Good afternoon, everyone, and thank you for joining me on the second day of the Needham Healthcare Conference. My name is Gil Blum, and I am a senior biotech analyst here at Needham & Company with a focus on immuno-oncology. It is my pleasure to have with me today Sam Kulkarni, the CEO of CRISPR Therapeutics. As a reminder for viewers who are watching through our conference portal, you are able to submit questions through the Ask a Question box below the video feed window. Sam, I'm actually not going to start immediately with CRISPR this time. There are some interesting things going on in the market these days. If you want to comment on any exposure to tariffs as it relates to CRISPR, that would be super helpful. Yeah, thank you, Gil, for having us. It is an interesting time in the market. Pleased to say that we have almost no exposure to any of the effects directly as a company from the tariffs. Obviously, there's the effect on the macro market and investor sentiment, but we have a pretty distributed manufacturing network. I think we make all our allogeneic CAR-T cells here in the U.S., in Framingham, Massachusetts. The effect, obviously, on the overall macro is a very different story. All right. Kind of a related question, pretty significant changes in the agency. Has that influenced your conversations and communications with the FDA? Yeah, I think, you know, if I may, I think biotech is at an all-time low right now because of several factors. There is the general notion that long bets are too risky given the interest rates, compounded by the fact that there is significant competition from China for traditional modalities, and this notion that the FDA may be going through a phase of change, which would make it riskier for companies. I think, you know, all those are fair worries. Luckily for us, in all those three aspects, we're somewhat protected. You know, I think in terms of the high interest rates for now, it actually benefits us given our balance sheet rather than hurt us, although it may hurt the macro sector. In terms of China competition, that's generally been focused on bispecifics, antibodies, or starting to, and some other traditional modalities. We have not really seen that as much with more advanced techniques like gene editing. While it can never say never, you know, it is unlikely that, you know, competitors pop up left and right on gene editing at this point. There have been competitors in CAR-T, et cetera, so we are somewhat protected there. The sort of the third notion is the FDA. You know, having spoken to people in this administration, you know, people like Dr. Oz or Dr. Makary, I have not directly spoken with them, but they all are very supportive of cell and gene therapies and innovation in biotech. Interestingly, even the Vice President visited one of the manufacturing plants in Ohio and made comments about cell and gene therapy and how we need to be competitive relative to China. While there is turbulence right now, I think overall the support is there at the very basic level. Again, fortunately for us, we either have an approved product or earlier stage programs. We do not have something that is like going into a BLA filing or something close to that type of event, which would be riskier in an area where, you know, things will be changing a little bit, especially around the organization of the FDA and the review teams, et cetera. All in all, not ignoring the sort of the macro forces that work in our industry or sector, but, you know, at CRISPR, we are in that position where we are somewhat protected against all three. Okay. Maybe a related question. Despite investor sentiment and kind of general malaise in capital markets, it has been a banner year for CRISPR-based therapeutics. What would you say are the key features of CRISPR's platform that maybe set you apart from some of the other companies in the pack that have shown quite interesting clinical data recently? Yeah, I mean, I think the field continues to chug along. You know, I was at, you know, a major meeting of healthcare providers, and they were highlighting Casgevy as sort of the shining example of how they bring cures to their patients. And these are hospital CEOs, et cetera, who were in the audience. At the same time, you have other data, you know, data from other companies also in the CRISPR area that all look promising. We just had the Breakthrough Prize awarded to David Liu, who's a good friend. I think, you know, overall, the secular change continues and progress continues. You know, we're making progress in terms of the different tissue delivery, in terms of the science, in terms of types of edits, in terms of the data, in terms of impacting disease. I think what we see day to day is sort of the investor cycle and pharma cycle more than anything else. From a fundamental basis, it has been and continues to be a good year last two years for CRISPR-based therapies. In a secular, in an environment, I'm careful to say secular growth, but in a secular growth from a fundamental standpoint, we are perched atop that sort of set of players because not only do we have good technology, we have a good business strategy around the indications we've picked and how we financed it, and we have the wherewithal to take it all the way to finish and bring it to the market. I'll talk more about our different programs, but I think that positions us nicely relative to other players who may either have issues with indication selection, balance sheet, and spend, or perhaps timing of where they are in the cycle. You touched on this, but in our view, some of the key features for the company are, first of all, you guys control your own manufacturing. You have a strong commercial partner, and you have a commanding cash position. On that last one, how are you guys husbanding your war chest here? Yeah, I think we're being quite prudent. I think just, you know, just to give a sense of how we think about burn, I think I was having an interesting discussion with an investor who is saying that, you know, market cap is not enterprise value plus cash. In the way they think about it, they generally think about cash divided by two plus enterprise value to get to market cap. And that may be applicable for most companies, but for us, when we have four plus years of cash runway, it doesn't quite make sense. You know, our cash is a strength, and our balance sheet is a strength, which allows us to be aggressive. That said, I think this may be our final year of spend at the levels at which we've been spending because, you know, for those who are new to the story, we have part of our spend sort of separately segregated as the collaboration expense related to Casgevy and sickle cell and thalassemia with Vertex. That's one bucket, which I'm hopeful that this year is the last year of spend on the program, and it starts breaking even and becoming accretive over the next several quarters. By the end of this year, hopefully, let's see. That spend goes away. The rest of our spend, we've been incredibly efficient. You know, we do all of CAR-T development, allogeneic CAR-Ts for CD19 and CD70. We have multiple programs on the in vivo side that we're advancing, including CTX310 for ANGPTL3, 320 for Lp(a), 340 for angiotensinogen, and other early stage programs, all within a burn that's less than $250 million a year. And forget burn, it's just, that's just the OpEx. You know, our hope is that we're profitable as a company by 2028. From here to that point of profitability or break even as a company, we expect that we need less than $1 billion. We have $2 billion on the balance or $1.9 billion on the balance sheet. Last reported K, which gives us a lot of buffer and flexibility should the macro markets continue to be in turmoil. We're not dependent on that external fundraiser at this point to do what we need to do with our pipeline. That gives us flexibility. Now, how do we use that flexibility to increase our competitive advantage? We're being very selective. You know, I think, you know, in our industry, as opposed to other industries where there's always a clearing price for an asset, you know, our industry is all about what else do we need to invest in an asset to make it accretive. What we don't want to do, we see a lot of attractive assets out there, I think we want to be careful about whether those assets are runway accretive or runway dilutive. I think that narrows down the set of assets we're looking at to bring in. We do see a lot of technologies that we continue to license in that are small deals just to augment our armamentarium of editing technologies. Excellent. I do want to spend some time on Casgevy. It seems to be that there's a certain level of disappointment on the street from the ongoing launch. Maybe what is your message for doubters here? I think I've been saying this for a long time. You know, I've talked to a couple of medical device analysts who look at Casgevy and are very comfortable thinking about the ramp and inflection, whereas a lot of the biotech analysts have a top-down way of modeling revenues and peak potential, which is, here's the overall population, here's the addressable population, here's who's most likely to take it, and what sort of penetration do we have against that addressable population, right? It doesn't work that way for these procedures. We're essentially doing genetic surgery on a patient, and it's a process where you collect the cells, you manufacture it, put it back into the patients, you know, transplant procedure, and there's a time limit, time that it takes and expertise that it takes. You know, it's more a bottom-up model where you have different centers or ATCs, as we call them, authorized treatment centers. We hope to, Vertex and I hope to bring 75 ATCs online. Once these centers are online, they will all start slow and say, "Why don't I do one patient in the first couple of months and see how it goes?" Over time, they'll be able to do multiple patients per month, as evidenced for Yescarta's launch, which started slow, and then ultimately centers were doing about eight a month at some of the centers, right, even though it's a complex procedure. You're going to see that bottom-up growth and a compounding effect because you have more centers in play, and each center is going to increase the velocity at which they treat patients, which together should compound into a very nice growth rate once you hit a certain inflection point. The second point I'll make is, you know, there are three curves to model, which is how many patients are initiated on Casgevy, which means they have prior authorization and have shown, have said that they're willing to undergo treatment like this. And second is from that line or that funnel, part of the funnel, how many actually get their cells collected in what time frame? And then third is how many of them are actually getting treated? What's complex about that funnel is there's a time lag between one to the second. If people are looking at, people are doing market surveys saying, "I'm calling a few centers here and there," and I see centers saying they have 20 plus patients ready to go. The number of demand is high, but the number of patients with cell collection is lower than we expect. It's because there's a time delay in between that to schedule a patient to come in, get their cells collected, and then manufactured, and then ultimately dosed based on what time frame is most appropriate for them. You are going to see this buildup, and it may seem slow initially, but, you know, personally, we wouldn't say that this launch is slow or a failure. I would say that the launch is going right on target in a way. We are, you know, not only have we built the infrastructure and network in the U.S. and Europe, but also the Middle East and other parts of the world, which all seem to be very attractive markets for Casgevy. All in all, I think, you know, while we have to go quarter by quarter, I feel very good about how this is shaping up. As it relates to potential market expansion, I know you guys have been working a little bit on label expansion, but also on non-genotoxic conditioning. What can you update us? Yeah, I think gentler conditioning or non-genotoxic conditioning is a very important priority for us as well as for Vertex. You know, I think Vertex have had multiple agents that they're testing in animal models. We're testing one agent based on a c-Kit antibody that we acquired with the toxin that we think is the best suited for this application. And we're making a lot of progress. You know, we're not going to talk too much about these agents until we get to the clinic, which is, you know, we're not going to be that far off. But that's something that can expand the market or the addressable market at least 3X from where we are today. I do want to spend a little more time than usual on the in vivo programs. I know we do not talk enough about them. One thing, and this is very high level, so bear with me. A point of contention that we have heard in the past as it relates to gene therapy and also gene editing is the idea that physicians treating patients with a non-fatal chronic condition are likely to prefer chronic therapy over an expensive one-time. The reasoning is that centers like the, you know, the fact that something is reversible and, you know, the potential for unintended toxicities. How do you guys counter that sort of thinking? Because I think that maybe is the larger value proposition for the company. Yeah, and these questions come up every so often, right? People ask all these same questions of siRNA not too long ago, who then are turning around saying, "Oh, siRNA is better than gene editing." You know, the world changes. You know, I remember in, you know, 2005 time frame, 2006, you know, BlackBerry was like the default. Everyone, all of us were typing with the BlackBerry, and we learned how to type very fast on it. When the iPhones came out, everybody in the business community said, "There's no way. I mean, there's no way I'm going to switch to an iPhone when I can, you know, BlackBerry is the way to go." The world changes. We all learn how to use different things, and, you know, people build off of platforms. You have to then think about this different indication by indication. The answer to your question about what is the market share that I likely see 10 years from now for a small molecule versus an antibody versus a siRNA versus gene editing will widely vary based on the target. Okay. LPA for us was the target that we picked early on because what we realized is that it's hard to target LPA with small molecules. It's actually very hard to target LPA with antibodies. And between siRNAs and gene editing, there's an inherent advantage for gene editing because it's a genetic effect. You know, you can measure people who have high LPA have high LPA by the time they turn two, right? It's not like it comes later in life. If you're a 20-year-old and you know that you have 400 nanomolar per milliliter of LPA and you've had significant MACE events in your family and you know it's coming, rather get a gene edit because that way that, you know, it's durable and you're reducing LPA levels for life versus an siRNA that you're going to take every three months to every, maybe even if it's every six months for 60 years of your life. It all depends on the indication, whereas there's other indications or targets where you have a small molecule, an antibody that have been on the market already, you know, take potentially even PCSK9 where, you know, an siRNA is on the market, and then you're trying to go into gene editing, it's a little harder. I'm not saying again, our surveys indicate that even there, PCSK9 gene editing may actually end up in the, you know, 15-20% market share, but in LPA, it's much higher than that, right? It's not, I'm not dismissing the question. It's a very important question that we asked ourselves time and time again, and we continue to ask ourselves with every target that we enter into is what is the likely advantage of our siRNA, assuming that siRNA is going to end up once every six months at the very least for these targets if it's valuable, and what is the likely competition from orals and antibodies that we should expect in these targets? I feel like both for ANGPTL3 and LPA and angiotensinogen, we've done enough work where we feel like there's going to be a very reasonable market share for gene editing therapies. You mentioned before some of the recent data published specifically for Beam here. Do you think this maybe changes the conversation somewhat? Does this assist in some of these? I mean, AATD is more of a fatal indication at an earlier time point, but it's helpful to understand this. Yeah, I mean, it's great data shows the, you know, potential for gene editing. You know, it's a one-and-done where you can do it in a safe manner. Liver, and you know, interesting to see additional data on different dose, higher dose levels on that. I think the one interesting calculus, you know, we've looked at a lot of indications and we've decided not to do some, for instance. You know, yes, on rare indications, it's great to do gene editing because it's, you know, it's a fatal disease and all that stuff. It also turns out the other side of the coin or the other part of the double-edged sword is that in rare diseases where it's fatal, the patients are much more compliant and they're willing to take injections every so often that I know, right? You have to titrate, you know, very carefully that, you know, what you do not want to end up doing is going after a small indication. You know, we were at one point working on an indication called GSD1A, and small indication where, you know, if you end up with a place where the numbers are small and there are other options available, you know, do you really have a market there, for instance, right? Why, you know, and it is not like the cost of developing these indications is much smaller. You know, for instance, sickle cell is 25,000 patients in the U.S., whereas something may be 250 patients, right? It is not one hundredth the cost of development. It is more like one-fourth the cost of development. You know, I would say that picking indications is a bit of an art, but I think the data from Beam and other companies are all just adding to this notion that gene editing is going to get better and better and better, and we're going to be able to address many diseases in a safe manner. I think the world, you know, mindsets will change. You know, right now the question is, why gene editing when you have siRNA? The question is going to become, why not gene editing? You know, why would you not gene edit when you have a one-and-done solution? Maybe going back to the discussion of LPA here, is there an expectation of changes to the regulatory landscape with Pelacarsen's data coming out? Is there a scenario where you may have to go against an existing siRNA? We do think the Pelacarsen data read is going to be very important because it would be the first, if it's positive, it would be the first instance of a pharmacological agent reducing LPA and in turn reducing risk of MACE events. You know, natural history studies have been very clear about the reduced risk with lower LPA, but it would be the first time we do it as a pharmacological intervention. I think if the Pelacarsen study is positive, we would make an argument that LPA should be a biomarker like LDL or triglycerides and allow for an approval based off of a biomarker as opposed to an outcome study. That is an important, you know, potentially side outcome that may come out of the Pelacarsen readout. I don't think we would ever have to do a head-to-head. It's just impossible to do that in this population, given the heterogeneity, et cetera, to really compare head-to-head. The other thing is we're going to have a, you know, the general canonical thinking is, yes, you may get approved off a biomarker, but payers are not going to pay unless there's an outcome study. Here it's different. I was just speaking with the, you know, executive at one of the larger payers. When they heard a story that we could actually develop something that's one-and-done that actually could be less expensive than chronic therapies, right? I mean, if you're talking about, you know, siRNA that's $30,000 a year for 50 years, you're spending a lot of money. You know, we could spend one-tenth of that and say, you know, charge $150,000 for a single-shot therapy. That payer economic argument is very clear. You may not have the same burden of proof in terms of outcome studies that the PCSK9 antibodies did and certain other examples as well. I will add there, though, do not foresee, you know, the agencies and payers actually requiring a very long follow-up to show stability of effects. I am thinking of the Roctavian situation here. Yeah, I think with gene editing, you know, you don't have the same effect as viruses. You know, the durability is a major question for a lot of gene therapies because it makes sense. You know, you have a certain number of particles that enter each cell, and as the cells divide, you're diluting the number of viral particles per cell. With gene editing, it's not the case. As the cells divide, you know, they carry the edit with them, right? We've shown now data in NHPs that go out two-plus years, and it's very durable reduction in LPA levels and ANGPTL3, and, you know, close to 90%. Same with data from Intellia and other companies as well. Gene editing is very durable. Yes, we'll have to do some follow-up. I think we are doing follow-up on our Casgevy patients, for instance, from the clinical trial for 15 years, but that's more around monitoring for safety on the chromosomal, you know, gene level versus anything else that may be around durability. Is there any guidance you can provide at this juncture for the two in vivo programs that are ongoing? Yeah, I mean, I think, you know, you said it might be a banner year for CRISPR. I see a lot of parallels to the 2018, 2019 time frame for us because we have a number of data readouts. We have, you know, 310, 320. We have our 112 update, and then our solid tumor update as well as diabetes. It is all in this year. We are basically, you know, going to define the future pipeline of the portfolio of the company based on these data readouts. What we have said is we are going to provide an update, top-line update on both 310, 320. Given the way the conferences work and everything else, it is most likely a company update top-line in the first half of this year for 310, 320, followed by a more detailed presentation at a conference. Excellent. Another really interesting program you guys have is the hypertension, CTX340. What kind of feedback have you gotten on the targets so far? You know, I'd be, I should say, even personally, even I was surprised at the level of support from KOLs for the angiotensinogen program, which at first glance, we all had to look at it with a bit of skepticism, saying, you know, are you going to permanently reduce someone's blood pressure? You know, why would you do that when you want to be able to titrate it and control it? You know, I think the first thing investors need to understand is the patient population here. We're talking about refractory hypertension. Some of these patients are taking four to five pills a day to manage their hypertension and have to take diuretics, et cetera. Okay? It is not an easy thing. Every time they take a different drug or something else, there is some drug-drug interaction and they have other issues. It is actually pretty dangerous for these patients. A lot of them actually, you know, end up falling, having other things happen to them because they're not able to manage their blood pressure. They, you know, they don't take their pills appropriately, et cetera. What we're doing is targeting angiotensinogen, which works upstream of the ACEs and ARBs. What you could do is by knocking down angiotensinogen, you could reduce blood pressure, the absolute blood pressure by more than 10 millimeters of mercury. Could be even much higher than that too, based on some of the siRNA data. You could always titrate these patients on a different agent. Could be an aldosterone pathway agent or something else, or even an ACE or ARB, because the kidneys do produce some angiotensinogen, so it's not zero. You could still titrate them in a much better way within range. You know, I'm pretty excited about the program because we'll be in the clinic this year. The readouts come very quickly, right? Within a month, you know if you're getting the desired effect, you know, typical factor, if you're getting the desired symptomatic effect essentially in patients. That can be a very fast path to the, you know, not just to the clinic, but through the clinic to approval. We're putting, you know, a lot of resources behind that program as well. For now, most of the targets you guys are looking at are in the liver. Are you also looking at extrahepatic targeting of other tissues? I mean, that's kind of the premise of CRISPR getting to other indications. Yeah. You know, in vivo editing for HSCs or hematopoietic system is a big focus for us. Now, fundamentally, there's an issue with that, which is you have to increase delivery to HSCs and be able to target the long-term repopulating cells that don't divide for editing, yet not have editing in other tissues, which is challenging because the liver ends up taking up a lot of the LNPs. There's liver detargeting. There's the notion of, you know, editing the long-term hematopoietic cells, et cetera. You know, more work is needed to make this and get this to the clinic. There are a lot of companies working on it now, but Vertex have a partnership with a company called Orna to find these LNPs that are liver detargeted and allow for HSC editing. We're doing a lot of work here at CRISPR around HSC editing, not just for sickle and thal, but for other indications as well, where you could directly apply this type of delivery that are, you know, maybe on the rare, not so rare diseases, but somewhat rare diseases with a big unmet need. Lastly, we're also looking at conjugations of lipids for organs like the kidneys and the brain, where there's new targets being identified for transport. That would allow for gene editing in an organ-specific fashion. Early stage work still, but something we're looking into. Super interesting. I did want to spend some time on CTX112 because, like you said, it's a very data-rich year coming. Maybe as a quick recap, differences between 112 and 110, which actually had a presentation at ASH. Yeah. When we presented at ASH, I thought it was remarkable data to see a response rate similar to autologous therapy, right? For the first time with an allogeneic program, C19 program. The second thing that was very encouraging is the biomarkers that we look at, which is expansion of the cells. We had upwards of 50,000 copies per microgram, and we're the only allogeneic program to have that, to show on that level of expansion, which is similar to an autologous program. Most other allogeneic programs have, you know, below 5,000 copies per microgram expansion. It shows that our cells are very potent, yet they have the safety profile of an allogeneic versus an autologous therapy, which allows us to bring these therapies to the community setting eventually. The two questions that folks wanted to understand or ask were, yes, the response rates were high, but you had a lot of indolent patients. By the way, you know, these indolent patients were very, very sick patients. It's not like it's easy to get responses in those patients. The second was, you know, what is the durability of response, especially in DLBCL? Third is, are you likely to work, you know, is your agent likely to work after bispecifics, given that bispecifics are all moving into frontline therapies? At least two of the three, one of the three, we did answer the bispecific question at JP Morgan by showing data on six post-bispecific or post-TCE patients, and we had a 100% response rate with allogeneic RT in those patients, which was remarkable. The question around what is the true response rate in DLBCL and what is the durability of response, we'll have more updates on this year. That's kind of a good lead in. You guys are going to be presenting data mid-year. Any guidance there as to what we should be expecting? Yeah, we haven't said where that's going to be. You know, we just said mid-year, we'll provide that update. You know, in that update, we'll also provide an update, albeit early, on autoimmune diseases as well. You know, we are bringing CTX112 into autoimmune diseases. Our relative competitive position is even stronger in autoimmune relative to oncology. You know, in oncology, there's a big question mark that everyone's asking about what's the market share that you project 10 years out between T-cell engagers, autologous CAR-Ts, and allogeneic CAR-Ts. In oncology settings, like, you know, let's say chemolignancies, because autologous therapies were there first and bispecifics moved fast, you know, allogeneic will take some time to carve out a meaningful share. You know, wouldn't be surprised if we're at a quarter of the share in those patients in the next several years. In autoimmune, there's a huge competitive advantage for allogeneic therapy versus autologous. You know, one, you don't have a head start with autologous therapies. Two, it's very cumbersome. You know, collecting T-cells requires you to stop patients on their existing therapies and they end up getting all sorts of flares in that period of time. It's hard to dose patients with autologous therapies. Allogeneic is available off the shelf. You don't have to take them off their therapies. Third thing is, you know, if there's any efficacy advantage that autologous therapies have or allogeneic, it may not matter here. You know, if you kill, whether you kill 99.8% of the cells or 99.9% of the cells, it won't matter because you're generally getting that B-cell reset. You know, unlike cancer, where if you leave one cell, it's going to come back as a cancer, you don't have that effect in autoimmune. The safety advantage is huge. You know, the safety advantage of allogeneic or autologous is meaningful because a lot of the rheumatologists don't want to deal with ICANS or don't know how to manage severe CRS. You're going to have a big advantage over autologous therapies. Relative to T-cell engagers, you know, it may be, my hunch is that allogeneic CAR-Ts with the one-and-done will have a deeper B-cell reset than T-cell engagers where you're going to have repeat dosing and slow depletion of the B-cells. I think that one-and-done reset is an important phenomena that led to the remarkable data that Dr. Schett showed, you know, in the last year. I think we have a very strong competitive position there. Maybe kind of another question as it relates to autoimmune disease. The level of expansion seen with CTX112 is very high, as you mentioned. Does that potentially change the calculus around lymphodepletion in these kinds of patients? Yeah, that's something we're exploring in the autoimmune setting. In oncology, we want to just maximize efficacy. Yeah, there's efficacy from the LD. Yeah. I think in autoimmune, it turns out, you know, that a lot of these patients already are on cyclophosphamide. You know, not only are they on cyclophosphamide, some of them are as high as 700 mg per meter square of cyclophosphamide. You are already at a very high dose of cyclophosphamide, and all you're adding is fludarabine. The question is, can you lower the fludarabine dose? Can you, you know, can you taper off of fludarabine or do it without fludarabine altogether? Those are things we're going to address in the trials over time. I did want to spend a minute also on solid tumors. Any updates you can provide there from CTX131? What should we be expecting? Yeah, I mean, you know, I think with our CTX130 program, we already had good, reasonably good efficacy in T-cell lymphomas, and we saw evidence of activity in solid tumors. We had a complete response in a solid tumor. Now, the issues where we were manufacturing that elsewhere at a CDMO, those cells, we wanted to bring it in-house, and we wanted to add these potency edits like Regnase-1, so we decided to go to CTX131. We'll see what the data tell us on the hemolignancies. I'm pretty confident it's going to work there. The solid tumors, you know, while we've seen signal before 130, like what level of increased signal are we seeing with 131, and how is that going to play out relative to competition is an important question. We'll have an update on that this year. Excellent. I want to remind the audience that we're pretty close to the end of our call here. If you want to enter questions via the chat, please do. Maybe a good place to kind of wrap things up, what do you think is maybe one item the street is missing when it comes to the CRISPR story? You know, I'll, since you guys went over to do company calls, you all asked two questions, so I'll have two answers for you. One is, I think there's on CASGEVY cost structure, there's an asymmetry in understanding. You know, there's analysts who put out notes saying, oh, you know, it's going to take at least $500,000,000 of sales to break even on that franchise because the cost structure is so high. That cost structure, that is incorrect. I think the cost structure for maintaining a franchise is actually much lower. It's the fact that we're doing label expansion and clinical trials and manufacturing expansion that's causing the cost to be high, right? You can always turn that off if you want to make the franchise profitable. The threshold number for making something profitable is that franchise profitable is much lower. That's one thing I'll say is missing. Second is, I still see a lot of investors who, you know, people are somewhat, you know, not locked, but go by chronological order of programs. I think people still ask us a lot of questions about when people say, what are your two most biggest home run programs? When I say LPA and 112 in autoimmune, they're pretty surprised because that's not the chronology of how we develop the programs. You know, we had 112 in oncology, we had type 1 diabetes, we have 131 in solid tumors, et cetera. Things change very quickly. Our portfolio is very different from what it was even three years ago. That's another notion that the street might be missing about where we are with our programs. Okay. All right, Sam, thank you very much for joining us today. It's been great to have you as always. Real pleasure. Thank you. Thank you.