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 the fourth in a series, and what an incredible series it's gonna be. As we look at today, we really have an incredible host and panel, which I think is gonna be really the memories and the expertise of this entire space. As we think of xenotransplant, it's always been on the cusp of history, like always on the cusp of excitement. What we see here today is two of the leading pioneers in the space, Dr. Robert A. Montgomery, Dr. Muhammad M. Mohiuddin will be talking about their experiences, and I think we're all super excited to see what they're gonna tell us about. We also see an incredible number of companies now emerging in this space, and so we have presentations today both from Miromatrix and also eGenesis. As we think of this incredible day, we're gonna open up with some opening comments from some of the different, you know, patient and physician advocate groups that we have. We're gonna start with Dr. A. Osama Gaber, who's the president of ASTS. We're also gonna have Dr. Andreas Zuckermann, who is the president-elect of ISHLT. We also have Dr. Paul Palevsky, who's also president of the NKF. Also, last but not least, we always have patients, which is so important to what we do at CareDx, which is Jim Gleason, who's the president of TRIO. Before we go to the first introduction, I just wanna say CareDx has been around for more than two decades. As I think of the hard work and sweat and tears we've put into building this company driven by mission, I think of the word xeno. Xeno is in such an incredible space and one which has, I think, gonna transform what we can do in the field of transplantation. It really takes the grit, and it really takes a lot of passion, but also a lot of hard work. I think what you'll see today is, although it's a one-hour presentation, it's taken decades in the making, and these are the leaders in the space. Now I'm gonna go 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 to be here today to say a few words at the start of this very exciting meeting. The concept of xenotransplantation has been a dream for the transplant field and the patients for many years. It's really important for me to salute the pioneers, the researchers, and the people who worked very hard, possibly for 50 years or more, to bring us so close to reality with xenotransplant. I'm excited that you're gonna 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. I wanna 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 wanna 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. His courage, his vision has allowed him to make a decision to be the heart transplant recipient. 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 President-Elect of International Society for Heart and Lung Transplantation. On behalf of the society, I really want to welcome you to the warm welcome. I want to also thank CareDx for organizing this. Of course, I am absolutely still astonished about this milestone in transplantation science and medicine that happened at the beginning of these years. I would keep it similar to our first successful heart transplantation in 1967 by Christiaan Barnard and maybe the first DCD successful heart transplant done by Bartley Griffith and some other people 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, who had, in the 1990s, was really envisioning clinically xenotransplantation for all organs. 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. This might really be the time when clinically xenotransplantation 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. I bow my head to the patient who underwent the first heart transplantation with a xenotransplant, and he always will be remembered also as a pioneer and a very tough person who went through all of this. I'm really excited to look forward what we can hear, what we can listen, what we can learn on this exciting new topic. I want to thank CareDx for organizing this meeting. 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 in the 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. 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. A severe shortage of organs resulting in a median wait time of over 50 months to patients listed for kidney transplantation and more than 4,000 patients on the transplant list dying while waiting for transplants. The opportunities that xenotransplantation provide are extremely exciting, although we recognize that there are still many barriers that are going to need to be overcome. In fact, the Kidney Foundation is hosting a workshop on xenotransplantation next month to address many of these issues. I want to just again welcome you to this exciting meeting and again thank CareDx for organizing it. I'm Jim Gleason. I'm a patient [who has] had a heart transplant for 28 years, and also happen to be the President of an organization for patients called TRIO, Transplant Recipients International Organization. I have the honor of being among these amazing people here to represent our patient community. Back 16 years ago, I was at Valley Forge Middle School, promoting organ donation as part of a panel. One of the students asked about xenotransplant. Honestly, I told him at that point I hadn't heard anything recent about it and probably thought it was good technology. Then we were invited, back in July of 2019, by Robert Montgomery to an event in New York City with other patients to discuss what it would take for patients to accept a xenotransplant. What an amazing conference you had there, Bob. I really appreciate being part of that. It was alive and well. Very excited about recent New York and Maryland successes with the next steps in xenotransplantation, especially with the heart transplant there in Maryland. I followed it closely. What amazing man to volunteer to be that next step in this amazing technology. This is an honor to be part of this panel, and I thank CareDx for giving this opportunity and look forward to hearing all these experts talk about what amazing things. I never expected to be alive to see this technology work in my lifetime. Here I am, 28 years out, watching this develop into something real. Over 100,000 people waiting for transplant. This is great. Thank you. Well, Jim, you can't top that out by there. I mean, I was reading the Oxford Dictionary this morning, and it says, "The definition of pioneer: one who's first person to prepare and open the way for others to follow." 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 with the xeno. Dr. Muhammad Mohiuddin, who led the program at Maryland, as Jim so nicely said. They're now gonna 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, Graham. Welcome everyone, 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. I just wanna you know briefly talk about what the barriers have been to clinical xenotransplantation. I'm sure most people realize that we have this sort of wall in front of us that you could only peek around until very recently. That wall was these molecular incompatibilities between the various animals that we have considered as donors for xenotransplantation and humans. What really comprises this wall are these sugar molecules that are expressed on animal cells and the enzyme that produces these molecules was lost during evolution between the pig and humans. Humans make what have been referred to as natural antibodies against these glycans. There's one in particular called Alpha-gal that actually contributes very significantly. Up to 1% of total IgG in the human body is against this one sugar molecule. 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 bloodstream. We have this natural response to it. 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 were 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 a organism could jump between the organ and a human and cause a zoonotic infection. The main concern with pig organs are porcine endogenous retroviruses, which are encoded in this genome. There are basically two 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 of them later. The other is really close to close, because we really think this is not as big a threat as we once did. There are over about 200 individuals who received porcine stem cells, skin grafts, or tissue that have been screened, and there's never been examples 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. These have been addressed in some of the pig constructs that are being tested by introducing human genes. Really up until about the past 10 years or so, there has been fairly inconsistent long-term outcomes in non-human primates, which has been the model that we've done our preclinical testing in. That has always been the question of how translatable the findings of non-human 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 one year at a rate of about 97%. The insufficient supply of organs, which is that results in all of these deaths every year, is kind of an existential threat. The excellent results in allotransplantation have really been put up as, you know, what we're trying to achieve with other things like xenotransplantation or bioartificial organs, which is at such an earlier stage in development. There's been a call for equipoise between the two, 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. As stated earlier, up to 50% of the people who are listed for transplantation never make it across the finish line. We really need a moonshot. 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. We've partnered with United Therapeutics to help develop both of these strategies. 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 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. Each one of those really focused on one component that needed to be tested. Like, for instance, docking or lunar orbit, all these things that were required to land on the moon had to be assembled in a way that was testable. I think going from a preclinical non-human primate to a first-in-human trial, phase I trial is a giant leap. That has, I think to some degree, kept us a bit stuck, where we have been for quite a while. We and others considered an intermediate step that might make sense for these kinds of high-stakes exploratory studies like xenotransplantation, which could essentially fail safe. Rather than putting a living human at risk, we could test this out in a recently deceased human. This concept, which I think at first seems perhaps, you know, a bit shocking, we have been thinking about for quite a few years. Jim did mention one of our focus groups that we did several years ago to try to see what patients thought about this, as well as, you know, transplantation. You know, there is precedence for this kind of thing. When we fill out our organ donation cards, one of the boxes is, would we consider donating an organ for research? Many people elect this. Anatomical donation, donating your body after death is as old as medical students. Right? We assembled legal experts and ethicists and religious leaders to think about the idea of whole body donation. This is someone who's unable to donate their organs. They're not suitable for donation, but really wanted to realize their altruism at the time of their death to make a difference. 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 kidney. Now, this had to be vetted. It had to go through all the regulatory organizations, which we did. On September 25, 2021, we performed this xenotransplant. This was a very simple genetics. It was an Alpha-gal knockout, which again is that sugar that most of our xenoreactive antibodies target. On the picture on the right, you can see at the end of 2.5 days, this pig kidney that we implanted not in the usual place where we put a transplant, but on the groin vessels, so the femoral artery and vein. Then we were able to cannulate the aorta with a tube that you can see on the left and collect coming out of that kidney. Then we performed the second xenotransplant again in this brain-dead individual whose family consented to have this test done. We again perfused this kidney with the deceased's blood by connecting the blood vessels and for another 54 hours. 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 deceased was disconnected from the ventilator. 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. Marked there with that blue stitch you can see a thymus lobe underneath the capsule of the kidney. The thymus is involved in educating the immune system and the T cells in particular. 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. This thymus can delete, and that's been shown in animal models, T cells that may be reactive against the kidney. These are the results of in terms of the urine output and the change in the function of the kidney. The dotted line in the middle is when we did the xenotransplant, and then the fluorescent green and blue are transplant number one and number two respectively. You can see that the function doubled after the time of transplant. We had excellent urine output. About a week after we did our first transplant back in September, a group at Alabama did a very similar experiment. The main difference was they removed the deceased's native kidney and placed two xenografts. This was a 10-gene pig that had four knockouts, including the growth hormone receptor and then a number of transgenes or knock-ins. On the right side of this 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 these toxins, and that's the creatinine. The reason why I think in the middle you can see a blue circle which demonstrates that there were fibrin and thrombi in the kidney. This is one of the complexities of doing a study in a deceased brain-dead donor, because this brain-dead physiology that can recapitulate some of the things that we see actually in rejection. This was always something we knew that, you know, was a possibility. I did see it in this kidney, these two kidneys. We didn't see it in our two kidneys, but this is something that has to be, you know, thought about and addressed in this model. I think you'll hear later a lot about bioengineered organs. We are using this same approach to test pig organs, pig scaffoldings that have been decellularized and then repopulated with human cells. Again, the idea here is that it can be tested in a decedent. You can see on the left side of the screen that bell shape container that has a set of bioengineered lungs that are being ventilated. Then the decedent's blood in an ex vivo fashion is being circulated through those lungs. Then we're able to test those lungs and the various parameters that you can get from that. Just, you know, I don't really have enough time to go into great detail about our two transplants, our two pig 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. 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 wanna have closure on their loved ones' death. I just wanna acknowledge our team, our very dedicated team. I also wanna acknowledge all the individuals whose shoulders we stand upon in doing these clinical studies, including the 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. Now I'm gonna pass to my good friend Muhammad to talk about his first heart transplant in a living human, which is very close to my heart because I'm a heart transplant recipient too. My whole family, we have a 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. You know, it's 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. 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, you know, paying the gods of this patient 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, you know, change it. They are anatomically, their organs are similar. They breed when in captivity, and they grow in size quickly, so the organ it gets to the size of humans quickly. They are consuming food, so we thought that they will build up particular issues. The physiology, we are finding out that it's also very similar. In a heterotopic model in the abdomen when you transplant the heart... Dr. Muhammad Mohiuddin, are you intending to share your screen? I didn't know if you were intending to share your screen at this point going on. I have shared my screen. Okay. Can you try again, please? I think there's an issue. Thank you. There we go. Thank you. Should I go back or? I just wanna show this picture because I wanted to, you know, honor our patient, Mr. Bennett, who devoted his life for this purpose. I was showing that, you know, when you transplant this xenograft, an unmodified heart, within minutes you see this picture where you can see microvascular thrombosis going on and seeing all the cardiomyocytes bind and with the interstitial edema and the red blood cells in that. What happens is that, as Dr. Montgomery described, we have circulating antibodies, we recognize the antigen on the pig, mostly the carbohydrate antigens, they bind to it. With the help of complement activate the endothelial cells and expose the lamina propria which attracts a platelet aggregation. Soon you have the clot formation and almost occludes the vessel and causes rejection. This is a typical immunosuppressive regimen that we have developed over years to suppress this kind of rejection. Besides taking on the genetic modifications, this includes induction with ATG and tacrolimus and also blocking complement with either complement or [myner]. We maintain these hearts on anti-CD40 for long period of time and then also on MMF. We taper down the steroids after a short period in about two months. This is just to check as a proof of concept what is shown in our heterotopic model, and the argument is that, you know, we were able to have long-term survival up to one year, up to three years almost. When we remove these antibodies completely, the anti-CD40 antibodies, all these hearts rejected. This is around like 784 days, the heart is beating well. As you can see here in the echocardiogram, the graft function was great. This is the histology on the left and around the time when we pulled anti-CD40. We noticed that even at that later stage when we remove the antibody, the hearts starts to reject and within two months the heart rejects. We are very confident that anti-CD40 is required at least in our system. The logical step was to transition into orthotopic model. Our initial, you know, results were not good. All our hearts were kind of failing within 48 hours. Our German collaborators discovered that, you know, if you use cardiac perfusion using the STEEN solution, which has a lot of ingredients including cocaine in it, the heart overcomes this 48-hour period here. That's what we did. We acquired this machine where we take the heart out, perfuse it for about two hours and then transplant it into the baboon. This is how this machine works. It's a non-ischemic cardiac perfusion method at 8 degrees Celsius at a 20 mm pressure. After perfusing it for two hours, when we transplant, all these hearts have overcome this 48-hour period which becomes a heterotopic cardiac xenograft that's functional. As while we are doing this, we're also with the help of Revivicor, our collaborators, where we're trying to genetically modify the pigs. For people who don't know how that's done, you know, the eggs are taken out from the pig, they are enucleated and the genetic material that's constructed a priori is inserted into the eggs. The eggs are then put back into the ovary and over a period of time these pigs are born with the genetic construct that we had inserted into the eggs. This is historical. You can see the different genes were identified, either they were knocked out or knocked in. These are the four that we knocked out in our ultimate pig that we used in this pandemic. There were three knockouts. These were carbohydrate knockouts and one growth hormone receptor knockout which we used to control the growth of the organ. There were several transgenes addressing 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 three genes and the western blot showing that the transgenes were adequately expressed. With this, you know, we progressively with gene modification and keeping our immunosuppression the same, you know, we have progressively increased the graft survival. In our orthotopic also we have now the survival of about like nine months. In one study with acceptance for publication. From that point on, we also, you know, were concerned about the growth of the growth hormone receptor knockout. This growth had growth hormone intact. As you can see, the hearts are pretty thick, whereas this is our nine-month survival. You can see that the graft, you know, did not get thick and it did not reject either. As you'll see here that, you know, this animal died of some infectious complication. This survival of four other baboons in our colony. Here you can see that no rejection, but also seeing the growth is multifactorial, and rejection plays a greater role in that growth. Where you can see that rejection was avoided. There was no signs of rejection after nine months. Now with this, you know, we decided to go to the NIH, to the FDA, to see if this is enough for clinical trial. They said, "No, you have to do more animal work." In the meantime, we came across the provision of the Emergency IND, and we decided to, you know, pursue it. Our cardiologist heart failure group identified Mr. Bennett. His medical history included non-ischemic cardiomyopathy, secondary to long-standing hypertension, bioprosthetic valve repair. He presented to outside hospital in a cardiogenic shock on multiple counterpulsations and intra-aortic balloon pump. Ultimately, developed multiple ventricular arrhythmias, arrhythmia risk requiring the ECMO support. He was on ECMO for the last 40 days, then, until the transplant. Then he was on ECMO for four more days after the transplant. His EF was around 11%, due to serious sarcopenia and inability to ambulate or feed, and the major reason of non-compliance, he was not a candidate for any other mechanical device. We sat down and, you know, this is Dr. Griffith, my partner in crime, who performed the surgery along with me. This is Corbin, the resident. This is a board exam office that shows the FDA timeline. It took about 10 days for them to approve this. This was good back and forth communication. When we got it approved, you know, we found out that we would need several other, you know, approvals from our institution, including the financial approvals, because the 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, but this patient was very sick. We had to tailor his immunosuppression. The immunosuppression regimen that I showed you before, you know, we had to change it significantly to fit the needs of this patient and also to prevent him becoming infected, which we basically were not able to do it. That's why we had to stop MMF after some time, and that's because his white cell counts were going down to almost zero, and we were afraid of full-blown infection. There were several other ways we were trying to measure the function and the status of the heart and the patient. The majority of tests, you know, we were using echocardiography, the stress echocardiography, to determine the function. We've done several different biopsies at different time points. Those cases were kind of different. A few also. Then with the help of CareDx, we developed this AlloSure and AlloMap, which I'll talk a little bit about. We were able to, you know, monitor the function of the graft. Even though not used as a major marker in other transplants, it was very informative in our case. We also did endothelial analysis and flow cytometry. Here you can see that 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 30 seems very good. You know, springiness of the heart. And this is day 14, as you can see. This is at about 60. But the numbers have gone down a little bit, but still you can see the contractility was great. Besides this, you know, we, with the help of CareDx, used AlloMap. AlloMap measures gene expression in human peripheral blood and mononuclear cells. There are 11 genes in AlloMap. There are two chosen and an algorithm score chain and validated to discriminate patients from rejection. Higher scores correlate with rejection. It is used only after two months post-transplant. Therefore interpretation is not as common in xenotransplantation model because the patient lasted only 61 days. We have examined the LMA score as well as details from individual genes to explore correlation with outcome and treatment that may inform on future heart xenotransplantation validation. We have this result, but you know, just because of publication, I'm not able to show it. Cell-free DNA, which we have proposed work in order to collaborate with Hannah Valantine, was also very helpful. You know, yes, it's in a process of validation. They're validating this process for use in xenotransplantation. I'm very confident that this process in xenotransplant models will be very helpful in future. Summary of what we know and what we can tell at this time and share with you, the patient had previous inflammation. It was severely depleted and had repeated infections, which complicated the recovery of the patient from surgery. There was involvement of multiple systems, including the kidneys, his heart and his musculoskeletal system. He became very cachectic. He lost about like 20 lbs during his stay. The immunosuppression had to be tailored based on, you know, his WBC count and, you know, other issues he was having. His kidney function was probably due to the dissection we noticed there during the surgery and had to be repaired and had a period of ischemia that also affected his valve. To the biopsy, we have not seen any typical signs of rejection. We have not seen any cellular infiltrate. All we have noticed is interstitial edema and some type of which may provide some sort of converting into fibrosis and causing the heart to get a little bit thick, via. This is all I can share at this time. We have a few publications in the past, and hopefully, we'll be able to share more after that. With that, this is my lab and them did most of the work. This is the group and or a part of the group that you know performed the surgery and took care of the patient. With that, thanks very much for your attention. Thank you, Dr. Mohiuddin, and thank you, Dr. Montgomery, for these really exciting talks. I was really struck how much effort and how much research is taking so many years and years of development to get to this point. Again, thank you. Today, we're announcing XenoSure and XenoMap, two names for 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 leading service for donor-derived cell-free DNA surveillance in human allotransplants with AlloSure. Our application across many different solid organ transplants provides us with unique insights that we hope to be able to apply to this field of transplantation. With the number of transplant recipients, as we know, is still very small, even in pre-clinical studies and obviously in clinical studies. XenoMap is based on our over 20 years of study of gene expression as a way to interrogate gene activity in transplant recipients. Our first product is AlloMap Heart, published in The New England Journal of Medicine and with over 15 years of use in the clinic now. We're nearing completion of development of AlloMap Kidney with multiple independent observational cohort studies. You know, it's with this that we want to bring to bear these data to benefit the xenotransplantation community. Initially, you know, we can help generate insights in the investigation in transplant research. Beyond that, I think we've already demonstrated some capabilities with investigational post-transplant monitoring in the clinic, with our extensive clinical use across all of solid organ transplantation. Then, of course, in the future, we anticipate the standard of care for xenotransplant recipients. Invaluable research and experience of all of those presenting who have already presented today and are presenting after this will inevitably lead to a rich future in xenotransplantation. 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. 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 in the stuff that we heard from out of Maryland as well as New York. Excited to introduce you to Miromatrix and another way to increase the number of organ supply out there in terms of bioengineering transplantable organs. As a public company, I need to give this disclosure. If you look at Miromatrix, our mission, similar to what we've 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 are 7,000 patients this year who are gonna go to their physician, be pre-screened, but not receive life-saving technology. That's really our mission. How do we supply that? We'll not only stop there. You know, the true need out there is probably 10x. How do we really serve that, and how can we fill that gap? Because each and every one of those, despite having the patient, each and every one of those is a patient and a family impact that we want to be able to help. We've attracted great strategic investors, including DaVita, Baxter, 30x, and we work with some phenomenal scientific and medical collaborators as well. With that, what is our technology? What is that ability to be able to bioengineer a transplant organ? What does that mean? Here's a short video that really describes what we're doing. Our patented perfusion decellularization technology starts with a functional organ from a pig that would normally be discarded. Next, we remove all the organ cells by first cannulating the organ, then flushing it with a simple solution that only removes the cells, leaving us with a pristine decellularized organ matrix that can be stored for over 12 months. Next, the decellularized organ is placed into a bioreactor, and we initiate our patented recellularization process. During this, human cells are introduced to the organ, and over the next 14-28 days, the organ are continuously monitored and perfused with the appropriate nutrients and oxygen to achieve the desired key growth parameters, resulting in a bioengineered organ. I always love that. I think it's really helpful to kind of give you a flavor of exactly how the technology comes together. Just to break that down a little more, you saw that we start with an existing organ. In this case, we start with the pig organ, as we heard about previously on the xenotransplant side. It does share in 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? For that, we actually took whole porcine livers, perfused and decellularized those, and then created several devices with that same process, and now have a great history of transplant of those devices in the pig without any adverse reactions conditions. The next step of the process that you saw inside the video is we 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. That aspect is really one of the key differences. Again, we're all, how do we get organs to patients? One of the differences in this process is we're using human cells instead of animal cells in that recellularization. Some of the things you heard earlier about animal viruses and other things, we've demonstrated that we're able to remove all those from the graft as we move forward. Highly scalable technology. I kind of put it similar, really well developed. We have 118 issued patents, 35 patents pending as well. If you dive a little bit deeper into this on the recellularization, we get this question a lot. How long does it take? It takes about two to four weeks from the time that we add cells back in there to be able to see that maturation. During that time, we're delivering nutrient and oxygen as we recellularize these grafts. The other question is where are the cells coming from? In our first generation of this, we use human donor organs, not placed for transplant, because they expire long after acute care time. We're able to bring those in, isolate out those prime T cells, and then infuse 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. Ultimately long-term, which is a longer development process, is the potential to use stem cells in this process as well, and ultimately create a transplant that no longer needs immune suppression. 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 two aspects 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 make a rapid advancement on the [ELAP] towards our IND, as well as on the liver and kidney guidance that we've given on that as we're targeting our first human clinical study, second half of 2023, first half of 2024 for those products. If we dive in a little bit deeper as well, you know, the thing that's important to us, and you saw inside the video, is really controlling our manufacturing. We built our own in-house manufacturing where you can kind of see the scale. 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 and manufacturing that's really been built on our past products that we commercialized as well. If we look at the data, what excites us on this approach as well as we move forward, on the kidney side, you know that first step, you have to go too in-depth into this, is how do you get the cells back in? You kind of see components on that, right? The vascular structure, glomerulus from the filtration standpoint, and nephron from the reabsorption. You can see our ability to get cells to relocalize the appropriate microenvironment and then to be able to recapitulate those structures. The first step that was important to us and important for any type of bioengineered organ is to demonstrate that you have vascular supply to solve the vascular challenge of tissue engineering that has always led this type of tissue engineering to very thin tissues. You got to have that vascular supply that doesn't thrombose to be able to make these complex organs. This is an angiogram of where we've recellularized a pig kidney, decellularized pig kidney with human endothelial cells, transplanted this back into a pig, and this is an angiogram after a week. What you can see is just beautiful patency that exists continuous through that. We're then able to recellularize the rest of the kidney and start to look at what that glomerular outflow is as that first level of functionality. Where we are today is about 30% decellularization overall on the kidney. Our goal is to get that up to 60%-70% through various optimizations to continue to build on that. That's going to be that gating point for us to be going forward with our clinical studies. If we just move on to the liver aspect of this, the liver is a full orthotopic transplant that we're looking at on this front. Here's some of our data on that. Again, first of all, in 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. This work was done at Mayo Clinic. And then we take out those clamps. You can see the nice perfusion of that graft as we start to perfuse through that portal vein. It doesn't bleed right up at the top up there because we haven't completed the circuit. Once we pull off the clamps off the cavern there, now you can see that complete perfusion. Now we've got perfusion of that. Now that's being perfused, you know, by the whole circulatory system at this point. The next step was to demonstrate that we see a functionality. We demonstrate that functionality by decellularizing a number of specific cells, specifically looking at albumin, look at urea output, but more importantly, look at some of the key things like ammonia clearance, where we can hydroce the mole down, and then we see nice kinetics of that clearance. That's important for overall liver functionality. 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 last year, where we transplanted this in essentially a ligated 80% liver where during volume assessment, CT scans, you should see that liver being there. It's absent, but you can see our transplanted bioengineered liver. Look at just over 48 hours. During that time, the controls, which just had the ligated livers, essentially bypassing the portal, you see that large level of ammonia accumulation demonstrated there in the acute liver failure. When we put in our grafts, you can see that the ammonia clearance, ammonia is still coming out, but it starts to level off. In some cases, it's coming back down. Again, carrying that functionality from what we were able to demonstrate on the bench now into a large animal model just really sets us up next for our first product and proof of concept for this. Similar to what you kind of saw Dr. Robert Montgomery talk about, on some of the lung stuff outside of the body, is that ability to harvest our organ outside the body. This is our external liver assist. We plan to keep our first IMT. It is the ability to take our bioengineered liver, house this outside of the body, and specifically look at the therapy of acute liver failure. 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. 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 regular study strategy to de-risk and accelerate towards human clinical data. Just that notion that we want to get it to patients as fast as possible. That started with a matrix, demonstrating and doing that proof matrix, having a track record of implantations associated with that, demonstrating that functionality on the bench to revascularization. We're now in the doorstep of our E-L ab to be able to start to look at that next level of bioengineered organs, to be able to get that kind of benefit. Then utilizing that data and proof of concept and other things as that stepping stone for fully transplantable liver and kidney. In summary, we talked a lot about this. You know, we really do believe that transplant is one of the largest existing unmet medical needs that exists out 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, you know, we're really looking to change the world of transplants and the patient experience. We see a future where people can schedule their transplants. Thank you for the time today. Thank you. I think we'll move right into the next presentation by Mike Curtis from eGenesis, looking at their genetically engineered organs. Go ahead, Mike. Super. Thanks a lot. Thanks, [Suresh] and the [CareDx] team for the invitation. 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 the porcine donors and eventually the primate and human recipients. I think the psychology behind doing that here is tremendous. What motivates us is the difference you can make in a patient's life if they gain in the case of a kidney transplant. A good allotransplant can completely transform a 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 was an unlimited supply of organs of high quality and consistent quality, you could envision a day where organ transplant becomes as routine as joint replacement has been these. That's kind of our overall goal here, is to change completely how we think about transplant. To accomplish this, you know, we've put in place the EGEN platform, and this is the platform that addresses both, zoonotic transmission, and immunocompatibilities between the porcine donor and eventually human recipients. At a high level, 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 of those modifications in a moment. We really are applying CRISPR-Cas9 and some of the most advanced techniques from molecular biology to introduce these edits. Then we do a process called somatic cell nuclear transfer, where we take that edited donor cell and make a porcine donor. Then we do a series of transplants, and I'll take you through some of our incredibly compelling transplant data today, through collaborations with some of the leading academic centers in solid organ transplant. To take a little bit through the edit, this was founded on the idea of using CRISPR-Cas9 to inactivate endogenous retroviruses. These retroviruses were discovered in the nineties, and at the time, it really, you know, slowed down the progression to the transplantation because of the risk of zoonotic transmission. As we all sit here into the second year of a worldwide pandemic or third year of a worldwide pandemic, I think we all can appreciate the potential risk of zoonotic transmission. What George Church and the team at Harvard showed was they could use CRISPR-Cas9 to inactivate the reverse transcriptase in the endogenous retrovirus. Now, every pig breed will contain anywhere from 50-80 copies of this retrovirus, and CRISPR-Cas9 is really the ideal tool to inactivate endogenous retroviruses. This seminal work was published in two 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. Bob talked about the [audio distortion] to the two transplants that he's done at NYU. We typically make what's called a triple knockout, right? This knocks out three enzymes that participate in carbohydrate synthesis, essentially eliminating acute rejection. This triple knockout was used in the kidney transplant that was done by Jayme Locke and the team at UAB. Very similar stuff to that edit. Where we've really been focusing on Mike Curtis's 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 7-12 regulatory human transgenes, regulating different mechanisms of compatibility, like coagulation compatibility, as well as mechanisms for rejection, like complement activation, innate and adaptive immunity. Any particular sort of transgenic donor that we produce will have anywhere from 3-15 edits in the porcine genome, and then they'll have the retroviral inactivation. We're currently producing the most highly edited and most compatible porcine donors out there. To do that, we've built a team both here in Cambridge of world-class pharmacologists, immunologists, computational biologists, and regulatory affairs folks. In the Midwest, in Wisconsin, we have again another world-class team of cloning folks who know how to clone porcine donors better than just about anyone, doing somatic cell nuclear transfer. This facility last year, we made over 500 transgenic donors. Recently, we began the build-out of a clean facility. This is the DDF. This is a facility where we can produce clean donors that will enable that progression into clinical studies. In all the transplant data I'll show you today has been done through a long collaboration now with the team at Mass General. We have recently established collaborations with Duke, University of Wisconsin, and are working towards establishing collaborations with other academic transplant centers. Before I take you through the transplant data, I think it's worth taking a few minutes to go through the renal non-human primate transplant model. I think Bob had mentioned this earlier about the translatability of non-human primate transplant to the predictability of what's gonna say about what's gonna happen clinically. A lot of the advances that have been made in allo transplantations 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 a surgical approach, most patients who may receive a kidney transplant receive a heterotopic transplant, and they maintain their own kidneys and a third kidney is added. All the data that I'll share with you today is a life-sustaining transplant in the non-human primates, where native kidneys are removed, and a single porcine kidney is installed. The challenge here is in the non-human primate, the supportive care is more limited than what's available for a patient in a clinic. For instance, there's no way to dialyze a non-human primate. If we see any delay in graft function or any challenge with the initial function of the graft, that can lead to the loss of the recipient because that happens quickly if you put a patient on dialysis or remove the kidney. We also see a higher risk of rejection in the non-human primate. These recipients are on immunosuppression. That can lead to opportunistic infections which you don't see clinically. For example, we see parvo sometimes in these recipients, and that could also lead to early demise of recipient. In the suppression front, these animals are on suppression that comes with some form of morbidity in the primate that you don't see clinically. An example of that is some body weight loss following sedation. 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 today, 500, almost 500 days of post-transplant survival can mean the early loss of the recipient. When we add all these factors together and we look at survival in that new primate, you typically see a distribution of survival. You see some short-term survival, midterm, and then what we're going for is long-term survival. 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. On this slide, on the leftmost part of this graph are three sets of data from the Summary Basis of Approval of the latest methods for the C to C associations receiving a renal allo transplant. This is modeling the monkey-to-monkey data. Let's just focus on the dataset to the left of the vertical line. These are five non-human primate recipients receiving an allogeneic transplant with the latest standard of care. You can see a distribution ranging from 50 days of post-transplant survival up to about 260 days, first median and then one as a min. This distribution of survival is what you'd expect. Clinically, in this particular trial, 90% of patients achieved a three-year post-transplant survival. When we think about the non-human primate model, we think about it as a positive prediction of the outcomes. If I can get to at least one year post-transplant survival in non-human primate, I have a reasonable expectation that we achieve at least that clinically, if not longer. Updated to the right, are series of 15 transplants that we've done with our lead, AP donor. This is EGEN-2784. We have several transplants that are ongoing, but you see a very similar distribution. Some recipients who lose early, some in the mid-transplant period, some now approaching over 500 days post-transplant survival. If you break that down into a little bit more detail on the next slide, our ongoing. Oh, I have control. The data set on the left here are our ongoing transplants. You can see two recipients now approaching 500 days and several ongoing. The goal here is to get as many, up to five recipients to the post- one year post-transplant survival. Just to talk a little bit about the completed transplants on the right. You can see here now completed a total of nine transplants, and we've looked at them, bucketed them by short-term survival, less than 25 days. These are typically some version of delayed graft function, a ureter stricture that can't be resolved, and we end up losing the recipient early, if not rejection. The middle bucket, most of these recipients, were suffering recurrent infections which contributed to early loss of recipient. Again, from the histology, the graft was doing well. We have recipients over 100 days post-transplant, and all of these suffering some kind of opportunity in support. For instance, the case of recipient 61-20, a recipient that was euthanized on day 240. This recipient had a nephrosis, so a 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 of poor animal welfare, we couldn't. That would never happen clinically. We would minimally go back in and re-stent or if we take the kidney out, put the patient back on dialysis. This is something that you can't do in a non-human primate. With this data, we're preparing to have our second formal interaction with the FDA around mid-year, in the form of our pre-IND meeting. Well, our intention is to go to the FDA and have a discussion with them about our CMC plan, our non-clinical safety plan, and then our initial trial. With that in hand, we prepare 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 and modified porcine islets in non-human primate models with type 1 diabetes and are starting to see encouraging signs in C-peptide levels. We also have a heart program, you know, and trying to do something very similar to what Muhammad and the team at Maryland have done. Then the last program is a liver perfusion, very similar to what Jeff had talked about using a tissue perfused approach. I think, you know, and just to summarize, I think we are producing the most compatible and safest through the retroviral inactivation, porcine donor organs that are available. Happy to take any questions. Thank you. Yeah. Thanks. 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 it's a time a little bit over, but I want to thank all of the vendors, particularly, you know, both you, Bob and Muhammad. I think it's been truly inspirational what you've done in pioneering the field. We just had a series of questions, but I think we'll just leave with one just given where we are with the presentation a little bit over. What is next for xenotransplant? I think some of the similar questions we're getting through, like when is the next single study or when do we expect more broad usage? We'll get Bob to go first, and I'll hand over to Muhammad second before I wrap. Bob. Yeah, sure. I think, you know, 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, you know, spoke today. Again, the timeline, you know, is probably a year or two before those are going to be underway. Thank you. Muhammad? It's the same thing. As I mentioned during the talk, they required us to do those transplants in non-human primates to move to the clinical trial. You know, we are in the process of talking to them and providing a plan to move forward. I anticipate in a year or two we should be starting those trials. Great. Thank you. For Innovation Day, given this opportunity, this has truly been the most exciting and fascinating. I think 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. I think, you know, seeing, you know, Jim or seeing Bob who both patients is just such an excellent reminder for us what we do day in, day out. Thank you for the physicians who did dial in to 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, day out. That's our mission. If investors are listening in, please continue to invest in this incredibly important field. The work you see is truly inspirational. If I think of what Dr. Mohiuddin and then Dr. Montgomery have done is just I really can't believe that we've just come in time. I think Jim put it best when you said, 28 years on, you never thought you'd be seeing this, and I never thought I'd see this in my lifetime too. I'm truly thrilled, and I'm so proud of the key ethicists and scientists, and thank you again for all your time and attention today. Thank you again for transplant patients. Bye now.