We can get started. I'm Yigal Nochomovitz, one of the biotech analysts at Citi. Next session is with the CEO of CRISPR, Sam Kulkarni. I cover CRISPR, I think, since the very beginning, since the IPO. So Sam, welcome. Thanks, thanks for doing this. Appreciate it. Thanks for having us. The year went by pretty fast. Here we are again. So I think a lot of people are familiar with the story, but I think it might be helpful if you just kind of frame the business case, frame the investment case. What's the near-term mission of the company? What's the grand vision for CRISPR? Yeah, it's great to have this chat with you, nearly eight years after our IPO. In fact, you know this, since you covered us from the beginning, we're about to hit 10 years as a company, in October this year. Which is hard to believe that time flies by this quickly. Everyone thinks, you know, "Oh, gene editing is a new thing, and it's a new form of drug discovery first, and it's a new modality for drugs." Here we are, on the cusp of what could be the first approved CRISPR-based medicine in the world, with exa-cel later this year. Here we are, having dosed over 200 patients across many different programs and platforms. And I'm also proud of the fact that over time, we've built our own manufacturing facility, we have our own development engine, so we have a fully, apart from the commercial piece, a fully integrated biotech company, and where we hope to take on not just few diseases, but tens of diseases over time. We've done all that while maintaining a very strong balance sheet and a capital base that allows us to take more risk. And I think we're very pleased with where we stand. And so the second part of your question, what's the business case going forward here, is we're through one stage of the company where we've de-risked the platform, brought hopefully, we'll bring something to patients in a commercial setting in the near future. And the next part of the journey for the company is, how do you become a $25 billion company in the next three to four years? And that has to happen with the parlay from exa-cel into other platforms. And as you know, we have our immuno-oncology platform, which we'll talk about more. We have our diabetes platform, and now we have a very scalable in vivo platform, which we don't talk about much. But essentially, if you can deliver CRISPR-Cas9 to the liver in a very efficient way and knock out genes or edit genes, there are tens of diseases you can go after, very much like what the RNAi companies did. And so that'll allow us to build a very, scalable but foundational platform that can be the, the, MO for growth for us for a long time to come. As you see these patterns over time, you know, the antibodies, the first 10 years, there was a certain pattern in terms of market acceptance and market excitement, same pattern you saw with RNAi. But if you talk to big pharma companies now, RNAi is just an established modality. It's just like any other drug development. It's not different than small molecules or antibodies in the way they think about it. And same thing's going to happen in gene editing, and I'm very confident that every pharma is gonna adopt gene editing as an important arm for drug discovery within their own pipeline. Okay, well, let's start with exa-cel, and hemoglobinopathies. You have the PDUFAs are announced, one in December, one in March. So can we talk a little bit about, you know, the AdCom and what, how do you think the FDA is gonna approach that? What is the tenor gonna be? What types of questions might they ask? I think we've also talked in the past as to whether there'd be one or two, 'cause there's two indications, obviously. So anything you can elaborate on there, some of it you may not be able to answer in great detail. Well, it's hard to predict. I mean, it's up to the FDA first. Definitely, I think, the AdCom date, by the way, came out in the Federal Register today, 31st October. Oh, okay. So it'll be towards the end of October. And, you know, it's hard to say what kind of questions, but typically, these AdComs will be one for a platform, is my guess. 'Cause you saw in the case of Bluebird, there was an AdCom for thalassemia, but not for sickle cell, 'cause a lot of the questions were covered around safety in the thalassemia AdCom. Similarly, I mean, you know, it's not surprising they want to do an AdCom because this is the first CRISPR-based medicine that's going to go forward for approval. And I think that, you know, it'd be good to get opinions from key experts, opinion leaders. And we appreciate the agency leaning in, in a way, in support of a new platform like CRISPR. In terms of questions, I mean, it's hard to prepare. We're prepared for all the questions in terms of what may come up and what, what we need to answer. It's hard to say what questions are going to get picked. We'll only know when the briefing book comes out, but, I wouldn't imagine anything that's too controversial in a way. I think they'll go through the standard questions around safety, efficacy, and the, the data set that we have, but we'll be prepared for all eventualities. Are there certain specific questions that you are, you know, really focused on making sure you answer very, very clearly if they come up, that are more controversial, specifically related to safety or? I can't imagine or think of any. I mean, our data set's, you know, pretty strong data set, one that comes around every few years in pharma. It's not often that you see a data set like that. The efficacy is very clear. You know, as opposed to the lentivirus type discussion, there was questions on durability. You know, our durability seems very clear. The bone marrow editing shows that the cells are, once they're edited, you know, they remain at that 80% editing level. You know, the patient benefit from clinical markers are very clear. Yeah. From a safety standpoint, we've done a, you know, very robust preclinical package for going to the clinic from an off-target standpoint and everything else, and we've continued to, you know, do more work to show that this is a very safe therapy, and it's, it can be a one and done type therapy for patients. So, you know, it's a very strong data set. I, you know, I can't say that there be questions, particular questions on one or another, but I'll just wait and see. Okay. What about Europe? You're, you're filing there, or you, you have filed there, so that, what do the timelines look like for, for that? Well, unlike the U.S., you don't have a specific Yeah Date where you're going to get approved or not approved, or, you know, what the decision date is. And so we continue to work with the agencies in the UK, with the rest of Europe in the EMA, and we hope that they can continue reviewing the file in an expedited manner. So obviously, you partner with Vertex. So assuming you get the approval on the eighth of December, how quickly can you be in the field and marketing the product? And what else has to happen in terms of ramp-up activities or pre-commercial activities before Vertex can launch? Yeah. Just so everyone knows, Vertex is leading the commercialization of exa-cel, and they are an incredible organization from a commercial standpoint. They have a lot of experience with cystic fibrosis commercializing a drug in the rare disease setting. They have a global footprint, you know, both... You know, right now, they have a very strong footprint in Europe, in addition to the U.S., all in a capital efficient manner. You know, this is not a, you know, a giant commercial organization like some big pharmas do, yet very effective. And there's a lot of work to do. You know, this is not one of those drugs where it's a very, it's a new modality, so you can't just hang up the shingles and expect that patients will show up. I think what you have here is, you know, work that you need to do on the payer front to make sure that they get all, get comfortable with, you know, where, how the drug is priced, what the efficacy is, what the benefit is to patients. You do have a somewhat fragmented payer landscape because you have the commercial payers, but then you have all the state Medicaids that come into play here, in addition to CMS overall. So doing all the work around just, you know, making sure they understand the therapy, the evidence Behind it, but then all the mechanisms are in place, would allow us to, you know, make sure that the, you know, that there's prior authorization and the therapy gets paid for. The second part of this is making sure the hospitals are all well-equipped in terms of, you know, the, you know, doing the transplant procedures. Now, while there's not a lot of transplant procedures that are being done at volume in these centers for benign settings, let's say allotransplant for sickle, that's because you don't get matches. The hospitals can handle a lot more. In fact, you know, in the cancer settings, they do a lot more transplants, you know, for AML and other indications. So the infrastructure is there, but we need to make sure that the qualified treatment centers know what they need to do. Even simple things like how do you freeze, thaw the product before you administer? All that, you know, obviously, we did that in the clinical trials, but we just need to make sure that's all there. And third, we need to make sure the patient experience is seamless, you know, when they come into the process, because you have to collect their cells, manufacture it, let them know when, how, what's the status of the manufacturing, when they're going to expect it back, and then they can set up a date for when they can actually infuse the patient. So all that requires, you know, supply chain infrastructure, requires account teams, or requires sort of a personal touch, patient service touch. And it's great to see Vertex pushing forward very efficiently, but very effectively in all fronts to make sure that everything's ready by the time the PDUFA date rolls around. So what do you think the uptake curve is gonna look like? I mean, given all, given all the operational details that you just outlined in terms of, you know, streamlining, is an institution gonna basically try with one patient and, you know, turn the crank and make sure everything's working before they start to, you know, dose 10 or more patients, for example, in the same institution? I mean, is that how this is gonna go or what? I think it'll depend on the investigator's comfort level. You know, a lot of the investigators, if you recall, you know, half the qualified treatment centers were part of the trials, so they already know Yeah How this works. So it's not anything new for them. A lot of these centers have a bolus of patients that are already waiting, you know, that couldn't be part of the trials, but they wanna get the therapy. You know, so I don't know that there's a lot of learning there that... You know, obviously, if there's a new qualified treatment center that comes on board that were not part of the trial, they'll have to go through more of the learning process. But I would expect that, you know, the key metric that we look at here, which is patient starts, you know, which patients have already been pre-authorized and where the cells are collected, I think that, you know, we expect that there'll be a strong signal once the drug is launched. The You know, it's very clear there is a strong unmet need for these patients. They're suffering from the terrible burden of the disease. They wanna do something. There's no other options for them, really, and they're willing to undergo a transplant process for something that could be as transformative as exa-cel for them. So my expectation is that the, you know, it's gonna be, it may surprise on the upside in terms of the number of patients interested and the number of patients who are gonna be part of this journey. Have you commented on sort of the share you would expect in sickle cell disease, among the, I think, around 40,000 in the United States? Like, what I mean, we have it in our model, and I forgot exactly, but it's somewhere in the teens, I think. But, I'm just curious where Well, there, you know, there are two aspects. When you say share, are you talking about? Are you talking about competitive share or just the No, your share. Yeah, your Yeah. So, you know, this, if you build out the model for how this may all play out, and Vertex will do, you know, the job of guiding and, and, and Okay And saying what we may expect in 2024 and 2025, et cetera. And we'll leave specifics to them, but if you think about this model, a lot of this is market development. You know, what% of patients are raising their hands to get a transplant-based therapy? It'll be less about market share between us and Bluebird, for instance. That said, our work, independently, CRISPR's work, as we're in the market, talking to patients and physicians, there's an overwhelming sort of lean towards doing CRISPR-based therapy from patients as opposed to any other modality. And how that's gonna play out with physicians in the mix of the decision and the patient and everything else, we'll see. The market will tell us. But I think given the fact that, you know, it's notionally a much safer approach to CRISPR-based edit versus anything else, and the fact that we have such strong data to date, I think will give us a tremendous tailwind as we launch this, together with, with other companies. But, you know, we wish Bluebird well, and we wish a nd we want the whole segment to grow very rapidly. Well, what do you have any learnings from Zynteglo that are relevant here that you wanna adopt for your launch or for o r not really? Some, but I, I don't think it's, you know, I don't think it's a very strong parallel. I think, you know Okay Obviously, what we're trying to do is take learnings from every launch in cell and gene therapy. There's learnings from Roctavian's launch, there's learnings from Yescarta's launch, there's learnings from, you know, the SMA launch that Novartis had. They all provide lessons. You know, for instance, Zynteglo in Europe is, I don't think, a very relevant learning for us because, you know, we're gonna do launch in our own way in Europe, for instance, with the payers, ad we have our own processes- Yeah And how we bring them on board. But each of these cell therapy launches, you know, I think if you think about the street, you know, not everybody's been able to predict them well. You know, there's always been... If you look at the range of expectations around some of the AAV launches, you know, there's a huge variance in, in what the expectations were. And I suspect the same thing's gonna happen with exa-cel. But that said, I do if you look at the whole setting, which is sickle cell disease, no other option, transformative data to date, and a very effective commercialization partner, I think that all points towards something that could be a very strong and durable launch. It's not just the strong bolus they're looking at. It's something that could keep growing for sevven to eight years, once you get a strong start. Yeah. Okay. What about the move away from the current conditioning regimen? You have this development program, the KIT ADC which I believe will potentially provide a softer, gentler conditioning regimen. And you've commented in the past that that could potentially expand the market considerably. So can you just walk through your thinking there, and how close is that to being tested in the clinic? Well, you know, if you think about it, today, we're looking at the U.S. market. There's 100,000 sickle patients or so, right? Nearly a quarter of them, 25,000 severe sickle cell patients, would be, you know, candidates for exa-cel... and that's something that could exa-cel could make a meaningful difference in their lives, whatever their baseline VOCs are and everything else, right? Yeah. In our clinical trials, it was two and above from a VOC standpoint that defined severe sickle cell. As you know, think about a gentler conditioning agent, that number could be 50,000 or more patients that potentially could benefit from a therapy like exa-cel with a gentler conditioning agent. In fact, it could be even larger than that. And that's one effect, which is the TAM increases. The second is, there'll be more patients willing to raise their hands, so the penetration rate in the market that we have will also increase if you have a gentler conditioning agent. That said, I think there's realities of how you actually bring a gentler conditioning agent into the mix here. One, we have to show independently that this conditioning agent is safe, and in a setting where we can measure chimerism, show that you can get a meaningful level of chimerism with the gentler conditioning agent. And once we demonstrate that, then we have to apply it in the sickle cell or thalassemia context. But we're this is a very high priority for us at CRISPR, and I think I'm pretty confident that in the next, you know, three to four years, we're gonna see meaningful advances in that direction. Okay. And then in terms of your response, do you wanna just review quickly for everyone's benefit, just the Vertex, the economics of the Vertex arrangement for everyone that's less familiar? Yeah. So we're partnered with Vertex. Used to be a 50/50 collaboration, now it's 60/40. Vertex have 60% of the global profits, and we have 40% of global profits. And that's, you know, similar ratio for cost share as we develop it right now. Yeah. We do have milestones that we expect from Vertex. If we get approved, there's a $200 million milestone that would come upon approval in a major market. That does. You know, for us, you know, at this point, if you look at exa-cel alone as a franchise, you know, we're, we don't expend any more money if things go well in terms of that franchise. And everything else is, you know, profitable, and eventually, it could buffer a lot of our expenditures beyond that into other franchises as we look into 2026, 2027 and 2028. I should have asked this before, but just so we're clear, assuming you get approval on December eighth, would Vertex launch in sickle right there, or is there a scenario where you would wait to get both approvals before you do the launch? Oh, no. I think we wanna move forward. I think patients are waiting. Okay. I think the time is, you know, of the essence in this market for patients, for physicians, and everyone else who are expecting this therapy. Okay. Okay. All right, let's talk about IO then, unless you have anything else you wanna note on exa-cel. All right, so, so CTX110 is the, you know, the, I guess, the original version of your CD19 CAR T, but you have some additional edits which you've made improvements with the Regnase and the TGF-beta, if, if I'm not mistaken. So can you just comment on how those advances are gonna improve the product as far as, you know, making the original CTX110 more competitive in an obviously very, very crowded space? Yeah, it's a crowded space, but we're very excited about these next gen programs. Mm-hmm. You know, I think what we've done y ou know, our original construct, CTX110, we inserted the CAR, we knocked on Beta-2M to give it a little more persistence for these cells. You know, sort of that construct, we improved upon that by making an edit called Regnase-1, which is a lesser-known edit, and TGF-beta R2, which is a better-known edit in the space and cell therapies. And what we did is a very massive scale screening to say: We have no bias. And everybody was saying, "Oh, we should do a PD-1 edit. You know, that's what we should do to make the cells more potent." We have no bias here. Let's just do a massive screen to say, what is the best edit that would make the cells more potent? And then we looked at the right quadrant and said, "Okay, these are the edits that were, you know, lesser." These were not very well-known genes, you know, like SOCS1 or Regnase-1 and the ones that were really the expected ones, like PD-1, didn't rise up to the top. So then we did another campaign to say: What is the best pairwise edit? 'Cause we can do more than one edit. What is the best pairwise edit among the good edits to get transformative improvement in the potency of the cells? And we came upon Regnase-1 and TGF-beta R2. Now, there were two other combos as well that were getting there, and Carl June, for instance, has a different combination with Regnase that also is somewhat equivalent in the cells. And the cell potency is 20x more. In manufacturing, the yields are a lot greater. The cells seem to retain a very strong central memory phenotype, even several days into a mouse model, for instance. The cells seem to keep going for longer in a cyto- with a cytotoxic potential is a lot longer for these cells. So you combine all those factors, and what we could have is something that could be 10-20x more potent than CTX110, assuming we can manage the safety. So we've started dosing patients with CTX112 now. We wanna see where it compares to CTX110. But, you know, one thing I'll say is already, I think what we're seeing is the expansion rates are much better for, even at the dose level 1 for 112 versus 110, for instance, which is what we expect. And I think if that all plays out, yes, you're gonna have a greater AUC for CTX112 versus 110, and that should lead to greater cell killing, and I think tumor cell killing. So we'll see where the data plays out, but I think we're feeling very bullish. I think the key question for us is, how does CTX112 position relative to CTX110 when we get to the end of the year? And do we wanna advance There's still a bit, like, a bake-off between the two or not? Not a bake-off per se, but, you know, right now what we said is 110 is so advanced. Yeah. If you get it to the market, the math works for us. You know, we launch with 110, it's very... It'll have a place in the market. It's not gonna be a multi-billion dollar product. It could easily. I can see line of sight to a billion-dollar product there. But if 112 is a lot better, let's say it's much, much, much better than 110, then we do have a question that we have to face. Okay. Whether we wanna do both or not. But at this point, we're all guns... You know, we're moving forward on 110, we're moving forward on 112, and once we have data for 112, we haven't said where we're gonna show the data. But, overall, I do feel like that could make a huge dent in the CD19 space, even if it's very crowded. In fact, ever since the Carl June papers come out, we've had inbounds from every pharma company that's in the space saying: "You know, we're very, very interested. Tell us what you see from your data, and even if it's very early data, we wanna see what the PK/PD data look like." And ultimately, I think we even had one pharma company say, "We think ultimately the best model for lymphoma, even in front lines, may be a allo CAR T to debulk the cancer, followed by three or four rounds of either antibody or a bispecific, and that's the cure, you know, in the space." So I, I, you know, the, the space is still very dynamic. I think, sure, Yescarta has done really well within the academic settings, but I think the, the market will transform over the next three, four years as well. So what is there some interplay between the Regnase-1 and the TGF-beta R2 that's causing this enhanced persistence as well as potency? Do these targets do they interact in some way, or is there some connection in biology, or is it just an observation from the screen you did? I think the potency, there's an interaction. You know, I think- Uh huh You know, what you're having is, the way Regnase works is there, it's pro-inflammatory by changing the expression of cytokines. Certain cytokines are overexpressed, that allow the cells to be more pro-inflammatory, but at the same time, it's a transcription binding protein that reduces the differentiation of these cells into effector type. So you have more central memory phenotype. The TGF-beta R2 works by preventing TGF-beta from reducing the efficacy of the CAR Ts, right? So it's a complementary mechanism. But somehow that combination seemed to work the best. You know, we tried other combinations. We tried Regnase-1 with PD-1, for instance. We tried Regnase-1 with SOCS1 or some other combinations, but this combination actually seems like the best from enhancing ultimately what the AUC is. We saw a very strong correlation with our 110 trials in terms of the amount of effector cells with the number of tumor cells, that ratio mattered, but also we saw that our cells, the effector cells, with 110 around day 12 or 13, the cells were around, but their potency became less and less, right? So it's not the persistence in terms of elimination by the endogenous immune system, was less the constraining factor, it was more the cell exhaustion. Okay. If you can have these cells persist for a month, but still be cranking at the full effect the entire time, you're gonna see a multifold improvement in AUC, and consequently, you should see a multifold improvement in cell killing or of the tumors. Remind everyone, what did you show for the six-month CR rate for the CTX110, and what do you want - how much better would it need to be with CTX112 to pivot for that? Well, I think, you know, where we are is our single-dose CTX110 6-month CR rate was about 20%. So 1 in 5 patients have a long-term durable response. I think that's where a lot of the allo CAR Ts may end up, in that zone. We did start a, you know, arm where we have 2 doses of CTX110. So we do 1 dose, and then 1 month later do a second dose, and our expectation was that's gonna improve the 6-month CR rate. We don't know by how much it'll improve it. So that's the data we haven't disclosed yet. That's coming up later this year? That's coming up. Okay. And then we have CTX112, where, you know, if that ends up in sort of the 30% range of 6-month CR rate, that's equivalent to Breyanzi or better, and close to Yescarta. That would in fact better than the bispecifics. So that definitely changes the equation if we're gonna be best in class in that space, beyond the bispecifics. So again, you know, nothing we need to think about right now. We're just right now operationally focused on both assets and moving as fast as possible. And then as we get to the end of the year and early next year, we'll make that decision on how quickly we wanna move both and what pace we wanna move both of them forward in. Okay. And I wanna make sure we get to the other topics, but just on the renal cell program, the same two edits, but that was not accidental. That... They seemed to be the best choice. What's the plan there for 131 to sort of- We're dose escalating in solid tumors. Okay. You know, in fact, TGF-beta R2 edit plays an even greater role in the solid tumors. I think a lot of what happens in the tumor microenvironment is TGF-beta related suppression of the CAR Ts, and which is why auto CAR Ts have not worked in solid tumor environments. There have been trials that have been done, but I think if you can prevent that TGF-beta related suppression of these CAR Ts, I think you could see a very strong signal. In fact, we saw responses with CTX130, which is the first gen program in solid tumors, which is very encouraging. And if you can actually amp that up and provide a greater exposure of the cytotoxic CAR Ts to the tumor cells without suppression, I think you could see a lot more activity. And that data is when? We're gonna get that, this- By some point next year. Next year? Yeah, yeah. And I think solid tumors, you know, the staggers are a bit longer. It takes a little longer to dose these patients. In the CTX112 next year, 112, I mean, I think, you know, 112. I mean, we're seeing the data, we just haven't made a determination when we wanna show the data. I mean, in fact- Okay You know, I think, you know, are we gonna provide some color commentary on PK/PD data? I don't know at this point. Okay. We are accruing data at this point. All right. Do you wanna make a decision... Is there a point where you wanna make the decision between 110 and 112, is that com Not at this point. We don't need to make any decisions. You know, I think you know, we're pushing both forward. We're built the organization in that fashion, in a efficient way, you know? Right. I think we don't wanna do it inefficiently, but at this point, playing in that franchise gives us that advantage of having both drugs there. Okay, so let's talk about the diabetes regenerative medicine frame. So first of all, just give us the history there. Like, how did this even- Yeah Happen? How did it start? And, it was ViaCyte, and then it was Vertex, and now you're here, right? So just- Yeah. What's the whole Let me give you the 20-year history in a way, which is, you know, nearly 23 years ago, the Edmonton Protocol was discovered, which was the fact that you could take cadaveric islet cells, assuming they were fresh cadaveric islet cells, and you can put a severe type 1 diabetes patient on immunosuppression and inject these cadaveric islet cells into the patient, and typically they go and find their way into the liver or some other place, that you could have, effectively could. These patients can be, their diabetes could be well controlled. Some of these patients actually, still 20 years later, are still well controlled, but the downside is they have to be on immunosuppression. Was that all, like, all three variants of the islet cells, like the alphas, the deltas, the betas, or was it a specific? It was mainly beta cells. Mainly betas. Yeah. Okay. You know, I remember in 2002, it led a lot of companies to pursue this field. I mean, J&J said they're gonna make a big bet in this in 2002. In fact, all the way to Bill Weldon at the time. And what happened then is people realized that working with cadaveric cells are very hard to find, you know, so people tried to say, "Let's create stem cell-based products that do the same thing." It all turned out that embryonic stem cells are a little harder to work with, you know, I think at the time, so it took some time. There were, you know, obviously some changes in the political environment, and some of the big pharma companies dropped out of working with embryonic stem cells. And it's also not scalable to do. And then we hit, you know, in 2006-2008 timeframe, people started working on iPS cells, and we had major breakthroughs, and all of a sudden, iPS cells became a reality. You know, right before the big recession, you know, there was so much excitement about iPS cells because if you walked around Japan, there was all sorts of trials ongoing, in artificial corneas, artificial retinas, because you could take iPS cells and make any organ that you wanted, you know, you could differentiate them. But it turned out that it was also, again, not scalable because it's very expensive to do, because you have to put people on immunosuppression, and you have to do it on an individualized basis. Otherwise, you have to do it person by person, which is very expensive, and that's where CRISPR comes into play. If you can use CRISPR to edit these iPS cells to make them immune stealth to the immune system, then you have a very scalable platform. And if you ask some of the leaders in the iPS space, they'll say, "The best thing to happen to iPS space is for editing to come into play." Similar to what happened with, you know, iPads and pen pads. You know, in the early 1990s, you know, there was a product that was called a pen pad that did everything an iPad can do now, but the Wi-Fi was not very prevalent, apps were not there, you couldn't do anything with it. So, you know, you had this great technology, like, that was not very usable. iPS is the same way. iPS technology is amazing. It was there, but it's not been very scalable. So that's the fundamental thematic bet we're making. So in 2017, we started looking at different options. In 2018, we did the deal with ViaCyte that had been working in the space for 18 years with Type 1 diabetes to make use the stem cells to make pancreatic endodermal cells or precursors of basically the beta cells. And they'd already done trials to put them in a device and implant them into patients with immunosuppression. And our immediate response was, "Let's edit them to make them stealth, so you don't have to have immunosuppression." That's the trial we're doing right now with 211, VCTX211. We'd done a deal, a 50/50 deal with ViaCyte, but ViaCyte got acquired by Vertex, so now we're a 50/50 partner with Vertex in this space. Now, it turned out that Vertex also had a parallel bet with the same thesis around iPS cells and editing, and it acquired a company called Semma. They had a different cell line that were also progressing. What we thought was, actually, it may benefit everyone for us to take our, you know, license our CRISPR technology to the Semma cell line as well with Vertex, and that's what gave us, you know, the deals we announced this year, which was in the early part of the year, we announced the $100 million or so deal with Vertex, we had that $70 million milestone come in recently. That was... These are all milestones, and then we have royalties associated with edited cells from the Semma cell lines. So we have some portion of participation in the Vertex efforts independent of us, and then we have our 50/50 program with which we're pursuing forward with Vertex. So at this point, from a Vertex perspective, they're pursuing; they're pushing everything forward. For us, we'll see where the 211 data come out, and that could be a transformative product if it works. But, you know, ultimately, I do think, given the data that Vertex has shown to date, the notion of edited cells in diabetes is going to be very powerful. In spite of everything you're seeing with GLP-1s and the transformative data with Ozempic a nd Mounjaro and everything else, it's still gonna be a very important product. What, what's the difference in terms of the edit with the Semma cell line and the one coming from ViaCyte? How are they different or- The edits with the Semma cell line have not been disclosed by Vertex. So Vertex owns those edits, and they will, you know, at the right point- You just licensed the technology- We licensed the technology. But it's not a 50 Build around it. Okay. That one, you know, it's mainly a Vertex program. Okay. We have we have royalties and milestones associated with it. The program that we've developed, VCTX211, with ViaCyte, is a 50/50 program. What have you disclosed what that edit is, the? The 211, yes Cloaking ... we've disclosed all the edits. You know, the immune cloaking is a combination of a Beta-2M edit, which we saw benefit from in the IO context. Yeah. We do insert a PD-L1, which also cloaks the cells, and an HLA-E that also further prevents NK cell attack. So those are a set of edits for immune evasion. Okay. We actually have a couple of edits for, to reduce cell stress. You know, a lot of this. There's a lot of endoplasmic reticulum stress that happens in these cells when they're cranking out insulin, and we've made a couple of edits, these are lesser-known genes, A20 and MANF, that prevent that sort of ER stress in the cells and increases their viability. Okay, so by what fold, you know, what factor are you increasing the beta islet cell population in the pancreas relative to the patient with... You know, in a Type 1 diabetic, there's really none, right? There are hardly any. Hardly any. You know, there's. You know, when you put these, we haven't disclosed the exact cell dose, but, you know. Okay You're looking at close to 1 billion cells, potentially, that you may need to replace to get reasonable efficacy from a C-peptide levels. So, the way you measure the insulin levels that's being produced is that these endogenous cells produce proinsulin that's cleaved to make insulin, and the by-product is C-peptide, and you can measure the C-peptide. Because a lot of these patients actually are taking insulin injections, so you don't want to measure that insulin Right That they're taking. But if you look at, you know, that requirement, I think, you know, you could be putting up to 1 billion cells in these patients. But again, 1 billion cells, because while the pancreas are a sort of banana-shaped organ with a lot of cells, the beta cells itself is a very small- Right fraction of those pancreas. Yeah, yeah. Okay, and then, as far as measuring the C-peptide, do you use the, the glucose tolerance test to do it, to do it in a controlled way? Because sometimes I mean, because I cover this other company called Biomeia, which you may have heard of, and, you know, there, the question when you measure. Well, some of the diabetes experts have said that when you measure C-peptide, you, you need to really do it in a controlled way, otherwise it can be all over the map. Yeah, but I think in these, you know, severe diabetes patients that we're looking at, you know, they have no C-peptide, right? It's really low. The baseline, you know, you don't get that... The signal-to-noise is a lot greater. Mm. Okay. And you've seen that, you know, Vertex disclose data, C-peptide data, for their first couple of patients with their Semma cell line, and it's very clear that, you know, they go from baseline of nothing to, to something. So it's different from the Biomeia concept, but, you know, a situation where there's some baseline- Yeah C-peptide production. Now this whole, the cells are implanted in a basically half a credit card sized wafer, right? Yeah. Just explain why that's necessary, I mean, if they're immune privileged and cloaked, why can't they just be injected without this housing, you know? Yeah, yeah. So I mean, that's a very good question. Ultimately, I think these cells will be just injected directly. Okay. You know, I think our initial notion was we weren't sure what the regulatory environment was going to be, and if, you know, if something goes awry with the cells, do we need the ability to pull the cells out? You know, if they're in a wafer-like device... You know, remember, we were making these decisions in 2017, 2018 timeframe, not knowing how the regulatory body's going to espouse an approach like this. And we thought maybe, you know, having them in a device would give us enough information on immune evasion, but also, if something goes wrong, we're able to pull it out. Okay. So it provides the safety. That said, I think where the field is coming out now is to say, you know, you just want to have fully differentiated cells that can be directly injected into the patient. Now, most of the injections are done in the portal vein, so the cells go into the liver and lodge themselves over there, but there may be other ways of injecting these cells as well. I think that's probably where the field's going to move to eventually. All right. Let's make sure we touch on the in vivo programs. So you want to just review what are the timelines there to getting into the clinic? I think it's soon. And the two programs, the ANGPTL3 and the Lp(a), how are they similar or different in terms of what you're targeting? From a technology standpoint, they're very similar. You know- Yeah I think eventually, this is a very scalable platform. What's been figured out over the last 3, 4 years is delivery of CRISPR-Cas9 to the liver is something that I think has been figured out, across multiple... Obviously, Intellia showed their early data, but other companies have also learned how to make these LNPs, and I think we have best-in-class LNP platform, together with mRNA, because that's how you deliver the Cas9. And I think, we've shown very good data in primates, and we hope to get into the clinic this year. So we, we said that we'll be in the clinic with the ANGPTL3, one of the programs this year, and then follow that soon with the, with the second program next year. The two indications, it's the same technology platform, and all it changes is the guide, for instance. That's what makes it very scalable. You know, we could do 10 programs for gene knockout in the liver if things start working, and very quickly follow the RNAi route, essentially, and do a lot of those targets that they're targeting, but better. Because it's a one-time treatment, you won't have any of the effects or safety issues with repeat administration. That's with the first two indications, you know, the way you look commercially at ANGPTL3 versus Lp(a) is very different. ANGPTL3 is more of a rare disease type of play. You know, in HoFH, you know, a lot of these patients are refractory even to PCSK9 therapies, and the only option they would have is something that's like ANGPTL3. So that's the population that you'd initially do some of the trials. There are patients who have very high triglycerides. In fact, triglycerides over 1,000 sometimes, where there's no other options, and ANGPTL3 is known to reduce triglycerides. So that's another patient population. So there's all these niche patient populations which you would develop it in without having to, I think, without having to do outcomes trials and get approval off of that. So that's why we picked ANGPTL3 first. That's sort of more of a rare disease type setting where we would, you know, we can do all this on our own. Lp(a) is a much bigger market. I mean, there's, like, 11 million patients in the U.S. alone that have elevated Lp(a) levels, and it's, you know, we're waiting for the data from Novartis next year. But if it's a clear outcomes benefit is, is demonstrated or a clear correlation between high Lp(a) and events is demonstrated, independent of LDL, for instance, then this becomes the hottest target in cardiometabolic medicine, you know, in the whole space, and we'll be in a pole position there. Odds are we would require the outcome trials, outcomes trial and everything else ultimately to make this a broad-based therapy. But again, you know, we can define populations that are very, very high Lp(a), for instance. You know, there's the number of stories where, you know, the investigators have told us, where there's people in their late forties, early fifties, marathon runners or very fit, all of a sudden have a severe cardiac event because of high Lp(a), where everything else is controlled. And more and more of this is emerging as we become a very important- Just explain, explain to everyone the basics, is that you're basically abrogating the Lp(a) gene, or what exactly are you- Lp(a) is a carrier of, you know... The people simplify this to good cholesterol and bad cholesterol, right? ApoB is really the intrinsic bad cholesterol that you're measuring that's carried in different vehicles. It's either carried in a LDL vehicle, it could be carried in a, in a triglyceride-like particle vehicle, or it could be carried in an Lp(a) vehicle. An Lp(a) vehicle is basically apolipoprotein(a) that interacts with apolipoprotein B in, into this, into this domain, and that, you know, can carry a lot of the ApoB in the, in the bloodstream. And so it's, it's independent of... You know, you could have very low LDL but still have high Lp(a) that carries all the ApoB. It's an independent risk factor is what's determined. It's emerged over the last probably, you know, 6 or 7 years, a very important target. In the U.S. practice, it's still not a typical lab measure. You know, you go to the doctor, they don't measure your Lp(a) levels. In Europe, they're starting to do it. If you go to Germany, for instance, they start measuring Lp(a), and it's gonna be demonstrated as a very important predictor of cardiovascular outcomes. What if this, if this Novartis, the HORIZON trial, I think, is... If it doesn't work, is that gonna change your thinking on this target or- Of course, I mean, I think Cross that bridge when you get there? Well I mean, it will change our thinking. Yeah. It would mean that you, you know, the cutoff that they've used, I think, is about 150 for the Lp(a) levels is high. You know, is it that or is it 400, you know? You know, what is the population where Lp(a) levels are so high that it overcomes any of the effect of LDL, and it's b y itself, the single biggest contributor risk? That's something that, you know, those trials, both the Amgen and the Novartis trials, will inform. They have slightly different cutoffs, but- Right You know, subpopulation analysis from that trial will be really important. Okay. All right. Thanks, Sam. This was a lot of fun. Thank you very much. Yeah, if I may do one last plug for CRISPR X. Go ahead, yeah. You know, I know there's a lot of talk about next-gen gene editing. We have... You know, people are saying CRISPR 2.0, 3.0, but we're doing all forms of next-gen gene editing. In fact, you won't believe the type of edits we can do now to, you know, essentially gene write, and that's something that's a big focus for us. It's set up in California, in the Mission Bay. We wanted to have a separate pool, a company within a company working on it. And I would say at this point that we're probably doing some of the most advanced gene writing technologies out there. We just don't talk about it until something becomes a program. You said you can do all scales from single base all the way to entire genes. Absolutely. Everything in between. Yes, and we're ultimately we wanna target inserting entire genes that are, you know, 3-4,000 base pairs. And so we're getting improving efficiency along all those fronts, and it's a huge part of, you know, my focus and, you know, I think this is all gonna change the number of diseases we can address with gene editing from tens to hundreds, if that all works. Hmm, okay. Awesome. Wonderful. All right. Thank you. All right, thanks.