Excellent. Guys, thank you all for joining. Pleasure to have Steve join us. I always mention this. Steve did the very first fireside I ever did at any conference, which was back as CFO of Juno, and we've been talking about cell therapy since. And I feel like some of the themes we've been discussing, even at Sana, are now very prominent in vivo CAR T in particular, across a lot of companies and a lot of players emerging. So Steve, why don't you kick it off? And I think maybe just remind us about the platform, but also remind us about how Sana is playing in vivo CAR T because it's fashionable and everyone's playing in there. But I feel like you guys are not necessarily just starting up in there, for example. Yeah. First of all, thank you everybody for joining. Thank you to Evercore for having us. I'm sure you guys recognize we may make a few forward-looking statements, so feel free to check out our 10-Q for risk factors. The company actually was founded on these couple of ideas. One is to be able to hide cells from immune detection and make cells to replace missing cells, and the other is to be able to deliver payloads to specific cells in vivo, and both of these seem to be working right now, and so probably the asset that people care the most about, or we spend most time on, is a drug called SC451. And the goal of this is a functional cure of Type 1 diabetes. Take a step back. Type 1 diabetes is a disease of about nine million people. It's growing very rapidly, about 15 billion by 2040. What happens is a person's immune system attacks and kills the pancreatic beta cell. That's known. The beta cell is the only cell in the body that makes insulin. So up until 102 years ago, a patient would die pretty quickly once they were diagnosed. Their cells would just starve to death. And with the advancement of insulin over the last 100 years, it's gradually gotten better, but it's still a disease where, with the best care, a person is going to live 10-15 years less. It is a life where you're making 140 executive decisions every day about what to eat and how many carbs am I having and how much insulin should I take. It's a disease where the whole time you're worried about too low of blood sugars, which can lead to death very quickly, or too high of blood sugars, which lead to long-term problems of blindness, amputation, heart attack, stroke, kidney failure, all kinds of things. It's a giant problem. What we've learned over the last 20 years is that a group led by James Shapiro in Canada showed that you could take islets. Pancreatic beta cell is a missing cell, and islet is its beta cell plus its support structure. Let's just call it that. You can isolate islets from a pancreas from someone who recently died and transplant them. If you give enough of those islets and you give immunosuppression, like you would get with an organ transplant, patients can live for a decade plus without any insulin. Normal blood sugar is off insulin. The problem is it's not a scalable supply source. It's a very variable supply source, and there aren't that many people for whom lifelong immunosuppression is better than lifelong insulin, so thousands of people have gotten this, but it's not a curative. It's not a scalable solution. Over the last couple of years, several groups have shown you can take stem cells, pluripotent stem cells, and grow them in a manufacturing process into islets and transplant them, and they really do work. It's a more scalable solution. It's a more predictable solution, but you still have the problem of immunosuppression, so it's not very likely to be something that's broadly utilizable. What we showed through the course of this year has been that we can gene modify islets, transplant them into a person, and these cells persist in function with no immunosuppression. It's actually a transformative result. I've never seen allogeneic cells transplanted without immunosuppression, and it gives us all of the pieces put together to make a functional cure for type 1 diabetes, which is a single treatment with no more insulin, no more monitoring, normal glucose, and no immunosuppression, so that program is most of the focus of the company. It can be, I think, a very substantial product. We have an IND that will hopefully be occurring next year. We've talked about IND and beginning the study as we move into 2026. So these two patients' data, that was not with an IND because I couldn't find it on ClinicalTrials.gov. So what we did before was we took a cadaveric islet and gene modified it at a low dose. And so what we were doing here is we're gene modifying a pluripotent stem cell and growing it into many, many doses, making it into islet, and then it becomes a replicable scale process. So the goal with the first drug was the first trial was just to see, could you see these cells survive and function? From here on out, our goal is to cure the patient. It is to see the cells survive, function, and eliminate their need for insulin going forward. But just so I'm clear, the two patients' worth of data? There's one patient. That is the same patient. That patient was done with a. That was day 28 and week 12, I think. We've done week month six. Okay. And we've month 12. But the one patient was done through a trial or back to a trial? It was done in a clinical study run out of Uppsala University in Sweden. I see. Okay. So it's one patient worth of data. So I remember last year when we had this chat, I remember you left it at either we engraft or we don't engraft. So it's going to be pretty straightforward. And I think as we sit here today, it looks like you were able to hit. If it did engraft, you'd either see if it worked. If it were engrafted, see if they evade the immune system or not. And they do. So now we're in the process of making the scalable solution. Makes sense. So the product and the process that was used in that patient, how meaningfully does it differ or not versus what's being? How many what? The product that was used in that one patient, how does it differ or not versus what's going into the IND? How does it differ? How does it differ or does it differ at all? That was a person died, a donor person died, donated their pancreas. So those islets were isolated. They were gene modified. So about 40% of all the cells were fully gene modified. We knocked two genes out. We knocked one in. And the rest of them were not. And so it was done at a low dose. And that's it. So now the real drug, you start with a pluripotent stem cell from a single donor that will be your product forever. We do the gene modifications. From that point forward, there's no more gene editing. There's a master cell bank that never gets changed. And it's our drug, hopefully in 2050 for millions of people. And that single cell will be made into trillions of cells. Got it. I see. Got it. I see. And you will take those stem cells. You will differentiate them into islets. And every patient is getting the exact same product, hopefully. Makes sense. Makes sense. And then also remind us, Steve, what's the data currently in the marketplace on stem cell-derived islet transplants that are out there? I think they occur, but the engraftment rate's not the same, and it's not as successful. Vertex has done this very successfully, published in the Journal of Medicine. They were 12 out of 12 patients who reached a year are insulin-free. They put it in the portal vein. It worked. Patients are on immunosuppression. But it worked. There's been another group in China that actually took a patient. They took a person who had type 1 diabetes and a liver transplant. So they were already on immunosuppression. They then made the patient's own blood cells back into pluripotent stem cell, grew them up into islets, and transplanted them with immunosuppression. It was an autologous pancreas. Again, that worked. That patient's doing very well. But again, they had to be on profound immunosuppression to overcome the autoimmune reaction. So what we have done is we've done these gene modifications that prevent the patient's autoimmune system from seeing this and prevents their allogeneic system from seeing it. Got it. So in the Swedish data set that was generated, you focused a lot on graft survival on MRI. And then you also focused a lot on C-peptide. And C-peptide. Are those the two parameters we'll be tracking, or will MRI not be as? Again, in this previous study, you want to see, did they survive and function. So you look at MRI. We looked at PET MRI. So you could see that they were insulin-secreting cells. You don't have those in your arm. We then looked at, so when an islet, when a beta cell makes insulin, it actually makes proinsulin. And when it's secreted, it's cleaved into C-peptide and insulin. So when you have C-peptide in your blood, it's a one-to-one number with how much insulin you're making. So these are people who had diabetes and had no C-peptide. Now they have stable C-peptide in this person. And then when this person eats, their C-peptide goes up. And again, you see this stably happening over six months. That's not our goal going forward. Our goal going forward is to give a high enough dose that you want to see those things. You want to see the cell surviving. You want to see C-peptide. But you want to have enough of a dose that they have a normal blood sugar, and they are completely off insulin, and they get to live the life that I live. Right. So what is that dose that you think will enable you to get there? And could you remind us what was the dose used in that Swedish? So in that study, fully edited cells was probably 60-70 million cells. If you look at the data from just the field, it usually takes around a billion cells to get to euglycemia. So that's around the right number. Okay. So the goal is, so as you're growing it, you need a billion per patient. Pretty much. Yeah, more or less. Okay. And where's the production right now in terms of getting ready for IND, in terms of the cell bank that you're populating? So we've had multiple meetings with regulators around the world, multiple meetings with the FDA, in alignment with what we need to do going forward. So we have to do two things to get to human testing. One is complete tech transfer and GMP manufacturing. Two is complete our GLP tox studies. They will happen. We've done all the studies that will need to be done already. It needs to be done in a GLP setting with the current kind of process, and off we go. Got it. So we could face slip-ups along the way. That happens all the time in these things. But generally, we'll get through them. It's a matter of when, not if. And I think we're far enough along and confident enough of what we have that we think that there's a high probability, no guarantees, that we're able to get this done in 2026 and start the study next year. And data come very quickly once you start the study. Right. So what does that development path look like then? I mean, presumably, you can get proof of concept. I mean, you kind of already have it, but you'll get it super fast on the actual sort of insulin production and A1C framework. I think the clinical pathway is very straightforward. You go. The challenge in this will be scaling manufacturing. We need to take a phase I manufacturing process and modify it into something that is really good enough for early commercial launch. Because that's what you have to have your registration study. You won't be able to change it. And again, I think that that's something we can get done. And then I think the actual clinical trial, if you look at, again, others in the field, they're doing a phase I, II, III program of 50 patients in aggregate. So I guess, where are the bottlenecks then on the scale-up? And where is it that you're spending most time on that? Or what is it that the company's still trying to figure out or working its way through? I think the hardest part of scale. So what we know, let's just say like a protein biologic. You're taking a cell, and you're getting it to spit out a bunch of protein. And all you care about is that protein. The antibody's the same every time. What we're trying to do is make the exact same cell, which is a very complicated function each time. And there are two challenges, I think, as you're going through this that are the biggest to scale. One is, as you go through all of the manufacturing, let's just say that, you end up with a risk of genomic instability. So you'll see problematic mutations arise. Let's just say mutations in genes that encode for DNA repair is the most common thing. And you probably don't want to transplant, as an example, a billion cells with P53 missing. It makes sense. You wouldn't want to do that. So genomic stability is part one. The second is product purity. So it's actually not that hard to kind of make these things. But when you're making them, you're going through normal development pathways. You go like you start out with a pluripotent stem cell, then it becomes like endoderm, then it becomes foregut, and then it becomes if you end up with some stomach or some GI tract, those aren't terminally differentiated cells. They'll just keep growing in the patient. And if this is going to be there for 10, 15, 40 years, you don't want a bunch of stomach growing in some other organ. It will transplant this in muscle. You don't want it growing in the muscle. And so genomic stability and product purity are the biggest challenges you get into making many, many, many, many cells. On the genomic stability, I guess, once you're sort of able to boil down to the cell, which you want to then grow off of, stability would just need time to be able to prove that, no? It took us years to make a cell line. I'm not aware of, I think, this has been a problem for the field broadly, where you gene-edit it and maintain genomic stability with a pluripotent stem cell. It's been super hard. I think that we got there a lot because of the cell line we're using, a lot because of the process that we're using, those two things. And then I think it took a little bit of luck. I don't think there's any way around that. I think you need all three to make it happen. Got it. Does FDA want to see a certain amount of time duration on stability side? There's a lot of testing that goes into this. Okay, and what type of testing? It's not time. It's many, many, many divisions, so I'm not going to get into what you do. But there's a lot of genomic testing that's done that you're looking for. First of all, the gene edits. Are they on target? The second is, do you have chromosomal rearrangements? Those happen as you make changes. You grow these stem cells. Little parts get clipped off, or 15 ends up on 13, whatever it is. Then you have to look for the risk of these cancer genes popping up, and then you have to look for do your cells do what they're supposed to do genomically? Do you have any mutations, any gene that matters for the function of the cell you're going after? Got it. It's rigorously, rigorously tested. And that's what a big part of what we spent the last few years on is getting that done. And then last year, getting alignment with global regulators on what you need to have to release a master cell bank in an area like this. Got it. How should I think about cell viability once the transplant does happen? How should I think about that? Think about what? Cell viability and. Hopefully, it's for decades and decades. Okay. We've seen that happen in the cadaveric islet transplant field. Competitors or others in the field are out several years with stem cell drugs. I don't see a reason why they'd be less. In fact, they might be more. And remind me, I think you mentioned. We've done mice with T1 [cross talk] no MHC I, no MHCII, right? What's that? No MHC I, no MHC II. So there shouldn't be NK cell attackable. So if you just knock out MHC class I and class II, NK cells will kill them. So then that's been the challenge of the field. And our insight was that overexpressing CD47 in the context of knocking out MHC class I and class II protects cells from NK cells. It protects cells from T cells. It protects cells from B cells. It protects cells from macrophages. So you overcome both the innate immune system and the adaptive immune system. And again, we've shown this in all kinds of in vitro assays. We've shown this in mice, humanized mice, monkeys. We've now shown it in humans across several different diseases and cell types. This works. And so now what we need to do is just put it in, put the whole system together, and put it into a human safely, and then see it scale. Got it. My last question. Based on some of the data you can generate next year, could it form the basis of a breakthrough designation? Could what? Could it form the basis of a breakthrough designation? Oh, I don't think that that's very challenging for us. Yes. Being able to get that. Yes. I think that's. I only say because, look, it may not be challenging given the biology that exists. And as long as it proves through on an in vivo basis, I'm asking because just from a markets perspective, oftentimes, that's a trigger for a lot of people to start paying attention to that, who may have been on the sidelines. So it's a realistic possibility off of phase I data. Agree. I mean, I don't know when. But I mean, I think these data would be. They fit all the criteria. Okay. How many patients' worth of manufacturing do you have ready for phase I? How many patients can you dose in phase I? Phase I, our goal, so if you look at the field, you would think that the phase I would be 12-15 patients. That would be the goal. You're ready for that by, let's say, March? I'm not saying when. We said next year, 2026, but my guess, you're not going to dose everybody. You're going to have some little stagger to begin with, and then we'll treat patients. Got it. Excellent. So the in vivo CAR-T, I'll go that very quickly. All right. So the in vivo CAR-T, what we do is we do cell-specific delivery of some type of genetic payload. And what we're doing in the case of the CAR-T is we're delivering a DNA plasmid. So we made two fundamental assumptions at the beginning of this program. And if they're both true, I think we have a best-in-class. Number one is that cell specificity matters. You do not want to go to off-target cells. So we believe that because it improves your manufacturability. It improves your immunogenicity risk. And it improves your safety profile. And pretty much everything else I've looked at, some of the cells end up in the liver and other places. The second is that you want to put in a payload that will integrate in the DNA. So you could do mRNA. But the math problem here is you might make 100 million CAR-T cells. You need to not make even 500, but you might make a billion. You're going to try to get rid of hundreds of billions of cells. So you can't redose yourself out of that problem. So you need to see logarithmic or exponential growth of your CAR-T cell. So that was basically the two assumptions. If we turn out not to be those two things aren't true, others have made other platforms that will be simpler to make. People kind of prefer mRNA to integrating DNA if they don't need it. We will have made things very complicated. If they both turn out to be true, I think we have best-in-class data. We can show in non-human primates, which is a very good system, that we can deliver specifically to T cells, that we make a CAR-T cell. They expand, like you'd expect to see with an autologous. It looks like an autologous cell. You give no lymphodepletion, though. You then see all the B cells go away in the blood. You biopsy lymph nodes. There are no B cells left. When the B cells come back, you see what you saw with Georg Schett's data in lupus, that you now are full of just naive T cells. So you've seen that B cell reset. So that's a very good biomarker, a very deep, effective, safe B cell depletion. So I'm very optimistic about this. It needs to come into humans. You're not a viral vector, are you? It's a VLP. It's a virus-like particle. It's a virus-like particle. So it has the manufacturing is very similar to what you would utilize for like a lentivirus. Got it. The targeting and things like that are different. Got it. Last question, I guess, again, on this topic, just to wrap it up. There's been some feedback that on some in vivo CAR-T approaches, you dose. And let's say you dose 10 patients, but two just don't develop any CAR-T at all. The what? You dose 10 patients, but two out of 10 may not develop any CAR-T at all. And this has happened on some programs. And this is like anecdotal feedback from pharmas that have looked at everybody's programs. In your opinion, why would that be happening? Or does that just explain some of the limitations of how tricky this stuff is in practice? So I don't know if that we have a very predictable effect in non-human primates. What you have with T cells is, first of all, in a patient, particularly someone who's been sick, who's been on many, many chemotherapies or many, many immunosuppressants, they may have different fitness of their T cell. They actually may have expression of different restriction enzymes that allow it to happen. They may have different immune systems that have some type of immunogenicity to what's already been put in there. I think all of those things could happen. Without knowing details of this, it's certainly. Or they may have other benefits. I don't know of many medicines that work at 100% of people, and so I wouldn't know without the details. But those three things all seem very viable, and T-cell fitness would be a big one. T cell fitness. T cell fitness is key. Fantastic. Well, thank you so much. This was very helpful. Thank you. I'm really looking forward to staying in touch to your phase I stuff.