CRISPR Therapeutics AG ($CRSP)

Good afternoon. Thank you, everyone, for joining us. We're really pleased to have with us CRISPR Therapeutics. And with me, I have Raju Prasad, CFO.

Raj, could you start by giving us a brief overview of where your portfolio stands today, your updated strategic focus on the cardiovascular and autoimmune franchise? And how you're thinking about technologies as you bring in new modalities, including [ siRNA ] and in vivo CAR-T?

Yes, absolutely. And thank you for having us at the Goldman conference once again, and it's great to be here. CRISPR is now over 12 years old, we're entering sort of our teen years as a company. And with that, in addition to CASGEVY, which is our approved product with commercial partner in Vertex, which I'm sure we'll talk about; we really have been focusing on the pipeline and identifying what our next second, third, fourth programs are. And you mentioned cardiovascular and autoimmune disease and we're looking at those therapeutic areas, specifically in how we build sort of the clinical development apparatus of the company as well. And I think with regards to how this pipeline is going to shape up and how it will frame the next phase of growth for CRISPR as a company, is that in the back half of this year, we'll have 5 clinical trial readouts across 3 programs. We have CTX611, which is an siRNA program with a partner, Sirius Therapeutics, and it's targeting Factor XI. Second, we've got CTX310, targeting ANGPTL3. This is a cardiovascular program as well. And here, we're looking to identify certain patient populations where we think we can provide a onetime treatment that could potentially be a best-in-class approach for an indication such as severe hypertriglyceridemia. And lastly, we have an allogeneic CD19 zugo-cel, where we'll have an update in both autoimmune diseases and oncology. And I think what investors should focus on out of all three of these programs and all of these developments is how are we charting the trajectory of each of these programs into potential pivotal trials, which we anticipate starting in 2027. Now you mentioned the ability -- our ability to bring on other platforms such as in vivo CAR-T. We can talk about that more as well. But I think this was -- in vivo-CAR-T in particular, is obviously in a very interesting moment in time from an industry perspective. And there's still what we feel is opportunity for best-in-class, where we have all the pieces, given we're a globally integrated biotech where we really can pull together LNP, mRNA and manufacturing at scale to potentially reach the promise of that as well. So we've got a lot going on, and I'm sure we'll go through most of it.

At this point, how focused are you on the allogeneic oncology platform? For two reasons. It seems like there's an emphasis on cardiovascular and autoimmune, but also as you bring in, in vivo, how do you think about the focus that would play out with that vertical?

Yes. I think the...

For oncology.

Yes. Yes. As you know, the beginning of allogeneic cell therapies was with an oncology focus. And in the last couple of years, we've now seen this amazing ability to translate this technology to autoimmune disease, where the initial data from the autologous patients are now in remission out 4 or 5 years. So it's truly a B-cell reset for the autoimmune patients. And there's -- in our view, there are going to be significant value created for allogeneic cell therapies in autoimmune disease. I think where we're trying to focus our oncology efforts is in areas where there's still an unmet need and where, for lack of a better term, the clinical trial process for approval isn't too onerous. What we're seeing in the autoimmune side of development is the autologous players are getting relatively sizable trials, saying that 25 to 50 to 75 patients single-arm trial sample size for approval. And on the oncology side, I think the trials are much more sizable, 250, 300 patient trials. And so when we look at the competitive landscape and our data set, I think it will be a critical strategic decision that we'll make in the coming months, where do we go bigger in autoimmune disease, where potentially you could bundle more indications for the same cost and -- versus an oncology where if you run a big 300 patient Phase III trial, are you really going to get the ROI on that? I think we'll have more to come, but I think you can kind of tell where we're leaning towards at this point.

Yes. And with 5 program updates expected in the second half, how should we think about the sequencing and relative importance of these catalysts in terms of both proof of concept and pipeline validation?

Yes. And it's a concept that I'll probably come back to another strategic questions, but we really look at our pipeline in terms of modality risk and target risk. And so with [indiscernible] and allogeneic CAR-T, we're really taking more modality risk there. CD19 and ANGPTL3 are pretty validated targets. When we did the Factor XI deal, Factor XI hadn't been fully validated in a Phase III trial. In fact, it was on the heels of the asundexian trial, which didn't hit its endpoint. Subsequently, asundexian hit a secondary stroke prevention trial, and so there has been some derisking there. But I think Factor XI in particular, is something where investors do understand the modality, they understand the value prop that we have with the potentially once every 6-month approach. There are several landscape readouts with milvexian with adalimumab reading out and then also Regeneron doing multiple Phase III programs for 2 antibodies for Factor XI. So I think that's going to be one in the second half of this year between outside data readouts as well as our own TKA study, where that's going to be of fairly big importance and not only from a understanding our drug product profile, but also understanding which indications we may go into in 2027. I think with CTX310, we'll will have a Phase I update on durability, [Audio Gap] indications. The Phase Ib will be focused more on individual indications where the population is more homogeneous. And you can sort of compare our efficacy to other programs a little easier. So for example, in severe hypertriglyceridemia, we've seen an ASO program with high 50% to low 70% triglyceride reduction. I think if we're able to get in that range in severe hypertriglyceridemia, we have the benefit of being a onetime-only treatment that can differentiate from those RNA therapies. And similarly, with the allogeneic CAR-T update, we'll have a meaningful number of patients. I say we'll probably have over 20 patients treated across our basket trial, and we'll have a sense of where we're going to take that forward in Phase III development as well. So really the cadence of these readouts in the second half will not only be data that I think is analyzable in the context of other modalities or other indications, but also will inform multiple pivotal trials, which will likely initiate in 2027.

Great. Maybe starting here with the Sirius-partnered Factor XI program. So this is currently in a Phase II study in patients undergoing total knee arthroplasty with top line Phase II data in the second half, can you frame expectations for the data, what the bar for success is in terms of Factor XI reduction in thrombosis prevention and also in the context of what we've seen from the competitive landscape?

Sure. Yes. So this is a pretty standard trial across multiple Factor XI programs. And I think it will show that CTX611 has a profile similar to these programs on thromboembolic rate, as you said. And so we've guided to a top line readout in the second half of this year. I think what you should expect there is a discussion of the percent of thromboembolic rates across the dose levels that we're testing in 3 dose levels of CTX611 and then enoxaparin, which is [Audio Gap] the other trials that ranges in low double digits tend to [Audio Gap]. So really, we're looking at a single-digit percentage for the CTX611 and our go-forward dose versus a double-digit percentage with enoxaparin. I think, in addition to that, we are running a multiple dose trial just to look at a regimen of once every 3 months and once every 6 months. So the plan is by the end of this year, we'll have our data, we'll have the readouts from competitor programs, which will tell us, is this going to be in DOAC-eligible patients, which we think is around 2 million patients? Is it could be a DOAC -- sorry, an AF all-comers population, which in atrial fibrillation, we think that's roughly 8 million patients? And that could be a $15 billion, $20 billion opportunity or -- and then we'll both the milvexian trial and [ abaloparatide ] trials hit, which will really define our pivotal development for this program. But the TKA study, I think, is an important trial for us to hit just to show that 611 is sort of on par with those other assets.

Noting a multibillion dollar TAM across all of these indications here, how will you prioritize the indications that you look to advance with regard to Phase III development?

Yes. I think from a PTRS perspective, the cancer-associated thrombosis and some of the venous indications are relatively derisked. I think where the questions arise for Factor XI is on the arterial indications. And as an asundexian from Bayer hit a wonderful secondary stroke prevention trial that started derisking these programs on the arterial side. Again, there's two major readouts. Milvexian will have an atrial fibrillation atrial against DOAC, and then abelacimab will have a DOAC ineligible Phase III that read out early next year. And I think the way we see it is cancer-associated thrombosis as sort of a low-hanging fruit, high-probability success, but lower market opportunities, say, about $1 billion market opportunity; the DOAC an eligible patient population, I mentioned 2 million patients. So it's roughly $5 billion market opportunity. And if the milvexian trial derisks the full atrial fibrillation market, it's roughly 8 million patients, $15 billion, $20 billion market opportunity. So you can see like there's sort of 3 levels of value capture that we can have. And a lot of it will be derisked before we had to make our decisions. And I think that's how we strategically planned that when we did this deal.

Great. And you also have an option to nominate 2 additional candidates with Sirius. Just maybe share details around the potential targets that could play out there.

Yes. I think as you astutely said earlier, cardiometabolic and autoimmune is sort of where our strategic focus from a TA perspective is going to be for the future. And so you can imagine that the siRNA programs will be sort of in that vein. There's -- the good thing about that aspect to the partnership is we've got a certain time point to name targets, we've got reserve targets. So what we want to do is make sure that we have a best-in-class asset that we're pushing forward. And Sirius has a great research engine with multiple -- company's expertise. So they've got folks from siRNA, Arrowhead. So it's a really good team. And so more to come on that. But it just goes more towards our strategic shift in our portfolio to being a TA-focused company, and having diversification of modalities.

Right. Your in vivo gene editing program in cardiovascular disease, can you frame expectations for the second half in terms of patient numbers and follow-up for CTX310? And what profile you're looking for across the homozygous and heterozygous FH populations but also sHTG to inform the go-forward decision?

Yes. I think -- so we had a Phase I trial in -- at the American Heart Association last year, we had a concurrent New England Journal paper. We've gotten significant positive feedback from that data set and -- both from the PIs as well as the patient community. And that's been fantastic. I think what we should expect from that trial is just more follow-up, where we're looking specifically at the ANGPTL3 reduction. And for just sort of a reminder, we saw about 80% ANGPTL3 reduction, which we think correlates to all the liver ANGPTL3 in those patients at the DL4 dose. And I think in the back half, we'll have a Phase Ia update where there'll be longer duration of follow-up there. The Phase Ib, again, is -- it's in different indications, and we're going to be having about, say, 10-ish patients in certain indications. I think where we're strategically looking at now, specifically is the sHTG population, we think that we might have differentiation over the APOC3 target. And I think if you look at the core CORE2 data, they did see an increase in hepatic fraction as well as an increase in LDL in the patients. What we know from the ANGPTL3 target is that we do get a significant reduction in LDL. In our Phase I, it was about 50% across the basket study. So we have that. And then there's also other ANGPTL3 therapies, RNA therapies that have shown reductions in hepatic fat fraction. So those two plus the onetime one-and-done approach, I think, gives us a unique profile to differentiate.

And it seems like you had, based on prior data, a synergistic LDL reduction of PCSK9 therapies. Just any thoughts there from the KOLs on how to think about that from a clinical standpoint on the forward?

Yes. I mean we definitely think that there's a mechanism that could be synergistic between PCSK9 and ANGPTL3. We've thought we've given some thought into a PCSK9 refractory population. At this point, we like the setup in sHTG, just given that the core CORE2 trial in AP was very statistically significant with 800 patients. The Arrowhead trials are going to have, I think, 400 patients or 500 patients. So if that looks very good, like that it will help us statistically power our trial, but we're hoping to have a more manageable enrollment criteria in our Phase III that could potentially be a low investment for a high return in that indication. I think, with PCSK9 refractory patients, I guess the question with LDL always is with payers, do you need a CVOT? And I think if we can avoid doing a large -- as a company of our size, if we can avoid doing a large CVOT to get significant commercial adoption first, we'll go with those indications. So we're leaning towards sHTG for that reason with something like a PCSK9 refractory, FH population maybe being an add-on indication later on.

Could you speak just with regard to sHTG about the competitive dynamics here, given you've got an RNAi and an oligonucleotide both in the market here?

Yes. I think, again, the ANGPTL3 target is going to be a big differentiation, we think. But we've always felt that there's going to be -- there's a continuum on small molecules, antibodies, RNA therapies and gene editing. And you can see from the patients -- and some of them have actually come out in like in NBC and some major media outlets. And you can see the profiles of the patients that are starting to develop for our therapy now. And so this one article was about a father and son that they both got the therapy in Australia. And I think from the son's perspective, he knows that his father had multiple heart injuries, heart attacks and got this therapy and did well. [ He ] was facing 30, 40 years on therapy and chose to get this approach, whereas the father had multiple heart attacks, was probably worried about -- the doctor is probably worried about compliance on therapy and the potential for another one to occur. And so having this ability to sort of live a normal life and not worry all the time about taking medications, particularly medications where you don't feel much different if your LDL is higher or lower on a day-to-day basis. So I think those two case studies, those two profiles are sort of where we think the early adopters can be. There are young patients that don't want to take 30 years, 40 years of therapy or older patients that have had issues of compliance.

Fair. On the next-generation Lp(a) asset, 321, what are you looking to learn from the HORIZON data to inform development here? And how will the gene editing asset be positioned versus competitor approaches?

Yes. I think the HORIZON study is going to be one of the biggest readouts in the back half of this year. I think between that and Factor XI in the cardiovascular space, those are probably the two most important targets that may be derisked. But with the HORIZON trial, I think us and I think everybody else that's looking at Lp(a) as a potential new biomarker for ASCVD is looking at the HORIZON trial to see both the 70 mg per deciliter cutoff as well as the 90 mg deciliter cutoff and see whether or not the -- it's a significant study. There are so many ways that this could go. It's hard to lay out all the scenarios. But I think with regards to our development, we really need to see in that -- particularly that high threshold cohort if that hits significance. With regards to our programs, 321, we do believe based on preclinical studies that it's a more potent guide RNA and we can get a more potent LP(a) reduction. Now whether we need that or not, we'll have to see. But I think it will be very interesting to see this HORIZON trial, and then there's also the RNA trial coming out soon after. But again, similarly, this is just an area where Lp(a) is known to be something that is genetically derived. It does fit the profile of something where a gene editor would get adoption where you know your LP(a) from an early age and you're staring down 40, 50 years of therapy or you take this onetime opportunity to cut your risk reduction significantly. So it's definitely -- we'll all be waiting with beta breath. I think you cover -- we'll cover this as well from multiple angles. So it will be a very interesting trial for not only the sector, but for patients as well.

Definitely. And you have Phase I study initiations this year that are planned for refractory hypertension with 340 and 460 in AATD. Are those still on track?

Yes, they're both on track. Just staying on the cardiovascular side first, I call the refractory hypertension trial probably the biggest disconnect between PI enthusiasm and investor enthusiasm. I think knocking down angiotensinogen and being able to make patients normotensive, particularly in this refractory hypertensive population where they're on 5 therapies plus a diuretic, could be pretty meaningful. And so we'll have more data. We're running some preclinical studies with some preeminent leaders in the space that will be published as well at some point. But I think that there's a real opportunity here to change the paradigm of how we think about hypertension. I think LDL and triglycerides, as you mentioned, there are other therapies out there. But here, to potentially make people normotensive, I think, could be very interesting. And I think at some point, the data will tell the story for us. But we're very excited about getting that program into the clinic and so our PIs, I want to -- sorry. I was going to talk about 460 as well. But just quickly here, this is almost the opposite of our issue in cardiovascular disease because I think there's a general consensus that gene editing will be taken up commercially in alpha-1 antitrypsin disorder. And so what we wanted to do is if we were going to bring a program forward here, we wanted to have a best-in-class approach. So our synthase editing technology, we think, is more efficient and more potent than approaches that are out there. And we're really aiming for that 18 to 20 micromolar of AATD production to get to normalization. And I think we're very excited about the opportunity there. We're leveraging our LNP from the cardiovascular program. So we have a good sense of where our therapeutic window is from an LNP perspective. And so we've modified the payload or we've developed this payload where we think we can get to those levels, those types of levels with this data. But that -- the initiation for that trial is in middle of this year. So not too distant future, we'll have human proof of concept there, which I think could be a significant value-generating event.

Before I jump into the autoimmune portfolio, just curious here, given the breadth of your cardiovascular portfolio and then this additional autoimmune, how are you thinking about taking these assets forward by yourself versus partnering them out?

Yes. This was sort of a reason why we did an opportunistic fundraise earlier this year as well was we never want to be in a position where we have to make a decision on any of our assets based solely on resource allocation. And I think we've put ourselves in that position where now we have over $2.4 billion on the balance sheet. And I think we have the ability to take these forward. Again, I think if we want to do a broad-based development in cardiovascular disease, to your point, there's sHTG, HoFH, HeFH, PCSK9; there's a lot -- and potentially CVOTs. If we decide we want to go in a broad-based development over there, maybe we do go find a partner. Similarly, if 611, if the Factor XI space hits on the milvexian trial, that's a huge market opportunity. There's probably several pharma companies that would be interested. I think in allogeneic CAR-T, I think it's probably more of a bite size that we can take. So we just need to see all these cards play out, but I think there is a world where we do look for a strategic partner to do some of these things because we're not running 8 to 10 pivotal trials next year, but we will be a pivotal phase company next year.

Pivoting here to zugo-cel, which is your allogeneic CD19 CAR-T program. Over 14 patients have been dosed across multiple autoimmune indications and the first 2 SLE patients remain in durable long-term remission. What stands out with regard to this drug's profile? And what gives you confidence that you can be competitive with the autologous and in vivo CAR-Ts and TCs and autoimmunity?

Yes. I think what we really want to show with this first data set is can we recapitulate the autologous profile? And the first 2 patients that we've put out data on are directionally trending that way. As you mentioned, the first patient is now in submission through 12 months. The second one is through 9 months. We've dosed 14 patients. We've gone through this chasm of the enrollment, which I think initially, there was a lot of bolus of companies developing in this space that's come down now through runway issues and strategic priorities for other companies, we've been able to bridge that chasm. In the back half of this year, we anticipate having over 20 patients in that data readout across the basket trial. I think where we stand in the context of the landscape and a lot of hype for TCs, we do believe that allogeneic CAR-Ts can be used in indications where there's a high severity as well as potentially CNS indications where those -- some of those other therapies may not be able to as readily cross the blood-brain barrier and have a therapeutic effect on the scale of a cell therapy. The benefits of allo over autologous from a supply chain, from a cost perspective, those -- everyone knows those. We think at the dose that we've got those remissions, the cost of goods for zugo-cel will be 10,000 or less. So in autoimmune disease, again, we have this benefit of a low cost of goods, high-margin product profile, even at a reasonable price point. And so we'll have to see where -- the in vivo CAR-T and we have our own efforts there. I think that's a very exciting place. I think allo CAR T will have its niche and its markets where it is the leader. Again, we're looking at myositis and scleroderma in addition to lupus. With scleroderma, for example, there's a 40% mortality rate with that disease. There's some pretty severe forms of that disorder where patients have ILD as well and lung function deficits. So if we're able to expand into those populations as well and actually have a maintenance of forced vital capacity or lung function, like that gets really interesting as well. So more to come on this, but I do believe that the CD19 allogeneic CAR-T product is a multibillion-dollar opportunity.

And can you frame expectations for the data in the second half here? How many patients? What length of follow-up could we see across the various autoimmune indications?

Yes. So the patient with the most follow-up is when we have previously 12 months. So back half of this year, say, 18 months ballpark. I think with regards to numbers of patients, we'll have over 20 patients dosed by then. There'll be some SLE, some scleroderma, some myositis. And again, we're looking at sort of the normal biomarkers, MCRIs scores, TIS scores with myositis and then dose remission criteria. We'll also have some description of B-cell depletion and recovery as well as some other cell markers. But overall, what we're really trying to show is we're recapitulating what we've seen with autologous therapies from an efficacy and safety benefit and then directionally, where we're going to take this forward into pivotal next year.

You also initiated a third Phase I study here looking at autoimmune neurologic indications. And maybe speak to what supports the asset's activity in CNS disease. And when we could expect first data from that study?

Yes. So when we had patients with -- in oncology with CNS involvement, we did see reductions with our first-gen program. So we know that the allogeneic CAR-Ts do cross the blood-brain barrier. I think when we were thinking about strategically where we could -- where an allogeneic CAR-T could benefit patients where a TCE or in vivo CAR-T may not be able to, I think CNS popped up as an area where that could happen because of the blood-brain barrier. So we've initiated that basket trial. We're enrolling patients. And so when we have that data, we'll share it and talk through if we do end up going in those indications as well.

Great. Maybe one last question here. So as you look to the forward, and we didn't get time to touch on these, but to -- touch on the multiple in vivo CAR-T efforts you have. You have a transient mRNA and a nonviral integrating CAR. And how you're thinking about this whole portfolio in the context of path to profitability?

Yes. So again, in vivo being at the scale we are in vivo CAR-T was just a way where we were able to leverage all of the aspects of our business, including the manufacturing. I think that's going to be the key differentiator long term. Can you create a scalable in vivo CAR-T that can really have superior binding, superior biodistribution and efficacy and safety? And so we don't think that, that profile has been fully generated yet. And so we have the ability to catch up and create a best-in-class profile there. With regards to profitability, and obviously, we have CASGEVY with Vertex, we do think that for us, at this point, it's a question of when and not if we will reach profitability. We've got $2.44 billion on the balance sheet. We have the ability to get multiple programs through pivotal and into commercial at our discretion and at our choice. And so we'll be able to supplement via BD deals and things of that nature, both on the buy and sell side. We have a lot of optionality, and we think we have a runway to profitability at this point with no need for opportunistic -- no need for fundraising. We can always be opportunistic about it, obviously. But we find ourselves in the position right now, 13 years in where, again, coming to the beginning, I think we're going through that growth phase in the next 12 to 18 months, we really will understand our second, third programs, our path to profitability and how we really get to that next level of $10 billion to $15 billion market cap that really defines a leader in biotech and not just a gene editing leader.

Great. Well, with that, Raj, thank you so much.

Thank you, Salveen.