CRISPR Therapeutics AG (CRSP) Earnings Call Transcript & Summary

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. So 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 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.

Yes. Thank you, Gil, for having us, and 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. But the effect, obviously, on the overall macro is a very different story.

Right. Kind of a related question, pretty significant changes in the agency. Has that influenced your conversations and communications with the FDA?

Yes. I think -- 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 render -- make it riskier for companies. And I think all those are fair worries. But luckily for us in all those three aspects, we're somewhat protected. 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. And we haven't really seen that as much with more advanced techniques like gene editing. So while I can never say never, it's unlikely that competitors pop up left and right on gene editing at this point. There have been competitors with CAR-T, et cetera. So we're somewhat protected there. And the -- and sort of the third notion is the FDA. And having spoken to people in this administration, people like Dr. Oz or Dr. Makary, I have not directly spoken with him, but they all are very supportive of cell and gene therapies and innovation in biotech. And 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. And so while there is turbulence right now, I think overall, the support is there at the very basic level. And again, fortunately for us, we either have an approved product or earlier-stage programs, we don't have something that's like going into a BLA filing or something close to that type of event, which would be riskier in an area where things will be changing a little bit, especially around the organization, the FDA and the review teams, et cetera. So all in all, not ignoring the sort of the macro forces that work in our industry or sector. But at CRISPR, we're in that position where we are somewhat protected against all three.

Okay. And maybe a related question. So despite investor sentiment and kind of general malaise in capital markets, it has been a banner year for CRISPR-based therapeutics. And 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?

Yes. I mean I think the field continues to chug along. I was at a major meeting of health care 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 are in the audience. And at the same time, then you have other data from other companies also in the CRISPR area that all look promising. We just had the Breakthrough Prize awarded to David Liu, who is a good friend. And I think overall, the secular change continues and progress continues. We're making progress in terms of the different tissue delivery, in terms of the science and the 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. But from a fundamental basis, it has been and continues to be a good year, last 2 years for CRISPR-based therapies. And in a secular -- in an environment, I'm careful to say secular growth, but in a secular growth from a fundamental standpoint, we are first to top 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. And 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.

And 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. And on that last one, how are you guys husbanding your war chest here?

Yes. I think we're being quite prudent. I think 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 market cap is not enterprise value plus cash in the way they think about it. They generally think about cash divided by 2 plus enterprise value to get to market cap. And that may be applicable for most companies. But for us, when we have 4-plus years of cash runway, it doesn't quite make sense. 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 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, and 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. But by the end of this year, hopefully, let's see. And so that spend goes away. And the rest of our spend, we've been incredibly efficient. 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. So our hope is that we're profitable as a company by 2028. And from here to that point of profitability or breakeven as a company, we expect that we need less than $1 billion. And so we have $2 billion or $1.9 billion on the balance sheet the last reported K, which gives us a lot of buffer and flexibility should the macro markets continue to be in turmoil. And we're not dependent on that external fundraise at this point to do what we need to do with our pipeline. So that gives us flexibility. Now how do we use that flexibility to be -- to increase our competitive advantage. We're being very selective. I think in our industry as opposed to other industries where there's always a clearing price for an asset, our industry is all about what else do we need to invest in an asset to make it accretive. And what we don't want to do while 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. And I think that narrows down the set of assets we're looking at to bring in. But we do see a lot of technologies that we continue to license in that are small deals just to augment 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?

Well, I think I've been saying this for a long time. I've talked to a couple of medical device analysts who look at CASGEVY and 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? And 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 in a transplant procedure, and there's a time limit time that it takes and expertise that it takes. So it's more a bottom-up model where you have different centers or ATCs, as we call them authorized treatment centers. And we hope to -- Vertex and us hope to bring 75 ATCs online. And 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. But 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. So 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 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 a 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. And what's complex about that funnel is there's a time lag between one to the second. So 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. So 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 dose based on what time frame is most appropriate for them. And so you are going to see this buildup, and it may seem slow initially, but personally, I 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. And would -- 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. So all in all, I think 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?

Yes. I think gentle conditioning or non-genotoxic conditioning is a very important priority for us as well as for Vertex. I think Vertex have 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. We're not going to talk too much about these agents until we get to the clinic, which is wouldn't 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 don't talk enough about them. So one thing, and this is very high level, so bear with me. A point of contention that we've heard in the past as it relates to gene therapy and also gene editing is the idea that physicians treating patients with a nonfatal chronic condition are likely to prefer chronic therapy over an expensive onetime. And reasoning is that centers like the fact that something is reversible and the potential for unintended toxicities. So how do you guys counter that sort of thinking? Because I think that maybe is the larger value proposition for the company.

Yes. 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. So the world changes. I remember in '05 time frame, '06, BlackBerry was like the default. Everyone -- all of us were typing with the BlackBerry, and we learned how to type very fast on it. And when 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 BlackBerry is the way to go. And the world changes. We all learn how to use different things and people build off of platforms. And 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 hey siRNA versus gene editing will widely vary based on the target, okay? So Lp(a) for us was the target that we picked early on because what we realized is that it's hard to target Lp(a) with small molecules. It's actually very hard to target Lp(a) with antibodies. And between siRNAs and gene editing, there's an inherent advantage for gene editing because it's a genetic effect. You can measure -- people who have high Lpa have high Lpa by the time they turn 2, right? It's not like it comes later in life. So if you're a 20-year-old and you know that you have 40 nanomolar per milliliter of Lp(a) and you've had significant MACE events in your family and you know it's coming, I'd rather get a gene edit because that way that it's durable and you're reducing Lpa levels for life versus an siRNA that you're going to take every 3 months to every -- maybe even if it's every 6 months for 60 years of your life. So it all depends on the indication, whereas there's other indications or targets where you have a small molecule and antibody that have been on the market already, take potentially even PCSK9, where an siRNA is on the market. And then you're trying to go with the gene editing, it's a little harder. And I'm not saying, again, our surveys indicate that even there, PCSK9 gene editing may actually end up in the 15%, 20% market share. But in Lp(a), it's much higher than that, right? So 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 over siRNA, assuming that siRNA is going to end up once every 6 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 Lp(a) 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.

And 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.

Yes. I mean it's great data shows the potential for gene editing. It's a one and done where you can do it in a safe manner, liver, and interesting to see additional data on different dose -- higher dose levels on that. But I think the one interesting calculus, we've looked at a lot of indications and we decided not to do some, for instance. Yes, on rare indications, it's great to do gene editing because there -- it's a fatal disease and all that stuff. But 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 don't know, right? So you have to titrate very carefully that what you don't want to end up doing is going after a small indication. And we were at one point working on an indication called GSDIa. And small indication where if you end up with a place where the numbers are small and there's other options available, do you really have a market there, for instance, right? And it's not like the cost to develop in these indications is much smaller. For instance, sickle cell is 25,000 patients in the U.S. where something may be 250 patients, right? But it's not 100 the cost of development. It's like more like 1/4 the cost of development. And so 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. And then I think the mindsets will change. Right now, the question is why gene editing when you have siRNA. The question is going to become why not gene editing? Why would you not gene edit when you have a one-and-done solution?

So maybe going back to the discussion of LP(a) here. Is there any expectation of changes to the regulatory landscape with Pelacarsen's data coming out? And is there a scenario where you may have to go against an existing siRNA?

Well, we do think the Pelacarsen data readout is going to be very important because it will be the first -- if it's positive, will be the first instance of a pharmacological agent reducing Lp(a), and in turn, reducing risk of MACE events. And natural history studies have been very clear about the reduced risk with lower Lp(a), but we will 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 Lp or Lp(a) should be a biomarker like LDL or triglycerides and allow for an approval based off of a biomarker as opposed to an outcome study. And so that's an important potentially side outcome that may come out of the Pelacarsen readout. I don't think we'd 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 the general economical thinking is, yes, you may get approved off a biomarker, but payers are not going to pay unless there's an outcome study. But here, it's different. I was just speaking with an executive at one of the larger payers. And when they heard the 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 siRNA that's $30,000 a year for 50 years, you're spending a lot of money. And we could spend 1/10 of that and say, charge $150,000 for single-shot therapy, that's going to -- that payer economic argument is very clear. And so 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 you not foresee the agencies and payers actually requiring a very long follow-up to show stability of effect. And I'm thinking of the Roctavian situation here.

Yes. I think with gene editing, you don't have the same effect as viruses. The durability is a major question for a lot of gene therapies because it makes sense. You have certain number of particles that enter each cell. And as the cells divide, you're diluting the number of viral particles per cell. And with gene editing, it's not the case. As the cells divide, they carry the edit with them, right? And so we've shown now data in NHPs that go out 2-plus years, and it's very durable reduction in Lpa levels and Lp(a) levels in ANGPTL3 and at close to 90%. And same with data from Intellia and other companies as well. So 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 gene level versus anything else that may be around durability.

And is there any guidance you can provide at this juncture for the two in vivo programs that are ongoing?

Yes. I mean I think you said it might be a banner year for CRISPR. I see a lot of parallels to 2018, 2019 time frame for us because we're -- we have a number of data readouts. We have 310, 320, we have our 112 update and then our solid tumor update as well as diabetes. So it's all in this year. So we're basically going to define the future pipeline of the portfolio of the company based on these data readouts. What we've said is we're going to provide an update, top line update on both 310, 320, given the way the conferences work and everything else, 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 with CTX340. What kind of feedback have you gotten on the target so far?

I'd be -- I should say 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, are you going to permanently reduce someone's blood pressure? Why would you do that when you want to be able to titrate and control it? 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 fur to five pills a day to manage their hypertension and have to take diuretics, et cetera, okay? So it's not an easy thing. And every time they take a different drug or something else, there are some drug-drug interaction and they have other issues. So it's actually pretty dangerous for these patients. A lot of them actually end up falling, having other things happen to them because they're not able to manage their blood pressure. They don't take their pills appropriately, et cetera. So what we're doing is targeting angiotensinogen, which works upstream of the ACEs and ARBs. And 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. And 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, it's not zero. So you could still titrate them in a much better way within range. So I'm pretty excited about that 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 factor if you're getting the desired symptomatic effect essentially in patients. And so that can be a very fast path to -- not just to the clinic, but through the clinic to approval. So we're putting a lot of resources behind that program as well.

So 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.

Yes. 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 and which is challenging because the liver ends up taking up a lot of the LNPs. So there's liver detargeting. There is the notion of editing the long-term hematopoietic cells, et cetera. So more work is needed to make this -- 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 cell, but for other indications as well, where we could directly apply this type of delivery that are maybe on the rare not so rare diseases, but somewhat rare diseases with a big unmet need. And 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. And so that would allow for gene editing in an organ-specific fashion. early-stage work still, but something we're looking to.

Super interesting. I do want to spend some time on CTX112 as 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.

Yes. So 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, CD19 program. The second thing that was very encouraging is the biomarkers that we look at, which is expansion of the cells. And we had upwards of 50,000 copies per microgram, and we're the only allogeneic program to have that -- to have shown that level of expansion, which is similar to an autologous program. Most other allogeneic programs have below 5,000 copies per microgram expansion. And 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. And by the way, these indolent patients were very, very sick patients. It's not like it's easy to get responses in those patients. The second was what is the durability of response, especially in DLBCL? And third is, are you likely to work -- is your agent likely to work after bispecifics given that bispecifics are all moving into frontline therapies. And at least two of the three or one of the three, we did answer the bispecific question at JPMorgan by showing data on six post bispecific or post TCE patients, and we had 100% response rate with allogeneic CAR T in those patients, which is remarkable. But the question around what is the true response rate in DLBCL and what's the durability of response, we'll have more updates on this year.

And that's kind of a good lay in. You guys are going to be presenting data midyear. Any guidance there as to what we should be expecting?

Yes, we haven't said where that's going to be. We just said midyear, we'll provide that update. And in that update, we will also provide an update, albeit early on autoimmune diseases as well. We are bringing CTX112 into autoimmune diseases. Our relative competitive position is even stronger in autoimmune relative to oncology. In oncology, there's a big question mark that everyone is asking about what's the market share that you project 10 years out between T cell engagers, autologous CAR-Ts and allogeneic CAR-Ts. And in oncology settings, like I say, heme malignancies, because autologous therapies were there first and bispecifics move fast, allogeneic will take some time to carve out a meaningful share. But I wouldn't be surprised if we're at 1/4 of the share on those -- in those patients in the next several years. In autoimmune, there's a huge competitive advantage for allogeneic therapy versus autologous. One, you don't have a head start with autologous therapies. Two, it's very cumbersome. Collecting T cells requires you to stop patients on their existing therapies and end up getting all sorts of flares in that period of time. So it's hard to dose patients with autologous therapies. Allogeneics available off the shelf. You don't have to take them off their therapies. Third thing is if there's any efficacy advantage that autologous therapies have over allogeneic, it may not matter here. 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. 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. But the safety advantage is huge. 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. So you're going to have a big advantage over autologous therapies. And relative to T cell engagers, 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 we're going to have a repeat dosing and slow depletion of the B cells. And I think that one-and-done reset is an important phenomenon that led to the remarkable data that Dr. Schett showed in the last year. So 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 kind of patients?

That's something we're exploring in the autoimmune setting. In oncology, we want to just maximize efficacy.

Yes, there's efficacy for ALD.

Yes. I think in autoimmune, it turns out that a lot of these patients already are on cyclophosphamide. Not only are they on cyclophosphamide, some of them are as high as 700 milligrams per meter square of cyclophosphamide. So you're already at a very high dose of cyclophosphamide. And all you're adding is fludarabine. And so the question is, can you lower the fludarabine dose? Can you taper off of fludarabine or do it without fludarabine altogether? And those things we're going to address in the trials over time.

I do want to spend a minute also on solid tumors. Any updates you can provide there from CTX131? What should we be expecting?

Yes. I mean 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. So we'll see what the data tells on the heme malignancies. I'm pretty confident it's going to work there. On the solid tumors, 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. So we'll have an update on that this year.

Excellent. I want to remind the audience that now we're pretty close to the end of our call here. So if you want to enter questions via the chat, please do. And 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?

I'll -- since you guys -- whenever we do company calls, you all ask two questions. So I'll have two answers for you. One is, I think there is -- on CASGEVY cost structure, there is an asymmetry in understanding. There's analysts who put out notes saying, oh, it's going to take at least $0.5 billion of sales to breakeven on that franchise because the cost structure is so high. That -- cost of 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. You want to make the franchise profitable. So the threshold number for making something profitable is that franchise profit is much lower. So that's one thing I'll say is missing. Second is, I still see a lot of investors who -- people are somewhat not locked, but go by chronological order of programs. So 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 Lp(a) and 112 in autoimmune, they're pretty surprised because that's not the chronology of how we develop the programs. We had 112 in oncology. We had type 1 diabetes. We have 131 in solid tumors, et cetera. But things change very quickly. So our portfolio is very different from what it was even 3 years ago. And 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.