard consistently for 50 years or more to bring us so close to reality with xenotransplantation. And I'm excited that you're going to hear from some of them very soon. On behalf of myself, the ASTS, transplant surgeons and transplant professionals, I would like to also thank the organizers for putting together the resources and the time to create this conference. And I want to assure everybody that we as surgeons and transplant professionals, are behind the researchers in their continuous efforts to bring this treatment into a safe and effective reality for our patients. Finally, I want to remember and honor those patients that were part of this experimentation throughout the multiple years that we've been trying to do xenotransplantation, particularly David Bennett of Maryland, whose courage, vision, has allowed you to make a decision to be the heart transplant recipient that we all watched with awe as his life was prolonged by this amazing procedure. Thank you very much.

Hello. My name is Andreas Zuckermann. I'm the President-Elect of the International Society for Heart and Lung Transplantation. And on behalf of the society, I really want to welcome you to be a warm welcome. I want also to thank CareDx for organizing this. And of course, I am absolutely still astonished about this milestone in transplantation science and medicine that happened at the beginning of this year. I would keep it similar to our first successful heart transplantation in 1967 by Christiaan Barnard and maybe the first [ ECP ] heart transplant -- successful heart transplant done by Peter MacDonald and Kumud Dhital in Australia in 2014. I think for me, it's like a childhood dream because when I was a young surgeon, I met the late David White right who, in the 1990s, he was really [ envisioning ] clinical xenotransplantation for all organs. And I never would have thought that it would come back as strong as it has over the last years when more and more information came up that this might really be the time that the clinical xenotransplant could be worked out and could be successful. I have to congratulate all the scientists and all the clinicians who have been involved in this very exciting new development of transplantation. And of course, I bow my head to the patient who underwent the first heart transplantation with xenotransplant, and he always will be remember also as a pioneer, a very tough person who went through all of this. So I'm really excited to look forward what we can hear, what we can listen, what we can learn on this exciting new topic. And again, I want to thank CareDx for organizing this meeting. So thank you very much.

Good morning. I'm Paul Palevsky. I'm the President of the National Kidney Foundation and a nephrologist at the University of Pittsburgh and VA in Pittsburgh. I want to add my welcome to those that we've already heard and thank CareDx for organizing this meeting. The National Kidney Foundation represents patients and caregivers taking care of patients with kidney disease, and we are extremely excited by the opportunities that xenotransplantation will pose. As I think all of you know, there are approximately 80,000 patients awaiting kidney transplantation in the United States and severe shortage of organs resulting in a median wait time of over 50 months for patients listed for kidney transplantation and more than 4,000 patients on the transplant list dying while waiting for transplants. The opportunities that xenotransplantation provides are extremely exciting, although we recognize that there are still many, many barriers that are going to need to be overcome. And in fact, the Kidney Foundation is hosting a workshop on xenotransplantation next month to address many of these issue. So I want to just, again, welcome you to this exciting meeting and again, thank CareDx for organizing it.

And I'm Jim Gleason, I'm a patient out 28 years after a heart transplant and also happen to be the President of an organization for patients called TRIO, Transplant Recipients International Organization. And next to me I have the honor of being among these amazing people here who represent that patient community. Back 16 years ago, I was at Valley Forge Middle School promoting organ donation as part of the panel. And one of the students asked about xenotransplant. And honestly, I told them at that point, I hadn't heard anything recent about it. I probably thought it was dead technology. And then to be invited back in July of 2019 by Bob Montgomery to an event in New York City with other patients to discuss what would it take for patients to accept a xenotransplant? What an amazing conference you had there, Bob. Really appreciate being part of that. And so it was alive and well. And so I'm very excited about the recent New York and Maryland successes with the next steps in Xenotransplantation especially with the heart transplant there in Maryland, followed it closely. And again, what amazing man to volunteer to be that next step in this amazing technology. And so it really is an honor to be part of this panel. And I think CareDx giving this opportunity and look forward to hearing all these experts talk about amazing things. I never expected to be alive to see this technology work in my lifetime. And here I am 28 years out, watching it developed into something real. Over 100,000 people waiting for transplant, this is great. Thank you.

Well, Jim, you couldn't have teed that up better. I mean I was reading the Oxford dictionary this morning and he said, the definition of pioneer, one who goes before to prepare and open the way for others to follow. So it gives me great pleasure to introduce two pioneers now: Dr. Robert Montgomery from the NYU program, Director of Transplant who was involved and led the program for the first kidney transplant that was done from xeno organ. And then Dr. Muhammad Mohiuddin, who led the program at Maryland, as Jim so nicely shared. They're now going to share their thoughts on exactly why we're so excited that xeno, which has always been around the corner, is finally here. Over to you Dr. Montgomery.

Thanks so much, Sham, and welcome, everyone, and it's wonderful to be with you all today. These are my disclosures. The most important one is that I have received and our team has received research funding from United Therapeutics. So I just want to briefly talk about what the barriers have been to clinical xenotransplantation. And I'm sure most people realize that we had this sort of wall in front of us that we could only sort of peek around until very recently, and that was -- that wall was these molecular incompatibilities between the various animals that we had considered as donors for xeno transplantation and humans. And what really comprises this wall are the sugar molecules that are expressed on animal cells and the enzyme that produces these molecules was lost during evolution between the pig and humans. And so humans make what have been referred to as natural antibodies against these glycans. And there's one in particular called alpha-gal that actually contributes very significantly up to 1% of the total IgG in the human body is against this one sugar molecule. And we think that those antibodies result from cross-reactivity between that sugar molecule and the surface of bacteria in our colon that must be kept out of our blood stream. And so we have this natural response to it. And these antibodies, when a pig organ is connected to the human vascular system and perfused, will immediately find plenty of targets on pig cells and cause a hyperacute rejection. That was the case up until the last really about 20 years when we're able to make genetic modifications in the pig genome to knock these molecules out from being expressed. The second really biggest concern that has been with us really since the beginning of xenotransplantation is the concern that organism could jump between the organ and a human and cause a zoonotic infection. And the main concern with pig organs are porcine endogenous retroviruses, which are encoded in the genome. And there are basically 2 ways to safeguard or mitigate against this. One is to try to remove all those sites, which has been successfully done, and you may hear a few words about that later. And the other is really close surveillance because we really think this is not as big a threat as we once did. And there are over about 200 individuals who received porcine stem cells, skin grafts, or tissue that have been screened and there's never been an example of transmission of this virus. There are also known incompatibilities in many pathways that are important that regulate certain things, particularly in the kidney, which is a very complex organ, things like our blood pressure, electrolyte balance. And then in some of the systemic pathways, like coagulation and complement, and these have been addressed in some of the pig constructs that are being tested by introducing transgenes. And really up until about the past 10 years or so, there had been fairly inconsistent long-term outcomes in nonhuman primates, which has been the model that we've done our preclinical testing in -- and then there's always been the question of how translatable the findings and nonhuman primates have been to humans. Now we're kind of victims of our own success in as much as Allotransplantation is wildly successful now. And someone who receives a kidney transplant can expect to have a functioning kidney and be alive at 1 year at a rate of about 97%. And the insufficient supply of organs, which is the results in all of these deaths every year is kind of an existential threat. And the excellent results in Allotransplantation have really been put up as the -- what we're trying to achieve with something like xenotransplantation or bioartificial organs, which is at such an earlier stage in development. And there's been a call for equipoise between the 2, which I think has somewhat inhibited our progression. Now if you ask 10 people, what is the number one unmet need in transplantation today? I think 9 out of 10 would say it's organ supply. There's always one contrarian in the group. And as stated earlier, up to 50% of the people who are listed for transplantation never make it across the finish line. And so we really need a moonshot. And bioartificial organs and xenotransplantation, I think, are the solar and the wind of organ supply that could give us an unlimited sustainable supply of organs. And so we've partnered with United Therapeutics to help develop both of these strategies. But today, I'll be talking mostly about xeno. Now one of the issues, I think, in the development of xenotransplantation, if you compare it to the real moonshot, so the Apollo program is that it's been difficult to test the individual components of this very complex technology, which I outlined a bit in that first slide, like they did during the various Apollo launches, and each one of those really focused on one component that needed to be tested like, for instance, docking or lunar orbit, all these things were required to land on the moon, but had to be assembled in a way that was testable. And I think going from a preclinical nonhuman primate to a first-in-human trial, Phase I trial is a giant leap. And that has, I think, to some degree, kept us a bit stuck where we have been for quite a while. And so we and others considered an intermediate step that might make sense for these kinds of high-state exploratory studies like xenotransplantation, which could essentially fail safe. So rather than putting a living human at risk, we could test this out in a recently deceased human. And so this concept, which I think at first seems perhaps a bit shocking, we have been thinking about for quite a few years. And Jim mentioned one of our focus groups that we did several years ago to try to see what patients thought about this as well as xenotransplantation. And there is precedent for this kind of thing. So when we fill out our organ donation cards, one of the boxes is would we consider donating an organ for research. And many people elect this. And then anatomical donation, so donating your body after death is as old as medical students, right? So we assemble legal experts and ethicists and religious leaders to think about the idea of whole body donation. So this is someone who's unable to donate their organs, they are not suitable for donation, but really wanted to realize their altruism at the time of their death to make a difference. And instead of donating organs, they donate their body for a series of studies or a test to be done, like testing an organ -- a xeno-organ or bioartificial organ. Now this had to be vetted. It had to go through all the regulatory organizations, which we did. And then on September 25, 2021, we performed this xenotransplant. So this was a very simple genetics. It was an alpha-gal knockout, which, again, is that sugar that most of our xeno reactive antibodies targets. And on the picture on the right, you can see at the end of 2.5 days, this pig kidney that we implanted is not in the usual place where we put a transplant, but on the groin vessels, so the femoral artery and vein, and then we were able to cannulate the ureter with that tube that you can see on the left and collect [ the urine ] coming out of that kidney. And then we performed a second xenotransplant, again, in this brain-dead individual whose family consented to have this test done. And we, again, perfused this kidney with the decedent blood by connecting the blood vessels -- and for another 54 hours and the picture in the middle is right after reperfusion. And then on the right side is at the end of the study when the kidney was removed and the decedent was then disconnected from the ventilator. And you can see on the left side, in addition to the genetic modification that we made, the alpha-gal knockout, we also transplanted a portion of the pig's thymus with the kidney. So marked there with that blue stitch, you can see a thymic lobe that's underneath the capsule of the kidney, the thymus is involved in educating the immune system and the T-cells in particular. And so the idea here is that there are a lot of amino acid variations between pig and human, a lot of neoantigens or targets for the adaptive immune system. And this thymus can delete, and that's been shown in animal models, T-cells that may be reactive against the pig kidney. And these are the results in terms of the urine output and the change in the function of the kidney. So the dotted line in the middle is when we did the xenotransplants and then florescent green and blue are transplant #1 and #2, respectively. And you can see that the function doubled after the time of the transplant. We had excellent urine output. About a week after, we did our first transplant back in September, the group at Alabama did a very similar experiment. The main difference was they removed the decedent's native kidneys and placed 2 xenografts, and this was a 10-gene pig that had 4 knockouts, including the growth hormone receptor and then a number of transgenes or knock-ins. And on the side of the screen, you can see in their publication. At the top is the urine output. One of the kidneys really didn't function in terms of producing urine much at all. The other one did make urine, but on the bottom on the right, you can see that the kidneys didn't appear to effectively remove some of the toxins and that looks at the [ creatinine ]. And the reason, why, I think in the middle, you can see a blue circle, which demonstrates that there was fiber and thrombi in the kidney -- and this is one of the complexities of doing the study in a decedent, a brain-dead donor because there's brain-dead physiology that can recapitulate some of the things that we see actually in rejection. And this was always something we knew that was a possibility. And they did see it in this -- these 2 kidneys, we didn't see it in our 2 kidneys, but this is something that has to be thought about and addressed in this model. And I think you're going to hear later a lot about bioengineered organs, and we are using this same approach to test pig organs, pig scaffoldings that have been decellularized and then repopulated with human cells. And again, the idea here is that they can be tested in a decedent. And you can see on the left side of the screen that bell-shaped container that has a set of bioengineered lungs that are ventilated and then the decedent blood in an ex vivo fashion is being circulated through those lungs, and then we're able to test those lungs in the various parameters that you can get from that. And just -- I don't really have enough time to go into great detail about our 2 transplant -- our 2 kidney transplants, but I'll just mention that the most significant finding was there was no evidence of hyperacute rejection, and very little evidence of an antibody-mediated rejection. And the main constraint that we had with that model is that, it was only a very short period of time that we were able to test those organs mainly because families want to have closure in their loved ones death. And I just want to acknowledge our team, our very dedicated team. And I also want to acknowledge all the individuals whose shoulders we stand upon in doing these clinical studies, including an individual that was mentioned earlier, David White and there are many others who really have gotten us to this point where we can actually test these in humans. Thank you for your attention. And now I'm going to pass to my good friend, Muhammad, to talk about the first heart transplant in a living human, which is very close to my heart because I'm a heart transplant recipient too. And my whole family, we have a genetic disease. We're all very excited about what Muhammad's team was able to accomplish.

Thank you, Bob, and thank you, CareDx for the invitation. This is an honor to be presenting here and sharing. I mean, as you all can imagine, we are waiting for our scientific publications to be released and until then, what I can share would be very limited. But I will try to share a little bit to give you some flavor. I would like to start by, like you all did, praising the guts of those patients who was brave enough to offer his life for this purpose and consented to this procedure. As you all know, we picked pig for several reasons, which are listed here. We now know the genome of the pig, so we can easily change it. They are -- anatomically, the organs are similar. They are -- breed well in captivity, and they grow in size quickly, so the organs get to the size of human quickly. And they are consumed in food, so we had that there will be less ethical issues. The physiology we are finding out that is also very similar. So in a heterotopic model in abdomen when you transplant the heart... [Technical Difficulties] I just want to show this picture because I wanted to honor our patient, Mr. Bennett, who devoted his life for this purpose. So I was showing that when you transplant this xenograft in unmodified heart, within minutes, you see this picture where you can see microvascular thrombosis going on and seeing all the cardiac myocytes dying and with the interstitial edema and red blood cells in there. What happens is that as Dr. Montgomery described, we have circulating antibodies that recognize their antigen on the pig, mostly the carbohydrate antigens. They bind to it and with the help of complement, activate the endothelial cells and expose the lamina propria, which tracks the platelet aggregation. And soon, you have the clot formation and thrombus occludes the vessel and causes rejection. This is a typical immunosuppressive regimen that we have developed over the years to suppress this kind of rejection besides working on the genetic modifications. This includes induction with ATG and Rituxan and also blocking complement with either cobra venom factor or [ Badinor ]. We maintain these hearts on anti-CD40 for a long period of time and also on MMF. We taper down the steroids after a short period in about 2 months. So this is just -- as a proof of concept, what we've shown in our heterotopic model in the abdomen is that we were able to have long-term survival up to a year -- up to 3 years almost. And when we removed this antibody completely, the anti-CD40 antibodies, all these hearts rejected. So this is around like 784 days, heart is beating well. And as you can see here in the in the echocardiogram, the graft function was great. This is the histology on the left around the time when we pulled anti-CD40. So we noticed that even at that later stage when we remove the antibody, the heart cell starts to reject and within 2 months, they have another heart attack. So we are very confident that anti-CD40 is required at least in our system. So the next logical step was to transition into orthotopic model. Our initial results were not good. All our hearts were kind of failing within 48 hours. And then our German collaborators discovered that if we use cardiac perfusion using the sustained solution, which has a lot of ingredients, including cocaine in it, the heart overcomes this 48-hour failure period. And that's what we did. We used the -- we acquired this machine where we take the heart out, perfuse it up for about 2 hours and then transplant into the baboon. And this was how this machine works. It's a nonischemic cardiac perfusion method at 8 degrees centigrade with 20 millimeters pressure. So after perfusing it for 2 hours, when we transplant it, all these hearts have overcome this 48-hour period, which we termed as perioperative cardiac xenograft dysfunction. So that's -- while we are doing this, we are also with the help of Revivicor, our collaborators, where we're trying to genetically modify the pigs and people who don't know how that's done, the eggs are taken out from the pig, they are enucleated and the genetic material that's constructed outside is inserted into the eggs and the eggs are then put back into the ovary. And over a period of time, they -- these piglets are born with the genetic construct that we have inserted into the eggs. This is historically, and you can see the different genes were identified, either they were knocked out or knocked in. And these are the four that we knocked out in our ultimate pig that we used in Mr. Bennett. There were three knockouts, which were carbohydrate knockouts and one growth hormone receptor knockout, which we used to control the growth of the organ. There were several transgenes addressing the complement dysregulation, coagulation dysregulation and also controlling inflammation. This is just to check that these genes were properly expressed and genes were knocked out like these 3 genes and the western blot showing that the transgenes were adequately expressed. So with this, we progressively -- with gene modification and keeping our immunosuppression the same, we have progressively increased the graft survival. And in orthotopic also, we have now a survival of about like 9 months in one study, which has just been accepted for publication. So from that point on, we also were concerned about the growth. So the growth hormone receptor knockout. This group has had growth hormone intact. As you can see, the heart got rapidly thick, whereas this is our 9-month survival where you can see that the graft did not get thick and it did not reject either as you will see here that this animal guide of some infectious complication, which cost the lives of 4 other baboons in our colony. So here, you can see that the typical rejection was also seen. So the growth is multifactorial and the rejection plays a greater role in that role, whereas as you can see, with rejection was avoided, there was no signs of rejection after 9 months. So with this, we decided to go to the FDA to see if this is enough for clinical trials. They said no, you have to do more animal work. And in the meantime, we came across this provision of emergency IND, and we decided to pursue it. Our cardiologists, the heart failure group identified Mr. Bennett. His medical history included non-ischemic cardiomyopathy secondary to longstanding hypertension, mitral valve repair. He presented to outside hospital in a cardiogenic shock on multiple inotropic agents and intra-aortic balloon pump. Ultimately, developed multiple vent arhythmias, arrhythmia arrest requiring the ECMO support. So he was on ECMO for last 40 days until the transplant. And then he was on ECMO for 4 more days after the transplant. His EF was around 11% due to severe sarcopenia and inability to ambulate for 3 weeks and the major reason of noncompliance, he was not a candidate for any other mechanical device. So we sat down and we -- this is my Dr. Griffith, my partner in crime, who performed the surgery, along with me, and this is Corbin one of our residents. So we -- this is our board in my office that shows that the FDA time line, we believe it took about 10 days for them to approve this with a lot of back-and-forth communication. And then when we got it approved, we found out that we need several other approvals from our institution, including the financial approval because this patient was not covered by any insurance. Finally, we got all these approvals and the transplant was done, and it was successful, as you all know, through the news. Here, I would like to mention some of the ways we had to deal with this patient compared to our baboons, which are healthy baboons, but this patient was very sick. And so we had to tailor his immunosuppression. So the immunosuppression regimen that I showed you before, and -- we had to change it significantly to fit the needs of this patient and also to prevent him from becoming infected, which we basically were not able to do it. And that's why we had to stop MMF after some time and -- just because he was -- his white cell counts were doing down to almost 0, and he was -- there was -- we're afraid of bone marrow suppression. So there were several other ways we were trying to measure the function and the status of the heart that is -- and the patient and the majority of that case, we were using echocardiography, the transthoracic echocardiography to determine the function. We've done three different biopsies at different time point. His low platelets were kind of deterrent for biopsy also. And then with the help of CareDx, who developed is AlloSure and AlloMap, which I'll talk a little bit about, we were able to monitor the function of the graft. Troponin, though not used as a major marker in allotransplant, but was very informative in our case. We also did antibody analysis and flow cytometry. So here you can see what was found to be the most important measure was the strain analysis. This is around like day 5, as you can see. The higher the number, the number in 30s means very good, stinginess of the heart. And this is day 5. This is day 14, as you can see. And this is about 6 weeks where the numbers have gone down a little bit, but still, if you can see the contractility was great. So besides this, we, with the help of CareDx, used the AlloMap. The AlloMap measures gene expression in human peripheral blood and mononuclear cells. There are 11 genes in AlloMap that were chosen and algorithms were trained and validated to discriminate questions from the rejection, higher scores correlating with rejection. So -- and it is used only after 2 months post-transplant. Therefore, interpretation is not straightforward in xenotransplantation model because this patient lasted only 61 days. We have examined the AlloMap score as well as details from individual genes to explore correlation with outcomes and treatment that may inform on future heart xenotransplantation evaluations. I do have some results, but just because of publication, I'm not able to show it. In fact, donor-derived cell-free DNA, which we have also worked in past with had an amount of time was also very helpful. So CareDx is in a process of validating this process for xenotransplantation, and I'm very confident that this process in xenotransplant model will be very helpful in the future. So summary of what we know and what we can tell at this time and can share with you. The patient had pre-existing conditions. He was severely debilitated and have repeated infections, which complicated the recovery of the patient from surgery. And there was involvement of multiple system include his kidneys, his gut and his musculoskeletal system. He got very sarcopenic. He lost about like 20 pounds during the stay. The immunosuppression had to be tailored based on his WBC count and other issues he was having. His kidney function was probably due to dissection we noticed during the surgery and had to be repaired and had a period of ischemia that also affected his bowel. So they -- in the biopsies, we have not seen any typical signs of rejection. They are -- we have not seen any cellular infiltrate. All we have noticed is interstitial edema and some of which, which in later biopsies were converting into fibrosis and causing the heart to get a little bit thick in the end. So this is all I can share at this time. We have a few publications in press. Hopefully, we'll be able to share it more after that. With that, this is my lab that did most of the work. And this is the group and -- or part of the group that performed the surgery and to care of the patient. With that, thank you very much for your attention.

Thank you, Dr. Mohiuddin and thank you, Dr. Montgomery for these really exciting talks, and it really strikes me how much has come before and how much research it takes. How many years and years of development to get to this point. So again, thank you. Today, we're announcing XenoSure and XenoMap, putting names on the tools that we've already talked about. XenoSure builds on our extensive experience with donor-derived cell-free DNA. We've been building research data in this space for over 10 years and have developed the leading service for donor-derived cell-free DNA surveillance in human allotransplant, we call AlloSure. And our application across many different solid organ transplant provides us with unique insights that we hope to be able to apply to this field of xenotransplantation. There's the number of transplant recipients, as we know, is still very small, even in preclinical studies and obviously, in clinical studies. XenoMap is based on our over 20 years of study of gene expression as a way to interrogate immune activity in transplant recipients. Our first product was AlloMap Heart published in New England Journal of Medicine, with over 15 years of use in the clinic now, and we're nearing completion of development of AlloMap Kidney with multiple independent observational cohort studies. And so it's with this that we want to bring to bear these data to benefit the Xenotransplant community. Initially, we helped generate insights in the many investigations in transplant research. But beyond that, I think we've already demonstrated some capabilities with investigational post-transplant monitoring in the clinic with our -- and our extensive clinical use across all of solid organ transplantation. And then, of course, in the future, we anticipate a standard of care for xenotransplant recipients. The invaluable research and experience of all of those presented -- who have already presented today and are presenting after this will inevitably lead to a rich future in xenotransplantation. So with that, I'll turn it over to our next presenter, Jeff Ross from Miromatrix, who's going to provide the latest update on their bioengineered organs.

Great. Thank you, for that. Thank you, everyone, for the opportunity today to be part of this conference. It was phenomenal to be able to see how far the field has come from hearing the stuff that we heard come out of Maryland as well as New York. Excited to introduce you to Miromatrix, and another way to increase the number of organs supply out there in terms of bioengineering transplantable organs. As a public company, I need to get this disclosure. But if we look at Miromatrix, our mission, similar to what we heard today, is to eliminate the organ transplant waiting list. We've heard about the numbers, over 100,000 patients waiting for an organ. I think the one that always sticks with me and resonates is that there's 70,000 patients this year who are going to go to their physician, be prescreened, but not receive life-saving technology. That's really our mission, how do we supply that. But not only stop there, the true need out there is probably 10x. How do we really serve that? And how can we fill that gap? It's because each and every one of those -- it's great having the patient focus, each and every one of those is a patient and a family and that's what we wanted to be able to help. We've attracted great strategic investors, including DaVita, Baxter, CareDx, and we work with some phenomenal scientific and medical collaborators as well. So with that, what is our technology, what is that ability to be able to bioengineer transplantable organs. What does that mean? Here's a short video that really describes what we're doing. [Presentation]

I always love that video. Hopefully, that's helpful to kind of give you a flavor of exactly how the technology comes together. Just to break that down a little bit more. You saw that we start with an existing organ. In this case, we start with a pig organ. As we heard about previously on the xenotransplant side, right? We share a similarity in size, shape, vascular density, our process allows us to remove all of those animal cells leaving us with that pristine matrix. Now one thing that we had to look at early on as well, is there any immune-related rejection with that? And for that, we actually took whole porcine livers, perfusion decellularized those and then created 2 medical devices with that through the 510(k) process and now have a great history of transplanted those products into patients without any adverse related conditions. The next step of that process that you saw inside of the video is we would place that into a bioreactor and then we infuse human cells into that to then be able to recellularize that organ using those human cells, that allows us to bioengineer the organs from that aspect, one of the key differences. And again, we're all, how do we get organs to patients? But one of the differences in this process is we're using human cells instead of animal cells in that recellularization. So some of the things you heard earlier about animal viruses and other things, we've demonstrated that we're able to remove all of those with the grafts as we move forward. Highly scalable technology and transplanted similar, really well protected. We have 118 issued patents, 35 patents pending as well. But if we dive a little bit deeper into this on the recellularization, because I get this question a lot, how long does it take? It takes about 2 to 4 weeks from the time that we add cells back in there to be able to get that maturation. And during that time, we're looking at nutrients oxygen as we recellularize these grafts. But the other question is where the cell is coming from? In our first generation of this, we used human donor organs, not placed for transplant, cuts, nicks, tears, long ischemia time. We're able to bring those in, isolate out those primary cells and then ischemia those cells back into our matrix that really what we believe allows us to have the fastest regulatory pathway to bring these to the patients that need it. And then ultimately, long term, which is the longer development process is the potential to use stem cells in this process as well and ultimately create a transplant that no longer needs immunosuppression. If we look at our pipeline, and I'll talk about this in a second, where is our data on this as well. I'll talk about ELAP that's using the liver outside of the patient, before moving it fully -- to a fully transplantable liver, which is our bioengineered liver, which is our MiroLiver and then our MiroKidney, which is our bioengineered kidney as well. We're making rapid advancement on the ELAP towards our IND as well as on the liver and kidney. The guidance that we've given on that is we're targeting our first human clinical study second half of '23, first half of '24 for those products. So if we dive in a little bit deeper as well. The thing that's important to us that you saw inside the video is really controlling our manufacturing. So we've built our own in-house manufacturing where you can kind of see the scale. And I like this photo because it starts to show how could you scale this up. We're talking about potentially creating thousands of grafts. You can start to see that footprint of how we're able to do that in our manufacturing. We don't outsource anything on the manufacturing side. We've got a fully integrated decellularization, humanized cell isolation and recellularization manufacturing that's really been built on our past products that we commercialized as well. So if we look at the data, what excites us on this approach as well as we move forward. On the kidney side, that first step and not to go too in-depth into this is how do you get the cells back in? And kind of three components on that, right, the vasculature, the glomerulus from the filtration standpoint, the nephron from the reabsorption. You can see our ability to get cells to relocalize to the appropriate microenvironment and then to be able to recapitulate those structures. For the first step that was important to us and important for any type of bioengineered organ is to demonstrate that you have vascular supply and solve the vascular challenge of tissue engineering that has always led this -- kept tissue engineering to very thin tissues. You've got to have that vascular supply that doesn't thrombose to be able to make these complex organs. There's an angiogram of where we recellularized the pig kidney -- decellularized pig kidney with human endothelial cells transplanted this back into a pig. And this is an angiogram after a week implanted. What you can see is just beautiful patency that exists, continue to see through that. We're then able to recellularize the rest of the kidney. We start to look at what that ureter outflow is, how is that first level of functionality. Where we are today is about 30% recellularization overall on the kidney. Our goal is to get that up to 60% to 70% through various optimizations continue to build on that. And that's going to be that gating point for us to be going forward with our clinical studies. If we next move on to the liver aspect of this and liver is a full orthotopic transplant that we're looking at on this front, here's some of our data on that. Again, first solving that vascular challenge. This was published in Nature Biomedical Engineering, the ability of us to revascularize that with human endothelial cells, transplant that back into a pig model, which work was done at the Mayo Clinic. And then we help those grafts. You can see the nice perfusion of that graft as we start to profuse through that portal vein. It's still going to be wide up at the top up there because we haven't completed the circuit. Once we pull off the clamp off the cable there, now you can see that complete perfusion. Now we've got perfusion of that. So now that's being perfused by the whole circulatory system at this point. The next step was to demonstrate that we can get functionality and demonstrate that functionality by recellularizing with liver-specific cells specifically looking at albumin, looking at urea output, but more importantly, look at some of the key things like ammonia clearance, where we can spike in high doses of ammonia and then we see nice kinetics of that clearance. That's important for overall liver functionality. So now that we have functionality on the bench, we want to take that into a large animal model. Again, we published this in Nature Communications Biology just last year where we transplanted this in and essentially ligated the native liver where during volumetric CT scans, you should see that liver be in there. It's absent, but you can see our transplanted bioengineered liver and then looked at this over 48 hours. During that time, the controls, which just had the ligated livers and essentially bypassing the portal, you see that large level of ammonia accumulation demonstrated in the acute liver failure. When we put in our grafts, you can see that the ammonia clearance -- ammonia is still coming up, but it starts to level off. In some cases, it's coming back down. Again, tying that functionality from what we were able to demonstrate on the bench now into a large animal model, this really sets us up next for our first product and proof of concept for this, similar to what you kind of saw Dr. Montgomery talk about on some of the [ ammonia ] stuff outside of the body is that ability to start with our organ outside the body. And this is our External Liver Assist, which we plan to be our first IND. And this is the ability to take our bioengineered liver, house this outside of the body and specifically look at this for the therapy of acute liver failure where we have patients today, 30% of the patients die who present with acute liver failure, 25% receive a liver transplant, because there's no good options for these patients today. This allows us to essentially do external liver dialysis for that patient while demonstrating in our first Phase I study, we'll be looking at safety and tolerability, but this still allows us our ability to look at time and dose-dependent biomarker changes and other things associated with our graft. So we're moving forward on this, really excited about where we're at on this. And then how this starts to play into our other products as well because we've always really had a focused regulatory strategy to derisk and accelerate towards human clinical data with that notion that we want to get it to patients as fast as possible. That started with the matrix demonstrating and getting that approved matrix, having a track record of implantations associated with that, demonstrating that functionality on the bench, the revascularization. And now on the doorstep of our ELAP to be able to start to look at that next level of bioengineered organs to be able to give that clinical benefit and then utilizing that data and proof of concept and other things as a stepping stone for our fully transplantable liver and kidney. So in summary, we talked a lot about this. We really do believe that transplant is one of the largest existing unmet medical needs that exist there, patients need it. We need solutions. We're excited about where we're going with this incredibly disruptive technology and had great support from strategic investors. I'll just leave it on this is we're really looking at changing the world of transplant and the patient experience. We see a future where people can schedule their transplant. So thank you for your time today.

Thank you. And I think we'll move right into the next presentation by Mike Curtis of eGenesis looking at their genetically engineered organs. Go ahead, Mike.

Super. And thanks a lot. And thanks to Reg and the CareDx team for the invitation and it's really my privilege to share with you some of the advances that the eGenesis team has made in the field of xenotransplantation over the past several years. We're leveraging modern advances in molecular biology and genetic engineering to improve the compatibility between porcine donors and either non-human primate or human recipients. I think my colleagues have talked quite a bit about the unmet need here. It's tremendous. What motivates us is the difference you can make in a patient's life if they get into in the case of a kidney transplant, a good allotransplant can completely transform person's life. I think as Jeff just mentioned, when we think about solving the organ shortage problem, it actually changes completely how you think about transplant, right? If there is an unlimited supply of organs of high quality and consistent quality, you could envision a day where solid organ transplant becomes as routine as is joint replacement, hip and knees. And that's kind of our overall goal here is to change completely how we think about transplant. So to accomplish this, we've put in place the EGEN Platform. And this is a platform that addresses both zoonotic transmission and the molecular compatibilities between the porcine donor and eventually human recipients. And at a high level, and as Muhammad talked about this a little bit, we start engineering a wild-type porcine cell. And we then do a series of modifications, I'll take you through some of the details on those modifications in a moment. And we really are applying CRISPR-Cas9 and some of the most advanced techniques in molecular biology to introduce the edits. And then we do a process called somatic cell nuclear transfer where we take that edited donor cell and make a porcine donor. And then we do a series of nonhuman primate transplants, and I'll take you through some of our incredibly compelling kidney transplant data today through collaborations with some of the leading academic centers in solid organ transplant. So to take you a little bit through the edits, the company was founded on the idea of using CRISPR-Cas9 to inactivate endogenous porcine retroviruses. So these retrovirus were discovered in the '90s. And at the time, it really slowed down the progression of transplantation because of the risk of zoonotic transmission. And as we all sit here into the second year of a worldwide pandemic or a third year of worldwide pandemic, I think we all can appreciate the potential risk of zoonotic transmission. And what George Church and the team at Harvard showed as they can use CRISPR-Cas9 to inactivate the reverse transcriptase in the endogenous retrovirus. Now every pig breed will contain anywhere from 50 to 80 copies of the retrovirus and CRISPR-Cas9 is really the ideal tool to inactivate endogenous retroviruses. This seminal work was published in 2 back-to-back science papers, where we showed we could inactivate it in porcine cells and then we showed we could actually inactivate it and produce live porcine donors. We currently have a small herd of retrovirally inactivated donors out in the Midwest. Most of the efforts for the past couple of years have been focused on the right side of this slide, which is, one, to inactivate enzymes that are responsible for hyperacute rejection. And Bob talked about the alpha-gal mutation in the case of the transplants that were done at NYU. We typically make what we call the triple knockout, right? And so this knocks out 3 enzymes that participate in carbohydrate synthesis and essentially eliminating acute rejection. This triple knockout was used in the kidney transplants that were done by Jayme Locke and the team at UAB, very similar sets of that edit. Where we've really been focusing is on the rightmost part, which is the introduction of regulatory human transgenes into the porcine genome to improve compatibility and promote long-term graft survival. We do this through a concept of a payload. Each payload will contain anywhere from 7 to 12 regulatory human transgenes, regulating with different mechanisms of compatibility like coagulation compatibility as well as mechanisms of rejection like complement activation and adaptive immunity. So any particular transgenic donor that we produce will have anywhere from 3 to 15 edits in the porcine genome and then we'll add the retroviral inactivation. So we're currently producing the most highly edited and most compatible porcine donors out there. And to do that, we've built a team both here in Cambridge of world-class molecular biologists, immunologists, computational biologists and regulatory affairs folks in the Midwest and Wisconsin. We have, again, another world-class team of cloning folks who know how to clone porcine donors, I think better than just about anyone, doing somatic cell nuclear transfer. This facility last year, we made over 500 transgenic donors. We've recently begun the build-out of a clean facility, we refer to this as a DPF. So this is a facility where we can produce clean donors that will enable that progression into clinical studies. And then all the transplant data I'll show you today has been done through a long collaboration now with the team at Mass General, but we have recently established celebrations with Duke, University of Wisconsin and are working towards establishing collaborations with other academic transplant centers. So before I take you through the transplant data, I think it's worth taking a few minutes to go through the renal nonhuman primate transplant model. And I think Bob had mentioned this earlier about the translatability of nonhuman primate transplant to predictability or what's going to say about what's going to happen clinically. A lot of the advances that have been made of allotransplantation have been pioneered in this model. I think it's important to take a few minutes to understand what the model is and what it isn't. In the case of the surgical approach, most patients when they receive a kidney transplant receive heterotopic transplant, so they maintain their own kidneys and the third kidney is added. And all the data I'll share with you today, these are life-sustaining transplants in the nonhuman primates, the native kidneys are removed and the single porcine kidney is installed. Now the challenge here is in the nonhuman primate, the supportive care is more limited than what's available for a patient in the clinic. For instance, there's no way to dialyze a nonhuman primate. So if we see any delayed graft function or any challenge with the initial function of the graft, we can -- that can lead to the loss of the recipient. If that happened clinically, either put the patient on dialysis or remove the kidney. We also see a higher risk of infection in the nonhuman primate. These recipients are on immunosuppression that can lead to opportunistic infections that you don't see clinically. For example, we see parvo sometimes in these recipients, and that could also lead to early demise of recipient. And then on the immunosuppression front, these animals are on suppression that comes with some comorbidity in the primate that you don't see clinically. An example of that is some body weight loss following sedation and animals lose their appetite for a couple of days following sedation and that little bit of body weight loss over the course of 100, 200, 300, 400, and I'll show you data to today, 500 -- almost 500 days of post-transplant survival can lead to the early loss of recipients. So when we add all these factors together, and we look at survival in that primate, you typically see a distribution of survival. You'll see some short-term survival, midterm and then what we're going for is long-term survival. And I think what we've said as a goal is at least 100 days-post transplant with some recipients getting out over a year, and we have recently achieved that goal. So on this slide, on the left most part of this graph are three sets of data from a summary basis of approval of belatacept for the treatment of patients receiving a renal allotransplant. So this is modeling the monkey to monkey, right? And so let's just focus on the data set to the left of the vertical line. These are 5 nonhuman primate recipients receiving an allotransplant plus belatacept with the standard of care. And you can see a distribution ranging from 50 days of post-transplant survival up to about 260 days and then one in the middle, right? So this distribution of survival is what you would expect. Now clinically, in this particular trial, 90% of patients achieved a 3-year post-transplant survival. So when we think about the nonhuman primate model, we think about it as a positive predictive clinical outcomes. If I can get to at least 1 year post transplant survival in a nonhuman primate, I have a reasonable expectation that I could achieve at least that clinically, if not longer. Now the data to the right are series of 15 transplants that we've done with our lead kidney donor. This is what we call [ EGEN 2784 ]. We have several transplants that are ongoing. But you see a very similar distribution. Some recipients we lose early, some in the mid transplant period, some now are approaching over 500 days post-transplant survival. If you break that down into a little bit more detail on the next slide, our ongoing -- I have control. On the next -- the data set on the left here are ongoing transplants. So you can see 2 recipients now approaching 500 days and several ongoing. The goal here is to get as many up to 5 recipients to be post 1-year post-transplant survival. And just to talk a little bit about the completed transplants on the right. And so you can see here now we've completed a total of 9 transplants. And we've bucketed them for a short-term survival less than 25 days. These are typically some version of delayed graft function, a ureter structure that can't resolve and we end up losing the recipient early. It's not rejection. The middle bucket, both of these recipients were suffering recurrent infections, which contributed to early loss of the recipient. But again, from histology, the graft was doing well. And then we have recipients over 100 days post transplant and all of these were suffering some kind of opportunistic infection or, for instance, in the case of recipient 6,120, that recipient that was used and is around day 240. This recipient had hydronephrosis or buildup of urine in the kidney. The surgeons went back in to stent the ureter, improving the health of the animal, wanted to go back in and re-stent, but because of concerns for animal welfare, we couldn't. Now that would never happen clinically. We would minimally go back in and re-stent or take the kidney out and put the patient back on dialysis. Again, this is something that we can't do in the nonhuman primate. So with this data, we're preparing to have our second formal interaction with the FDA around midyear in the form of a pre-IND meeting. Our intention is to take this to IND within the next -- well, our intention is to go to the FDA and have a discussion with them about our CMC plan or nonclinical safety plan and then our initial clinical trial. And with that in hand, then we would be prepared to go to the clinic. In addition to the kidney program, we also have a very active islet cell program. Where we're studying porcine islets -- genetically modified porcine islets in nonhuman-primate models of type 1 diabetes and are starting to see encouraging signs on C-peptide levels. And then we also have a heart program, planning to do something very similar to what Muhammad and the team at Maryland have done. And then the last program is the liver perfusion, very similar to what Jeff had talked about, about using an [ ex-fetal ] perfusion approach. I think -- and just to summarize, I think we are producing the most compatible and safest through the retroviral inactivation porcine donor organs that are available. So happy to take any questions.

Yes. Thanks, Mike, and thanks, Jeff. I think the questions are coming through, and we'll forward some of them to you afterwards as well. I know for time, we're a little bit over, but I want to thank all the presenters, particularly both with Bob and Muhammad, I think it's been truly inspirational of what you've done as pioneers in the field. And just we had a series of questions, but I think we'll just leave with one just given where we are with the presentation a bit over. What is next for xenotransplantation? It seems the theme of the questions we're getting through like when is the next clinical study or when do we expect more broad usage? So I'll get Bob to go first, and then I'll hand over to Muhammad for second before I wrap. Bob?

Yes, sure. So I think we're all trying to move towards the Phase I trials, IND-enabling work that is ongoing now I think, by each of the investigators that spoke today. And again, the time line is probably a year or 2, before those are going to be underway.

Thank you. Muhammad?

It is the same thing. As I mentioned during the talk, they required us to do those transplants in nonhuman primates to move to the clinical trial. So we are in the process of talking to them and providing a plan to move forward. And I anticipate right in a year or 2, we should be starting those trials.

Great. Thank you. Well, for Innovation Day, given this is our fourth one, this is truly being the most exciting and fascinating. I think really as we move the field of science and innovation, this is just truly incredible. At CareDx, we're really proud to continue to drive innovation. I think this is so important for the field of transplant. And I think seeing Jim or seeing Bob, who are both patients is just such an excellent reminder for us what we do day in, day out. A thank you for the physicians who did dial into everything you do for transplant patients. I think for the investors, just always remember, it's about how do we make a difference for the transplant community. That's what we do day in and day out. That's our mission. And so if investors are listening in, please continue to invest in this incredibly important field. The work you see is truly inspirational. I think of what Dr. Mohiuddin and Dr. Montgomery have done is just I really can't believe that at this point in time. I think Jim put it best when he said, 28 years on, he never thought to be seeing this, and I never thought I'd see this in my lifetime, too. So I'm truly thrilled and I'm so excited that CareDx as part of this. And thank you again for all your time and attention today. Thank you again for transplant patients. Bye now.