All right, welcome back, everyone, to the next session of Citi's Virtual Oncology Leadership Summit. I'm Yigal Nochomovitz, one of the biotech analysts here at Citigroup. Remember, if you have questions for Sam Kulkarni, the CEO of CRISPR, who's our next speaker, just email me and I will be able to just check the email and relay, relay the questions. So Sam, again, thank you so much for, for taking the time to speak with us in an incredibly, incredibly busy schedule. Obviously everyone is, is, is pretty familiar with, with, with your story, but still I think it'll be helpful just to set the scene at a very high level. You know, what, what are the long-term goals of the company? What are the what are some of the key, the key priorities for, for 2024, and what should people be watching for? Thanks. Yeah, thank you, Yigal, for having us at this conference. Always enjoy these fireside chats with you, whether it's virtual or in person. It's an important time to do it given the stage of the company. We're almost a decade into starting the company when we started, you know, since we started the company, and we're here where we've gotten the first CRISPR drug approved in the world, which is a remarkable achievement. But we've also put our portfolio into a strong position to parlay this initial success into something that could be multi-asset, multi-therapeutic area, with different growth levers that could get us to becoming a sustainable company, in the not-too-distant future. I was just reading an article today about the 100 Billion Club and how Vertex and Regeneron are part of the 100 Billion Club, and but they, you know, both were started in 1988 and 1989. It takes 30+ years or longer to get to that kind of level, and it took Genentech just as long, maybe a little bit shorter. But you know, hopefully we can be on the same trajectory with CRISPR and do it in an even faster time timescale, just like we've been much faster getting our first drug approved relative to some other companies that are stalwarts in the biotech space. So you know, for us overall, the mission remains the same, which is to create a great company, you know, great biotech company that's getting drugs to the clinic, but also through the clinic to patients to help patients with severe diseases across a number of different therapeutic areas. I think from a business standpoint, we want to take a stage-based approach where, you know, we've completed one phase of the company, and now we're looking at this, you know, we're in the middle of the second phase of the company where, you know, a number of our portfolio drugs will declare themselves and we'll see what, what's working, what's not, over the course of the next 12-18 months that would dictate the next stage of growth for the company, before we ultimately become a sustainable, profitable company. Okay, great. Well, let's obviously start then with the tip of the spear in Casgevy, which obviously was recently approved and the launch is underway. Obviously Vertex is leading the charge there, so they're maybe limited in what you can say in terms of detail. But at a high level, you know, what can you tell us about the early metrics to the extent possible, the 12 sites centers of excellence, which are beginning the deployment of the therapy, the uptake so far, any anecdotes, any feedback from the marketplace in terms of how the launch is going? Yeah, thanks for that question. You know, at the outset I'll say that, we're really glad to be partnering with Vertex. They are the best positioned company to launch a drug like Casgevy for these indications. They have the experience with rare diseases from a commercialization standpoint. They've they have the organizational nimbleness and flexibility to deal with the launch that's different from a typical biopharma launch or a pharmaceutical launch that we've seen in the past. I think the biggest thing is the data are remarkable in what we presented and what we got approved off of. You'll see eventually a lot of patients benefit from what is a transformational drug. With that qualification, I also, as you said, you know, we're not able to make too many comments about the CASGEVY launch given Vertex is leading the launch and we'll let them set the tone and provide the metrics and provide the updates on how it's going. But from my own experience, you know, and this is regardless of what I see on the launch, which is the physicians are tremendously excited. The entire healthcare system is excited about CASGEVY. You have, you know, a number of initiatives popping up from the government side, for instance, from the White House, on enabling launch and access to medicines such as CASGEVY through CMS across the different state Medicaid organizations. So there's a lot of energy brewing in the system to enable CASGEVY, which may not have been the case with some other cell and gene therapy launches. You know, I think the number one question we got at JP Morgan was, you know, if Roctavian was, it didn't really meet expectations and the launch didn't go as planned, what makes you think that CASGEVY's any different? And I think they're apples and oranges. I don't think you can really compare the two, apart from the fact that they're both, you know, fall within the cell and gene therapy bucket because the indications are very different, the unmet need is very different, the party commercializing is very different. And so, you know, broadly I would say what we're gonna see is strong patient demand 'cause that's what we saw in the clinical trials. What we see is a lot of physician enthusiasm, judging from what I've seen at least, directly. And I see the system gearing up to support a launch for a drug that's transformative as Casgevy. So, we feel generally good about how it may all go, but again, with the caveat that Vertex will be the one providing sort of the metrics, the guidance, et cetera, for how the launch would go. Though, I mean, I know you can't say a lot of detail, but will Vertex be presenting what those metrics are in terms of the, you know, who's in the queue, like who's done the port, who's got the patient start forms filled out, you know, which centers are seeing more of the patients? Do we gonna get that level of detail or not necessarily? Vertex will provide the, you know, the guidance, you know, and they have, for instance, provided guidance now on the number of ATCs that are qualified, which is an important metric in all this. They have provided some guidance around some of the payer discussions, especially the contract with Cigna and the early access in France. So I think you will see more information from Vertex, but it's hard for me to comment on what they're gonna guide on. Okay, fair enough. But then moving sort of back to your development of the product and making it, you know, potentially better for patients, you have a program where you're going to potentially be moving away from the busulfan preconditioning. This is the c-Kit ADC. Where does that stand in development? Because I, as you've mentioned before, and I think it was originally highlighted at your R&D day back in New York City a few years ago, that that could potentially widen the funnel quite substantially in terms of who would be amenable for Casgevy. Yeah, you know, this is a very important initiative for us and for Vertex. You know, I think we both recognize that, singularly a gentler conditioning agent could significantly expand the addressable population. But not only that, in terms of the addressable opportunity, it's also significantly gonna accelerate the uptake of Casgevy, in the population that's eligible. So, you know, it's hard to say, is it a 3x, is it a 4x uptake difference? If you have a gentler conditioning agent, all depends on the data that come out with it. But, but, in general, I think it'll make, it'll, it'll pave the way for greater uptake in the population. So from our end, you know, we did talk about it at the innovation day that we held a couple of years ago where we had a CKIT-conjugated toxin, CKIT antibody-conjugated toxin, and this ADC showed very encouraging early data. Subsequently, since we, you know, that disclosure, what we've done is to acquire a GMP-level antibody from a company called Magenta that disposed of its assets. And that's a—it's a great antibody that has high affinity but very fast clearance, which is important in this setting 'cause we don't want the antibody hanging around to impact the product that we're—edited product that we're putting into patients. And we've actually licensed in a toxin that we think is best suited for this purpose. It's not as toxic as a maytansine or some of the toxins used in the cancer settings. And we, with this conjugate, we're now doing all the studies, whether it's mouse studies or NHP studies, to demonstrate that there would be engraftment in the hematopoietic system using this ADC for conditioning. That's it. All these take some time to first get to the clinic and then get it, you know, into the mode of treatment in clinical trials, and then ultimately approval. But it is a high priority for us. Now, I think Vertex also has signaled that it's a high priority for them. They have their own agents that they've developed, across different targets and, you know, which is great for us because we're gonna move in parallel and ultimately put the data side by side and decide which agent we best for, for gentler conditioning. And regardless of whether we've developed it or Vertex, I think it'll accrue towards CASGEVY, from a benefit standpoint. meaningfully increase the value of that program. Just one question I'm getting from an investor on this. I know you may be allowed to answer, but Vertex, I don't believe they've announced a European price yet. Do you know anything about when that might happen or is that a question for them? A question for them, you know, I think what we, what I can say is they've been very responsible about how we've priced CASGEVY overall. You know, I think the studies from ICER and also from other agencies has indicated the pharmacoeconomic is far greater than where CASGEVY has been priced, so far in the U.S. You know, I think Vertex will continue to take that responsible path, in Europe as well. Okay, let's move on to your, your programs then in allogeneic CAR T. So I think the last update was last December, and you mentioned that you were prioritizing the next gen set of assets, the CTX112 over the CTX110. So, this of course is the Regnase-1 and the TGF-beta receptor 2 knockout. So, why did you decide to do that? What is, what is the edge that you get from, from 112 over, over 110 and how will it help you accelerate the development? Yeah, we're quite excited about our next-gen CAR Ts. A little bit of history here, what happened, which is, you know, we had our first-gen program CTX110 and CTX130 that went into the clinic in the 2018 timeframe. At the same time, we said, you know, we already had a lifecycle management or plan to improve the products where we did a very large screen, empirical screen to find other edits that make these cells more potent. Because what we were realizing is the cells actually persist for about a month in patients. So the persistence is not as much the issue as it is exhaustion, you know, but the cells were getting exhausted about day 14, in the patients that we treated. So we said, what, what if we made the cells more potent and also, somewhat exhaustion proof where they keep going until they're eliminated by the, by the host immune system? And, we did an empirical screen and found these edits like Regnase-1. And we also noticed that a pairwise edit of, of, of the highly prioritized edits had a synergistic effect. So even better than a single edit. You know, these were targets that weren't as, had, didn't have as much notoriety in the, in scientific publications at the time. So, we started, you know, we, we were talking to a number of other companies that were also in the space and it turned out that one of the other companies had also done a large screen. And, they had come up with the same edit as the top edit for making CAR T's more potent. Now it turns out that last year Carl June published a paper showing that Regnase-1 again is the best edit they can make in CAR T's. And that's gained a lot of attention since after its publication. This is a transcriptional binding protein that somehow regulates cytokine release, but also the maturation state of the T cells. So with the Regnase-1 edit, particularly in combination with another edit, we find that the cells, the CAR T's retain more of the central memory phenotype, a little more naive and not fully differentiated, but at the same time produce more pro-inflammatory cytokines that make the cells much more potent. And so we landed upon this edit. And then as we were thinking about the notion of solid tumors and the solid tumors, you know, resisting CAR T's, and a lot of it was TGF-beta mediated. So we said that if you can take out the TGF-beta receptor, and that's where we edited out the TGFBR2, then the cells will also be resistant to that sort of defense mechanism that tumors have, through TGF-beta secretion. So those are the two edits we prioritized. And together they had a lot of synergistic effect and they had no other side effects on the CAR T's health or T cell health, or expansion in manufacturing. And so far I think our decision to move from the first-gen to the next-gen seems like a very good decision. You know, we haven't disclosed any clinical data yet, but we did say that we're seeing greater expansion, we're seeing better PK profile from the next-gen CAR T's versus the first-gen, and we're also seeing greater manufacturability, and the yield improvement that allows us to operate at a much lower COGS than we were with the first-gen products. So more to come this year, but we're moving along both CTX112 and CTX131 through dose escalation at this point. We're now into relevant doses where we're starting to accrue data that we'll disclose at the right time. Okay. What sort of COGS savings might you anticipate just in order of magnitude for the new pro with this new approach? Yeah, I think we've seen at least 4-5x decrease in COGS. So we're now talking about COGS in the regime of $10K-$15K or $10K, you know, $40K per patient, maybe $10K-$20K and so, you know, depending on where we land on the dose. But it's significantly lower than autologous CAR Ts and gives us great flexibility from a pricing perspective, and, you know, capital efficiency perspective in general. And then with respect to some of the other competitors in the allo CD19 space, you know, we know who they are. Thoughts on, on how you might differentiate? I mean, you, you obviously have a very good approach here with this dual knockout you just discussed, but maybe a little bit further behind in terms of showing the initial clinical data. Yeah, I mean, I think at this point, you know, there was the big CAR T versus NK cell battle. And I think if you ask most experts in the space right now, they'll say that CAR T are more potent than NK cells, you know, I think in general, whether it's IPSC derived or LT donor derived, and especially with the, when compared to these edited CAR T or edited T cells. So I, I think, you know, in that regard, I think CAR T are looking very favorable. I think in regards to competition within the CAR T space or allogeneic CAR T space, you know, you have one approach, where there's a PD-1 edit, there's another approach where there's a different conditioning agent, another approach where there's, you know, a different substrate with gamma delta T cells. We'll have to see how the data play out. You know, a lot of this now is depends a little bit on patient selection. You know, I think, the realities with auto CAR Ts being, you know, getting the second line approval, it gets harder to find patients that have the right characteristics to put on your trials. So the numbers, you know, with small numbers, you may not get the right marker of what's better, what's worse. But I feel that we're the best position because we're not using a very high LD regimen. We're not using a CD52 agent. And so our, we're much more tolerable conditioning, for patients. And, our CAR Ts are more potent. And that gives us a big advantage as we compete with bispecifics and auto CAR Ts in the large B cell space. How does the yield input occlusion compare with the typical what you see in the autologous CAR T's? Is it on par or is it lighter? Our Flu-Cy regimen is on par with auto CAR Ts. Okay. But I've, you know, we've seen other allogeneic players use an enhanced LD, where you have a much higher level of Flu that's administered. And that, you know, makes it tricky because then you're exposing the patient to infections and other side effects, which make it tricky to compete, from a commercial standpoint. And so you mentioned you're gonna share the initial CTX112 data and B-cell malignancy. Can you say a little more specifically when you might see that? Of course, you know, with the handoff to Vertex for the commercial program, everyone is focused on your catalysts internally. So is that something that we could expect this year or unclear yet? Yeah, most likely we'll have data from 112 this year. You know, we're trying to figure out which conference and where it makes the most sense. But, you know, we're moving through dose escalation pretty quickly, which also is an important indicator, which, you know, enrollment in our trial is always an indicator of how, you know, how PIs view the particular product. And so I think we've had no issues enrolling patients and, and finding patients, even if it's crowded. The, the big, you know, for investors, the question we always get is, you know, how are you gonna compete with autologous CAR Ts given their earlier lines of therapy and, and now with bispecifics? But the conundrum here is, you know, there's, there's about 25,000 eligible patients in second and third line, DLBCL or lymphoma settings. But only about, only about 25% of them are getting treated with an autologous CAR T or less, right? And we already seen some flatlining of autologous CAR T revenues, which tells you that it's only available in certain centers and it's not gonna be broadly used in community settings. And so the conundrum we have is there's 75% of patients where there's an unmet need. Yet with all the clinical trials starting in these large academic medical centers where there's a lot of autologous CAR T easily available, how do you manage that dynamic of doing clinical trial in an expedient fashion and getting an approval so that you can serve the unmet need in the remaining 75% of the market, or maybe even in the full market if you can position appropriately? The other thing that we're also seeing is, you know, bispecifics came with a lot of fanfare. You know, if you look at some of the estimates from analysts not too long ago, but, you know, the durability of bispecifics is still an open question. I think, you know, there was a recent publication on Glofitamab where the, you know, people are losing complete responses a year, over a year into the therapy, or a year and a half out as well, which, so it's, it's not, it's the, the data have not been the same as auto CAR T's, but I think allo CAR T's could get there, in terms of long-term durability. All right, let's move on and talk about the new initiative, also announced, I think, in December on autoimmune. You're planning to start a phase one in SLE, in lupus. Where does that stand? What are the gating steps to get that going? I mean, you know, I think at this point it's nothing extraordinary in terms of the gating steps. I think we do have to get regulatory approval, and then do the site initiations and get the IRB approvals and get to dosing patients. So, we're on track to with what commitment we've made, which is to open the clinical trial in the first half of this year. And we'll provide updates as we go along. I think this is an incredible opportunity for us. Somehow the stars have aligned for allogeneic CAR T in autoimmune settings with the data that were demonstrated or shown at ASH last year by Schett and others. You know, point number one is if you get a full B cell depletion, you do reset the immune system for these diseases. The B cell depletion for Allo CAR Ts looks very similar to what we see with auto CAR Ts. You know, I don't think there's much difference. That's point number one. So Allo may work just as well as auto CAR Ts. Second is for auto CAR Ts, it's gonna be hard to move very fast because the trial sizes are larger. To get approval, you may need more than one, you know, phase three trial to get approval. And for auto CAR Ts companies to be able to do a 400 or 500 patient trial is gonna take a long time. With Allo CAR Ts, you can move much faster since it's available off the shelf, just like you would with an antibody or a small molecule. The third point is, you know, this whole notion of T-cell leukemias, rising even at a small fraction out of the CAR-Ts treated patients that the FDA published on recently is posing a question or casting a shadow with some of the sites we've talked about in terms of using auto CAR-Ts in the autoimmune population. You know, it's different in the oncology setting, where there's a greater tolerance for such risks. And so, you know, the stars have aligned for allo CAR-Ts or allo, you know, CAR-NKs or whatever, solutions that you may bring into autoimmune. And then within the allo space, we feel like we're best positioned because we have a pivotal ready manufacturing process. We have low COGS compared to a lot of other players. I think CAR-Ts will be better than NK cells in terms of B-cell depletion ultimately. You know, we have healthy donor-derived CAR Ts have greater data than iPS-derived CAR Ts at this point in terms of showing this B-cell depletion. So, you know, from many different standpoints, we feel like we're best positioned out of all the players in terms of moving very fast against this opportunity, which could be much larger than the oncology opportunity. And it's evident also from all the pharma interest that we're getting on in this particular indication. Okay. Quickly, what are your thoughts on, you know, you have the CD19. Do you think that there's an advantage to having BCMA as well or no for the first, for lupus and other autoimmune? And what is your plan for the preconditioning? How's that gonna go? Yeah, you know, we're gonna start with standard preconditioning, like we do with auto CAR T's in the oncology settings. Eventually we wanna see if we can go lower, and make it even more tolerable and easy in the preconditioning. But we wanna de-risk by starting at the, at what we have right now. I think, you know, in terms of targets, obviously there are people trying CD20, CD19, CD20, and BCMA. I think CD19 gets to the sort of the larger population cells that are being depleted at even earlier stage of differentiation relative to more mature B cells that you would do with BCMA. And so if we're using CD19 to eliminate that population and create that B-cell reset, CD19 should be a better target, relative to CD20 or BCMA. But we'll have to see what the data tell us. Maybe there's some synergy between targets, but at this point, CD19 seems like the best bet. Okay. Quickly, let's talk solid tumors. The RCC study doesn't get a lot of airtime. What's the next data update there? I know there was some early data you'd shown with the first gen product. You got a CR in one patient. You've now moved on to the same two edits we just discussed for the CD19 now compared with the CD70. So, just give us the quick update there so we can move on and talk about other aspects of the company like the in vivo. Yeah, no, you know, I think our PIs who are doing our solid tumor trials are pretty excited about CD70, you know, with the, they were a bit disappointed that we decided to move to the next gen from the first gen in some ways. But it for us, it made a lot of sense. They were disappointed. I would thought they would've embraced that, you know? Well, I mean, they're excited on one hand, but they, you know, feel like we've lost some time because they wanted to just keep going with 130 because, you know, we did see the complete response, which they'd never see in these settings. Even the stable disease outcomes that we saw in patients were long-lasting stable disease outcomes in these patients. Again, you know, these are patients who die pretty quickly from in these metastatic settings, and we saw encouraging data. Then Allogene obviously showed some PRs as well with their CD70 effort, you know, indicating broadly that this target is a valid target in RCC and perhaps even other solid tumors like lung cancer and pancreatic cancer. So we're moving, you know, through dose escalation. The dose escalation takes a little longer for solid tumors and CD70 versus DLBCL 'cause the stagger, you know, the time between scans is longer and then the stagger is a little bit different. But we are, you know, approaching what could be therapeutic doses now in CTX131. And so we'll have plenty of data that we accrue this year. We haven't determined when we would disclose the data, but that's another one that's moving on track. And then there's some others. There's the anti-GPC3. There's an anti-PTK7, another, an anti-LIV-1. Just where, where do those stand? Yeah, so I think, I think, you know, GPC3 is a unique construct. We actually partner with an academic institute, Roswell Park in Buffalo. They are actually manufacturing and putting it into trials as an autologous CAR T. And we have the option, should the data look good, we have the option of making it a CRISPR program, an exclusive option. So we financed a different entity to create this CAR T and get into clinic. And then we get to see the data and decide if we wanna, you know, move it forward rapidly, as an auto CAR T or an allo CAR T. And then we have other targets that we've looked at where we've done all the preclinical work, and have it ready on the shelf. And should we start seeing good data on solid tumors, we're gonna click go on other targets like LIV-1. Okay. All right, let's talk about in vivo. It was a super interesting area for you. What, at a high level, let's start with the delivery strategies. So like the LNPs that you're using, tell us about the technology there, how they're different or potentially have advantages, relative to other approaches. And then we can move into the targets. And of course, you showed some very nice NHP data last year, knockdown data, which looked good. Yeah, we're excited about our in vivo platform. We looked at a lot of different LNPs, and we licensed in this LNP from a provider we haven't disclosed who they are yet. And this LNP has, you know, even greater potency than some of the LNP data we've seen from other gene editing companies to date. What's also interesting is you don't need conjugations like a GalNAc conjugation or other targeting moieties to get uptake in the liver at a very high efficiency. So we showed nearly 70% editing in whole liver, which equates to about 100, nearly 100% editing in hepatocytes, with this LNP platform. We feel like, you know, it's relatively safe in NHPs, and we have that therapeutic window to get very high editing without having any safety issues. And it should be a very scalable platform. Should we be able to show that with our early products, 310 and 320? So, it's even more scalable than the allogeneic CAR T franchise in a way because if we show good data with 310 and 320 and, you know, we find out very quickly because you can find out editing in, you know, within two or three weeks of dosing a patient. Should we show that we have three or four other programs and we haven't disclosed those targets yet where we're ready to go and bring it to the clinic in rapid succession, assuming we ungate them. So, can you tell us a little bit more about the NHP data? I mean, you just mentioned it, but to me, to my mind, it would seem very translatable to a human clinical trial in terms of the target and the modality. Would you agree with that? Absolutely. And that's, that was, you know, Intellia that first demonstrated that. And they showed that, in fact, the potency could be even higher in humans relative to monkeys. And you can achieve the same editing levels with a much lower dose, when you do the allometric scaling, in humans. So, the translatability is very high, which is why we're so bullish on these programs given the NHP data that we had, both from an efficiency of editing, durability of editing, and a safety standpoint. What are, I mean, what does your modeling or what does the biology tell you about the percent? Is there some sort of threshold in terms of editing percent that you need in the liver to achieve a read-through to a clinical endpoint in these settings? Is there a goal in terms of what you need to see? Yeah, I think both for ANGPTL3 and LPA, we wanna get as high editing as possible because there's very clear correlation that, you know, disruption of those genes results in better cardiovascular outcomes based on natural history data. So with ANGPTL3, which regulates lipoprotein lipase, I think we wanna get relatively high editing. But you know, it's a relatively linear scale, I think, as you go, you know, in terms of the dose response, at least that's what we saw in the monkeys. And you'll start seeing benefits even earlier. You know, with ANGPTL3, there in certain settings, you can use pancreatitis as a biomarker, for instance. And so you don't have to wait for all the outcomes data to understand if you're getting the benefits from editing. And then you can also titrate and see if different levels of editing have different levels of benefit. But generally at this point, starting off, we wanna get as high editing as possible within the safety margin. So the studies are underway. Just remind everyone when they started. It's two separate; it's one cohort for 310, one for 320. How are you deciding who goes into which cohort? I mean, I would think you could; some of these patients could potentially be eligible for both. How are you doing that? No, I think with the ANGPTL3, a lot of them are patients who are, you know, either refractory to other agents like PCSK9. There are a bunch of patients that have homozygous familial hypercholesterolemia. There are some patients that have very high triglycerides in addition to high LDL. So those are the populations we're starting with in, with ANGPTL3. It's very similar to the development path that Evkeeza, Regeneron employed for Evkeeza, which is a successful drug. It's an antibody targeting ANGPTL3. And what, what, other siRNA companies are doing. With Lp(a), it's a different population. You know, there are patients who are very healthy otherwise and have well-controlled LDL, but Lp(a) is an independent risk factor, which again has very strong natural history associations in terms of levels of Lp(a) and cardiovascular risk. Now, there are two big RNAi trials ongoing for LPA with different cutoffs of LPA, which will read out in the next 12 months. That will, you know, directly show you the outcomes benefit or hopefully show you the outcomes benefit from disrupting the LPA gene. What we're doing is similar to what the RNAi are doing, but it's, except it's a one-time intervention. And, I think there'll be, there'll be a lot more patients on LPA that'll be eligible here relative to ANGPTL3. ANGPTL3's more of a rare disease model in terms of development as we're thinking about it. LPA, you know, our estimate is there's over 10 million people with high LPA in the U.S. alone. So it's a large market and, which is why it's been of great interest to all the pharma companies. Okay, thanks for, thanks for clarifying that. So in terms of the timelines for the, the data, are we gonna see some, some initial look this year? Is it gonna be, what, what are we gonna see? Just some, some biomarker data? I mean, obviously outcomes is gonna require much, much larger studies. So I assume that's not, that's not in the cards, at least for the initial, these initial patients. Yeah, I think a first test for us is to see that there's, you know, protein knockdown or, which is easily measured, right? With ANGPTL3, for instance, within two to three weeks of dosing a patient, you can measure the ANGPTL3 levels. And if that's knocked down 80%, it's a very clear indication that you're getting the desired outcome from the edit, from the editing perspective. So that, that'd be the first step. I think beyond that, I think we wanna look at a number of biomarkers. Ultimately, I think it may need to do a randomized control trial. It doesn't have to be outcomes-based trial, but a randomized control trial with the select biomarkers. And then, you know, we'll see on outcomes trials. But for LPA, we may need, we'll need an outcomes trial. For ANGPTL3, we may not. Okay. Makes sense. And as far as the% knockdown, I mean, it's just different genes. So, would you expect similar% knockdowns for Lp(a) versus NHP ANGPTL3, or are there other specific reasons why they may not be similar or given a similar dose, similar patient? It should be very similar. You know, in our NHP data, again, we showed near about 70% reduction in NHP ANGPTL3 or Lp(a) in whole liver, which equates to near 100% knockdown in hepatocytes. So, you know, if you get the Cas9 into the hepatocytes, you're gonna see the knockdown. It's almost 100%. So, I wouldn't imagine there'd be much big differences between the two targets. And that's the beauty of this very scalable platform. I think the data we see from 310 and 320 will translate beyond to the next four or five targets that we've lined up as well. How many can you say how many patients we're gonna get in these initial buckets for 310 and 320? I mean, have you disclosed that level of detail? Yeah, we're gonna do a standard dose escalation. You know, I think, you know, we'd like to get to a dozen patients or so in terms of data disclosures. So it depends on how fast the trials move and what the timing of that disclosure might be. But, not different from what other companies have done for early data, you know, dose escalation. You have outlined that as a data point for 2024 to show? We have not, no, we have not guided to data on 310, 320 for 2024. We said we'll be accruing data and we'll make a determination mid-year based on how fast the trial's moving or whether we could or could not, you know, have a data disclosure this year. Okay. And then what other settings or targets would you be contemplating next? Would they be cardiovascular or elsewhere? We have both common and rare diseases lined up. We hope to disclose those targets mid-year this year. These would rely on the same LNP platform for liver delivery. But you know, given you know, it's a very competitive space, we wanna, we don't wanna disclose the targets yet, but we will at some point this year. Okay. All right, let's move on and talk about type 1, type 1 diabetes. Again, that's partnered with Vertex. Can you talk about where that stands with the phase 1 and when might we see the next data update there? Yeah, so, you know, we're continuing our trials with CTX211. You know, I just to give a little bit of history, we started these programs partnering with ViaCyte, which then got acquired by Vertex. So we're partnering with Vertex, to a certain extent. We, you know, just to diversify our bets in the space, we licensed our technology to Vertex, for their gene-edited, hypoimmune cells that they're developing with their own cell lines. And they'll provide guidance on how it's moving and what stage that's at relative to the other unedited cells they're moving forward in the clinic as well. We have the programs that we had collaborated on with ViaCyte, namely, at the time was called VCTX211. And that program is continuing in clinical trials. We had a bit of a slowdown as we sorted out how we would work in a joint model with Vertex, but then, ultimately Vertex decided to opt out of the 211 program to focus on their own programs. And so we now have the program fully, wholly owned and we're restarting the patient enrollment in these trials at this point. So we'll have more to say on diabetes, but ultimately, you know, I do think this whole notion of IPS-derived organ transplantation is gonna be a huge factor in how we think about medicine in the future. You know, as long as we can deal with neurodegeneration, you know, people will live longer and a lot of organs are gonna be replaceable that'll allow people to live longer. Type 1 diabetes is the best test case of whether we can replace our pancreas with iPSC or stem cell-derived hypoimmune cells that produce insulin. So can you just expand a little more? 'Cause you might, you have the device, obviously, which is sort of this, as I understand it, like a half a credit card size implant, which, but you also have the device-free approach, which where the cells have been engineered so that you may not be subject to the immune rejection. So can you just expand on what, where the priority is there and which of those would be the one that you would take forward to, you know, late stage studies? Yeah, I think on the, you know, the device approach is obviously the one that's in the trials right now. On a device-free approach, you know, I think there are a few conditions that we have to think about. One is from our perspective, we'd like to put a switch in those cells if we go with the device-free approach, because we're injecting these cells freely into the patient and we don't know where they end up. And if something goes wrong, we'd like to be able to turn those cells off, and just have them die. So we're working on a switch in these next generation cells, for a device-free approach. They also need to be differentiated at different levels than in the device approach where we don't differentiate them all the way to allow them to find their niche within the device. I think there are a number of things to consider here, and we're continuing to invest in this space. I do think this whole approach is gonna work eventually. We'll see how the competitive forces stack up between the different companies in the space. But at this point, we feel good about where we stand. I mean, is the goal to reduce insulin dependence in the type 1 or potentially just remove the need for insulin? Or is it to, you know, improve, keep them on their basal insulin, but then have an improvement on HbA1c? Like, how are you thinking about the mix of factors to get disease amelioration? Well, ultimately we wanna have, you know, make them free of insulin. That's, that's the ultimate goal. But in the near term, I think, you know, what we're, you know, one of the things that to look at is the reduction in hypoglycemic events or, you know, better control of their sugar. And, a lot of these patients who have A1c's above eight, et cetera, you know, they have, you know, a lot of the risk is in hypoglycemic events. And I think if we're able to temper those, control those where you don't have such high vacillation, I, I think that also goes a long way. But ultimately we wanna dial up the dose of the cells to a point where the insulin requirement is very low, if, if, if not zero. Okay. What is the next data update specifically then for 211? And which endpoints? Is it some of the ones you've just mentioned that we're gonna see? Yeah, so we'll provide some guidance mid-year this year. I think, you know, the key endpoint, obviously, you know, what we're trying to figure out with 211 is we made these edits, particularly the insertion of a PD-L1 gene and HLA-E gene, in addition to the beta-2M edit. And what is the immune evasion that these cells have, in the presence of, you know, host T cells or host immune system? I think the threshold question here is, can we achieve hypoimmunity, or hypoimmune cells that are stealth and protect themselves against the host immune system? And if that's something that we achieve with these cells, everything else is titratable. You know, we can dial up the cell dose for more insulin production, or we can, you know, dial it down if we need to. So, it's but the threshold question is, are these cells able to evade the immune system? I mean, if you go into late stage studies with the device, what's the TPP in terms of durability? I mean, I know these are still questions you're working out, but I mean, is it like a rechargeable thing where you'd have to do a surgery and put a new one back in after several years or you would hope to somehow reset the pancreas in such a way that they would just be reset to a lower set point for insulin? I'm not sure how to think about it that way. Yeah, all good questions. We need to get to it once we see some initial data. But the, you know, with, with the device approach, you want it to be durable for at least three years. Yeah. If not more. 'Cause anything short of that, you know, would mean that you're doing surgery each time to replace the device and that's probably not feasible commercially or not gonna have huge uptake. So durability in the device is key. But, you know, I think with cell injection, as long as there's no immune rejection, that could happen more frequently, you know, then you don't have to have the same level of durability for a device-free approach. But I think those are things that we'll have to sort out as we see initial clinical data. And then sort of just to wrap up, Sam, obviously there's a lot going on on the innovation curve in terms of next generation approaches, version two, three, four, five, and higher for gene editing, different enzyme systems, different Cas systems. There's a lot of new companies that are in that space. Where are you in that life cycle in terms of some of the new efforts at the discovery stage? Yeah, we're doing, you know, we don't think of it as first gen versus next gen editing in a way or CRISPR 2.0 and 3.0 and 4.0, you know, all the terms that these new companies are employing. You know, it's like antibodies. I think we need to do fit for purpose. You know, if you look at certain indications, you'll have, we have to pick what the most superior approach is. In some cases, the best approach for a certain indication may be, reverse transcriptase-based editing. You know, in certain cases, it may be, insertion of a large gene, with a, retrotransposon. You know, in other cases, it may be base editing. So I think these, they're all, you know, different effector functions that you're, you're adding onto a Cas9 ultimately. So the picture of a Cas9, CRISPR Cas9 goes from molecular scissors to sort of a molecular UPS truck that's bringing cargo to a particular part of the genome where you're loading an effector protein to do a desired modification on the genome. And whether it's a reverse transcriptase or whether it's a deaminase. And so if that's the mental picture or mental model, we're looking at saying, here are the diseases we wanna go after. And for this particular disease, this is the best approach. And we're, we've developed all these, you know, quote-unquote next gen editing effector molecules, to go along with our Cas9s, to use them as we need to. I think we do have the IP to cover all of it because we have issued claims that say, you know, that name all these effector proteins conjugated with the Cas9 in a, to be able to make a genetic modification on the genome in a guide-dependent manner is covered by our IP. Now there's other IP that may be necessary, et cetera. We'll sort that out indication by indication. But this is a huge focus for us. We've set up two units, one in Boston, one in San Francisco to do all the next gen editing. And it's going very well so far. Awesome. And then sort of last question, obviously you've got very healthy cash balance to say the least. I think over $2 billion and you raised even more just recently, with high interest, high demand I should say. So how are you thinking about capital allocation? You know, where do you wanna put the dollars to work amongst the programs that we've just discussed? What, what's the, are there new areas where you wanna invest further? Just tell us at a high level, you know, how you're thinking about deploying that capital, over the next, you know, over the next several years. Yeah, absolutely. I mean, the first threshold condition for us, you know, as in the way we've designed the company is, we always knew that it takes, sometimes takes 20-25 years to become a $75 billion-$100 billion company. It doesn't come easy in terms of company trajectory. You don't become a $30 billion company overnight. Now, there are some cases where it's moved much faster, like Argenx. But it takes some time. So we wanted to put ourselves in a position where we have line of sight to profitability now, at some point, depending on Casgevy success. But we have enough cash balance where, you know, should macro conditions really worsen even, we're still in business. So we're gonna be hanging around the hoop in a secularly growing area. And, you know, any dislocations from a macro perspective only provide us more opportunity, given the strong balance sheet. That said, we also wanna be very aggressive where others are being defensive in terms of investments in delivery technologies, especially to enable some of the next-gen editing approaches, and also autoimmune. You know, autoimmune's not gonna be an inexpensive proposition should there be good initial data because there are a number of indications to expand into. The The trials are larger. And we wanna be able to finance all that to take full advantage of what could be a, you know, what, what could be a pole position for us, in a rapidly emerging area. And so, that, that's what, that's what led us to topping off our balance sheet. But it gives us great flexibility. That said, I think, you know, we continue to remain very disciplined because the last thing you wanna do when you have a big balance sheet is to lose that fiscal discipline that ultimately needs to work to return, to have that return on invested capital that we are all looking for in biotech. All right. Thank you so much. Great discussion as always, Dan, Sam. Good luck with the progress, and we'll be chatting soon, no doubt. Thank you. Wonderful. Thank you y'all. Welcome.