CRISPR Therapeutics AG Aktie

Hello, everyone. I'm Max Skor, biotech analyst with Morgan Stanley. And before we get started, for important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures.

And with that, I'd like to welcome Sam Kulkarni, CEO of CRISPR Therapeutics. Thank you very much for joining us today.

Thank you for having us.

So maybe just to start off, Sam, you can kind of set the stage for us, walk us through CRISPR Therapeutics' key priorities, milestones through year-end and where the portfolio stands overall.

Yes, happy to. And '26 has been a great year for us so far as we move to the next phase of the company. But what we have are several layers of value. One is CASGEVY, which is our commercial product for sickle cell and thalassemia, which we are partnered with Vertex On, and that's showing a very nice trajectory from a revenue standpoint, and we expect that to be a multibillion-dollar opportunity.

The second is 3 assets that could potentially be ready for Phase III next year or pivotals next year. And these are namely CTX310, which targets ANGPTL3. This is for a 1-shot reduction of cardiovascular risk by using CRISPR/Cas9 to reduce the ANGPTL3. We have zugo-cel, which is an allogeneic CAR-T, which is off the shelf, very convenient, and it could do a onetime immune reset for various B-cell-driven autoimmune diseases.

And the third being CTX611, which is our siRNA, which we're partnered with a company called Sirius on for Factor XI, which has the promise of anticoagulation without the risk of bleeding. And that can be applicable in many different settings and indications such as stroke prevention. So those 3 assets represent the next layer of value for us.

And then we have 2 early assets in the clinic now. One is for A1AT, which is our first advanced editor, which has leapfrogged Gen 2 editors to be something very efficient and potent and very precise. We call it SyNTase editing. And that's going to dose patients soon. And CTX340, which is for refractory hypertension, where we actually target angiotensinogen, and that can result in a pretty meaningful reduction in blood pressure in patients very soon after being edited. And those 2 will have data in the not-too-distant future.

So we have other programs beyond that. One of them is CTX321 for Lp(a), which kind of hangs in balance based on HORIZON data and also type 1 diabetes. And the last layer of value for us is our very prolific and productive research arm. And we have a best-in-class in vivo CAR-T now, both in the form of a transient CAR-T based on mRNA, but also permanent CAR-Ts based on editing where we insert the CAR into cells and that's permanent.

We have in vivo HSC editing, where we directly edit hematopoietic stem cells, which can be durable and many other things that we're working on. So all in all, a very rich portfolio, but we have the strong balance sheet to move all these programs forward ourselves and really change the face of medicine along many different dimensions.

Great. So maybe we'll start with CASGEVY, move on to some of the more mature assets, and then we can talk about the future from there, if that sounds good. So the FDA recently expanded the CASGEVY label to children 2 years of age and older, adding approximately 5,500 potentially eligible patients with sickle cell or transfusion-dependent beta-thal. How should we think about the pace at which pediatric expansion could translate into patient referrals, treatment center readiness, initiations and ultimately revenue?

Yes, it's a great tailwind for us on CASGEVY. I mean, Vertex in their last disclosure announced revenues of about $76 million for the quarter. And also, more importantly, said that they're initiating over 100 patients per quarter. And that puts you -- if you just do the math in terms of future revenues at around a $2 million price tag that you're already looking at future revenues well north of $0.5 billion and getting closer to the $1 billion mark, which makes it a blockbuster.

And I think that tailwind of pediatric expansion is only going to add to the number of patients that are being initiated per quarter because with a lot of these -- with kids, you have more children's hospitals at play and they're used to these kinds of procedures. So they're going to be more productive as well as there's a bigger addressable population.

And not to mention the fact that I think with these diseases, you want to treat these kids earlier and earlier. The sooner you treat them, the better because you don't have any organ damage or any permanent damage that will be caused by these diseases. So all in all, I think a very favorable dynamic for CASGEVY over the coming quarters.

Okay. So more broadly, what are you seeing in regards to the movement of patients through the CASGEVY treatment journey? Where is the greatest remaining friction between referral, initiation, cell collection, conditioning, et cetera? What are you seeing as potential bottlenecks? And what's the team working on to remediate that?

Yes. Since at this point, most of the bottlenecks have been worked out by our partner, Vertex. I think initially, when we started the launch, there's a lot of work required to get the reimbursement set up fully to be well oiled in terms of prior authorizations, getting all the approvals. And mind you, we had to do this not just in the U.S., but several jurisdictions around the world. But good news is we have very strong payer coverage.

Second thing was to get each of the hospitals contracted and you have individual requirements per hospital potentially based on their own IT systems and what they needed to get these patients in the flow. So that's all been done. And then the last thing is the manufacturing capacity, and we're steadily increasing the capacity as we see more and more demand coming to be able to serve the needs of all these patients.

So I would say at this point, most of those elements of friction have been dealt with, and we're just now awaiting the patients to come into the funnel, move through the funnel and ultimately get treated. It still does take over 6 months, potentially 9 months plus to get a patient from initiation to treatment. But at some point, it's going to stop mattering because it's just a matter of getting into the funnel and then getting through the funnel and getting treated. So all in all, I think that's looking very good and could be the basis for steady growth for a long period of time from here on out.

Is there anything you would look at potentially to decrease that time? Or will 6 months always kind of be the low end?

Yes. I think we'll do everything we can, but it's not the manufacturing that's the major contributor to the time. I think the actual manufacturing itself happens pretty quickly. But a lot of patients opt to do exchange transfusions -- for instance, you have 2 to 3 months where someone is doing exchange transfusion before they're even collected. And then after the drug is manufactured, sometimes people wait because they have to get their life in order, they have to take a break or they need vacation from work, et cetera.

And so you do see some wait time there anyway. So it's never going to be 1-month. But at the same time, it doesn't matter at this point. I think we just want to get the -- what matters for the patients is the guarantee that they're going to get the drug product if they go through the journey. And that's where our main goal is to have that assurance for the patient.

The last thing also I'll say is the other tailwind that we should think about as we look at the next few years is gentler conditioning. I think Vertex will disclose more on gentler conditioning over the coming months. But I think that a gentler conditioning agent that allows a patient to just do a 3-day hospital stay or less instead of a 2-week or 3-week, that's going to be a big tailwind as well. It's going to expand the addressable market where some of the more moderate patients will also potentially opt for CASGEVY. So I think that's another factor that we're preparing for as we think about capacity expansion, not just in the U.S. but globally.

Yes. I was going to ask that question on gentler conditioning, but also in vivo hematopoietic stem cell editing, any updates around that?

Yes. It's a major focus for us to do direct hematopoietic stem cell editing, and it requires a lot of different things to come together, whether it's the LNP platform, the targets and the type of editing you're doing, we're making very good progress. In our corporate presentation, we showed durable editing of hematopoietic stem cells over a 6-month period. And we didn't say which edit that was, but what you can see that being applicable to a number of different indications and diseases.

You could modulate several factors, whether it's porphyrias, whether it's autoimmune conditions, et cetera, that you could do if you can actually establish a platform for HSC editing, not to mention the fact that sickle cell and thalassemia will be the huge beneficiary of that. And so the life cycle of the franchise for us and Vertex is that we have CASGEVY in its current form. We have CASGEVY with gentler conditioning agents.

And then in the '32, '33 time frame, you're going to have in vivo HSC editing that's going to come to patients that will allow us to like treat many more patients than what the current affordability indicates, right? We go beyond Western Europe and the U.S. and potentially even treat patients in Asia and Africa to get rid of this bad disease.

Okay. That's helpful. Maybe we can pivot to CTX310. You recently presented data at ESC. Maybe just put the data update into context. I have a few follow-up questions, but maybe introduce the audience to what was presented.

Yes. This is a fascinating target that was elucidated about 15 years ago. It's called ANGPTL3, angiopoietin-like [ lipase ] 3 and the basis is natural history data as well as some work that was done in the Boston area. But it starts -- there's a village called Campodimele in Italy, where people have a naturally occurring mutation in the ANGPTL3, which it's a loss of function variant and these people just have lower levels of ANGPTL3.

And it turns out that the cardiovascular risk in this village is a lot lower. And while it's not statistically significant, they all tend to live longer. So a naturally occurring mutation in ANGPTL3 resulting in a greater lifespan, lower cardiovascular risk. And we're just following the genetics, right, and following natural history data. And if we can recapitulate the same knockout, it's not to be the same mutation, we can knock down ANGPTL3, it basically is a protein that acts on lipoprotein lipase and endothelial lipase. And these lipases are enzymes that chew up the cholesterol, right? So you're unhinging those lipases of the enzymes to reduce your cholesterol levels. And when you knock down ANGPTL3, no surprise, your triglyceride levels, your LDL levels all come down.

And in the Phase Ia data that we presented, we presented some early data last year at AHA and then continuing data at ESC, which shows that we get dramatic reductions at the higher dose levels of ANGPTL3 up to 80%. It's not 100% because there's some ANGPTL3 produced outside the liver, okay?

So we're pretty much maxing out the liver editing, ANGPTL3. And when we knock down ANGPTL3, you get near 50% reduction of LDL cholesterol, near 50% reduction of triglycerides. Now it's a little variable because different patients in the Phase Ia, it's a mixed population. Some people have high LDL, some people high triglycerides. So that's really encouraging.

And then we presented data at ESC that shows that, that edit is durable. If you knock it down 80%, it remains knocked down 80% a year later. And that is a very good sign because it means that it's durable for life essentially. So it proves the -- lays the groundwork for a one-and-done gene edit that's going to reduce your bad cholesterol for life.

We'll have more data coming soon in our Phase Ib, where we've segmented the patients into severe hypertriglyceridemia, mixed dyslipidemias, refractory hypercholesterolemia, et cetera. But the first one, we're going to -- that we're moving forward, obviously, is severe hypertriglyceridemia, and we'll get a greater sense of the data for that population later this year in terms of what is the triglyceride reduction that you get there? And what else are you seeing in terms of LDL reduction, hepatic fat fraction, et cetera.

And so from the ESC data, if I could just ask, what did these data teach you about dose selection, patient level variability, durability you've commented on, but just the therapeutic window as you advance into the Phase Ib?

Yes. It's -- basically proves that at the highest dose levels, that we did in the Phase Ia, which is about [indiscernible] need to go. It's very safe and it's durable essentially, laying the groundwork for our Phase Ib where we picked the fixed dose based on that highest level dose. There is some variability between patients because they're all different types of patients. Some have both high LDL and high triglycerides. Some have low LDL but high triglycerides and vice versa.

And that obviously leads to -- if you have normal LDL triglycerides, you're not going to see much reduction because you're already normal. But essentially, it's a very clear indicator that ANGPTL3 was dose-responsive reduction. And if it's reduced to a certain level, it remains reduced for a long period of time, it's durable. And it gives us a good window into what the dose is that's safe that we can go forward into Phase Ib and potentially pivotal.

So I think the Phase Ib data as we get later this year is the last piece of information we need before we can go to the regulators and say, how do we start a pivotal trial for ANGPTL3 in population A or population B.

So that's a great segue into the Phase Ib data. Could you just set expectations, what clinical and biomarker evidence would support advancing into this indication? How will you determine which population offers the most practical first registrational opportunity?

Yes. Each of these populations will have a different level of information or evidence, right? So you have in severe hypertriglyceridemia, I think what we're trying to get a handle on is what is the level of triglyceride reduction you see in patients with very elevated triglycerides. If you look at the siRNA trials, they usually had a cutoff of about 500 milligrams per deciliter as their triglycerides, lowest triglycerides, so 500 and above.

We're trying patients that are well above that. And we're trying to get a handle on how much triglyceride reduction there is and then all the other biomarkers such as what happens with LDL, what happens with their A1c, what happens with hepatic fat fraction. So I think we'll get a handle on that, and that will allow us to say, are we getting the same reduction that you see with siRNA for triglycerides? And then what is the population we want to go after? What's the cutoff of triglycerides that we want to go after in a Phase III trial. So that's for triglyceridemia.

For refractory hypercholesterolemia, what's very interesting is ANGPTL3 is synergistic with PCSK9. We had patients in our Phase Ia that were on PCSK9 therapies, had reduced their LDL, but still high, uncontrolled LDL even after PCSK9 therapies. And they had 50% reduction on top of PCSK9s, right, indicating that ANGPTL3 is very synergistic with PCSK9 therapies. And so there's that population of refractory hypercholesterolemia, which we'll get to next. I think we want to do in a phased approach, but our immediate focus right now is severe hypertriglyceridemia.

Okay. And as you commented on, there are siRNA approaches out there. Could you just talk to the value of a one-off treatment? I'm not asking you for a price or commitment for a price, but just help us think through what the value proposition looks like.

The value proposition is for everyone -- for patients, today, we're saying, okay, if there's a once every 3-month siRNA, why would you do a onetime treatment. But that question is going to flip. If you have a onetime treatment that's safe, why would you just not do that? Because people still have compliance issues. People leak into -- sometimes they miss a dose at 3 months, they may go into the fourth month or whatever. And you get this sawtoothing effect with siRNA. And so not every patient is compliant. So why would you not just not reduce the bad actors that lead to cardiovascular risk once and for all, right? So that's sort of the primary argument for why you would do that.

Second thing is, I think ANGPTL3 is probably a better target than APOC3 for these patients. And that's because you're also getting LDL reduction in addition to triglyceride reduction. You get better glycemic control with ANGPTL3, it seems like than some of the siRNA or ASO data. And you could actually potentially have better liver fat reduction with ANGPTL3 relative to APOC3. So I think all those point towards ANGPTL3 being a better target as well.

And I think as we look at the data, data will tell us, but eventually we feel very good about the prospects because if you have that as a solution to patients, and by the way, the pharmacoeconomic benefit, if we price something at about 5x siRNA pricing, that's a big value to the system essentially to employers, to the government because you're eventually over a lifetime going to spend a lot less on these patients.

Okay. That's helpful. Let's move on to CTX611 and zugo-cel. Maybe if you could just briefly introduce CTX611 and then we can move on to the Phase II, what looks like a successful readout and benchmark expectations?

Yes. Factor XI is going to be a very interesting target. Some people are saying now it's going to be a $20 billion category in the pharmaceutical space and a lot of big pharma are very interested in Factor XI. And the reason for that is because there's always been this holy grail with anticoagulation. You had these DOACs that came on into the scene -- several -- almost 2 decades ago now that had a major anticoagulative effect, but they cause a lot of bleeding risk. So many, many patients are not able to take DOACs because of the bleeding risk.

What if there was this holy grail that says you get anticoagulation, but you don't get the bleeding risk. And that's what Factor XI represents because our bodies have 2 pathways. One is an intrinsic pathway and one is an extrinsic pathway, that's tissue factor pathway that both come together at Factor Xa. And Factor Xa is where the DOACs act. And so both pathways converge into the clotting cascade. And we're only turning off one versus both. And because DOACs act on Xa, they turn off both.

And so the promise is for indications like stroke risk. If you have stroke risk, a lot of patients who have strokes, whether it's a transient ischemic stroke or if it's a major stroke, many of them go on baby aspirin or something like that because they can't take DOACs. And some people try low-dose DOACs, et cetera, but it's not very effective. You could have a once every 6-month injection of Factor XI that dramatically reduces your stroke risk. Same with AFib patients who have similar risks.

And then there's a number of indications like the total knee arthroplasty, you get the knee surgery and then you have major risk of DVTs or even pulmonary embolisms. You can take all that away because you don't have thrombus formation. And that's where 611 comes into play. This is our first-in-class and potentially best-in-class siRNA that has deep durable reduction of Factor XI up to 95% in our Phase I studies.

And now we're doing a Phase II study in a total knee arthroplasty setting, and we'll read out the top line from the Phase II study at the end of the year. And if that's positive and some of the other Phase IIIs are turning out to be positive, then you have a big category here that where we're very well positioned versus small molecules and even biologics. And we're doing this together with -- this came through our BD efforts with the molecule was developed by our partner, Sirius Therapeutics, but we're developing it together, and we're actually responsible for all the Phase IIIs and ultimately commercialization of this asset.

Yes. So if you could just briefly kind of walk us through the potential registrational path and also just thinking about the competitive landscape, where you sit amongst your peers?

Yes, absolutely. I think to get to registration, I think we need to have information from this Phase II study that shows that it has a therapeutic effect in patients. Also some more information on our MAD dosing to understand how multiple doses work in terms of both Factor XI knockdown, but also aPTT levels, et cetera. And once we have that, we can put a package together to say here's a Phase III.

And the different indications where we could go, one -- the obvious one is secondary stroke prevention. There's also the DOAC ineligible AFib patients, where there's a major trial called LILAC that's being conducted right now for secondary stroke prevention, you had a positive trial for asundexian in Phase III. You have a milvexian trial reading out soon and potentially some other indications like cancer-associated thrombosis.

There are drugs like RYBREVANT from J&J, where it's an ADC and you take the ADC and you get -- 30% of patients get thrombus formation. They get VTEs, events, et cetera. So lots of cancer patients suffer through that. And you can do for any of these cancer patients before they take their chemo or their ADCs, you could prevent any of that happening by dosing them with the Factor XI beforehand.

So there's multiple places you can take this, but that's something we'll unveil. We will disclose as we get past our Phase II study as to where we want to take it forward. But I think we're very well positioned relative to small molecules and antibodies because small molecules right now are twice a day dosing essentially because you get these peaks and valleys in aPTT even through the course of the day. And it's inconvenient from a compliance standpoint, whereas once every 6-month injection subcu is much easier for patients.

And with antibodies, you may get these, again, very high peak reductions, but it's every month. And by the way, it's not very reversible in case you hit your nose and have an emergency or something like that because the antibody still circulates. Whereas with siRNA, you can simply replace the factor through plasma and you reverse it in case of an emergency. So several things, nuances why an siRNA is much better in this setting than an antibody or a small molecule.

Okay. That's helpful. And then maybe let's just touch on zugo-cel and then we can talk about the future. But how are you weighing the relative opportunities in autoimmune disease, oncology, plans going forward?

Yes. Our major focus with zugo-cel right now is autoimmune diseases. And the logic is as follows. I think what you're seeing in autoimmune diseases is a real opportunity to cure these autoimmune diseases with a onetime reset of the immune system for B-cell-driven diseases. And these are numerous. There's rheumatology indications like lupus, myositis, scleroderma, there's heme indications like ITP, there's neuroimmune indications.

And everyone is excited about TCEs, but T-cell engagers may not always be durable because the issue is they don't have deep penetration into the tissues, nor do they help the CAR-Ts traffic or the T cells traffic to the site of disease. Whereas CAR-Ts do traffic to the site of disease are very deep penetration. And the dynamic we have right now is that allo CAR-T can move very fast relative to autologous CAR-Ts, which take time from an enrollment perspective, there's safety overhang with autologous CAR-Ts. Even if it's 1 in 50 patients, you have that issue.

And so allo CAR-T off the shelf is right available, and I think could be very important. In vivo CAR-T, it's still early phases. I think we have a lot more to see in terms of data before it becomes something real. So at this point, we see a major opportunity for zugo-cel to be the leader within the allo CAR-T space, especially because we have these edits that make them much more potent and autologous-like relative to other allo CAR-Ts or allo NK cells.

And so we're advancing this in a basket trial across indications. But by the end of this year, we will certainly have a greater N in terms of patients, but also a greater follow-up across some of the subsets. So we'll have -- systemic sclerosis, for instance, we'll have a reasonable number of patients. Myositis will have a reasonable number of patients that would indicate in these indications, can we get to a Phase III and pivotal start soon.

Meanwhile, we'll continue the basket expansion with neuroimmune trials. And the other fact of this thing is in neuroimmune indications, I don't think that TCE is really going to make a big dent because TCEs don't penetrate the blood-brain barrier and go into the CNS system. Whereas we know with our allo CAR-T, zugo-cel, that it does go into the CNS system and there's activity there. We've seen that with the oncology setting where people had CNS manifestations and the CAR-Ts did go into the CNS and there was a response for mets in the brain.

Okay. That's very helpful. And maybe briefly before we dive into maybe the broader questions in the last 6 minutes, could you just lay out kind of the clinical catalyst path ahead, things we should really be focused on maybe through year-end and then early '27?

Yes. I think CASGEVY will be a steady cadence of updates every quarter. And obviously, next year, I'm sure Vertex will guide to what the year will look like because we have a lot of forward visibility. Among our clinical assets, I think you'll look for key data on each of these 3 assets that we move into Phase III. For 310, I would point to our Phase Ib data that's for severe hypertriglyceridemia, and that's the data set you'll see by the end of the year.

For zugo-cel, you'll see data from the MAD basket trial, but I think we'll have more data for one of the subsets, one of the indications that kind of tell us how we're going to move forward into Phase III there. With durability, we'll have reasonable follow-up, but not all the follow-up we need, but reasonable follow-up. And then for 611, we'll have the top line data just at a very high level in terms of the control arm in enoxaparin versus the drug arm, which is CTX611 and what the differences look like in terms of VTE rates.

And we'll have more information on bleeding risk, et cetera, at a later time point, but at least we'll get the top line data on these 3 assets. So that's key. And then the data for A1AT and refractory hypertension will most likely be next year, but not too far into the future because with A1AT, we're already starting at a reasonable dose that's efficacious versus dose escalating from beginning because we have a platform designation for our LNP platform. So we'll have data from A1AT.

And then for refractory hypertension as well, you don't have to wait a long time to see what happens to the patients. Within days of getting gene edited, the blood pressure is going to likely drop. And so you can see what that looks like. So I think we'll have more catalysts early next year for those 2 assets as well.

Okay. That's very helpful. I guess one other question that just interests me. I mean, gene editing was in its infancy. We're coming to a new age almost. It's expanding. You're even moving beyond the liver. There's competitors in the space that are advancing, moving to the clinic and closer to commercialization. As you look out across the landscape, what kind of excites you? What frontiers are you really focused on? And maybe a couple of concerns or things that have popped up recently?

Yes. I think there's -- broadly, the platform is advancing, right? The editing platform is improving and improving. And with our SyNTase platform, we can do precise editing with very high potency. The delivery solutions are improving. But for us, broadly, as a company, we look at 2 axes for improvement. One is delivery. So we want to get beyond liver into the hematopoietic system, into the immune system, into other organs like kidney, CNS, et cetera, muscle. And that's 1 axis for improvement is more and more expansion across disease organ systems.

And the other axis is on editing is going beyond correction to whole gene insertion as well. And I think at this point, even whole gene insertion into the liver is probably solved. We have to get it there in terms of clinical candidates, but that's a whole set of rare diseases that we can tackle that way. And so I feel pretty excited about this next phase of gene editing.

And I think you've seen that. I mean, if you saw what happened with Moderna and the excitement around these advanced therapies, I think we're past the sort of the bottom on cell and gene therapies, and we're now into this phase where like a Genentech, by the way, Genentech was in a bottom in 1988 or something like that, right? And then there was a big second wave of growth. I think you're going to see a similar second wave of growth. And hopefully, we're at the vanguard of that growth as we take cell and gene therapy into the future and change the face of medicine.

Okay. And then maybe 1 or 2 more questions if we have time. But in regards to the rise of China innovation, how is it changing your, I guess, competitive positioning, your thoughts on R&D and BD strategy?

Yes. I think you've seen tremendous innovation coming out of China, but largely in sort of the antibody space and ADCs, now siRNAs. And fortunately, they haven't done as much in gene editing. And I think that still gives us an opportunity to be ahead of a lot of the Chinese companies in gene editing. What that means for us in a lot of IP is that we're going to keep it know-how. We're not going to file all the IP right away because we want to take it longer.

And also, I think from a BD standpoint, we are looking at assets in China continuously. And we did 1 deal with Sirius Therapeutics. We may do more -- but I think we definitely have a very close look at what's happening out there. It is a threat for the entire American biotech ecosystem, but it could also be an opportunity.

And then one last question, AI implementation. How is AI being leveraged within CRISPR Therapeutics, your thoughts on it, any takeaways?

Yes. I was sort of an AI skeptic not too long ago, but now complete convert because we're seeing productivity gains everywhere with AI. Take, for instance, our FDA filings, our medical writing, all those operational elements, AI is helping us move that much faster. So that's just allowing us to -- with the platform designations we're getting from the FDA plus AI improvements, we're able to move very quickly in terms of execution of assets into the clinic. And we leverage the Australia, New Zealand phenomenon and do trials out there and also China.

The second part of it is product design. I think this was -- I expected -- I don't think this is going to be as helpful. But as we do various things around editing or even looking at different mutation phenomenon that may play out, there was a paper that just came out last week that took 6,000 mutations that have been observed in humans and said, what is the likely outcome of those mutations are knocking gene X, Y or Z.

You can do these massive simulations around mutations. We can do massive simulations around product design that we're not able to do before to come up with better answers, whether it's codon optimization or whether it's picking the right locus to edit. So all in all, I think we're probably just at the beginning of AI making a difference to what we do, but we're heavy adopters in AI, and I think it's particularly useful with CRISPR-based gene editing.

Great. Well, thank you very much, Sam. Really appreciate you attending.

Thank you for having us.

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.

All right. Thanks very much for joining us here this afternoon. Last cab off the rank, but certainly one of the better ones, I think. Welcome back to the William Blair 46th Annual Growth Stock.

My name is Myles Minter. I'm a senior biotech analyst here at the firm. I cover the neurosciences and genetic medicines. I also do cover CRISPR Therapeutics, which will be the topic of today's discussion alongside Sami Corwin, who can't be here today.

Before we do get started with this chat, I do have to point you to important disclosures that are available at williamblair.com for people in the room and also people listening online. And with that, it's my pleasure to introduce Raju Prasad, the Chief Financial Officer of CRISPR, joining us here from Boston.

Maybe we can start with just a sort of brief overview of the company. Obviously, you're a leader in the genetic medicine space here, first CRISPR-approved therapy with CASGEVY, which is well and truly on its way into launch. Maybe talk a little bit about the product profile there and then also what you're working on in your pipeline, that would be a good place to start.

Yes. Sounds great, Myles. Thanks for having us again this year, and it's always great to be back in Chicago at the Blair Conference. CRISPR Therapeutics now is over a decade old as a company, and it's been almost 15 years since the first discovery of CRISPR as a technology and the seminal paper came out in 2012. And so we're really hitting this sort of adolescence as a field of gene editing.

And we do believe that we're one of the leaders having the only approved product to date in CASGEVY, which is partnered with Vertex Pharmaceuticals. And right now, as a company, we're sort of going through the growing process of determining what is going to be our next second, third and fourth programs that will end up pushing towards commercialization.

And what we've done is we've taken several therapeutic area strategic bets. And so we've got clinical programs in cardiovascular disease, in autoimmune and oncology as well as in siRNA franchise, which we did to not only diversify our product portfolio, but also to provide us with an additional clinical catalyst that is going to come in the second half of this year.

So going into the back half of '26, we actually have a very active catalyst calendar, which will help chart the trajectory of the next phase of this company, but we'll have 5 clinical readouts. And on top of that, we're also putting 2 additional programs in the clinic, which we're hoping to have data in the next, say, 12 to 18 months. And so this is really an active period of clinical development for the company. And this is all layered on the foundation of CASGEVY, which, as you mentioned, is really starting to produce meaningful revenues, and we anticipate growing over the next several quarters.

Yes. I appreciate that. Maybe we can start with CASGEVY. I think it's roughly 500 patients that have been initiated down that treatment path. But there's potential where the geographies are currently approved for 60,000, I think, was the number that yourself and Vertex have put out. So talk to us about how 500 goes towards that 60,000 number and the evolution of that product profile, that would be helpful.

Yes. I think one aspect of the launch where we think we've done a very good job, we think, of building the foundation in 2024, but maybe the investor community hasn't appreciated it fully of the infrastructure that needed to be built before the more sort of normal metrics of revenue recognition reporting comes out is the fact that with a therapy like CASGEVY, which has the transformative impact and the clinical benefit risk profile is fantastic for patients is that there was a foundational year where we had to onboard what we call ATCs and bring sites up and then patients start a journey where they -- as you mentioned, they're initiated, they get their cells collected, they are then manufactured and then we receive revenue -- or Vertex received revenue recognition on infusion.

And so as we built the foundation of these ATCs, and we're now well over 75 ATCs, we've now brought in 500 patients, as you mentioned, into the top of the funnel of the patient journey, and we've infused about 100 or a little over 100 patients where we've recognized revenue over the past several quarters. We're now entering this phase where we can start growing the funnel and do so in a global manner, which we are the only therapy that is globally approved and commercializing outside the U.S.

And I think what you're now going to start seeing is some of these numbers grow. And the good thing that we're seeing in the funnel is that we're seeing a very low dropout rate. So once patients contribute to -- or sorry, they join the journey, they're really going to see it through to the finish.

And I think as we've seen in sickle cell development and in the sickle cell population, this is a very devastating disease. CASGEVY now as of the latest update has patients free of their crises for 5-plus years. And as we've seen from some of the development candidates and even one fairly recently, it's very difficult to get a product approved and keep a product on the market that has a significant disease-modifying potential that CASGEVY has.

So we're -- we think we are just at the beginning of what we continue to believe is a multibillion-dollar opportunity, and we're very happy that we have a worldwide leader in Vertex leading the commercial launch.

Yes. Makes sense. I believe Vertex has said that CASGEVY at least for this year is going to be a meaningful contributor to their $500 million ex-CF revenue. You're in a 60-40 profit-share split there. What's the cadence of getting CASGEVY to meaningful profitability for CRISPR as a company?

Yes. And we get this question a lot. I think our stance is it's not a question of if but when. Again, we see significant demand. Patients are doing very well. The ones we've -- that are self-identified from the trial are running marathons now, they're climbing Mount Everest. And so we're very happy with the clinical profile of the asset.

I think from our perspective, we see there's various layers to our collaboration with Vertex. We've got the CASGEVY partnership, but then there's also targeted conditioning, which is going to help hopefully expand the TAM of CASGEVY. And then we also have an in vivo HSC collaboration where we're 50-50 partners and not 40-60. And we put some data earlier this year from an NHP study where we're seeing a good editing, over 50% editing that is durable.

And we think that as we continue with sort of with the patient in mind and sort of expanding the TAM and the potential opportunity to treat as many sickle cell patients as possible, we'll continue investing in those with CASGEVY. So from a CRISPR perspective, the collaboration expense item includes all of those contemplated activities. So if we are later showing that flip to profitable is because we're investing significantly in some of these other efforts. And I think that's obviously a good thing for us and sickle cell patients.

Yes. Makes sense. So definitely sounds like more patients are going into that cell collection phase. They're highly committed to see it through to infusion of the product, which is a curative therapy here. How do we think about layering on more patients or more geographies? I know we've had the BLA submission from Vertex in the pediatric population that's under the Commissioner's Priority Review Voucher Program there. How do we think about expanding geographies, layering more patients to build that number on top of that sort of organic growth curve of just patients where it's already approved coming in for that collection and then infusion?

Yes. I think we're excited that the 5- to 11-year-old BLA application was submitted or sBLA application and that we're also very excited that the FDA bestowed the Commissioner's National Priority Review Voucher on that and discussions are ongoing between Vertex and the agency. I think when you think about that population and you think about the degenerative nature of sickle cell disease, you want to treat patients earlier.

And I think hopefully, if it is approved, we'll see patients getting the benefit earlier in their lives and living a healthier life from earlier. I think as far as -- we've got approval in the Middle East. We think that there's 23,000 patients or more in that territory with CASGEVY under the current profile and roughly 35,000 patients in the U.S. and EU5. We think that the demand is there for this therapy.

And 60,000 patients, it is priced at $2.2 million. It's a very meaningful TAM with the product profile the way it is right now. And as I mentioned earlier, the ways to expand this TAM are the target conditioning as well as the in vivo HSC profile. And again, those are very important priorities for the company at this point.

Yes. And then just maybe talk a little bit about the competitive landscape. There is another product out there that is approved. Just what you're seeing from those dynamics. And then you've obviously made mention of some earlier data that 5 years out, durability, it's not an easy thing to accomplish. So maybe how you're seeing [indiscernible]

Yes. I mean I think it's best to sort of subquote Reshma, the CEO of Vertex, saying that it's very -- knowing what they know now as a very large organization and some of the complexities of getting up to scale and getting the foundation built for CASGEVY, it's very difficult for a small company. And I think we could even say this from our vantage point of being a smaller company and seeing Vertex execute -- to be able to execute on a launch like this. And so again, we're very happy we made the decision to partner with Vertex. We think they've done a fantastic job. But we do think that, that does give us a competitive advantage versus some of the smaller players that are coming to market or perhaps come to market.

Yes. Makes sense. I'd be amiss to say when the CLIMB-151 study data came out, we talked about the pediatrics, there was, unfortunately, a death in that trial, likely due to the busulfan preconditioning. You mentioned it earlier, but maybe you can give us a little bit of an update as to how you're working on next-generation sort of preconditioning regimens for products like CASGEVY and how important that could be for potential uptake?

Yes. I mean I think there's inherent risk with busulfan conditioning, and it's unfortunate, obviously, that occurred with the patient. But yes, I think it just highlights the importance of finding a regimen that you can take the busulfan out or have a targeted approach or even the in vivo HSC approach where potentially there's no conditioning. And I think there's an in vivo CAR-T space that has seen a lot of positive news flow recently where I think there are learnings that you can take over -- take from in vivo CAR-T development to in vivo HSC development.

And we're trying to utilize some of those approaches as we do have an in vivo CAR-T program, and we put some data out on. I think from a target conditioning perspective, the way that it structurally works with Vertex is we have our own efforts. They have their own efforts. They've done several deals around this -- the target conditioning landscape with other players. And we sort of come together and sort of bring the best of both worlds and sort of decide a program to take forward. I think when that update does occur, Vertex will be able to provide that. But we're excited about the opportunity to do that for, obviously, some of the risks you mentioned that are inherent with busulfan conditioning.

Yes. Makes sense. We're jumping around a little bit, but you did mention in vivo CAR-T, and that's all in the headlines, particularly from an M&A perspective as well, a couple of very large early-stage deals but important ones. Most of those, I think, have been focused in the oncology applications. Maybe you can talk to us a little bit about how you're looking at an in vivo CAR-T program and the data you put out there.

Yes. I think when you think about our company and our scale and our know-how, because we have a liver-targeted pipeline that uses lipid nanoparticles and we're able to manufacture those in-house, we sort of had the components internally to really progress an in vivo CAR-T effort. And I think we're looking at it both from a transient mRNA perspective as well as looking at nonviral permanent CAR approaches as well, given we have gene editing technologies that can do that in a site-specific manner.

And so on the transient side, this is -- we're able to deliver mRNA focused with targeted lipid nanoparticles. We put out some data with our first quarter earnings release where we're seeing depletion of B cells, a repopulation with a naive phenotype at pretty low doses, I think similar to, I think, some of the competitors that have been acquired. And then one aspect that we think is differentiating is that we're getting mRNA expression for 14 days.

And we think when we're thinking about a best-in-class approach, we think that there's optimization that can be done on the binder, on the lipid nanoparticle formulation, on the payload, but also the CMC and the manufacturing. And I think the company that can figure out those 4 aspects is going to win in the long term. And we do think that, that there is still room for differentiation. And so we're advancing that pretty -- based on our preclinical work, we're advancing that expeditiously given the competitive landscape.

Makes sense. Makes sense. Moving maybe to the in vivo liver-directed pipeline. I cover numerous companies in the space. And I think the one question that it's very top level, but it always comes up is you're going after a permanent editing solution here and maybe in indications where there are available chronically dosed therapies, so like in cardiometabolic, like a PCSK9 inhibitor, we get a ton of questions from investors, like how do you choose the right indications for a technology like this?

And are patients willing to put up with the theoretical risks that are associated with that if there are other chronically dosed therapies available like siRNA, monoclonal antibodies, that sort of thing. So how does CRISPR think about indication selection for your liver-directed programs?

Yes. So I think we're taking a -- with our clinical programs, both 611, 310 and zugo-cel. I think with 310 and zugo-cel, we're taking modality risk. I think that the target is pretty well defined. We think that there's a high PTRS that it's going to work. If we knock down the target, it should have a therapeutic benefit. With 611, we think we're taking a target risk and the modality has been proven out, right, or is more well accepted by investors.

So for 310, we do believe that there are indications like severe hypertriglyceridemia where if we're able to get in the range, so say, 50% to 70% triglyceride knockdown, right, in the range of the ASOs and siRNAs, we do believe that in SHTG, where acute pancreatitis is a pretty severe endpoint that there will be patients that are amenable to a onetime treatment. And we have the benefit in this modality of basically seeing the pivotal trials for Ionis as well as the pivotal trials for Arrowhead and sort of understanding the powering behind those trials and sort of -- and hopefully, that will guide our development as well as our Phase I data that's going to be out in the second half.

So we're really in the mode right now of putting our clinical data out. It will be a meaningful data set in patients with SHTG as well as some other of the indications, but then looking to see how we take that learning as well as the landscape to power our trials to put us in the best position to advance this asset into Phase III.

Yes. Yes. I followed the APOC3 inhibitor story for a while now and pretty game-changing looking data coming out of that class. This obviously slightly different, but related to the triglyceride lowering in SHTG. Questions that are coming up for that opportunity is 3 million patients or so in the U.S., but maybe not every single one of them is at really, really high risk for AP. How do you look at that population when you're talking about 310 and where you're actually going to run these studies?

Yes. I think we are focused on patients with AP just given that, again, it's a severe endpoint that if we're able to produce a onetime and you never have to have an event again, similar to sickle cell in some ways, that, that would be a tremendous benefit for patients. I think where we see differentiation from the APOC3 inhibitors is that ANGPTL3 programs don't increase hepatic fat fraction and then also they do not increase LDL. We actually decrease LDL pretty meaningfully.

So we think that there is an area of differentiation. And then I think we do believe that, again, we are -- there's -- inherently with any new modality, there's going to be commercial risk. Right now, it does seem the way that our valuation is geared. We are taking the commercial risk right now, but we do believe that. And based on the profiles that we're seeing for patients in the clinical trials, we had the -- I actually had the pleasure of being at a site and talking to a patient.

And there are patients out there that fall in a couple of categories, but I'll just highlight a couple for case studies. So there's a 35-year-old patient where this is in a major media article where his dad had significant triglycerides and he did too. And so his dad is older, and he knows that he's staring down the barrel of looking at 40 years of chronic therapies. And so he said, why not, right? Why not take this onetime therapy and sort of hopefully have a lifelong benefit.

And then there's patients that are older that have had a couple of heart attacks. They've had events and they're worried about, oh my God, if I miss an infusion or if I miss a pill, like am I going to have a heart attack like the next week because I don't have the same triglyceride-lowering or LDL lowering. And so you can imagine in a -- in something like cardiovascular disease where there's millions of patients that are afflicted by these, these patient profiles, I'm calling them out one, but it's a pretty meaningful market opportunity.

And so if you're thinking about a onetime therapy, and we're not talking about a -- this is not CASGEVY where it's going to be a multimillion dollar price. Our cost of goods is relatively low in that $10,000 to $20,000 range per patient. And so you're talking about not a significant price to treat these patients.

I see we've got 7.5 minutes. So we're going to switch from gene editing, and I found this a really interesting move from your company, your collaboration and licensing with Sirius and stepping into the siRNA frame. So a couple of questions on that program. Why Factor XI with the target for siRNA and why not do a CRISPR approach for that? That's the first one. And then questions that I get is, is this like a diversification away from CRISPR's roots here? And should we expect more of those sort of deals and becoming more of a modality-agnostic company? Or is this more -- this is a unique target. This was a unique application for this siRNA. We thought it was a good opportunity and then our roots are still with the CRISPR/Cas9 technology.

Yes. I think from a from a research perspective, we'll continue to be a CRISPR company, right? We've built the flywheel. We can go from idea to DC to IND in about a year, right? So that will continue to be the flywheel. And we've got CTX460, which we can talk about for alpha-1 antitrypsin disorder as well as CTX-340 for refractory hypertension. So those are homegrown candidates. What happens-- so with the Sirius deal, again, we are -- now we're a $5 billion-plus market cap company.

And we're trying to get ourselves to $15 billion, $20 billion, become one of the leaders in biotech now instead of just the gene editing leader. And so we are making this transition from a -- just being a technology-focused company to a therapeutic area company modality agnostic. And when we were doing our CV work, cardiovascular work, we came upon Factor XI as a target. But this is a target that we felt that you don't want to knock it out permanently. You want to knock it down.

And so we did diligence in the space. Sirius Therapeutics has -- their CSO came from Arrowhead. Their -- one of their Board members is the CEO of Dicerna. And so we had some connections there, and we felt that a 50-50 partnership in this space was a good way to attack it, just given how big the markets could be, and there's a few competitor readouts from some pharmas that could determine whether this is a $3 billion market or a $10 billion market.

And so yes, we're -- this is the lead asset for siRNA. It's a first-in-class. We think it has a best-in-class profile as well with well over 90% Factor XI knockdown. And so yes, we're guided to a second half Phase II readout in total knee arthroplasty, which should tell us the anticoagulation effects of our siRNA asset as well as the bleeding risk compared to enoxaparin. And in this time frame, these other trials from Bristol and J&J for Milvexian will read out. Novartis will read out the abelacimab program with which they acquired Anthos for.

And so we'll have a very good sense going into next year of where we're going to take this Phase III trial or if we're going to run multiple Phase III trials. Obviously, we were happy to see asundexian from Bayer have a very positive result in secondary stroke prevention. So we do know that this is going to be a large market opportunity. It's really just understanding how many billions the market opportunity will be.

Just given your interest in the target, I have to ask the question that the data has not all been positive with Factor XI, a lot of debate in the space whether a certain company may have underdosed their oral inhibitor in one of those AFib trials in particular. What's your viewpoint just kind of putting it out there, like I think it works in stroke, doesn't work in AFib, like do you think that it was just a trial design malfunction? Like how broad do you think this opportunity could really be?

Yes. I mean I think -- again, we sit at a privileged vantage point where we'll see both the Bristol J&J trial that is against DOAC as well as the abelacimab trial, which is against placebo and DOAC-ineligible patients. And so the way we view the market, again, the milvexian trial is the whole pie, right? It's all patients with atrial fibrillation. And then the abelacimab trial is about 30% of patients that are ineligible for DOACs because of bleeding risk.

So again, for a company of our size, 30% of this market is probably still a $5 billion to $8 billion opportunity. The whole market is Eliquis-like numbers. And so either way, I think for us, it's a significant value-creating event.

I do want to touch quickly on zugo-cel predominantly in autoimmune indications, just given the widespread interest with CD19 CAR-T for autoimmune diseases. I was just at the American Academy of Neurology. There were 2 companies there presenting some pretty interesting data in myasthenia gravis. You've kind of mentioned some indications that you go after, and you've got a basket trial ongoing. Maybe just give us an update on that program and where you see the company going given the plethora of indications that it could be applicable for.

Yes. I think this is going to be one where there's clearly from seeing in the autologous programs and the academic study out of Germany, this is clearly a transformative moment for B-cell targeting and B-cell depletion and B-cell reset in autoimmune diseases. And I think the level of investment that's come is commensurate with how important of a finding that happened in Germany about 4, 5 years ago.

I think from our perspective, we've shared some early data, but encouraging data. So we shared that 2 patients with lupus are now in remission from disease. One is out a year, the other one is out 9 months. And then we have a basket trial, as you mentioned, but we're doing actually 3 basket trials. So we have a rheumatology basket, which is lupus, scleroderma and myositis.

We've got an ITP and WAIHA trial, heme basket; and then we've got a neuro basket, which we just initiated as well. I think when we think about what we want to prove with our data readout in the second half of this year, one, we want to recapitulate and show, which we've shown early data, but with additional patients that we really are having the same impact on B-cell depletion, on B-cell repertoire on -- with our allogeneic therapy, which, again, our cost of goods is significantly lower, $10,000 versus autologous therapies.

So we want to show that. We also want to -- and we want to show that the expansion profile that we have is enough to produce durable benefits. And I think we're showing that now with some of the data we've shown to date. The last piece that we need to answer is which indications should we take this therapy into where we think we can win. And there's 2 areas where we think are green spaces for us.

I think one is areas of severe disease where the benefit risk profile will reward something that can get really deep B-cell depletion. For example, scleroderma has a pretty significant mortality risk. Myositis is a pretty devastating disease. So we think -- and those are areas where we think the trial sizes could be relatively manageable to get a fast approval as well.

The other area that I think you alluded to is in the CNS, where we think cell therapies can cross the blood-brain barrier. We don't think TCEs can -- will have as good of an effect there. And I think in vivo CAR-Ts may not, at this point, have the expansion to get the B-cell depletion in the CNS. So we're pretty focused on running that CNS basket.

Again, I think in areas where autologous has proven it out, we do think allogeneic does have several meaningful benefits over, obviously, supply chain, obviously, cost of goods. But then there's also the ability to not have to take patients off their concurrent medications because you don't have to harvest their cells, right? So there are areas where we think that we are very competitive with allogeneic -- sorry, autologous therapies if we're able to recapitulate the same efficacy.

And so that's what we're going to have in the back half of this year. We're going to have 20-plus patients in this [ neuro ] basket. And so we're able to be really able to hopefully answer the question, are we producing the same efficacy as autologous and where we're going to go and how -- and what our pivotal trial design is going to look like. So next year's -- second half of this year, we're going to have 5 clinical readouts. We're going to be positioning 310, zugo-cel and 611 for pivotal development in 2027.

And on top of that, we have line of sight to a pretty significant ramp in CASGEVY based on the 400 patients -- 400-plus patients that are in the funnel right now waiting to be treated. And so we're setting up to have a very catalyst-rich 6 to 12 months, and we're very excited about the opportunity for CRISPR to really become a leader in biotech.

Makes a ton of sense, and thanks very much for joining me today, Raju. Really, really appreciate it. We will now transition to the breakout, which will still be in this room.

Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome Sam Kulkarni, the CEO of CRISPR Therapeutics. Thanks so much for joining us today, Sam.

Thank you for having us.

And we're going to do a fireside chat format. So maybe for those who are new to the story, if you can give a 1-minute intro to CRISPR.

Yes. I'll try in 1 minute. But CRISPR has been around for over a decade now as a company, and we've gone through different phases. The first phase of the company was to get CASGEVY on the market, and we successfully did that with our partner, Vertex, and that's being commercialized by Vertex right now, and the trajectory looks really strong for CASGEVY as it gains scale. And that's an ex vivo CRISPR engineered cell product that essentially replaces the faulty hematopoietic stem cells.

Beyond that, the next generation of products, there's 3 assets that have shown encouraging data that hopefully should be Phase III ready by the end of the year or early next year. And these are -- this is namely CTX310. This is for liver editing of ANGPTL3 that reduces your LDL cholesterol and triglycerides by 50% almost with a single injection or single infusion. And we showed some promising data at AHA last year.

The second asset is an ex vivo allogeneic CAR-T named zugo-cel, and we're developing this across a number of autoimmune indications. And again, we'll have data by the end of this year, but I think it's very promising asset that's completely undervalued in general as -- in the sector of autoimmune.

And the third asset is an siRNA, a long-acting siRNA once every 6-month injection of -- it's called CTX611. It's against Factor XI. It's basically think of it as a blood thinner that -- but with no bleeding risk or less bleeding risk. And that is applicable in many, many different situations, and that could be -- that could apply to hundreds of thousands of patients or millions. So a potential blockbuster in the making. And that had encouraging Phase I data. And by the end of this year, we'll have Phase II data in a TK setting. So that's the second layer of the business.

And then the third layer of the business, obviously, is everything else beyond that. We have 2 assets that just went into -- are going into the clinic or have gone into the clinic. One is for refractory hypertension. You have patients who take 4 or 5 medications a day to manage their blood pressure. You could do a single infusion and reduce their blood pressure dramatically and have a major difference in how their lives look.

The second is for a rare disease named alpha-1 antitrypsin. And that one, I think we have a best-in-class product, whether it's gene editing or RNA editing, and I'll talk more about that.

And lastly, I think we have an LP(a) reducing asset, CTX321, where we've gated the further development of it based on a large trial from Novartis named HORIZON, which will read out this year, hopefully. So that's sort of the third layer. And then obviously, a lot more exciting things like in vivo CAR-T and in vivo HSC beyond that. So all in all, I think we have a very rich and broad pipeline. And I think all those layers that I talked about, I think it looks very encouraging as we get through the rest of this year.

Got it. Where do you start right after in vivo CAR-Ts?

In vivo HSC editing. This is the direct hematopoietic editing with a single injection. And we showed monkey data where for -- it was durable. We get almost 50% editing of hematopoietic stem cells. And that would mean that you can treat all the 1 million sickle cell patients around the world versus right now at the price point we have, you're looking at a much smaller subset in the U.S. and Western Europe and Middle East, perhaps that are getting treated.

Right. Yes. Makes sense. And that's a great overview. I want to dive into the different programs that you mentioned there. Maybe starting with 310 for ANG3. You mentioned the data at AHA last year where you showed close to 50% LDL reduction and then triglyceride reduction of 55% after a single shot. What's the current status of the program? And how many sHTG and refractory hypercholesterolemia patients and duration of follow-up can we expect in your second half...

Yes. We haven't said exactly how many, but what we -- in the first -- when we reported the data, we had 15 patients worth of data and only 3 were at the highest dose level where we showed efficacy across the dose levels, but the best efficacy at the highest dose. And so then we went into an expansion phase where we're looking at different types of patients, whether it's severe hypertriglyceridemia, where there's very high triglycerides, but they may be okay on LDL and other parameters.

We have refractory hypercholesterolemia where people -- in fact, we had 2 patients who were already on PCSK9 therapies that had a further 40% drop in LDL cholesterol after ANGPTL3. So refractory hypercholesterolemia, all the patients, whether it's -- they're on PCSK9 or other therapies that are refractory to other therapies. And then there's mixed dyslipidemias. People who have maybe not severe high triglycerides, but reasonably high triglycerides, but also have reasonably high LDL. And so there's different populations.

And last, obviously, is the Homozygous Familial Hypercholesterolemia. So we're trying to get more patients in each of these subsets, so we can actually get a little better handle on what the right dose is for each subset. The -- if you are on Kalshi or Polymarket, you bet that the most obvious Phase III to do would be severe hypertriglyceridemia because there's not many options for very high triglycerides and you want to do a one and done. But I think we're evaluating the data in this Phase Ib, and we're also seeing what the best dose level is, and that will dictate what the Phase III design looks like. But it's not super complex. It's just we need to do more patients.

Got it. And is there anything specific in patient baseline profiles that you're focused on at this point? And any anecdotal observations from the study that you can share?

Yes. I mean it's -- every patient's journey has been very, very interesting to observe. We got to talk to one of the patients who got dosed. The person had 9 heart attacks, okay? And one of the latest heart attacks, luckily he had his dog with him and the dog went and called the neighbors to rescue this guy, and he's tried every other therapy and including PCSK9s. And these are people who really need benefit, and that's something that works durably. They don't want to be -- if they're not compliant even for 1 cycle of siRNA or something like that, they end up with these spikes, which is not good.

And so a one-and-done therapy for these kinds of patients is really interesting. And the fact that ANGPTL3 works on top of PCSK9 certainly is a very synergistic combination in the long run. So I think ANGPTL3 will emerge as the best target. And within severe hypertriglyceridemia, I do think it's a superior target to APOC3. And the reason for that is there's been observations of liver fat increases with APOC3 that you don't see with ANGPTL3. And ANGPTL3, you actually see the converse. You see a reduction of liver fat. Again, it's not high big numbers, but you see a reduction. So I do think ANGPTL3 might end up being a very, very powerful target in medicine.

Got it. And you mentioned the PCSK9s and at AHA, you had some interesting observations in those patients who are on PCSK9. Anything new on that front? Could you potentially enrich for those patients? And could that even be like a regulatory path forward there?

Yes, absolutely. I mean that's why the post refractory, I guess, you can call it hypercholesterolemia uncontrolled on PCSK9, right? They're not really refractory. There's effect of PCSK9, but they're still not -- they're not controlled is an interesting population where you could get a faster approval potentially. So we're looking at all these populations. We have a steering committee composed of the top, top cardiologists in the country, including Dr. Steve Nissen. So I think we're getting the right advice to then be able to do the Phase IIIs.

Got it. And what percentage of hepatocytes are successfully edited at dose level 4? I don't know what you can say on that front. And is the magnitude of lipid reduction consistent with that level of editing? Or is there a functional amplification?

Yes. I think at the high dose levels, what we've shown with our LNP platform is the highest dose level, we're getting nearly 100% editing of the liver. It's hard to confirm that because we can't biopsy someone. But if you do all the modeling, you would expect that ANGPTL3 reduction will be about 80% if you do 100% editing. And that's because some ANGPTL3 is produced in kidneys and other organs. So it's not 0. So I think at the maximum doses, you've reached 80% ANGPTL3 reduction, which kind of confirms our hypothesis that all the liver cells are edited.

Got it. Makes sense. And so maybe talk about next steps for the program? And is there a clear path to an accelerated approval strategy? Or how should we think about different -- what this registrational study could look like?

Yes. I think there's a lot of benchmarks to look at. And I do think with gene editing, you probably don't need as many patients. So for instance, for the siRNA trials or the ASO trials for severe hypertriglyceridemia, you had about 1,000-patient trial. You may not need a 1,000-patient trial for gene editing because the effect is so profound. And you can still rely on acute pancreatitis events, et cetera, as secondary markers for these trials.

I think for populations that you just alluded to, which is potentially refractory hypercholesterolemia or even some mixed dyslipidemias, we could just use LDL as a biomarker for approval and get an accelerated approval. So I think the -- we don't want to talk too much about our strategy right now. But by the end of this year, once we meet with regulators and get the go-ahead, that's when we'll talk about what the impending Phase IIIs are.

Got it. Makes sense. And so let's shift gears to Lp(a). A lot of interest and excitement around what Novartis is going to show in the second half of this year when it comes to MACE benefits. What are your expectations on the outcomes? And how will those data inform your strategy?

Yes. I think the entire industry is watching the HORIZON trial with a lot of anticipation, right? I think this is the first trial. Everyone believes and it's known through epidemiology studies that if you have high Lp(a), it's almost 6x more atherogenic than LDL cholesterol. So if you're born with very high Lp(a), you have a high risk of MACE events, and that's been -- we continue to see that.

What has not been ever shown in a randomized controlled study is whether the reduction of Lp(a) pharmacologically will reduce that risk. And for what subsets and what is it for every person or not, we don't know that. But I think HORIZON trial will show that. Now unfortunately, the asset -- the HORIZON trial is based off an ASO that's not the best reducer of LP(a), right? So you're only getting about 70-ish percent reduction.

So it may not be the perfect asset or the drug to demonstrate this effect. But I do believe we're going to see reasonably -- reasonable reduction of risk, whether that ends up being 15%, 20%, we'll see. We'll find out. And I'm actually particularly more curious about the subset analysis because my personal hypothesis is that high Lp(a), high LDL will certainly have a greater benefit versus high Lp(a) low LDL. And the rationale for that is I think LDL is a bad actor that starts some of the inflammation and some of the nucleates the plaques and then Lp(a) logs on to it.

And so if you have low LDL, you may not get that. But if you have high LDL, you certainly have more of those nucleating events. And so let's see what happens with the HORIZON trial, but that -- we're ready to go with our -- we have CTX320, which had about 73% reduction of LP(a) at the highest dose, but we have CTX321, which is targeted to get 90% reduction at the highest dose. So we'll see which one we advance forward based on HORIZON.

Got it. Makes sense. You've got some optionality there based on the HORIZON data. And for alpha-1 antitrypsin, you mentioned it could be best-in-class. You've shown preclinical data with your SyNTase editor and you're planning to enter the clinic middle of this year. Can you talk about the patient population you aim to enroll and the bar for success relative to the base and prime?

Yes. I think the reason we're very bullish about our A1AT asset is -- so this disease for those who are new to it, which is it's basically you have a misfold -- you have one mutation in your alpha-1 gene that creates a -- what's called a Z allele. It creates a misfolded protein that doesn't do its job and that has a protective function in the lungs essentially that is missing against elastase, and that's what causes the disease.

And so in all our preclinical studies, the patients that have this Z allele have about, let's say, 5 to 6 micromolar of alpha-1 produced, enzyme produced. And the question is how much do you increase it? And if you look at this model that's very predictive, it's called the rat PiZ model. It basically recapitulates the Z allele in a rat, not a mouse in a rat.

And in that model, I think our competitors showed about 2x or 2.5x improvement in the baseline level of AAT production. So if you -- if the baseline were 5, you'd expect that you'd get about 13 or 14 micromolar of AAT production, baseline is 6, it's a little higher than that. So -- and that's what's recapitulating in the clinical trials in humans.

And so our preclinical models show that there was nearly a 5x improvement in baseline over baseline. And so would that recapitulate in humans? We'll see. But we're going to put that in clinical trials soon. And if it is restoring AAT to about 25 micromole -- 20 or 25 micromolar, which is what normal people have, that's effectively a cure. And so that's why we're pretty excited about that editing. And that also is our first foray into SyNTase editing. This is an extremely precise editor that's much more -- it's right now shown to be much more potent than the prime editing that was described in literature.

And we've made a number of improvements to make it that much more efficient. And I think we're going to carry that forward across a number of other programs too that we have not disclosed yet. So a very powerful editing platform that applies to both sort of base editing as well as RT-based editing.

Got it. That makes sense. And from a regulatory standpoint, BEAM has helped derisk the space by getting kind of a clear path for alpha-1. How does that influence your clinical trial design and potential for an accelerated approval path? And when you think about time lines versus BEAM and other competitors, where do you see CRISPR?

Yes. I mean I think BEAM has done a great job derisking the regulatory path, and I think we'll follow the same in their footsteps in a way. And so I mean it's a pretty big population. So I don't think being 2 years behind is going to be a significant deterrent to a commercial launch. There's lots of patients that can benefit from gene editing and the more options there are for patients, the better off you are a society.

Got it. Okay. And from a COGS perspective, how do you think about COGS per dose for this program? And how do you contextualize this versus chronic therapies like RNAi or chronic modality?

I think COGS -- the COGS question is going to go away for gene editing because it's getting lower and lower over time. It may end up being -- if it's only a onetime dose, you're going to end up with a higher gross margin overall, right, because you don't have to manufacture for every dose eventually.

So let's say, an siRNA is priced at $20,000 per year, right? And you price gene editing at $80,000 to $100,000 for once in a lifetime, your COGS are for 1 dose, whereas siRNA COGS are going to be for several doses over time. So one, there's a great pharmacoeconomic benefit for society. If you think about a 20-year-old with high Lp(a), you're going to have this person take 100 doses of siRNA. I don't think it makes sense. You should do a onetime gene edit. And the margins are -- support normal drug-like margins.

Yes. Yes, it makes sense. So let's shift gears to 611. So you've got the long-acting every 6-month dosing for Factor XI siRNA asset, and this is for thromboembolic disorders. And we'll get a first look at Phase II data in patients undergoing total knee arthroplasty in the second half of this year. How much data is going to be in the update? And how are you setting expectations around this readout?

Yes. Yes. For those who are new to this, asset, CTX611. So our bodies have 2 pathways of clot formation. And one is directed towards -- one is called intrinsic, one is called sort of extrinsic. So if you get -- hit your nose on something and you're bleeding or if you have an injury, scrape your knees, there is a tissue factor pathway that ultimately forms the fiber and the clots. But there's an intrinsic pathway that's more dangerous that typically results in thrombus formation.

It goes -- it's a Factor XI pathway that goes from Factor XII, Factor XI then down to Factor Xa. Factor Xa is the node. Factor X is a node where both the pathways meet. And so DOACs, which these were amazing medicines like Xarelto that were created against Factor Xa, multibillion-dollar drugs act at that node. So they both shut down both pathways of clotting.

And that's what leads to increased bleed risk if you take a blood thinner, right? You're a blood thinner for AFib and you hit your nose on something, you're going to end up in the ER. So what we're doing is by going with Factor XI, you don't shut down the extrinsic pathway. You still will get a clot if you have the tissue factor pathway active, but you basically shut down any of the risks from thrombus formation.

And the TKA study or total knee arthroscopy study is the perfect way to test this hypothesis because you get a knee replacement. You can't -- you're immobile, you have very high chances of clot formation or thrombus formation, you could -- there's a chance of pulmonary embolisms and all that. And people don't really take enoxaparin for that.

But you could -- because you can't take a DOAC because you have surgery, you're going to bleed if you take a DOAC. So you end up taking -- but if you take a Factor XI, you have a much lower chance of these embolisms or a thrombus formation or VTE formation, but still prevent that bleeding. And so that's why this has been a good sort of baselining to see how good a therapy is in this space, which milvexian did and abelacimab and Regeneron all did PK studies.

That's not the end market. I mean that's the most promising. It's just the stepping stone towards very attractive markets. And there are 2 big studies reading out from other therapies. One is called Librexia for milvexian that's going to read out hopefully this year. And then there's a study called LILAC from Novartis -- one for a small molecule, one for an antibody.

And those 2 studies are positive, we're looking at a $20 billion category here. And we may end up having the best drug in the category because it's once every 6 months, it's an siRNA. You actually have reversibility because if you have an siRNA, you're on an antibody, you can't just give somebody plasma and hope that they start clotting again because the antibody is going to work on that, too.

But with an siRNA, you can do that. You can just give Factor. and it works. So it's reversibility. And because you're cutting off Factor XI at the root, you never have a chance of Factor XIa formation. And all the drugs, antibodies and small molecules are acting on Factor XIa. But if you just take that route out, you never have that branch issue essentially. So several reasons to believe we have the best-in-class asset in what could be a very attractive category, and we're 2 readouts away from establishing this as a very attractive category. And Bayer's success with asundexian in secondary stroke prevention is a great bellwether for this whole category.

Got it. So in your readout, is there a specific bleeding event rate and VTE prevention benchmark that you want to achieve?

Yes. I think it's -- there's no specific. It's basically just comparing versus enoxaparin to see how much reduction in VTE rate you have. If you look at some of the antibodies, you had like 15% for enoxaparin arm and it was like 7% or something for the drug arm. So it's something in that range. We just want to show the drug is active in this segment. It's sort of a gating thing to then start a Phase III essentially.

Okay. And where are you at with the Phase II? What kind of visibility do you have into the study? And how many patients could be in that?

This is a 400-plus patient trial, global trial. So it's a big trial. Enrollment is going well. That's about what we've said so far. So we're on track to put top line data out end of this year.

By end of this year. Okay. And for the 2 competitor readouts, what are your expectations for those? And what are -- how does that read through to CRISPR?

Yes. I think the 2 readouts, one is Librexia, which is for AFib patients. What happens for these AFib patients is that because of the anomalies with their -- how their hearts beat, the blood flow is such that you increase the chances of clot formation, et cetera, in the compartments of the heart and elsewhere. So they generally go on these blood thinners if you're on AFib. And so the Librexia trial is for all AFib patients, whereas LILAC is for the DOAC ineligible AFib patients. And even that is a big market, right? And so very high chance that LILAC is successful. Librexia, hopefully successful as well. And I think that's category defining essentially.

Right. Makes sense. And if they miss in the studies, I guess, is there still a chance that 611 could do better?

Absolutely because it's a better agent. I think it's much higher inhibition of Factor XI than some of the small molecules. Again, there's different assays to measure it. So it's hard to say apples-to-apples at this point, but we think we have a best-in-class asset.

Got it. So let's shift gears to Zugo-cel, your next-gen CD19 program. We're expecting a comprehensive update second half of this year for both oncology and autoimmune. How are we setting expectations for that update?

Yes. We're proud of what we've done with zugo-cel. Pound for pound, we're getting the same activity in an autologous CAR T with an allogeneic CAR-T. And the cost of goods with the allogeneic CAR T is sub-$10,000 per patient, and it's immediately available. And we're -- on the autoimmune indications, we're only a year behind the autologous players, right, a year, maybe 1.5 years behind, but we're going to catch up very quickly.

My suspicion is by the -- if you look at the end of last year, you had maybe 60 to 70 patients dosed with autologous CAR-T in autoimmune disease and like 5 patients dosed with allogeneic CAR-T. This year, by the end of this year, you're going to see that there's almost 2x more patients dosed with allogeneic CAR-T as opposed to autologous CAR-T. I think there it's going to flip very quickly because it's going to move down much faster. And you're getting deep B-cell resets.

And we had -- we showed data for 2 lupus patients in our update. These patients are several months out completely drug-free. They can't believe it. These patients -- they've all lived their lives. They got -- started getting lupus in their early 30s. And they've always taken like multiple drugs all the time, and they still feel really crappy because these diseases cause all sorts of manifestations.

And now they're living normally. Patients who could walk couldn't walk 10 feet without trouble -- some trouble, now can run several miles. The profound changes in how they live their life. And I think the effects cannot be ignored. I think more data will come out and will support this, but we think zugo-cel will also go into Phase IIIs in the not-too-distant future.

Got it. And that's going to be autoimmune or oncology?

For autoimmune. I think oncology is a tougher put because there are so many indications or so many agents already approved. So autologous is already very freely available for most patients in the U.S. In oncology, I think -- so we're making our bet in oncology with LNP-based integrating CAR-Ts. You saw the recent data from a company called Kelonia, which Lilly acquired, and there was data from Legend yesterday, and these were viral-based primary CAR-Ts.

What we're going to do is an LNP-based integrating CAR-T that's a simple injection and it should create autologous -- essentially the same as autologous CAR-Ts and get rid of your cancers. And that shouldn't be -- that's probably in the not-too-distant future, we can get that to the clinic as well.

Got it. Okay. And for the autoimmune data update, what are you going to be able to show there for that data update?

Yes. We haven't said how many number of patients and things like that, but we'll have a reasonable number of patients across the first trial we're doing, which is lupus scleroderma and myositis that we opened trials in ITP and wAIHA as well, and we now have a trial open for neuroimmune indications.

You look at things like MS, right? And people think, oh, here's a disease that's solved or NMO. And you take these B-cell depleters like Ocrevus or Kesimpta and you deplete your B cells. But if you look at their -- for those patients who allow measurement of their CSF fluid. You look at the oligoclonal bands and the disease is still there. So something is still slowly chewing up their brain cells while they think they're cured. And so it's not a cure. I think with CAR-Ts, I think you're going to go get to the root of this into the brain, into the CSF, into the spine and get it of those pathologic B cells once and for all.

And that, I think, is truly a cure for these patients. And so I think we're expanding zugo-cel across all these indications.

The targeting CD19, is that sufficient? Or do you think you could need a dual targeting just to prevent relapses?

It seems like it's sufficient because, yes, there's some activity of BCMA, but at some point, the BCMA, the mature B cells die. It's really the -- you want to get of the clones at the baseline with CD19, and that seems to do the trick.

Got it. And I wanted to ask on CASGEVY. What's the latest that you're seeing there? It seems like momentum is definitely picking up. There's been about 500 cell collections to date. Talk about how many of those are going to convert to getting treated.

They should all convert. I mean I think patient when they start a journey, and they should all end up getting dosed eventually. I mean there's maybe one isolated cases here or there. But if you look at today, Vertex announced that they had initiated more than 100 patients in the last quarter, right? That's more than a patient a day that's getting initiated. And that's all forward revenue.

If you just did that math, that's $800 million of revenue, right, that's in the future. So I'm convinced CASGEVY is going to be a multibillion-dollar opportunity. And with scale will come profitability and with scale will come efficiencies and everything else, too. And we can -- I think we're the only ones approved outside the U.S. In the U.S., we're going to get major market share as well. So I think that's on a very good trajectory as well.

Okay. So I think we're out of time. Maybe in closing, if you want to highlight key catalysts that investors should be focused on.

Yes. I think I would just say for investors, most investors are focused on CASGEVY, but we have 6 other assets reading out in the next 12 months. I mean data will tell the tale. But in many ways, I think people should also start looking beyond CASGEVY as we expand our portfolio into several exciting assets.

Got it. Thanks so much for joining us today, Sam.

Thank you.

Hello, everyone. My name is Alec Stranahan. I cover CRISPR Therapeutics at Bank of America. Thanks for joining this session with CRISPR. And pleased to introduce Sam Kulkarni, the Chief Executive Officer at CRISPR for this 30-minute fireside. Thanks for being here, Sam.

Thanks for having us.

Yes. Great. Well, maybe just to kick off, you've described 2026 as kind of a stepping stone year, some pretty important early readouts from 6 programs in the second half. I guess how do you sort of prioritize the focus within the company on the earlier stage versus supporting CASGEVY? And where are you sort of directing investors sort of in the remainder of this year?

Yes. It's an exciting time for the company. We've been around as a company for about 11 years. The first phase of the company was all about CASGEVY and bringing that to the market to patients that really needed a drug, that were suffering from sickle cell and thalassemia. And upon the completion of that phase or as we got that to the end of the clinical trials and into commercialization, we started a number of other programs.

And at this point, we're in the second phase of the company where these assets are starting to mature, and we're seeing more data. So we have 6 assets, as you said, that will all have data in the next 12 to 18 months. And those are one bucket of that is in cardiovascular. That's with CTX310 that targets ANGPTL3. This is a program that can reduce your LDL cholesterol and triglycerides by almost 50% with a single injection. We have zugo-cel, which is a cell therapy for autoimmune disease and a single infusion of that can reset the immune system and treat not just 1 or 2, but several autoimmune diseases.

We have CTX611, which is an long-acting siRNA that basically is the promise of a blood thinner, efficacious blood thinner without the risk of bleeds. So that's another powerful concept that could be a $20 billion market. And then beyond that, we have the extension of some of these programs like CTX340, which is a program that treats hypertension by targeting angiotensinogen, which is upstream of the ASR pathway. And that is an important target that can actually reduce their systolic blood pressure by over 10 mmHg.

So that's a powerful concept. And of course, we have Lp(a), which is a highly watched event in the industry. This is the HORIZON trial from Novartis that can inform which way Lp(a) goes. And finally, we have a foray into rare diseases with alpha-1 antitrypsin. And we think we have a best-in-class product for that program. So yes, our plates are full with a number of these assets. And by the way, we have preclinical platforms as well that we're moving forward. How do we think about resource allocation? I think CASGEVY, over time, we expect the spend on CASGEVY to keep going down at some point, it will turn profitable.

And then we have to get to what the Phase IIIs are for these assets that we just talked about and then advancing the preclinical to clinical. So it's hard to put exact numbers on this, but right now, it's 40-40-20. It probably becomes more 30-50-20 over time. But I think we're keeping a careful eye on all this. And we gained tremendous efficiencies by doing a portfolio of products versus one.

I guess when we think about CASGEVY and sort of how that's helping you build a growing base on the top line for supporting the rest of your clinical investments. I guess maybe at a high level, like how is that launch tracking with your expectations? What are sort of the trends you're seeing end of last year and the beginning of this year sort of on the scripts? And any other comments coming out of the 1Q print that you'd highlight?

Yes, it's gaining a lot of momentum. It's very different from typical launches. Typical launches, you can start tracking new Rxs or total Rxs right away, and patients are getting treated right away. Here, we're talking about a 1-year lag between a patient coming into the program per se and saying, I want to get CASGEVY to ultimately getting treated and then for revenue recognition. And the reason for that is you have to collect the cells, manufacture it, get it back.

Now that causes a sort of -- it takes time to build up. So initially, when you build the ATCs up and you have this time period between initiation and infusion, revenues sort of take a while to start ramping up, but you're seeing that ramp now. And if you think about the funnel in terms of 3 different parameters, one is the number of patients initiated and what that means is the patient has gone through a referral, expressed an interest in getting CASGEVY. Oftentimes, they're already preauthorized from an insurance standpoint.

Then those patients then move to the next step of the funnel, which is cell collection and then finally to infusion. And there is a time lag between all of these. But if one starts inflecting, if initiation start inflecting, you're going to see -- a quarter or 2 quarters later, you're going to see an inflection in collections and a quarter or 2 later, you're going to see an inflection in revenues.

And what we said in this recent 1Q print, as you called it, which is in the first year of launch, 2024, we initiated about 100 patients. This is our partner, Vertex, leading commercialization. The second year of launch, '25 was 300 patients, over 300 patients. So it's a 3x increase. And in this 1Q update, we just said that we have over 500 patients initiated.

So you're seeing almost exponential progression in terms of patient initiation and that momentum continuing, which should translate to greater revenues. And the other thing is we're establishing this around the world. We're continuing to get tailwinds. For instance, we've now submitted for a pediatric label. Right now, the approved label in the U.S. is 12 and above in terms of age. We'll get it down to 5 and above, because you want to treat kids early before there's any damage to their vascular system, any damage to their organs; that's a tailwind, that's going to help.

The second thing is the reimbursement. We just announced reimbursement agreement in Germany. And that, of course, was one of the hardest ones where a competitor of ours have tried to go in there and then withdrew their product because they couldn't get reimbursement. But with CASGEVY, we have a reimbursement agreement. So those tailwinds will start to add up and continue the momentum well beyond what we're seeing right now.

Great. And I guess when we think about the conversion of patients in the funnel to revenues, I guess, what kind of visibility do you have? And what's sort of the timing around that exponential growth, as you said, in the new patients going on or getting the cells extracted, right, for the manufacturing, how does that acceleration kind of then accelerate the top line growth?

Yes. I mean I think that's why I said it's probably -- there's some lag, whether it's 2 quarters or 3 quarters from initiation to revenue. It's hard to say at this point, but it's a certainty that it all falls through because you're not seeing patients drop out of the journey. So it's just a matter of time. And over time, that time lag won't matter because you're going to have a constant shape of the funnel, if you will, is the equilibrium around that timeline from initiation to launch or to getting infused and recognition of revenue.

So overall, I would say we have forward visibility. Our partner, Vertex was very bullish on the expectation. I guess they didn't guide to the exact number, but generally positive guidance around how they expect CASGEVY to do. And I think from what I hear from physicians and patients, the word is getting out there. This is without sort of the classic DTC marketing and all that stuff. All the patients know about it and more and more patients are interested in getting therapy, which is great for the entire population.

Yes. No, that's great. And I know you're also developing, I guess, conditioning agents and pursuing in vivo HSC editing to sort of broaden the access further. I guess, how material a difference could gentler conditioning make in real-world uptake? Has this been sort of a barrier from your experience? And I guess, when could that data be available?

Yes. I mean we haven't guided to when gentler conditioning might come into play, but it will be a major tailwind for the product. And the reason for that is it expands the population. You go from just the most sickest of sickle cell patients to saying, even the ones with moderate disease should actually get CASGEVY.

And what you're looking at then is just potentially a 3-day hospitalization. So it's -- that's why it's called gentler conditioning and it's very targeted depletion of the cells of the HSCs to make a room in the mirror. So we feel very good that that's going to be the next leg in the life cycle of the product. And that's going to expand the addressable market almost 3x if we can show that this -- using gentler conditioning can lead to the same results that we saw with the full busulfan conditioning. And I would expect that the value of the product would significantly go up whenever we fully disclose the timeline of gentler conditioning that's coming into play.

And I guess as we think about the commercial landscape, there are, I guess, alternatives for patients with beta thal and sickle cell disease. In practice, when physicians are choosing between CASGEVY and, say, like a lentiviral approach, what are sort of the key decision factors there? And is CRISPR winning those conversations?

I think, right now, ex U.S., CASGEVY is the only option, right? You don't have any other products available for patients. So that conversation is different. Obviously, it's just do you want to do a curative therapy and when do you want to do it. In the U.S., in some of the sites, both CASGEVY and Lyfgenia are available. And you're seeing some share split at the moment.

But generally, what we're finding is that the physicians now that they understand that CASGEVY has a lot of manufacturing support. There's strong company behind it with Vertex and us, and it's a reliable sort of partner to deliver the drug product to patients, I suspect that you're going to see more and more patients shift towards CASGEVY.

And one simple reason because when you have a viral versus a nonviral product, I mean, you're safer picking a nonviral product because you just don't know the unknown, unknown of having a retrovirus-based product. Now not every patient will care about that nor every physician, but I think you're going to see a share shift towards CASGEVY that will be palpable.

I guess circling back on the pediatric review, you've got a commissioner's review, I believe, for that. So that could be available soon, right, if I [indiscernible] word on sort of the expedited review there. How do you think of that as a TAM expander getting patients? Like is there a higher demand in younger patients for sort of a onetime treatment like this from your experience?

Well, it's just another bolus of patients, right? And I hope with the agency, we get that approval soon to go into these younger patients. The other thing is you're going to get a number of other centers into play in a big way. A lot of children's hospitals are actually very good at doing these types of procedures, and they can start bringing their patients into the mix and become some of the higher prescribed centers. And so the pediatric expansion definitely will be a tailwind, not just from expanding the number of patients available on the bolus, but from a center activation standpoint as well or the center velocity of treating patients. So we expect that to be a major positive.

Okay. Any other tailwinds or headwinds that you think could impact CASGEVY this year? I know we saw $43 million in 1Q, but is sort of the way that the Street is thinking about the escalation in sales, is that realistic?

Yes. We don't see any headwinds. At this point, really, it's -- our partner, Vertex is doing a wonderful job executing against the program and A lot of it is operations with supply chain, with all the patient handling and everything else. So they're doing a great job. And I think I only see positive momentum with the program. So it's talking to say where the 3 expectations are. There's different analysts who cover CRISPR versus Vertex, et cetera. But generally, we feel comfortable about the trajectory of the product.

Okay. Great. Well, I do want to maybe shift gears here and talk about the pipeline, which I'd say is equally or even more exciting for sort of the future growth for the company. But maybe just starting with CTX310. This is your LDL-lowering ANGPTL3 asset. I guess you showed a single dose reduction LDL, triglycerides safe early profile. What sort of response thresholds in homozygous FH and severe hypertriglyceridemia would be maybe sufficient to design a registrational trial? Like what do you think is sort of the bar for investing further in this program?

Yes. For those who are not familiar with the program, we showed some landmark data in a late breaker at American Heart Association last year. And these data were for 15 patients that received CTX310. And one, the LNP-based delivery was very safe. We barely saw any elevation of liver enzymes. And even if there's some elevation, it self-resolves within a very quick period of time. So it's very safe.

So you have this prospect of going out there, get sitting in a chair for a 3-hour infusion and your liver cells are edited and you're going to have 50% lower LDL or triglycerides for the rest of your life. And that's a pretty powerful concept in how medicine may evolve for cardiovascular -- to treat cardiovascular risk or prevent cardiovascular events based on some of the risks that are seen earlier.

So where does this take us on the program? Obviously, something like that is momentous, but people are still trying to get their handle around how is gene editing perceived by the physicians, et cetera. And this is where I see a big disconnect. If you look at our inbox on the info at CRISPR, we get so many requests from patients around the world wanting to do gene editing for their triglycerides for LDL cholesterol. Physicians are universally excited about what the prospects are here. And by the way, this is not going to be expensive million dollar therapy. It's going to be much -- actually going to save the system money at the end of the day by doing it one and done.

So I see something -- CTX310 having unlimited uncapped value, but it may take some time for the value to be recognized. And I think a lot of that will be based on going to the FDA or the international agencies to say what is the path forward for a Phase III.

And to your question, for HoFH, which is Homozygous Familial Hypercholesterolemia, I mean, the bar is very low. All you have to show is that there's further reduction of LDL cholesterol post agents like PCSK9. And we already showed that for 2 patients in the initial data set. For severe hypertriglyceridemia, which is a large population, by the way, much larger than people think, again, the bar is not very high because you're already seeing a lot of triglyceride reduction. We just need to do it in a few more patients and put the data together and go to the FDA and say, this type of registration trial makes sense here or not.

And I suspect you're going to see a favorable opinion from the FDA in terms of how big a trial needs to be and how fast we can go. So I think that will be the unlock on CTX310 and similarly for CTX340 is to get regulatory guidance around what a path to registration might be. And that will come soon enough.

Yes. And I guess on CTX340, different target here. But I guess when this enters the clinic in the first half, what is sort of a twice yearly -- or what does the CRISPR edit offer like a twice yearly siRNA in this indication? And is there kind of a minimum efficacy or blood pressure reduction that you'd want to see?

Well, the benefit of a gene edit for blood pressure is, let's say, people have varying degrees of high blood pressure. You can just basically reduce everyone's blood pressure by 10 to 15 mmHg and still modulate with a different medicine, right?

The problem with siRNAs, you have one that's every 3 months, you may have one that are once every 6 months or whatever, right? But towards the end of the dosing period, you're going to get a creep up in their blood pressure. And that's kind of dangerous for these patients because all it takes is one hypertensive event and something fatal could happen or something bad could happen to the patient.

So what you want is the consistency of blood pressure so you can manage these patients. And that's what -- that's the promise of CRISPR gene editing. Even with the best siRNA out there for Lp(a), you saw that after 2, 6-month cycles, only 80% of the patients were -- remained in control for the entire period of time. So towards the end of the dosing period, you're seeing people be out of control from what's recommended.

So I think at some point, this question is going to flip and say, why not do gene editing because it's safe. Why would you take -- if you have LPa, for instance, and you realize that when you're 15 years old, why would you take twice a year siRNA for the rest of your life when you could gene edit, it does not make sense. You could have compounded toxicity for putting a lot of RNA material into your liver over a long period of time. Like you don't know what the effects of those are.

So I do think that this question will flip and primarily led by the physicians because they all see this as a better way to treat patients.

Yes. That was actually something I was thinking of, too, is like which patients actually derive the biggest benefit. These are large disease areas. Is a patient with 30, 40 years of life ahead of them, is that kind of the ideal patient group versus, say, a 60-year-old with hypertension or high LDL? Like is there a way to sort of like break down the market opportunity here? Would you even want to do that at this point?

Yes. I think we're doing a lot of work on that. I think it's going to -- one of the access is going to be attitudinal as well, whether it's a 30-year-old, a 50-year-old or 70-year-old, there is an element of patient saying, "I'll take the risk and do gene editing, right?" And that's what happened in our sickle cell patients and trials. It wasn't that all the patients that came in were the sickest of patients. Some people who said, "I'll take a chance because I can't live with my disease anymore." And you're going to see that, I think, over here is more of the axis.

The other axis is you're going to get -- for genetic conditions like Lp(a), you know pretty early in your life that you have high Lp(a). And if you have high Lp(a), some people have Lp(a) levels above 300 milligram per deciliter. You probably want to take it sooner rather than later. So you want to do it as young as possible.

With hypertension, you're likely to get it more at later phase of your life. So you're going to be older. But some people have very high blood pressure that's uncontrolled and they won't have a choice but to do it, right? And then you have LDL, which is a different follow where you have to segment the population in many different ways. Do they have high LDL and high triglycerides? Do they only have high LDL? Have they tried PCSK9, what it's going to be.

But the thing is whichever way you slice and dice, it's a huge market. And so we're playing in major markets in a way, a global scale where we could benefit all sorts of people at different levels of risk.

It's not like you'd have to break that down preemptively to run like a pivotal study that you could wrap your arms around, right?

Yes, we don't have to. I mean I think like if you can do a severe hypertriglyceridemia trial based on pancreatitis events, that is a registrational path that can get us there and get us a label. And beyond that, I think you can -- the label and the marketing will all -- we can obviously influence it. But I don't think we need to priority determine exactly what the market sizes are and the market potential.

Yes. Makes sense. Maybe shifting gears to autoimmune and oncology. I think zugo-cel, great name, by the way. That's a new name.

No coincidence because we're based in Zug, Switzerland, but it just happened.

I see the connection. Yes. I guess, are the CR rates in DLBCL sort of tracking with what you would have hoped? And you're expanding into multiple autoimmune indications. I guess, how do you prioritize these different arms of development? And is there maybe a minimum data set you need before you have registrational conversations with the FDA?

Absolutely. I think zugo-cel is the best-in-class allogeneic CAR-T for CD19 because of the edits we've made to it. And it's autologous like efficacy, but with the convenience of allogeneic and the cost of goods like allogeneic.

So in oncology, we showed nearly 70% CR rate with zugo-cel with at least 2 of the patients at the time of data cut were past 12 months. It's durable. Now what we've done also is start dosing patients with a BTK combination pirtobrutinib. And it's seen from some of the investigator-initiated trials that somehow the BTKs actually potentiate the CAR-Ts even more. So we end up with -- in that study, it was almost 80% CR rate. So if we can push that up even more, we can be better than autologous therapies.

But I think our strategy in oncology is to potentially get an approval of a single-arm trial in late stage and then pick off patient populations in frontline that perhaps cannot -- are not eligible for auto, that are failures on bispecifics, et cetera, because we did show a really good response rate on bispecific failure patients as well.

In autoimmune, our goal is to lead the pack and become the predominant or preeminent player in autoimmune disease. And that's our #1 focus. Our Chief Medical Officer, Naimish Patel, came from Sanofi, where he was leading the autoimmune franchise there, and we're translating a lot of the learnings into how fast we can move in autoimmune indications with zugo-cel. This could be an Argenx-like platform.

Any disease that's B-cell mediated, you could have a onetime reset that gets rid of the disease. And so we're -- we started with this trial called AID-500, which we were dosing patients with lupus, myositis and scleroderma. Now we've expanded into 2 other diseases, ITP and wAIHA where we're dosing patients. And now we just opened an IND for neuroimmune because we've seen [indiscernible] hyper on in vivo CAR-T, we haven't seen those CAR-Ts go into the CNS system, whereas zugo-cel, we have evidence that it goes into the CNS system, actually can eliminate B cells in the spine or in the brain.

So that has tremendous implications for indications like multiple sclerosis, NMO, et cetera. So we've started that trial for neuroimmune indications as well. So it's literally all systems go for us on zugo-cel. And we announced that we dosed 14 patients for our 1Q update, and we'll provide further updates as we go along.

That's great. Obviously, autoimmune CAR-T space is heating up and it's quite competitive. Do you see -- is that kind of a fire lit under you guys to really accelerate things and push forward? Or how do you sort of maintain your lead given the wealth of development going on?

Well, I think we're in a good position because the auto CAR-T can only go so fast, right? There's a natural governor on how fast you can go. And so we've seen that whether it's a big company like Novartis or BMS or a small company like Cover or Cabaletta, even though they had a 3-year lead, they can only go so fast number of patients.

I suspect that by the end of this year, we'll have dosed more patients than some of the autologous companies because we can go that much faster and so we'll catch up to the autologous players. Now you have a second set of threat in terms of the TCEs, and they can move equally fast. You've seen some of that.

But we don't think it's going to be a onetime reset in an elegant, beautiful way that we can do with CAR-Ts. So we have a competitive edge over TCE that may require multiple dosing and you still come with the risk of CRS, et cetera.

And then finally, the in vivo space, in vivo CAR-T, we're working on that as well. We have our own in vivo transient redoseable CAR-Ts that show complete B-cell depletion in monkeys with 1 or 2 doses. But I think it still has -- there's more work to do to get that to patients and see what the effects are on patients. So at this point, I do like -- I think we're in pole position. And as long as we execute, we can actually lap everyone else, but we'll have to show that over the next months to a year in terms of execution.

Okay. That makes sense. I want to ask about your siRNA collaboration with Sirius. I know we talked about the benefits of a onetime gene editing approach over siRNA and like LDL and those indications. This is a different application. Is this more just the right tool for the job? Or anything to read into sort of you're leaning into siRNA through the partnership?

Well, I think the way this came about is we were building a cardiovascular franchise with ANGPTL3 and LPA, and we were talking to all our members about what else is exciting in cardiovascular medicine. And Factor XI kept coming up. The promise is you have very effective blood thinners out there in the market. These are Factor Xa-based drugs, but they come with high bleed risk, right?

If you're on blood thinners, like especially if you're old and you're taking it for stroke risk or whatever, you have an injury, you could bleed to death. So is there -- what's the holy grail is to have the same level of blood thinning without the bleed risk. Now you don't want that for life. So you don't want to gene edit your Factor XIa because that would be something that's unnecessary, let's say, you're doing this for an acute phase after surgery or something like that.

But we do believe that all of medicines moving towards long-acting. I don't think in 10 years, you're going to be taking a pill a day. You're going to be taking once every 6-month injections or once a year or gene editing for life. And that's going to be the majority of medicines. And so we are going to play the long-acting aspect with this factor of siRNA that right now seems like best-in-class. It could be once every 6-month dosing. This is with our partner, Sirius.

And there are so many indications you can go in, whether it's secondary stroke prevention and the patients that are not eligible for DOACs, whether it's patients that are -- that have peripheral artery disease, post revascularization. So all these are trials we could do. Now of course, there's some -- any attractive space, there's going to be competition. There are some antibodies from Regeneron and Novartis that are also playing in the same space and a couple of small molecules. But I think an siRNA approach could be the most powerful approach, especially with this dosing convenience.

Okay. Great. Well, it looks like we're out of time. Plenty going on at CRISPR over the next 12 months. So looking forward to seeing the updates. And Sam, thanks so much for the conversation.

Thank you very much.

Thank you.

Good afternoon, everyone, and thanks for joining me at the first day of the Needham Healthcare Conference.

My name is Gil Blum, and I'm senior analyst here. I specifically cover immuno-oncology, and it is my pleasure to have Sam Kulkarni, the CEO of CRISPR Therapeutics with me today.

So Sam, maybe you don't need much of an introduction, but maybe a good place to start just 2025 really marked a transition for the company. Maybe just looking forward, how this company think about the pipeline as we move past CASGEVY. And maybe for those who are unaware, maybe a quick overview across therapeutic areas, where you guys are making progress.

Yes. Thank you for having us, Gil and we're very excited with where we are as a company. The first -- for those who are new to the story, CRISPR was founded about over 10 years ago now, and the first phase of the company was about getting in the -- first this platform to patients, and that's what we did with CASGEVY which is the first approved CRISPR drug in the world that's treating a number of patients with sickle cell and thalassemia today with our partner, Vertex.

The second phase was to then use the same platform, both ex vivo and in vivo to advance a number of different programs forward. And that's where we are today, where we have potentially 6 programs that would read out in the next 6 to 12 months.

And then there's obviously a Phase III beyond that, which I won't talk about today, but it's really how do you create even more transformative therapeutics once we have this phase parlay from one drug in CASGEVY to multiple other clinical readouts.

Where we're focused today? I think we're very committed to building 2 franchises. One is a cardiovascular franchise, and we have a number of programs there. And the second is an autoimmune franchise, where we have a number of programs. We also play in oncology and we'll talk about that a little bit with zugo-cel that applies across both autoimmune and oncology.

And with -- obviously, within the cardiometabolic realm, we have a type 1 diabetes program as well. And we're expanding into rare diseases like alpha-1 antitrypsin.

So all in all, we're -- in this period of time, we've been expanding the portfolio quite a bit. We believe we have best-in-class programs across number of areas, and I look forward to discussing those with you today.

Perfect. So, some facts so we're going to start with CASGEVY. Generated over $100 million of sales last year, a sizable chunk in the fourth quarter. What should be expectations for 2026? And should we foresee the momentum carrying forward?

Yes. I think CASGEVY has had a nice uptick or trend in the last couple of quarters. I think what's important to realize is after we launched CASGEVY, this is not a typical medicine where people get initiated right away and get a medicine and you see revenues right off the bat. This requires a lot of an installed base build, if you will, where we have authorized treatment centers that can actually deliver this medicine to patients. And that's similar to some of the more complex medical devices but that also forms a competitive moat because once you build that, it's very hard for others to do the same.

At this point, we have over 75 authorized treatment centers around the world, and Vertex has established those in all the jurisdictions in which we've been approved. And if you look at the trend line of patient cell initiations, collections and infusions, the initiations is a leading indicator of where we may end up with infusions. And what you're seeing there is a significant number of patients were initiated in the last quarter in over 100 patients.

And I think at that rate, what you'd see is a clear path if those patients translate to get their cells collected and then ultimately to get infused, you're looking at a multibillion-dollar opportunity. And that's what Vertex and us have been saying about CASGEVY and why we're so excited about the prospects and why we continue to invest so much in making this a drug that can bring cures to many, many patients.

All right. When did you think that we're going to start seeing these revenues hit your P&L?

Yes. I think what -- we haven't commented on when the franchise will become profitable for CASGEVY. The one thing, as you look at our collaboration expense right now, it's hard to disaggregate what's true CASGEVY profitability versus investments we're making towards gentler conditioning and also towards in vivo editing for sickle cell and thalassemia. And so we are with the long-term mindset. We continue to invest in the overall franchise, if you will, together with Vertex. And -- but we're confident that the franchise will turn profitable in the not-too-distant future. And I think it will start buffeting not just our overall R&D spend at CRISPR, but our entire enterprise-wide spend in a meaningful way.

So maybe you should spend a second on mitigating transplant-related mortality. Kind of what do you think are the lead strategies? And where do you guys think you're going with this [ Ex U.S. ] kind of market access?

Well, I think from an access standpoint for CASGEVY, it's been very heartening to see very good coverage across regions and jurisdictions. So I think in the U.S., we have the CMMI pilot, which all the states have signed on to, which has been terrific in terms of supporting these patients and giving access to these medicines to patients. Ex U.S. as well, I think there's been good broad coverage for CASGEVY across both thalassemia and sickle cell. So I think as you compare what options these patients have, which is whether to go for a haplo transplant, whether they just do matches or to take medicines that don't really change the underlying disease like hydroxyurea. I think this is the one option that patients have to return to normalcy. So I think when you look at comparisons and the payers recognize that, which is why you have such good access to this medicine or this therapy across all these regions.

I do want to spend a pretty significant portion of our time on in vivo program. One point of contention that we hear a lot is this idea that gene editing should be preserved for your dangerous fatal indications and that nonfatal chronic conditions, physicians and patients probably prefer chronic therapy over an expensive one-time gene therapy with the reasoning centering under reversibility of chronic dosing. So how do you guys counter this kind of thinking? And where do you hear feedback that contradicts this?

Yes, absolutely. I mean I think there's a big delta between what physicians are saying to us and what the investor community is asking, right? This question the investor community is asking is very different from what we're hearing from not just KOLs but even regular physicians.

And there's always going to be this disconnect because even in 2007, people were saying there's no way iPhones going to be better than BlackBerry, right? It just takes time for investors to catch on to certain things that are inevitable in terms of trend. And the question is going to flip to why not gene editing.

Take the example of some of these patients. NBC just published a story about this father-son duo. The father had its first quadruple bypass at the age of 29 and have had several cardiac events, very high triglycerides and LDL. The son was diagnosed with hypercholesterolemia and the age of 14. For these patients or people at the very young age, you're saying you're going to give them siRNA or medicines all through their life. And it's just not the best option for these patients.

And in fact, even those medicines don't provide full control. I mean these -- the 2 patients we're talking about here, we're on anti-PCSK9 antibodies and couldn't control their LDL. And after one shot of gene editing, their vitals are looking or their LDL, triglycerides and all the lipids are looking much better than anything they've seen before.

And the reason for that is with gene editing, it's permanent. It's -- there's no issue of compliance once you've done it. And you don't get this sort of sawtooth effect that you might see with siRNA towards the end of the dosing period.

And so this question at some point, will flip to why not gene edit, why would you do chronic therapy, if you can just gene edit once. And you don't even have the question of it being a very expensive therapy. In many ways, gene editing is going to save the system money because if you think about when it's going to be priced, it's going to be priced at around potentially 4, 5 years worth of siRNA therapy, and you're looking at people who potentially might take 25 years of siRNA therapy which is a very high cost of the system.

So all in all, I think the arguments are very clear why you do gene editing. The bigger question is, how is this going to unfold? Is it going to go from more serious patients to moderate patients to everybody? Or what is the rate of acceptance of gene editing. But it's eventually an inevitability that a large majority of patients are going to be gene-edited.

A big portion of the ability to conduct this technology well is selective in vivo delivery. Can you tell us at least a little bit about what -- how CRISPR's strategy is different maybe than some others. I mean I don't know if you've disclosed a lot regarding your LNP delivery system, but now being able to target specific tissues is key to some of these indications.

Absolutely. I think this is a major vector for us. If you think if you ask us in a world where you have this typical hype phase [ hype ] cycle, right, people had -- there's a lot of hype around gene editing and then there was a bit of a bottoming out. And we may be passed that phase. But in that period of time when lot of others have reduced their investment in platform, we're actually increasing our investment in the platform.

And the 2 vectors that we're most focused on right now, one is extrahepatic delivery. So we already have shown some promising animal data for bone marrow editing with LNPs, and we're going to use LNPs for other organs, including CNS delivery that we're working on. These are all conjugated LNPs.

And the other vector is gene correction or gene insertion. We've gone from gene just disrupting genes to potentially correcting a few genes with single base pair anomalies to now being able to correct or even insert entire genes into the -- into various tissues or various cell types.

And so as those vectors develop, you're talking about a number of large rare diseases. It's an oxymoron, but some of the more prevalent, I guess, rare diseases that can all be targeted, whether it's muscle or CNS or other organs. And so I see the platform unfolding the way we expected it to and the power being of the platform unleashed across different diseases.

And speaking of which, we're going to walk a little bit indication by indication here. So starting with 310 and ANGPTL3 targeting. So really encouraging early signal for LDL-C reduction and triglycerides. How are you thinking about the total addressable market here? Who do you think is the patients that are best amenable for something like this?

Again, as we spoke about before, I think all the markets will unfold as there's more and more data, especially around safety. If you look at the homozygous FH population, that's only about 1,000 to 2,000 patients in the U.S. So it's a small population, but that's probably the most straightforward path to doing a Phase III and getting approval, especially because ANGPTL3 seems to be synergistic with PCSK9.

And then you have the SHTG population, and that's about 3 million patients or people in the U.S. alone, of which nearly 1/3 of them have acute pancreatitis. So if you look at those 1 million patients and the fact that you don't need a full outcome study here, the endpoint could be a reduction in pancreatitis, gives you a path for approval in about 1 million people in the U.S.

And ANGPTL3, I think, can be a better target than APOC3 in these patients, especially because APOC3 has been shown to increase LDL.

And then finally, I think you're looking at various forms of mixed dyslipidemias starting with there's heterozygous familial hypercholesterolemia, where there's about 1 million patients. They have different types of mutations, especially around -- there's several mutations being described now with LDL receptor genes, and so they have various dyslipidemias of either triglycerides or LDL.

And then you have just refractory hypercholesterolemia, those that don't respond to PCSK9, et cetera. So you have several million more people that could actually be eligible for a therapy like this, not to mention someone who's saying, I have family history of heart disease, and I just want to control my LDL now. So I think you're going to see eventually millions of people being treated with therapies like ANGPTL3 or CTX310 which targets ANGPTL3 and it's a built-in bispecific in a way because it addresses both LDL and triglycerides.

What should we expect for disclosures from this program in the second half of the year?

Last year at American Heart Association, we disclosed data for 15 patients in our dose escalation part of the study. Now we'll disclose data for -- obviously, there's durability data from that initial set of patients dose, but also now what we're doing is a Phase Ib, where we're showing the specific effect in each of these subpopulations.

And we'll show data from as it applies to subpopulations at different -- at the right dose level to figure out what the go-forward dose is going to be in a Phase III. And I think this is also data that we would take to the regulators and hopefully, that's the basis for some of these designations like RMAT that allows to have a seamless dialogue with the agency about how to develop this for the broader population. And so that's something that we intend to do in the later part of this year and should be part of the broader update on this program.

I want to spend a minute also on the LP(a) programs. Where do you guys stand on this given we haven't seen any of the pelacarsen data [ ever ] highly anticipating us now.

The data for pelacarsen from the HORIZON study is one of the most anticipated readouts for the entire pharma industry. And this is a trial for those who are new to the LPA field. It's very clear from population studies that high LPA equals high risk of cardiac events or high MACE risk.

And it's better to have low LPA, but is pharmacologic reduction of LPA sufficient? And will that actually reduce your risk on a go-forward basis, is something that has not been shown before and the HORIZON study attempts to do that.

And I think we'll see what the level of benefit is that we'll see from HORIZON that inform our go-forward path for CTX321 or 320. We have 2 assets that both reduce LPA levels, and we want to get the most potent asset, which could be CTX321. But based on what we see from the various subgroup analyses of HORIZON as well, we'll decide what the cutoff should be for our Phase II studies for LPA going forward.

So to be defined.

To be defined based on HORIZON, which makes -- I mean, I think that's what happened is we had CTX320, where we completed dose escalation. We had a pocket of time here before HORIZON trial readout in terms of deciding what the go-forward path is. So that's why we're parallel processing a second asset, CTX321, and we'll make the decision based on HORIZON data.

Great. I do want to also talk about treatment-resistant hypertension. Just to remind people what this program is, what the target is, what kind of patients are we thinking about here?

Yes. So CTX340 which we said we committed to starting a clinical trial in the first half of this year, and we're on track. CTX340 targets angiotensinogen. Angiotensinogen is a substrate for the entire RAS pathway that regulates your blood pressure. And it's been shown through sRNA trials that are being conducted by Roche and Alnylam, that reducing the level of -- circulating angiotensinogen, which is mainly produced in the liver can have a profound effect on your blood pressure.

In fact, they showed across 3 trials, systolic blood pressure reduction anywhere from 9% to 19% in various sub populations. And so what are we trying to solve here? We're trying to say is, there are patients with refractory hypertension that are on 4 or 5 different medications. They have some combination of ACE inhibitors, ARBs that block the angiotensin receptors, you have renin inhibitors and you have aldosterone pathway drugs as well. So people are on different drugs to try to -- manage their blood pressure.

If you can just reduce the angiotensinogen in circulation and get a baseline reduction that's meaningful for these patients. Not every patient may come back to normal blood pressure, but you've basically brought these patients back from 4 or 5 different agents a day to potentially 1 agent a day even if they're not fully normalized. And that's a pretty meaningful improvement for these patients because, one, not everybody is compliant.

Second is all these drugs have side effects that compound as you take on many different medicines, and so this will be another paradigm shift where you could potentially completely alter the blood pressure profile and reduce the solid blood pressure, while keeping it safe by the way. There have been no hypotensive events in the cardiac trials reported to date with the sRNA.

So people say, why not just take a once every 6-month injection if you can -- or once every 3-month injection if you can -- but I think gene editing again, gives you the baseline that doesn't have a sawtooth effect. God forbid, you take patients off their regular medications because they're an sRNA and towards the end of their dosing period, they have elevation of their blood pressure and something bad could happen. And so it's better to sort of have a nominal -- but have a consistent control that's predictable in these patients so you can titrate everything else.

Okay. Just given that the data is out there, where do you think the bar is for early clinical study?

For the reduction in systolic blood pressure? Well, I think even high single digits, low double-digit reduction of solid blood pressure is a pretty meaningful win for these patients. I think some of these patients are severely higher than what normal is in terms of blood pressure, but if you can reduce it in double-digit levels probably much closer to normal. That's a very major improvement for these patients.

And we'll spend a second also on your own foray, that's siRNA that's CTX611. How does this vertical fit in with all the other things you're doing? Is there like cross-program synergies or learnings here?

Yes. That's how this program started in a way or I guess started for us, which is we're committed to building a cardiovascular franchise. And one of the other areas that's very exciting in cardiovascular medicine is the anticoagulation space, which hasn't seen much innovation for a long period of time.

And it's very synergistic with what we're doing with all the other cardiovascular trials. But Factor XI is not a target that you want to permanently edit. And so an siRNA it makes a lot more sense, and we're talking about potentially a once every 6-month siRNA because you're only using this sort of for a certain period of time. We're not lifelong going to use this drug against Factor XI. You're going to use it when you need anticoagulation after surgeries, but you don't want to have bleeding risk, you may need it if you have certain conditions where you may take it for a long period of time such as secondary stroke prevention or you could do it if you have certain conditions like Afib.

But I think this is something that you want to use when needed. And an siRNA actually is -- could be far more beneficial than an antibody, which some companies are developing or small molecules. And the reason for that is by effectively eliminating Factor XI at the route source, you never give it a chance to form Factor XIa, which then ultimately forms Factor Xa, which is the central node in both the intrinsic and the extrinsic pathways of coagulation.

So what we're doing here with Factor XI is effectively shutting down one of these pathways, which is important for thrombus formation. But at the same time, allowing the -- preventing bleeding by allowing the tissue factor pathway to continue to remain active. And so that sort of logic behind this program. It fits in with the rest of what we're doing in cardiovascular medicines. And the sRNA vertical is still genetic medicine, is still nucleic acid medicines that fits from a capability standpoint as well, whether it's manufacturing, analytical, et cetera.

You have guided for some data in the second half of '26 from this program. Just maybe a brief recap of the trial design and what should be looking for?

Yes, an important trial in this space for Factor XI therapies is the TKA study. It's a total knee arthroplasty surgery. And when you -- when people have their knee replacements, for instance, they're not very mobile. And during the recovery, there is a very high chance of DVTs. And some of these could be even be fatal.

And so they -- most patients get some sort of agent to prevent DVTs from forming like enoxaparin. At the same time, you can't use DOACs in this setting because you get a lot of bleeding if you use DOACs after you're recovering from a surgery. So that's not possible either. So even with agents like enoxaparin, you've got a 1 in 5 chance of forming a DVT, some more severe than others.

But can you prevent that from happening with the Factor XI agent? And that's what we're trying to test here with our trial and see if we can reduce that percentage. And that's what some of the other Factor XI agents have shown.

But it's a good trial where you have a control arm and you can actually see where you stand in the kind of pecking order of different therapies for Factor XI and -- informs to a large extent, where you're to invest in trials going forward. Some trials are obviously very large, like the asundexian secondary stroke prevention trial was thousands of patients. Others will be smaller like cancer associated VT reduction, for instance.

But we have -- we'll determine our path forward on a Phase -- for Phase III based on this TKA study and also forms the basis for going to the regulators because we'll have a much better sense of the PK/PD and how the drug is acting in patients.

Great. I don't want to skip zugo-cel. I know you guys have like a lot of subjects. But I'm going to ask something that is out of order for me just because it's fresh off the process this morning. Any thoughts on kind of the futility, nonfutility data from Allogene this morning. Very interesting study looking at frontline DLBCL as it relates to MRD positive.

Yes, absolutely. Congrats Allogene for thinking of this paradigm of consolidation post standard frontline treatment. And the data tells you that there are we always think of some of these frontline therapies as curative like R-CHOP et cetera, but they're not. There's still some cancer cells left and you want to consolidate those.

And I think it shows that cell therapies can get to places that biologics may not. And that same paradigm carries over into autoimmune disease, which is why I'm so excited about it for cell therapies in autoimmune diseases. And whether it's this paradigm or the paradigm we're doing where we use cells to deplete all the cancer cells and then consolidate with something like pirtobrutinib continuous dosing.

I think both these paradigms can be very meaningful. And I think, hope it brings back investment for cell therapy in oncology, which has largely been out of favor to a certain extent at this point. For us, our -- we're fully committed on the autoimmune front with zugo-cel and we're progressing multiple indications in parallel, but we also have this pirtobrutinib combination, which I think could be very interesting in the oncology setting.

Spending a second on the value proposition for autoimmunity. You guys did see, about [ 17% ] Grade 3 CRS in your studies. Again, this is in oncology. I mean is this an issue or there's a different tolerance for CRS in autoimmune disease.

In autoimmune, you probably will not see the same level of CRS. And the reason for that is because the B cell burden is a lot lower. In a cancer setting, the B cell burden is probably almost 10x that of what you're seeing in autoimmune disease. You don't have an overabundance of B cells, you just have pathogenic B cells. And so unlikely that you're going to get the same level of CRS and also the doses we're exploring in autoimmune disease are lower than what we're doing in oncology settings.

So let's talk a little bit about the autoimmune direction. You've mentioned this multiple times in recent presentations. Just trying to understand the investment and kind of -- where do you think you're going as it relates to an indication? I know there's a pretty large basket study that's ongoing, but if you can give us some broad strokes here.

Absolutely. I mean we're expanding indications as we speak, we're going from the room basket, initially, we were going after SLE, myositis and scleroderma. We've now expanded it to ITP and wAIHA and we're looking to further expand into other indications, particularly in the CNS realm. So we're quite encouraged by what cell therapies are doing in general in the autoimmune arena. And this is where we don't think that typical biologics or even TCEs can have this one-shot cure that we could get with cell therapies. And that's where we're -- that's where we're so bullish on the whole opportunity across all these indications.

And as it relates to data disclosures in 2026?

We'll have an update on zugo-cel second half of this year. We'll tell you where we are in both autoimmune and oncology. And hopefully, by then, we also have a path forward from the regulators in terms of what a pivotal trial might look like in some of these indications.

Maybe in a personal note, I mean -- hopefully not another SLE study. I feel like we've seen too many of those.

Yes. I mean that is a conventional thing you were saying that there are too many studies for SLE, and it's hard to enroll patients. But we continue to see a lot of unmet need even in SLE. And particularly because some of the biologics and even some of the TCE trials may not be doing the trick of immune reset. So -- but we'll provide more information on how we're taking this forward.

Okay. And a little bit of other category, just what updates can we expect this year from CRISPR's regenerative medicine portfolio?

Yes. On regen med, I think we're taking -- bringing for CTX213, which is our iPS-derived multiple edited cells. We're -- we haven't said exactly when we're going to get into clinic with that. It's more likely to be next year. But at the same time, I think the edits we have on there may be best-in-class. You have 3 or 4 companies that are pursuing this sort of approach, but the market is huge. And it's really going to come down to whose data are better. But the edits we've picked for immune evasion as well as making the cells more robust. We're very confident in that I think it was going to work the best.

Great. Maybe we'll use the last few minutes just to discuss. What do you think people are missing about CRISPR? What would you highlight as something that people should be paying attention to, but maybe they're not?

Well, I mean, I think we have a very huge pipeline. In fact, we didn't even talk about A1AT and that program 460 is going into the clinic soon. So we have 7 assets outside of CASGEVY that we're advancing. And we'll have data for at least 6 in the next 12 months.

And yet, I think a lot of the attention is on CASGEVY. I mean that's typical human nature is to focus on the lead asset. And we're confident that as CASGEVY is going to turn the corner inflect here. And we see a meaningful contributor not just to us, but also to Vertex, even though they're a much bigger company. And as that happens, I think the focus will shift towards our other programs. And we'll be in a position with data across a lot of other programs to say what's the next leg of the company.

And I think we're doing all this from a sum-of-parts perspective, if there are other companies in each of these spaces. And if we -- we're doing all of this in a relatively lean fashion that all the other companies are doing singular with singular focus, but we can potentially be best-in-class across all these. And so as cell and gene therapy comes back in favor, we're poised to lead it from the front. And In fact, sort of consolidate some of the -- consolidate various pieces of the space to become the leader in the space by far.

And I think that's sort of the goal. And Phase III of the company will tell -- it will be now we're going from becoming a $5 billion company to a $15 billion company in the next 3 years. Phase III of the company will be how do you go from a $15 billion company to a $50 billion company or more and I think that's also something we're working on now, which we won't talk about. But obviously, there's transformative medicines out there that we can create that, that could completely change how we think about therapies even for common diseases.

It doesn't hurt to have a strong balance sheet either.

Absolutely. I think that's the advantage we have is we have a strong balance sheet, yet we're efficient and that allows us to invest in multiple areas, especially when others are retrenching.

As always, I appreciate your time.

Thank you.

Okay. Welcome, everyone. I'm Yigal Nochomovitz, biotech analyst here at Citi in New York. This is our February event, which is our Virtual Oncology Leadership Summit. We've been doing this for a few years and have a great lineup today. And in this session, we have the senior management from CRISPR. So we have with us Sam Kulkarni, who is the CEO; and Naimish Patel, the Chief Medical Officer. So welcome both of you.

And for those listening, remember, you can just e-mail me, [email protected], and I will relay any questions you may have over to Sam and Naimish, if you have any. So obviously, it's an oncology event, but it's obvious that you guys do have more than oncology. But that being said, maybe we'll focus the discussion there initially and then perhaps broaden it as time permits to some other topics.

So Sam, maybe if you could start talking about the oncology programs that you are engaged in perhaps with the ex vivo program in zugo-cel previously CTX112. Just tell us at a high level about the construct, about the design there, what you sought to achieve to improve the properties of that cell therapy and then we can move into some of the details in terms of the data you've shown in the plans for further development.

Yes. Thank you, Yigal, for having us, and it's always a pleasure. As you mentioned, at CRISPR, we're doing quite a bit across different disease areas. We have a commercial product for sickle cell and thalassemia together with Vertex. But beyond that, we have cardiovascular programs and the cardiovascular franchise. We have a franchise in autoimmune disease with our allogeneic CAR-Ts. And we have effort in type 1 diabetes with regenerative medicine approaches in addition to what we're doing in oncology. But I think oncology is remains core to our efforts, particularly because we have what I believe is a best-in-class allogeneic cell therapy platform. And I'll talk more about that with regards to zugo-cel and other efforts. And we also have an emerging platform for in vivo CAR-T, both transient and permanent CAR-Ts which can apply in autoimmune diseases and in oncology.

So right now, what we have is our main area of focus or effort in oncology relate to zugo-cel, and zugo-cel was formerly known as CTX112, which was a next generation product after our initial efforts with CTX110 all this targeted towards CD19. And what makes zugo-cel special is that this is an allogeneic CAR-T. In other words, it's a CAR-T made from healthy donor-derived cells in our own manufacturing plant in Framingham, Massachusetts. And we've made advanced edits to these cells to make it much more potent than the first generation of allogeneic CAR-Ts and almost get autologous like efficacy with a better safety profile that could have meaningful impact in heme malignancies like DLBCL, but also beyond that.

Okay. I think it would be great if we could talk in some detail about those edits because they're obviously important and unique and what -- how you effectuated them and what properties they convey in terms of potency and durability?

Yes. I'm happy to start with the edits, and I'll ask Naimish to add some comments as well. But the main edits we make with zugo-cel, some are required, which is you want to knock down -- you want to insert the CAR-T, obviously, which is the primary function and primary way of making a CAR-T. But the way we do it is much more elegant than viral approaches. We actually insert the CAR into the TCR locus. So we get a double effect. We knock down the TCR, which prevents graft versus host disease. And we knock in the CAR into the TCR locus with endogenous regulatory control.

Beyond that, we make edits for both potency and persistence. So we make an edit in the beta-2 M locus, which effectively knocks out the components of the MHC Class 1 presentation. So declaring these allogeneic cell as foreign. So if you knock out beta-2 M, you don't have a flag waving that says that they are foreign cells and gives you more persistence because your host immune system, particularly the T cells will not eliminate these allogeneic CAR-T cells as fast as they would if they didn't have the beta-2 M edit.

And then beyond that, we have 2 proprietary edits that are really important in making this generation of CAR-Ts more potent than the previous generation. One is called Regnase-1. And this is a central mediator of cytokines and various factors produced by the cells. And by knocking out Regnase-1, what you're doing is making these cells retain a more naive phenotype, which allows for more expansion and more durable effect and reduces exhaustion in these T cells while at the same time, make them more cytotoxic. And that is an important edit that we validated, but others in the field like Carl June have validated as well.

And the other edit is TGF-beta receptor 2, which effectively prevents TGF-beta-mediated cell exhaustion or prevention of potency from these cells. So those 2 edits confer significant potency. So I guess the overall strategy, we learned from our first-generation CTX110, which is the cells, allogeneic cells are not going to last forever in the patients. They're -- without any persistence edits, they last about 15 days with some persistence edits like beta-2 M, they last about a month. But the bigger issue was in the month that they persist, they were not active the entire time because the cells got exhausted by day 11 day 12. And what we did is by making these additional edits with Regnase and TGF-beta R2, we ensure that the cells are active all the way through the time which they have in terms of the persistence window. So we effectively increased the AUC or the activity under the area for these cells in the time that they have to kill the cancer cells.

Okay. And in terms of -- you mentioned it's donor-derived. So -- an allo. So how many -- how broad of a population can you cover with the set of donor-derived batches? And do you have to deal with HLA matching or things of that nature as well or not?

Naimish, maybe you can.

Yes, absolutely. So yes, our studies, we have not HLA matched, and we've seen no -- but we do sort of measure HLA subtypes of patients. We haven't seen any correlation either between HLA and cell expansion. And so basically, there's no requirement for matching. And so there's no limitation in that way. And we've also redosed patients. So some patients who had a partial response to the first dose might get a second dose to deepen the response. And we don't have any evidence to suggest that there's any immune response or anything like that. So it's a pretty nice system because of the immune evasion edits that we've put in, that doesn't seem to be an issue.

Okay. And anything special on the lymphodepletion regimen that you need to do? Or how does that work?

Yes. And part of the reason we did this is because we didn't want to what other folks have done in this area is to get better expansion and better persistence of the cells, they basically had greater levels of immunosuppression. So larger doses of the LD regimen or adding some sort of biologic to produce a long-lasting cell depletion. We use a standard CAR LD regimen that's used with autologous in oncology as well. And that's all -- that's a very sufficient. And just to add on to what Sam was talking about, if you look at the expansions from the prior generation CTX110 to now zugo-cel CTX112, dose for dose, we're seeing a significant level of increased expansion at every dose and at the highest doses at the doses that we're taking forward to Phase II, we see cell expansions akin to what's seen with autologous CAR, which was really the objective in making these edits.

So we're very happy with what we have now that we can at least equal the efficacy of autologous CAR and -- but have the same treatment regimen.

Okay. So maybe, Sam, if you could talk -- just -- we got through the basics of the structure of the asset. But what about the strategy in oncology. Where do you -- and you mentioned autoimmune, where do you want to take this asset? What is your goal for how you want to develop it? Obviously, the allo market is extremely interesting in the United States to expand the reach of cell therapy to a much broader population. And we've seen those arguments made quite broadly by not only you but others. So just kind of just walk us through the strategy here in terms of where you're going to focus. I mean we have some early data. We can talk about that in a bit. But before we get to that, what's the kind of the long vision here for this program?

Yes. I think for zugo-cel, we're very bullish in the program, and we believe it's going to have impact in both autoimmune and oncology. At this point, in autoimmune, we're all in, in a way that we're rapidly enrolling patients. We're expanding the number of indications we're treating from lupus at myositis and scleroderma where we started to now include ITP and wAIHA, and we're probably going to add more indications because we just think allogeneic CAR-T is going to be the winner in autoimmune. The reason is as follows, which is the cost of goods of allogeneic is sub-$10,000. It's very scalable relative to autologous cell therapies where we've seen remarkable data.

Second is, it's very convenient. You don't actually have to stop the treatment that patients are undergoing to harvest T cells like in autologous therapies and that which may cause flares. So here, you can just continue them on and then treat them with the allogeneic therapy and then pull off all the medications once the CAR-T has done its work.

And the third is we think the efficacy and potency is going to be equal, if not better for allogeneic CAR-T without any of the safety risks like ICANS that we've seen with some of the autologous therapies. And that's because these cells will get eliminated eventually after they've done their work, but you've caused the immune reset. And the reason in autoimmune, we feel very good about it is even if you get 99.9% of cells in autoimmune disease, you basically reset the immune system. In oncology, you have to get 100% of the cells because even one cancer cell may come back as a cancer later on to get durable efficacy. But autoimmune, I think it's very clear that allogeneic CAR-T can do the job, our allogeneic CAR-T can do the job, just as well as autologous therapy, and it will be a very safe option for patients because the cells disappear after they've done their job and you have lower safety risk in terms of ICANS or CRS at the dose we're expanding in. So in autoimmune, I think where all systems go.

In oncology, what we need to demonstrate. One is, yes, we get very high CR rates, but do you get durable CRs. And with CTX110 when we started off with the first-generation allogeneic CAR-T, we did get about 40% CR rate at the beginning, the first month. And then -- but if you look at 6-month CR rate, that number dropped to about 20%, because half the CRs were not -- the cancers come back and that's because the cells were not as potent. Now what we see with zugo-cel is that we pushed up the initial number quite a bit, almost 70%. And I'll talk a little bit more about the data in DLBCL and we've potentially pushed out the durability as well because you're getting very deep reduction, almost MRD negative in almost all cases in terms of eliminating the cancer. And so we feel good about what the durable CR rate is likely to be. And we have this additional weapon now by combining with a BTK inhibitor for pirtobrutinib that actually can ensure the durability because if there's -- let's say, we eliminate 99.99% of cell there's 1 cell left, that it will get taken care of by the BTK over a course of maintenance.

So overall, we think the -- on autoimmune I think we'll have more data to show, but we feel very, very confident that this thing is going to work and it's going to be a very transformative product for patients. In oncology, we have to show a little more data, especially with this combo. We've already shown that the CR rate is much higher for 112. But if we can show that it's durable, then we have a winning product in oncology as well.

I want to invest...

Sorry, just one -- and of course, the field is moving forward, right? So there's bispecific autologous CAR-Ts that are showing even better in oncology, even better response rate. So there's also some evidence that suggests that BTK inhibitors might enhance CAR-T cell activity during the expansion phase. So we're really targeting for even a higher efficacy bar with the combination than even our early mono data shows data that might be at least as good as an autologous CAR, a monogenic. But really, the bar is getting raised. So we're really looking towards something even better.

And just when investors think about this program. I mean, you're kind of going parallel track here in oncology and autoimmune or are you going to make a determination, which one to do? It seems like autoimmune is very much happening. Oncology, is that still -- you'll evaluate, you'll see how the data would be [ thiore ] potentially and then make a decision? Or can you just talk about which -- how you're going to pursue both or one of these programs with this asset?

Yes. Yes. We're pursuing both in parallel right now. I think the key not catalyst, but the key determination of how to move this forward is going to come after regulatory discussions. And I think typically, our math is an important designation that these programs get that allow us to have very fluid discussions with the regulators as to what the path forward is. At this point, what we've seen is that the FDA -- in the U.S., the FDA have given very favorable guidance to companies in the autologous CAR-T space for autoimmune indications, small trials that can get them to registration and approval. And for oncology, I think the -- we're going to ask the same question. Can you do a single-arm trial that can get us to registration? Or do you need to get -- do RCTs, which obviously make it harder to get to approval. And I think so in autoimmune and oncology, we're parallel processing.

And by the end of the year, we hope to have these discussions with regulators to understand what the path forward is. And at that point, we have to make the decision based on each indication individually, how do -- what is investment required and how can we get to the finish line. But at this point, I do believe that it's likely that regulators are -- allow a path forward that's not too burdensome in terms of registrational trial for both oncology and autoimmune indications.

Okay. So then let's talk about a bit on the autoimmune in terms of which indications you've explored. You've had some data, obviously, in SLE, but then there's some other studies you mentioned, ITP and wAIHA as well. So which -- where do you see the most promising potential amongst these different autoimmune indications? Or again, is it just -- it's a data-driven question, clearly, too?

Yes. No, great question. I mean I think just to add a little bit of same, I think the data we have today, both in oncology suggest that zugo-cel is as active as an autologous CAR-T. What that means is in the autoimmune space, that the efficacy is good enough to provide long-term remissions in a number of different diseases. In oncology, I think because the field is sort of now even moving ahead there. We're looking for something a little bit more the combination therapy. But on the autoimmune space, the key breakthrough, I would say, with CAR-T is the fact that Sam mentioned, immune reset, we're able to deplete the B cells so that the pathogenic B cells are all gone and the B cells that return with CAR-T cell therapy are naive B cells and they're no longer pathogenic and patients can get long-term remission without any background immunosuppression or any therapy, and that's been shown very well for a number of years and follow-up and Georg Schett's group in SLE and a number of other diseases.

So we have a rheumatology basket trial where we're looking at SLE, inflammatory myositis and scleroderma. And we're now recruiting actively in all 3 indications. We've shared some first couple of patients were recruited in SLE, and we've been able to achieve a 0 disease activity to SLEDAI of 0 in both those patients. And in 1 of the patients we have up to 9 months of follow-up now off any background therapy with complete remission. So -- and all the biomarkers, there's complete B-cell depletion at day 28. There's a good CAR-T cell expansion. It's all pointing in the same direction that we're getting the immune reset. So that's very exciting. So the -- we've already also started a second trial in ITP and wAIHA and there's been some case reports both from China and outside of China in ITP showing patients that are heavily pretreated and have failed multiple different MOAs having lasting durable return of platelet counts after CAR-T cell therapy.

And similarly, there is a recent patient also published in warm autoimmune hemolytic anemia. And these are spaces where we're not seeing other CAR-T players actively advancing. So it's a bit of a white space for us as well, but also there's evidence to show that CAR-T cell therapy similarly provides that immune reset and long-term remission. So that's another exciting study that we've now kicked off and look forward to data in the second half of this year.

You have -- from looking at the data now, it looks like you have, I mean, a very strong asset, right? I mean even in these 2 SLE patients, it seems like you've achieved what you want to achieve unless I'm missing something, it seems very good.

Oh, absolutely. We're -- there are a number of different places we could take the rheumatology side. There's SLE, there's inflammatory myositis and scleroderma, each in their own are high unmet need indications. And then there's things like interstitial lung disease that cuts across all 3 of those things that are also incredibly high unmet need. We're definitely trying to target places where we could potentially be first. And so we're thinking very deeply, but we're very happy with the results we're getting, absolutely.

Okay. So for a first sort of registrational trial, you want to offer any thoughts as to where you might go first. As you say, look for something that's less competitive, like an ITP or wAIHA or scleroderma perhaps?

Yes. I think all those things are on the table for us. I think the data readouts that we'll have in the second half of the year, we'll have more patients across those things will help guide the direction, but all those things are fairly exciting. I don't know, Sam, if you're going to say something as well.

No, one of the differences as we look at the autoimmune space versus what happened with oncology, autologous and allogeneic are moving almost on par in terms of timing, right? In oncology, what happens -- autologous has started about 6 years before allogeneic approaches started. So it was a little bit hard to show in that patient population, how one is better or worse. But right now, we're seeing both of these move on par.

The second dynamic that's very interesting is that there are trials out of China generating data that are almost like signal seeking that we can follow. So we'll follow our own data, but we'll also follow data that we're seeing from others. And as Naimish mentioned, data on ITP and wAIHA coming out of China. So in lupus, we're already getting sort of our best case, which is one patient is already a month 9 at SLEDAI 0, second patient at SLEDAI 0 and coming off the meds that they were on originally. And so I think we're already seeing that. We just needed a larger end in some of these indications and we look forward to sharing that data second half of this year. And we have a lot more centers now enrolling as well. So that should pick up as we go along.

Okay. Okay. So data for some of those sub studies or those -- the basket trial in the second half of the year.

Yes.

Yes.

And then as far as doses and things of that nature, although are you still in that exploratory -- I know with these 2 lupus patients, you did $100 million. Are you looking to change that? Are you happy with that?

Yes. No, absolutely. I mean the things we're looking at is beside -- because the clinical response piece takes a little bit longer, is looking at both the T cell expansion as well as B-cell depletion. And for both of those patients, it was great in terms of especially 0 B cells detected at day 28. So it certainly is a very active dose. I mean the questions that we need to answer is that will that dose be the same dose across these indications? Or would certain diseases require a different dose in other diseases. Right now, we we're all -- everyone starting at the same dose, all indications and the data will still drive that, but we're certainly happy with the B-cell depletion we're getting at $100 million, and that aspect of it should be similar across diseases.

Okay. And then maybe, Sam or Naimish, we're in the Lilly partnership on [ thiore ], just tell us a little bit more about how that came about and you have not generated any data there yet.

Yes. There is a paper an abstract at ICML this past year by a group at the MGH in Brigham where they combine a different CAR-T, an autologous CAR-T with ibrutinib, another different BTKI. And they were able to show in LBCL CR rates above 80% in that study. And that really got us excited about the prospects of the combination. And there is some data, as I mentioned before, that inhibition of BTK enhances the CAR-T cell activity, preclinical data out there. And so they made mechanistic sense as well. And so we approached Lilly, who also was interested. And as I mentioned, the oncology, it's -- and Sam mentioned, it's a bit of more moving target, right, where the autologous CARs have been out for years. And now people are coming forward with bispecific CARs and doing RCTs against monospecific CARs because the efficacy is that much better. That combination, I mentioned, that efficacy is on par with a bispecific CAR.

And so if we can reproduce that with zugo-cel and pirto, I think we'll set up better to actually compete against what's coming down the pipe in oncology. And so we -- the studies are ongoing. We don't have data yet to share, but we're really excited about it.

You would do this study in the patients that are the second-line LBCL patients? Or who would you target initially for this combo?

Right now, the study that we're doing is largely third line plus patients that are being studied, and that's very similar to the population that was studied in that Brigham MGH investigator-sponsored study.

Okay. And then if you were to move forward with an approval with this, say, with this combo, that would be in that setting? Or would you potentially do go earlier and try to go up against maybe the second line people that had failed in auto CAR-T in the frontline? Would that be a consideration or not?

Yes. I think this is where I think we'll have to -- it's going to be driven by the data and the regulatory discussions. I think, Yigal, I guess this strategically, what we could do is pick off a lot of the niche areas in this space because it's still a big market. For instance, what we could do is try to get approval with a single-arm study in relapsed/refractory setting in third line. But then do trials, for instance, in frontline ineligible patients or patients who are ineligible for CAR-T or TCE. And there are a lot of them that can't tolerate even 6 cycles of R-CHOP, for instance. There are patients who are ineligible for CAR-T in second line. Because I think the alternative, which I think some of the other -- one of the other allogeneic CAR-T players are doing is if you try to go head-to-head against established standard of care in second line, it's going to be a very expensive trial. If you have to do an RCT versus either a TCE or an approved CAR-T.

And given the wealth of opportunities we have at CRISPR and our -- the number of things we're developing, we want to be very thoughtful about resource allocation. So at this point, where we may try to get to is third line plus or relapsed/refractory setting, get that approval, get certain pockets of patients, such as the elderly population that cannot tolerate full cycles of approved frontline therapies, other patients that are ineligible for CAR-T for various reasons.

And I think that will expand the areas where -- once we get a label, we can always expand where we go. And especially in Europe, once we get a label, I think we'll get a lot of adoption because odds are we're going to price this much lower than autologous CAR-T. And for systems that -- for the European systems, that's a huge benefit. We'll actually get a lot of traction. We're actually getting a lot of traction even in Middle East, for instance. And you saw another allogeneic therapy approved in the Middle East recently, and that's because some of these systems cannot afford to provide an autologous CAR-T for every patient. And also there is an issue of availability and turnaround, whereas an allogeneic CAR-T can get them similar efficacy for these patients but much more convenient and cost-effective. So I think we just want to get on label. In fact, we're actually dosing patients in oncology in India. And that could -- that would never be possible with an autologous therapy or even the first generation allogeneic therapies because the cost of goods are too high and you wouldn't have any profit margin.

But given where we are with our cost of goods, it's actually a thing that's possible. And so there are significant markets outside the U.S. as well where we could develop zugo-cel. And for us, it's all marginal returns because we're investing in zugo-cel anyways across autoimmune and oncology from a platform perspective, we're going to be making a lot of the drug. So if you can get on label carve-out niches in oncology that eventually could add up to a couple of billion dollars of revenue that, I think, would be a very good strategy.

And you mentioned pricing, you wouldn't price like the auto CAR-Ts, how would you approach the pricing question, if you get approval for zugo-cel in both the oncology space and the autoimmune space, what would be the approach there to harmonize.

Well, we think is that current autologous therapies in oncology price around $350,000 to $400,000 effective price. And the chatter is that in autoimmune disease, these therapies are likely to price even higher in the $700,000 to $800,000 range. And I think for the systems, that's a pretty challenging setup. I agree that there's cost of treating these patients is high, et cetera. But if we're able to price our allogeneic CAR-Ts in the $200,000 range or slightly lower, I think we just increased access quite a bit. And we still preserve margins that will return -- provide returns for shareholders and for the company and fuel further innovation. But I think we just will be able to access that many more patients if we're able to do that in the Western markets. I think our pricing in India and parts of Asia and other markets, we'll have to think of even lower cost manufacturing there which we're in the process of doing, if we establish manufacturing there that allow us to price even lower.

In the last few minutes, can we just touch on the in vivo CAR-T, you mentioned the 2 flavors, the transient and the permanent. Can you speak to those a little bit and then where you're going there?

Yes. I mean, this seems to be a very hot area right now. I think the unlock essentially has been that you can deliver these cargo, whether it's mRNA encoding the CAR or editing machinery into T cells in the body using either viral vectors or LNPs. And our strategy in this space has been twofold with -- we're firmly entrenched on LNPs versus viral vectors because I just think that eventually, LNPs are going to win out. These are much more deterministic in how you manufacture them, much more reliable. And the biological effects that you see are less stochastic than viruses where you may have safety events or you may have unwanted integration or unwanted activation essentially. So we're firmly putting efforts into LNP mediated delivery and then we have 2 efforts.

One is LNP mediated transient CAR, where we've engineered the mRNA that encodes the CAR in such a way that it's much more persistent and durable. So instead of a lot of competitors who have 3-day or 4-day detection of CARs, we're likely to see much longer detection of CARs, potentially even greater than 10 days. And that will lead to a more deep depletion of B cells in this case, the CD19. And so that's our transient CAR strategy. We actually have other engineering elements as well on the transient CAR that improve the persistence of these CARs and enable expansion. But transient CAR is likely to be more effective for autoimmune indications than oncology. In oncology, you may not get the level of expansion with transient CAR to see complete elimination of tumor cells. So for oncology, we're developing permanent CARs. In other words, we're actually going to deliver the CAR as a donor template plus the editing machinery to create fully integrated CAR-Ts in vivo.

And that's actually moving nicely as well. So we can -- we have engineered elements where the DNA donor template is not immunogenic when we deliver it and integrating machinery is efficient enough that we get a certain percentage of T cells with the integration of the CAR. And that will be game-changing in oncology, right? If you can do no conditioning, 1 injection and have permanent CARs, you will completely eliminate the tumors and that actually could work for a lot of solid tumors as well because you could potentially think of more than 1 target in that case that you go after. And in a way that's relatively safe as well. But I think data will tell over time. But we're pretty excited about both these platforms, and we're doing the engineering to make them best-in-class on both fronts.

With the nonviral integrating, you would get essentially stable CAR production indefinitely in the lineage in the immune lineage? Or would you still have some erosion over time if you lost it -- if it was lost from the genome or something like that? Or what is the time frame?

Yes. I mean I think you will -- there is a risk of B-cell depletion because you will have permanent production of CAR from these T cells. Now what you've seen with autologous CAR-Ts, is yes, you get permanent T cell editing of T cells. But eventually, if the target is gone, they kind of go away. The T cells quiet down and they just get eliminated and they die and you don't have permanent B-cell aplasia. In this case, you have to make sure that the same effect is what you see with the permanent CARs and that they do their job if it's in the case of CD19 or whatever they get it of all the CD19-positive cells. And when there's no antigen, the cells either go through autophagy or something else to just get eliminated and you won't have a permanent B-cell depletion effect.

And then -- but you can still do all the edits, the revenues and the base probably, all that can happen with this in vivo approach. Is that correct?

Yes, we probably will pick different edits than Regnase because I think we want to be -- safety is our most concern. We want to make sure that we don't turbocharge these CARs either given they're permanent. But we can actually make those edits in a slightly different way. These include using shRNA and other elements to affect -- have the same effect on editing without multiplex cutting of the genome.

Got it.

I mean in some ways, it's not that different from say an autologous CAR, where you have permanent integration of the CAR. And -- but over time, the T cells do exhaust. So even if they might be detectable, they're not actually active in some patients, they're not even detectable anymore. And because they're actually now native cells or not allogeneic cells, you don't necessarily need the potency edits that you do with allogenic cells, but the data will sort of drive things like that.

Yes. Okay. Okay. Well, this was a short session. We didn't cover a lot of other things. And in the world of CRISPR related to your cardiovascular programs and your other -- your diabetes programs and others. So we'll have to come back to that on another session. But this is a good -- very, very helpful and enjoyable. So thank you both.

Thank you for having us..

Thank you for having us.

Good morning. Thanks for joining us for another session at the 44th JPMorgan Healthcare Conference. I'm Brian Cheng. I'm one of the senior biotech analysts here at the firm. On stage, we have Sam from CRISPR Therapeutics. I will now pass the mic to their CEO, Sam, for a short presentation, followed by a live audience Q&A. Sam, the stage is yours.

Good morning, everyone. Thank you, Brian, for the introduction. We're very pleased to be here today to present the progress and updates for CRISPR Therapeutics. Before I jump in, here are FLS statements. We're nearly a decade into our mission of transforming medicine with gene editing by developing cures for patients with serious diseases. And today, we're very happy to be in a very strong position with progress across 4 franchises. With heme, we have an approved product on the market today, together with our partners, Vertex in CASGEVY, which has a multibillion-dollar revenue potential. We continue to expand the addressable population that CASGEVY can address. And we have efforts ongoing for in vivo gene editing that can significantly improve access for patients suffering from sickle cell disease.

Beyond that, we have a tremendous focus on our in vivo platform where we're doing in vivo gene editing of the liver. We published transformative data for CTX310 in November last year, together with the publication, I'll talk more about that data for hypercholesterolemia. And we have a best-in-class RNA that we've expanded our platform with a partnership with a company called Sirius. And this is an siRNA targeting Factor XI that's in Phase II trials.

Beyond that, we have a very exciting early preclinical pipeline targeting LP(a), angiotensinogen for hypertension as well as rare diseases like A1AT. We're actually very excited about our CAR-T platform as well. We presented some data at the end of last year towards the -- in December with zugo-cel, which is formerly called CTX112. Very, very encouraging response rates in DLBCL and oncology setting, but also very exciting in the autoimmune setting for SLE myositis and a whole host of other diseases where we can do an immune reset.

We also have efforts, which may be new to most of you with in vivo CAR-Ts. And here, we have early data in the preclinical realm, which shows that you can actually achieve in vivo CAR-T with a single administration. And finally, with type 1 diabetes, we have proof-of-concept data from CTX211 in humans, which showed that cells can survive and be stealth in the body, and we're advancing CTX213 as a best-in-class islet-cell therapy for type 1 diabetes. Here's the pipeline and a snapshot showing the progress across these various franchises that I talked about.

But let me start with hemoglobinopathies. CASGEVY was approved at the end of 2023 in a landmark approval. It's now approved in multiple jurisdictions around the world. Our partner, Vertex, has set a tremendous groundwork in commercializing this therapy by setting up more than 75 authorized treatment centers around the world. And what you see in this chart here is tremendous momentum for CASGEVY between 2024 and 2025. The number of patients that are initiated have gone up 3x, the number of cell collections, the first cell collections have gone up 3x.

And now we're seeing that momentum translate into more cell infusions. We're very happy that we've reached the goal of over $100 million in revenue. The exact number will be disclosed by Vertex in a regular basis, usually in the regular communications. But the revenues are ramping up, and we feel very bullish about CASGEVY and its trajectory. And we want the momentum to continue in '26. One of the things that we highlighted in 2025 was the data in a pediatric population.

One of the things with gene editing is you want to treat patients earlier and earlier. The earlier you treat these patients, the less organ damage, the less pathophysiological effects that may happen from the disease. And what we showed are the data are tremendous for children in the 5- to 11-year age group for both sickle cell and thalassemia. And that will significantly expand the addressable patient population as well.

And what's been really reassuring is the payer coverage for CASGEVY has been good around the world. In the U.S., the CMMI pilot has been very successful and adopted now by most of the states that assures coverage for this patient population. And globally, I think we have very good coverage in Europe. And I think we're also seeing momentum around in other markets as well. In the Middle East, the coverage has been universally good in Saudi, Qatar, Bahrain, et cetera.

So overall, we feel very good about CASGEVY momentum in 2026. One of the things we do, and this is the same philosophy that's shared by Vertex is to have continuous innovation. Once we're very committed to sickle cell disease and beta thalassemia, and we are advancing gentle conditioning agents that would expand the addressable population for CASGEVY. And I think these gentle conditioning agents based on ADCs or antibody drug conjugates will be very meaningful in the patient experience, how long the patients have to be hospitalized and ultimately, I think how many patients can get CASGEVY.

Beyond that, we're also quite focused on doing in vivo editing of HSCs or hematopoietic stem cells. And here, what we're doing is taking the gene editing machinery encapsulated an LNP or lipid nanoparticle and directly injecting that into the patients. And that would edit selectively the hematopoietic stem cells. And if you're able to do that, you don't have to go through a conditioning or through an ex vivo transplantation. And that is a core focus for us.

On this platform, we've made tremendous progress over the last 2 to 3 years. And here is example data that we're showing in NHPs with a single dose of an LNP mRNA, and we show editing hematopoietic stem cells. And what you see here is that the editing is durable and kind of reaches its plateau of around 50%, which we believe is best-in-class for HSC editing. And if we're able to translate this, and I think the translation usually pretty -- it's not very difficult from NHPs to humans, although we have to go through many more manufacturing steps, et cetera.

What this shows is a proof of concept that you could do in vivo editing of HSCs, and that can expand the addressable population meaningfully, not just for sickle and thalassemia but for a number of other indications. There are many indications where you can directly edit hematopoietic stem cells. And these range all the way from diseases like SCID or the bubble boy disease to more larger diseases that are not rare that can be addressed with hematopoietic stem cell editing.

Now going to the in vivo vertical. What we presented data on November 8 last year with ANGPTL3 at the American Heart Association, and we had -- we garnered a lot of news because we're entering a new world in the world of heart disease. We published simultaneously in the New England Journal of Medicine. And what we have is a patient coming in and getting a single infusion over 2 to 3 hour, maybe 4 hours, and you get this infusion off the gene editing components and your liver cells are edited, in this case, for ANGPTL3. And within 2 to 3 weeks of that editing, you see a dramatic reduction in this case, in your cholesterol measures, LDL and triglycerides.

It's a onetime paradigm-changing treatment to treat severe hypercholesterolemia, severe hypertriglyceridemia and many of these conditions that ultimately lead to heart disease, MIs and heart attacks, et cetera. And so not surprisingly, got a lot of coverage. And the basis for this type of edit comes from natural history studies. On the left is this picture of a village in Italy, Campodimele, where there was a publication where they saw that nearly 50% of the population had a naturally occurring mutation in ANGPTL3. And these people all had hypocholesterolemia or low cholesterol levels of LDL and triglycerides.

And there's an association that they all live longer. So it turns out that they have less heart attacks, less MIs or less cardiac events. And the same thing was seen in the 2010 publication, which showed that for both heterozygous and homozygous mutations in ANGPTL3 control for other mutations that were not occurring in these patients, you could see that the LDL cholesterol is lower with 1 gene that's impacted and then 2 genes that are impacted, you get even lower LDL. And you want to be at that 50-milligram per deciliter target for LDL cholesterol and similarly for triglycerides.

And so what did our data show? We did a dose escalation study with 15 patients. And what we see is that at dose level 3.5 and DL4, which is 0.7 milligram per kilogram of the gene editing material, you get almost complete editing of ANGPTL3. Now 80% is about the max you can get because ANGPTL3 is produced both in the liver and other organs. So the liver production is about 80% of ANGPTL3. And what we're seeing is we're saturating edit, titrating the edit at about 0.7 mg per kg. And what that led to in these patients is a dramatic reduction in LDL and triglycerides.

At the highest dose, you had almost a 50% reduction in LDL cholesterol. And for those -- I don't know how many in the room will have or those listening have high cholesterol, but people try all sorts of medicines, statins, et cetera, you get 10%, 15% reduction. Sometimes it goes away if you're not consistent. Here, you do a onetime "Procedure" gene editing and you have a 50% reduction in LDL cholesterol. This is very, very powerful. And similarly, we saw a 55% reduction in triglycerides at the highest dose.

Now some of the data are jumpier because the baselines are different for different patients. Some patients may not have -- may have high triglycerides, but already had low LDL, so you wouldn't see a further reduction in LDL. But what's very remarkable in these data, one, is that even some of the patients had a PCSK9 therapy ongoing, and they still saw a dramatic reduction on top of a PCSK9 therapy, showing that ANGPTL3 is very synergistic with PCSK9. The second point is there were patients -- one of the patients had over 1,000 milligram per deciliter of triglycerides, for instance, which is very hard to control with siRNA.

There's an absolute limit to how much you can reduce triglycerides with an siRNA because it's that absolute limit. But gene editing, you don't have that absolute limit. And you saw dramatic control for even patients that have very, very high triglycerides. And overall, it's very safe. There were a couple of patients that had infusion reactions. There was -- were patients -- there was one death, but that was not deemed related to the therapy. It was well after the patient was treated 180 days later. But -- and this shows that the patients are very serious. They all are -- have had secondary -- the risk of secondary events for these patients.

But having a very safe approach for editing where you can have a onetime reduction of LDL and triglycerides, it's quite remarkable and paradigm changing, and I think it's going to change how we think about heart disease. The markets -- obviously, the market is huge because every patient with high cholesterol or high LDL or triglycerides could be eligible patient for this type of therapy. But for us, even in the near term, if you look at the very severe patient population, SHTG with triglyceridemia, the homozygous familial hypercholesterolemia or the heterozygous familial hypercholesterolemia and you take a subset of those patients that are very serious, for instance, those that have very high acute pancreatitis events, even that is a very, very big patient population.

So I think what we're sitting on here with CTX310 is it could be a multibillion-dollar opportunity and something that could have a dramatic impact on the cardiovascular landscape. Next, we're coming to LP(a). This is another one which is less known in a way. When you go to the doctor, people measure LDL and triglycerides, very few doctors measure LP(a). And it turns out as more and more studies emerge that LP(a) is 6x more atherogenic compared to even LDL cholesterol. And this has been shown with natural history studies, population studies and reducing LP(a) hopefully should alleviate any risk or secondary risk.

Now there's a major trial ongoing by Novartis, which is called the HORIZON trial, which is the first sort of trial that has a pharmacologic intervention with LP(a) reducing siRNA or ASO, and we'll see what the data show us from an outcomes basis. But what we did is we developed CTX320, which is our first-generation LP(a)-reducing agent, and we saw up to a 73% reduction in LP(a) levels from CTX320. Now we have the benefit and luxury of time before the HORIZON data come out and we can decide what our path forward is for a Phase II or a Phase III. And so what we've done is actually develop a second asset, which we call CTX321, which was in preclinical studies shown to be twice as potent as CTX320.

So if HORIZON trial shows that about 70% reduction of LP(a) is sufficient to have benefits and outcomes, CTX320 is there. But in parallel, what we'll have is CTX321, which should get us to 80% or 90% reduction of LP(a) levels. If you do the cross comparison between CTX310 and 320 and 321 based on NHP data or preclinical data, basically CTX321 can be projected to have much higher reduction of LP(a). And so that will dictate how -- at the end of this year, how we proceed forward with Phase II or Phase III studies, obviously informed by HORIZON trial.

Then we have 2 additional programs that are very, very exciting. One is CTX340 targeting angiotensinogen. And this is probably the only agent that has shown this level, 53 millimeters of mercury, this level of blood pressure reduction in this mouse model. No siRNA or no other agent has been able to do that. This is a dramatic reduction in blood pressure. And it doesn't happen when there's no high blood pressure. It only happens if there's high blood pressure, you get this reduction. So this is going to the clinic soon, and we'll have data on this not in the too-distant future.

The second one I want to talk about is A1AT. We have a new platform called synthase editing, which does very precise editing of the A1AT mutation that causes A1AT, which is the E342K. And this is very, very potent. Even at 0.1 mg per kg dose, we're seeing substantial editing and saturating editing at 0.5 mg per kg dose, which is lower than what we saw with 310, CTX310. And what you're seeing is a complete reversal from the Z-AAT, which is the pathologic version with the mutation to M-AAT, which is a normal version and on the right side there. And I think this is a best-in-class therapy for A1AT from a gene editing standpoint.

And then I'll talk about our siRNA platform, which is a new platform for us. We did a deal with Sirius Therapeutics in 2025. And with that, we acquired CTX611, formerly known as SRSD107, and this targets Factor XI. The anticoagulation market is a $20 billion market, but there hasn't been much innovation in this space for a long time because some of the DOACs that target Factor Xa have been very good at anticoagulation, but that comes with severe bleeding risk. And there are many, many patients that cannot access DOACs and still rely on heparin or other agents, including vitamin K because they're not eligible for DOACs.

Factor XI only works on one of the pathways that relates to thrombosis, but -- that relates to hemostasis, but if you target Factor XI, you can prevent thrombosis. And that opens up a huge opportunity where you could have an siRNA agent, it's once every 6 months that does the anticoagulation part without any of the bleeding risk. And that becomes the holy grail in the space of hemostasis and thrombosis. The data presented by Sirius are incredible. This shows that nearly 6 months out, you get 93% reduction with 95% peak reduction in the Factor XI antigen. And with siRNAs, it actually is reversible as opposed to antibodies. And that gives us another big advantage over antibodies as well in this class of medicines.

I'll skip forward. This is the clinical trial design. We have a Phase II trial that will have a top line data hopefully, end of this year, in the second half of this year at some point, and that will be the gold standard in the TKA study, the total knee arthroplasty study. We also have a [indiscernible] design with the CV study, which informs dosing paradigm going forward for this therapy, which also will generate a lot of data this year. And I don't have to belabor the market opportunity with this therapy. This is in the billions of dollars. This is a very, very large market opportunity. It will be competitive, but I think we have a best-in-class siRNA.

And then going on to CAR-T with zugo-cel, if you look at the CAR-T, it's almost -- it's over 13 years now since Emily Whitehead story and the emergence of CAR-Ts. And CAR-Ts originally developed in oncology, started with autologous, then there was allogeneic with healthy donors, allogeneic with iPS-derived, and then we have in vivo going from viral and nonviral approaches. And I think the blue areas of what CRISPR strategies are. We went with allogeneic with healthy donor, and that's what zugo-cel comes from, and the data looks very, very good.

Because we use editing, they're almost as good as autologous, but with the cost of goods is much lower and the ease and convenience of an allogeneic. And with in vivo, we're going with nonviral approaches because we think ultimately, that's what's going to win compared to viral approaches. So this is the design of zugo-cel and the 2 potency edits, the Regnase 1 and TGFbetaR2 make these very, very potent and almost autologous-like in its phenotype. And these are the expansion data.

So if you look at expansion data, when you put the CAR-Ts, zugo-cel in patients, one of the key things is how do they expand. And what we show here is expansion in NHL, which is in the oncology setting compared to expansion in the -- with SLE patients in the autoimmune setting. And you see comparable expansion. And the expansion here is much higher than any of the other allogeneic CAR-Ts or CAR-NKs out there. And you're seeing deep B-cell depletion on the right side. And this is just in line with autologous therapies where you have about a 90-day median for B-cell reconstitution in these patients.

This is very, very important. If the B cells come back in 20 days, you don't have the immune reset. You need to have a deep immune reset, similar to autologous therapies that we've seen data for. And here are data, and there's a couple of elements that are new here. We had -- in December, we showed patient data for one of the SLE patients who was in drug-free remission up to 6 months. And here, we show that, that patient is still in drug-free remission at 9 months.

And the second SLE patient also has gone down to SLEDAI score of 0. And by the way, these patients are severe patients. These patients have tried 9 or 10 other agents and not gotten better, right? And they take 1 dose of zugo-cel and they're SLEDAI 0, and it's an amazing improvement in their lives. These patients are young, young females who've had a dramatic change in their life after treatment with CAR-T.

In oncology, here are the baseline characteristics, very severe patients, all high risk, several primary refractory, all with SPDs above 2,000 millimeter square. And in these patients that are very sick, that -- many of them have actually gone through T-cell engager therapies and not responded, one even went through an auto CAR T before and then they were treated with zugo-cel and they had complete responses. This is remarkable. I don't think there's any other allogeneic therapy out there that has shown responses after auto CAR T.

And what we have is a 70% CR rate with zugo-cel in the oncology setting, which gives us a lot of confidence in moving this forward. At the same time, the safety profile is very tolerable with a 17% CRS rate, Grade 3 CRS rate. And what we're doing is further embellishing the prospects for zugo-cel in oncology by doing maintenance with pirtobrutinib. And we have this agreement with Lilly now to do -- to use a BTK inhibitor because what you're doing is you're doing complete B-cell reduction with zugo-cel and then you're preventing maturation of any remaining B cells, and that can give you very sustained and durable responses.

And this -- there was an autologous CAR-T data set released last year that showed that this combination can be very powerful. And I think this is something that could be a very important option for patients. There are a lot of elderly and frail patients, for instance, that cannot take R-CHOP even. They do mini R-CHOP. There are patients that are not eligible for auto CAR Ts that don't have access to auto CAR Ts. And I think doing this type of model where you do a deep depletion and get them to CR with zugo-cel followed by pirtobrutinib can be very important.

And finally, what I'll leave you with is our in vivo CAR-T approach. It's a very proprietary LNP system with proprietary mRNAs sequences and modifications that we've made for both transient CAR where we put the mRNA expressing the CAR in the LNP and you express the CARs that last a few days and deplete the B cells or any target that you're going after, but also integrating CAR-Ts that can have permanent CAR-Ts based on LNPs without using any viral elements.

And here are some snippets of data, and we'll have a lot more of these data over the coming year. But here is a monkey experiment where we express GFP instead of the CAR. And we show that day 1, day 2, day 3, nearly 50% GFP expression in 50% of cells express GFP. And these are T cells that are targeted. And that is actually best-in-class for NHP studies, showing expression for transient CAR. And what we show is very targeted. On the right side, we show in mouse experiments that if you do the same thing with the liver targeted LNP, you see a lot of expression in the liver or with -- but with the control or the LNP that we have, which is targeted towards T cells, you have no expression in the liver.

So it's directly targeted immune cells and you get very high expression. And this is data for transient CAR, but we also have permanent CARs we can make with the same solution where we actually integrate the CARs into the T cells. So that's very exciting. And then finally, with our type 1 diabetes effort, with CTX211, we saw really encouraging data where in 5 patients, we had C-peptide production out to 12 months. And you saw that means the cells were surviving without any immunosuppression out to 12 months in patients after implantation.

Now -- but we were doing this in a device context and the device did have fibrosis. So I think we want to get away from that device fibrosis and do directly injected cells. And we have CTX213, and here are data with CTX213 in an STZ mouse. This is a mouse that has artificial high levels of glucose. And you see glucose control within 14 to 15 weeks after implantation. You have C-peptide levels that are in the 1,000 picomole range with a pretty low dose of cells. And you already worked out the [ stealthal ] elements of this with the CTX211 trial. So I feel very confident about CTX213 and moving this forward, and this is probably best-in-class in terms of C-peptide production.

So final slide here, we have a lot to look forward to. We just have -- one of the things people say with CRISPR is we have so many things going on. But the good news is the technology is so powerful that we can actually do all of these in a very cost-efficient manner across franchises. We'll have updates on CASGEVY. We'll have updates on in vivo HSC on the heme franchise.

On the in vivo side, we'll have data for 310. We'll have data for 611, 340 and 460 will enter the clinic. And obviously, with the LP(a), we'll see how 320 and 321 stack up in comparison the HORIZON trial. And finally, with our CAR-Ts, I think we'll have data for rheumatology, but also we expanded that trial now to include ITP and wAIHA and similar to oncology. So it's going to be a very exciting '26 and actually a very exciting few years to come. And thank you for the opportunity and happy to answer any questions.

Well let's start the Q&A session. For those who are in the audience, if you have any questions, feel free to raise your hands. For those joining us virtually, you can submit questions on the portal.

Sam, lots of data updates in this slide deck, lots to digest here. Let's start off with more of a big picture question. How should we think about 2026 focus? There are multiple catalysts in front of us. Which component in the catalyst timetable do you think investors really need to take a close look at? Which program are you most excited about?

Yes. I think if you think about the value of the company, you can actually think about it in 3 parts. There's CASGEVY and the commercial aspect, right? And we'll have continuous updates on that. There are 3 Phase I assets that have shown exciting data so far, right? 310, we have 611, which is our siRNA and we have zugo-cel. And for all 3, the question is a little more data, but also what's the regulatory path forward? And what's the pivotal trials we're designing for those. I think that's as a company, those are things that we're working through right now, especially with the FDA and regulatory agencies around the world as to what that path forward is.

So that's the second part of the value. And then we have this third tranche of value or a third set of value drivers, which is all the preclinical assets that are going to become clinical assets soon. Like A1AT program could be a crown jewel for us, for instance. It's a best-in-class program that's better than any solution out there that will go into the clinic soon. AGT is something I was talking to some of the KOLs after our American Heart Association presentation for 310. And they were very, very excited about AGT because refractory hypertension is very hard to treat and is actually one of the main reasons for mortality for patients that are older.

And so that's another program, for instance, that's in the preclinical realm. And so that's sort of the framework for how we think about '26 as sort of this stepping stone pivotal year that tells you what the Phase II of the company is going to look like.

So since you mentioned pivotal trial for some of these early proof-of-concept indications, let's start off with AAT. I think this is where it gets interesting. You start to hear a little bit more clarity on the regulatory path forward there. What's your take for your AAT program as you start to really think about what that's going to look like 2, 3 years down the line? And just layer on top of that, how do you see your program differentiating from others?

Yes. One thing I'll say on the regulatory front is this FDA, I think, has been very, very supportive of gene editing. I've had a number of interactions with the leadership of the FDA, and they're very forward leaning. And you saw that with one of our peers' disclosures this morning about a pivotal trial that has 50-ish-odd patients, right? I think that's a very good sign for how the FDA are looking at gene editing.

And I think you'll probably see a similar path forward, not just in rare diseases, but also common diseases like autoimmune. We have to work through that. But I think that's -- I suspect that as the year unfolds, we're going to see a lot of regulatory clarity for a number of programs for us. On A1AT, the big question is, I think a lot of these types of diseases are going to get treated earlier and earlier in life. And what you want, if it's your child getting treated or someone you know, you want the best possible solution for that patient or that person suffering from this mutation or this disease.

And what you want is as normal phenotype of AAT production as you can get, which is in the 20 to 25 micromolar range. And so we'll see where our data stack up. But from a preclinical rat models, which are very predictive, it shows that we may be the best-in-class. If you take the same dose, 0.5 mg per kg and say how much M-AAT production is happening in these rats and just look at everyone else's data, we're far superior. So I think that's why we want to be -- we do think this is a very important value driver in our portfolio.

So I think if you look back at a year or 2 years ago, when you look at the same field, competition once to get at 11 micromolar, that's sort of the magic number that people want to aim at. As we think about the bar, I think certainly, the investor community has really shifted away from 11. We're shooting for higher. Where do you think the bar is now for your program? And ultimately, how do you win from the biomarker perspective? Is it 20? Or is it 25? Where do you think ultimately you want to show?

Yes. I mean there are a number of KOL calls and things that have happened in the last few months. But the closer you get to 20, the better off you are. Now does that mean that if you get to 18 micromolar, that's a bad solution for patients? Probably not. I mean that's actually a pretty good solution compared to where they are now, which is 4 to 5 micromolar of AAT production, right? And you want to do it earlier in life because you don't want any of the damage happening in the lungs.

And so the higher you get the better. And I think that's what I'm saying is if you have a program that gets to about 15 micromolar versus one that's 18, I think patients are going to choose the one that's 18. Now you have to put everything else in context, what's the safety profile, everything else, et cetera, what's the body of evidence on this trial versus another. But I think our goal, and that's the beauty of the CRISPR platform or gene editing is you can try to get near physiologic levels and get better and better and better. So that's our quest with every program. We want to make it better and better and better as we go along.

And then switching gear into the in vivo side of the story. The cardiovascular space, you're really moving forward with ANGPTL3 and LP(a). LP(a), the hurdle seems to be waiting for what HORIZON shows, then you pick the winner to move forward. Do you see the path forward here as kind of a pick one scenario where you're deciding to pick ANGPTL3 versus LP(a)? Or do you ultimately think that you'll pick one and then partner off the other assets?

Yes. I mean it's a good question. This is one of the things -- if you think about the 3 assets I talked about that have shown encouraging Phase I data, right, we have 310, we have 611, we have zugo-cel and we have LP(a). Can we develop all 4 on our own? Probably not. I think we'll probably need to partner one or the other. But I think we have the luxury at this point with our balance sheet to continue developing these to a point where we have to make that decision, which is not -- may not be in '26.

But that said, pharma interest is definitely on the ascendancy in terms of cell and gene therapy again. There was a period of time in 2018, 2019, everyone was very excited and interested. Then we had a few years where there wasn't as much interest from big pharma. But I think as we get into beyond rare disease into common diseases, we definitely are seeing a lot more pharma interest. So I think we'll have more optionality than people imagine in terms of what to do with these different programs.

And any questions from the audience?

My name is Charles Bruce, I'm from Mayo Clinic. I have a sort of broader question. How will society afford these? And how are you impacting early development with ultimately being able to afford all of these life-changing treatments?

Yes. One of the interesting things here is we're actually trying to reduce the cost of health care to the system. If you -- and we're working with Mayo Clinic on trials, for instance, with the first-generation programs like CASGEVY, they are expensive because they're very expensive to make. But if you look at our cardiovascular programs, it's not hard to imagine that these could be priced sub-$100,000. And if you look at siRNAs that are priced at $10,000 to $15,000 per year, and this is a onetime solution, you're actually creating pharmacoeconomic benefit to the system by using gene editing.

So same with our allogeneic CAR-Ts. Our allogeneic CAR-Ts now are on a per patient basis, truly less than $10,000 per patient. In fact, we're doing trials now in India with an allogeneic CAR-T because they just can't afford autologous CAR T. So I do think onetime interventions sort of gene editing procedures will reduce the cost eventually. But we have to be able to continue investing in the near term to get to that point. It's not going to be an immediate switch.

Dr. Diana Ramos, California Surgeon General. This is very exciting. My one question is, are there any outcomes and differences compared for race and ethnicity? I know there's some response differences for black communities, specifically for hypertension medications. Do you see any of that with the medications or with the CRISPR technology? Or are you looking at that?

Yes, absolutely. There are lots of differences. In fact, if you look at PCSK9 and the identification of PCSK9 as a risk factor, there was a parallel research going on in France and from -- with a physician in Montreal, who is a scientist out there in France and then one in Dallas. And the Dallas population had a lot of the -- had a higher proportion of black participation in that trial. And there's -- what we've seen is there's SNPs that are out there that are specific by race that render risk differently to different populations.

And so this is something that's going to -- as we get more and more sequencing, we're going to learn more and more about. And in fact, the thalassemia that you're seeing in Thailand is very different from the thalassemia that you're seeing in the U.S. And so we can actually treat all of them differently now as opposed to sort of a blanket trial that says, here's a dose based on a general population versus a tailored solution.

Neil McCallum, nice to be here. I'm just curious your take on AI and clinical trials.

Very, very broad question. And it's -- well, I'll just tell you is what AI is doing in the world of CRISPR. It's actually generally in the pharma world is impacting efficiency of trials, how we think about reducing the cost of trials, et cetera. But for us, the places where it's coming into play the most is protein folding, but now also mRNA folding and mRNA secondary structures when we design mRNA for CRISPR. Then the third one is guide selection or where to interrogate in the genome and AI is helping. The data sets are not as big as some other areas, but it's getting bigger. So those -- our AI efforts right now are largely focused on the preclinical realm and not yet going into the clinical, but eventually will.

I'll ask the last question here. When you look at the cell therapy space, I think your peers have seen a lot of challenge in getting the credit for things like autoimmune and B-cell lymphoma. What's your take on that? And how do you see zugo-cel kind of breaking that barrier where we sit today?

Yes. I mean I think it's for a good reason. I think a lot of the allogeneic therapies, the first-generation ones were not as good as autologous therapies, right? And I think we want the best solution for patients. And in the oncology setting, if you kill 99.9% of the cells versus 100% of the cells, the cancer is going to come back. And what we did is our first generation similarly was not as good as autologous. But what we did is continuously innovate and now we have zugo-cel, which is a second-generation product that seems to be as good as autologous with all the convenience.

And I think that's when you're going to see credit as we can generate more data. And in the autoimmune setting, you get 99.99% of the cells. That's actually still a very good outcome because it's not a tumor, it's not going to come back as easily. So we are very, very bullish in the autoimmune space. We're expanding trials. We mentioned ITP and wAIHA, but we're going to go in targeting other indications as well. I think the immune reset concept is going to be a major way we treat autoimmune diseases.

Thank you so much for your time. That's all the time we have. Thanks for joining.

Great. Good morning, everybody. Thanks for joining us. I'm Terence Flynn, Morgan Stanley's U.S. biopharma analyst. Very pleased this morning to be hosting CRISPR Therapeutics. And today from the company, we have Sam Kulkarni, who's the company's CEO and Chairman. Just before we get started, for important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

Sam, thanks so much for joining us today. Really appreciate you taking the time to be here with us.

I thought first to start, we'd start on strategy. And so obviously, the company has CASGEVY approved with Vertex, and you have 3 additional pipeline areas in cardiovascular, autoimmune and oncology, which I know we'll talk about. But maybe you could just talk about your priorities, what you're focused on for the remainder of this year heading into next year, and then we can dig into some of these topics.

Yes. Thank you, Terence, for having us. It's always great to be back at this conference. We're sitting in a very interesting place as a company. We're about 10 -- more than 10 years into the journey as a company to take this powerful editing platform called CRISPR and turn it into transformative medicines. And 10 years out, we have one approved drug in CASGEVY, which I'll talk more about, and we're very encouraged by what we're seeing and how it can change the lives of patients with sickle cell disease and also what it means for us as a company. But we're then sitting on a number of pipeline drugs where we're going to have readouts in the next 12 months.

As you said, we have different verticals. We have our cardiovascular vertical where we have -- we're going after important targets like ANGPTL3 and Lp(a) with gene editing in the liver, this is in vivo gene editing. And we also have an siRNA targeted towards Factor XI that kind of was a nice bolt-on to that cardiovascular franchise. So that's sort of one pillar that we're quite focused on, and we're building capabilities.

The second pillar is in autoimmune and oncology with the same asset, CTX112, it's a CD19 allogeneic CAR-T. Now I know there have been lots of ups and downs in the allogeneic field, but I think we truly have the best-in-class allogeneic CAR-T that acts just like autologous CAR-T. And in autoimmune disease, I think this could have transformative potential given what we're seeing with the data with autologous CAR-T. And if you can recapitulate that or replicate that with allogeneic CAR-T, I think it's that much more scalable across a number of indications. Obviously, there's a lot of news about in vivo CAR-T, and I'll talk about how that plays out. And again, in oncology, the opportunity remains even after having all these auto CAR-Ts and bispecifics, there are still a number of patients with DLBCL that don't get access to any of the advanced medicines. So we continue to pursue our oncology efforts with CTX112.

And then finally, I think as we look beyond that, we have other drugs that we're developing in our diabetes field. There's a publication showing you can actually transplant islet cells into a patient and they can be hypoimmune for several months. And I think we have something that could be very competitive in the diabetes space as well. So all in all, I think we're feeling very good about the pipeline, lots of readouts to come over the next 12 months, and we're, from a balance sheet standpoint, really well positioned to prosecute all these assets.

Yes. Okay. Great. That's a good segue to my next question is just obviously, a lot of different programs you walk through right now. You guys do have one of the stronger balance sheets in the SMID-cap biotech space. But are there select opportunities to partner here? Obviously, you took that approach with Vertex. But as you noted, the company was maybe in a different place when you did that deal. So how are you thinking about the opportunity set on partnering business development here on the forward for a lot of these different assets?

Yes. I mean we definitely have seen a lot more pharma interest in the last year than in the 2 preceding years. I mean, I think in the 2018, '19 time frame, we saw a lot of pharma interest and it kind of ebbed and flowed a little bit. What we've realized -- we come to the realization that if our cardiovascular assets work, when I say work, they're like best-in-class, they have really good data, and they have autoimmune potential. We may not be able to take all these forward ourselves, not from a dollar standpoint, but from a resource and bandwidth standpoint. And so we have seen a lot of partnership interest, particularly in the cardiovascular area lately. You saw a deal this morning for another important target IL-6 in cardiovascular.

And that's, by the way, how we ended up with Factor XI. We were pursuing ANGPTL3 and LPA, and we were talking to a lot of the key opinion leaders about what are the targets that we see that's really interesting. And Factor XI kept coming up. And by the way, the other one that came up a lot was IL-6 in ASCVD. Now LPA is a -- could be a huge blockbuster, a number of people with high LPA and it's recognized that it's very high atherogenic risk. And so there's a lot of interest there. There's emerging interest in ANGPTL3, especially with the recent deal that we saw with siRNA and ANGPTL3 as well. This could be a target that could be better than PCSK9 potentially even for LDL reduction.

We'll see how the data all turns out when we put it all side by side, but not just triglycerides, but also LDL reduction. And autoimmune, there continues to be interest. There is a little bit of churn in the space as people -- as pharma companies try to figure out what's better. Is the best solution for a patient in allogeneic CAR-T with the condition that we have right now? Is it -- or is it in vivo CAR-T where there's no conditioning, but you have to do repeat dosing. And I think my belief is allogeneic CAR-T is better. And in fact, especially as we get to gentler conditioning, you see much better elimination of these germinal centers in the lymph nodes in the secondary -- if you take secondary lymph node biopsies, et cetera.

And I think there's interest there as well. So long story -- long-winded way of saying that we haven't made any decisions on what we would partner right now, but there is -- continues to be a lot of discussion with pharma. And I think over the next 6 months, I would say, as the cards unfold on our data, I think we're better positioned to decide what we want to partner and what we don't want to partner.

Okay. Great. Do you see most of the inflection around your own data? Or are there external data points, too? I mean, Lp(a) for example, I know Novartis, everyone is kind of waiting for their study or what other external data points? Or do you think any of these companies are kind of looking to as they think about opportunities?

Yes. I mean I think that is -- the HORIZON readout from Novartis is an extremely important readout for the space in general. I think that -- and it's one of the reasons we're positioning behind that. I think what we want to do is we want to position our gene editing assets ahead of some of these -- or right around some of these big readouts. And HORIZON trial for Lp(a) will be the first trial where in spite -- we know that with all the population studies that low Lp(a) is better. But does the pharmacological intervention or pharmacological reduction of Lp(a), does that lead to better outcomes or not? That's going to be the first readout.

And then what is -- what are all the subsets we're going to see? What does it matter if they have high LPA and high LDL versus low LDL. I think I'm very interested in some of the subset analysis. And I think it will most likely read out positive and the subset analysis will be very interesting. We're positioned ahead of that. And I think that can be a very valuable asset for us. And then as I said, there are trials around Factor XI as well with milvexian and the recent acquisition by Novartis of Anthos. I think that trial will read out next year as well. And those will position us as we begin our Phase II study here.

Okay. Great. Just one last one on the strategy front. You are talking about the policy environment right now. I'd just be curious to get your take on kind of FDA and genetic medicines broadly, where you think the pendulum stands in terms of your kind of FDA interactions? And are they leaning in on genetic medicines? Are they being more cautious as you think about the framework that they're approaching these therapies through?

Yes. My take is the leadership of the FDA, Dr. Makary, in particular, are leaning in on genetic medicines. How much that's percolated into all the teams on the ground level is it takes some time. I think, for instance, very close to Peter Marks before as well, and we worked on quite a bit on CASGEVY. The previous regime, I would say the FDA were leaning in -- would lean in more on clinical data but had very high requirements around CMC. And I think that's one of the reasons the entire cell and gene therapy space was a little bit at a competitive disadvantage, which is it costs a lot to develop these assets.

And now that we have an siRNA asset, it's almost 3x cost to get to human POC with gene editing versus siRNA, even if it's in vivo. And that's just not a good competitive situation as you have all these competing modalities. But I think this regime is very sensitive to that. And I think there's active work ongoing to both change guidelines and regulations to make it such that they can do clinical trials in the U.S. easily, have some of the CMC requirements be phased where you don't have to do it all in the early going.

So that's a very good development. How the current regime is positioned relative to data and how they look at approvals, et cetera, it's an unknown. We don't know yet. There haven't been good case studies where they've had to make a decision one way or another. There will be a few coming up actually in cell and gene therapy. So all in all, I'm pretty encouraged, and there's actually a task force looking at everything quite closely on the regulation side. So the next few months will tell us where we may land.

Yes. I know the commissioner had done these like listening tours. Did you get any feedback from any of those or hear anything from the biotech listening tours?

The listening tours were 90% listening and very little feedback. But off the record, there has been feedback. I think just around the complexity of what's been built on the regulations. I think with cell and gene therapy, we have these guidelines and regulations all overlapping, right? So it's unclear how -- one, what's the primary thing to go by is the guideline or the regulations. And the second is oftentimes with these CBER drugs, too, the therapeutic area teams have come in at a certain point of the drug to help. And so who's primary? Is CBER still primary? Or is it the division of hematology, for instance, that actually makes the decision. I think some of those things are being sorted out, and I would say they're getting decluttered to a certain extent.

Okay. Great. Maybe we'll move over to CASGEVY. Can you kind of give us an update on the launch? I mean, I think you and Vertex posted sales in the second quarter of about $30 million. You've reached your target of activating 75 sites. And I think about 250 patients have been referred into those sites. And so maybe just talk us through some of the dynamics that brought you there, but also on the forward, how are you thinking about the outlook? I'd say back half is pretty well understood. But as we think about '26, maybe you could just give us some of the puts and takes that we need to consider as we think about the run rate.

Yes. I mean for those who are not familiar with CASGEVY, CASGEVY is an autologous cell therapy product. We're taking the patient cells. It takes a 2- or 3-day collection cycle to take the cells and send it to our manufacturing facility, manufacture it, send it back and then the patient has to undergo chemoablation and then they basically get the cells and then hopefully, it's a cure for life. I think the sales cycle or the way the commercialization model works is much more akin to medical devices than it is a traditional pharma launch. You're selling a mini procedure in a way. And the same thing happened as in medical devices, let's say, you're getting a hip implant or something else. You kind of get -- you see the doctor, you get measured for it, things are ordered, then you schedule surgery and then you get the surgery. It used to be a lot longer cycle, will get shorter and shorter over time as the centers get experienced.

But I'm very encouraged by the fact that we have over 75 ATCs or authorized treatment centers globally, 10 countries or 10 jurisdictions where CASGEVY is approved, very strong payer reimbursement. And if you look at the trajectory of patient initiations or referrals, that's already starting to inflect. And then the question is how long before it starts -- the cell collections start inflecting and how long before the revenues start inflecting. So there's like a 3-part funnel with CASGEVY revenues. One is how many patients are coming in. And it's very clear to me that the demand equation is not the problem. There's a lot of demand from patients. And the word of mouth and everything else that's happening in that population is pretty strong.

There's like WeChat groups and WhatsApp groups and all that kind of stuff. Then the question is there's -- it's taking a little time in cell collections. And the reason for that is a lot of patients are opting to do exchange transfusions where they get transfusions for a couple of cycles before they go in and schedule a collection. Some patients are choosing to do fertility preservation ahead of doing the cell collection. And then you get to the cell collections.

And after the cell collection, the manufacturing itself is relatively fast. Some patients may require more than one cell collection, but even if it after it's manufactured, there is definitely a patient preference of when they want to get dosed because they have to be in the hospital for 3 weeks or so. And some -- a lot of patients in the U.S. don't want to get dosed in the summer. Patients ex U.S., may want to get dosed in the summer because there's nothing else they can do during that time. So there's definitely some interesting dynamics in terms of how this all goes. But if you look at the secular growth in patient initiations, you're going to see compounded growth for a long time to come, and that gives me a lot of confidence.

And when you look at the referrals into the sites, is it pretty equally spread out? Or do you have kind of like almost like a concentration among kind of the big sites that were involved in the trials? Or is it pretty evenly spread across these?

There's definitely different sites with different productivity. I think if you look at the Yescarta sales at the end of the day, the sites got to a point where they were doing 8 to 10 a month, right, once they got fully used to doing an autologous product. And I think you might see the same increase in productivity over time with the sites. So not only do you have more sites, you're going to have more productive sites. And that's just going to lead to greater and greater throughput of cell collections, and that's the key to dosing patients. There's really not much falloff once your patients get their cells collected to actual revenues, although it takes a little bit of time. So I think that -- those are all very -- those are leading indicators, and they're very positive looking ahead into the next couple of years.

Yes. And where is most of the falloff? Is it from the referral to the cell collection? Or is it from cell collection to infusion? Like meaning which step would a person decide like, okay, I'm going down this path, but then they -- for whatever reason, they make a decision not to. Does it happen upstream? Or does it happen more downstream if you look at it on a percentage basis?

Yes. Once you get cells collected, I think very little fall off. I think from referral to collections, also, there's been no falloff because we have a pretty strict criteria for what we call initiation or referral. I think by the time they've come into sort of gone through the referral and everything else, they generally have done prior authorization and already get scheduled for collection. So I would say that, that funnel is pretty tight in terms of the correlation between referrals and ultimately revenues.

Okay. And just 2 more here before we go to the pipeline. The CASGEVY JV profitability, just remind us kind of how you guys have framed that, where you are in that ramp? And then what that means for your balance sheet, I guess?

Yes. I mean I think our goal as a company is to be breakeven, if not profitable by 2028. And it's something that we've said in the past, too. I think we feel like that's a real possibility. In terms of near-term profitability on CASGEVY, we're not commenting on that. Vertex may do some guidance early next year. But in general, I think with the franchise, one of the things we also realize is that the costs do go down in some areas beyond a certain point, especially as we finish up clinical trials. We have clinical trials ongoing right now for a pediatric population. There's long-term follow-up, et cetera, but some of those costs will start coming down as well. So the true cost of commercialization or the classical SG&A is not as high as people think it is. COGS obviously are higher than a typical pharma launch. But all in all, I think we're happy with how the profile is developing.

Okay. Do you anticipate an improvement in cost of goods over time as you get more throughput? Or is COGS more of like steady state at this point?

No, absolutely. I think we're -- Vertex is now leading the charge to continue to improve both cost of goods from a cost perspective, but also just making it more seamless, faster manufacturing, faster throughput in a way. So lots of efforts ongoing. We continue to invest. We're all very bullish.

And you mentioned in vivo approaches broadly in the beginning in terms of some of your pipeline opportunities. We do occasionally get questions on in vivo editing approaches for sickle cell beta sale. Just maybe update us kind of your thoughts on how far away those are, if there's any prospects that those could ultimately reach the market.

Yes. Eventually, I mean, I think the way we see the life cycle, obviously, Vertex and us are very committed to the space. So we're all in, we're doing all approaches. The next step might be gentle conditioning. I think there are a lot of agents out there that have shown tremendous progress on gentler conditioning. These are ADCs where you can actually selectively ablate the long-term hematopoietic stem cells and not ablate the neutrophils, et cetera. So you don't need a much longer hospital stay, it's possibly a 3-, 4-day hospital stay to get these cells transplanted, the side effects of potential busulfan, et cetera. So that might happen in the next 4 years.

And I think in vivo HSC editing could be 8 years by the time it's on the market. While I'm very encouraged by the fact that we can actually edit in vivo now in mice and NHPs, one of the things that's really important is you actually want to have a very selective profile. You want to edit only the hematopoietic stem cells and not other cells because for a disease like sickle cell, the bar will be high in terms of off-tissue editing. And I think that work, we're spending a lot of time thinking about that and there are ways to do it. It will just take some time to move through clinical trials.

Yes. Okay. Great. Maybe we'll pivot to the pipeline now. We'll go through cardiovascular first. We were talking a little bit about Lp(a) at the beginning. Maybe, I guess the one update from your program is your data now is coming first half of '26. So maybe just talk to us about what drove that? And then as you look at that Novartis data that's coming out, what are you going to be most focused on there beyond just obviously the kind of primary endpoint? Are there any other nuances as you think about, okay, should we pull the trigger to advance our program further because of XYZ, which we saw from the data?

Yes. I mean I think it made sense for us to wait for the HORIZON data. I think the key things we're looking -- first of all, is LP(a), pharmacological reduction of LPAs that result in better outcomes, right? And one of the things that we're looking for from the data -- that data set would be how does the level of baseline level of LP(a) correlate with improvement in outcomes. I don't know what the powering is going to be as you look at people with, let's say, greater than 200 nanomolar per liter Lp(a) versus greater than that or something like that, right? So there's different cutoffs that we want to look at. And that's going to be important.

The second is how does -- how do other markers correlate? Like, for instance, if you have high LDL and high LP(a), is that far worse than high LP(a) alone, for instance, and low LDL or normal LDL. And I think those 2 are really important markers I'm looking for. Other than that, I think there'll be a lot to learn in terms of level of reduction needed. Everybody talks about reduction in terms of percentage terms, right? Even Lilly presented their data, and they basically were saying that they're getting 90-plus percent reduction. But it all depends on baseline. I think what is the target you want to get to.

With the LDL world, it's very straightforward, just get it down as much as possible. In the LPA world, that paradigm has not been set. And I think at the recent ESC conference, there was a lot of discussion about what is the target on LP(a) reduction. And I think there was always a school of thought that Europeans had a different view versus the U.S. -- American cardiologists, and I think they arrived somewhere in between as to what the ideal target is for LP(a) reduction. So those are all things we'll be watching for ahead of presenting our own data on Phase I.

Yes. And what about -- this is obviously a secondary prevention trial. I know the companies have talked about high-level primary prevention studies as well. How do you think about translatability from here to primary? Because when we talk to the KOLs, they'll tell you that primary is the bigger commercial opportunity, and that's really where you need to get to. So how much read-through is there in your view from this study to primary?

Tremendous readthrough. Ultimately, as humans, I think we are going to be in a different world where we're going to see risk factors and change of risk factors early on in life. We had this case of a 22-year-old kid who came -- whose LPA levels were like 600 nanomole per liter. That kid's father, uncles all had a heart attack in their 40s. You know this kid is going to have an MI event or some MACE event early in life. And it's genetic. You know that the levels are high. So why would you not reduce the levels of LP(a). And I think that's one example. But the -- and by the way, the administration is super interested in this.

I actually did a fireside chat just like this with Dr. Oz, and he's highly interested in LPA. And he's like these are -- as you think about national priority vouchers and things like that, these are national priorities in their mind, targets like LPA, things that are a huge burden to society in terms of not just cost of the health care system, but productivity, et cetera. So then there's -- you take something like Alzheimer's. If you're born with 2 copies of APOE4, if I knew I took over APOE4, I've been doing everything I can to say, how do I prevent this risk of Alzheimer's. You know you're going to get it. It's just a matter of when.

So I think we're going to get to a world where people are starting to do these longevity genetic tests now, and you can do these 15 tests and tells you what your longevity score is, for instance. And LPA, Alzheimer's, et cetera, is on there. And you're going to want to change these early on. So the world is going to move towards primary prevention. I don't know what the regulatory framework required would be to get to that point. We just want to make sure -- that's why I think this world is going to change. We want to be -- this is going to be a secular growth space in gene editing. We want to be around to see all those major inflections. But I think LPA will be one of the first test cases for primary prevention.

And the National Priority Review voucher, is that your speculation? Or do you think Dr. Oz is -- there's already companies that are talking to them about that for Lp (a)...

Well, Lp (a) is one example, but I know there are a lot of companies talking to the regulators to see what the National Priority Voucher really means because there are elements of national competitiveness in there, what the target means for the American population. And I think it's not 100% clearly defined what they meant. But I think these types of targets do make sense from what we're hearing, which is reducing overall cost of health care, right, is a national priority. American competitiveness, getting ahead on certain medicines ahead of other countries, and obviously, all the unmet need for patients, et cetera. Not to say that Lp (a), we haven't heard anything directly on Lp (a), but those kinds of things seem to fit with what we've heard.

Okay. Great. Maybe before we get to ANGPTL3, I wanted to go to your Factor XI because again, I think this is a newer program for you. But maybe just from a strategic side, first talk to us about the decision to go into RNAi or siRNA here with this given your platform in kind of CRISPR and how this aligns with that platform?

Yes, absolutely. As I said, the origins of looking at Factor XI was we were quite enthusiastic about Lp(a) and ANGPTL3. We were having a lot of discussions with different key opinion leaders. And we always have -- when [indiscernible] dinner with them, we'd ask them what else are you interested in? What else is interesting in the target space? And Factor XI came up a lot. People said, look, there hasn't been much innovation in the clotting anticlotting space for a long time. It's similar to what happened in LDL. You had this dead period of like a decade where not much innovation happened after these big CTEP trials that failed. Everybody got out of it.

And then there was like this -- now there's a boom in terms of lipid management happening right now from an innovation standpoint. The same thing that happened in the anticlotting space. And the other one that came up was hypertension. There's all of a sudden new renewed excitement in the hypertension space that after sort of a decade where there wasn't much happening. And so we looked at Factor XI and said, this is not something on gene edit, right? They want to permanently reduce Factor XI. But the holy grail of preventing clots and everything else is you want to prevent clotting, but you want to not have bleeds because those -- you could be on Factor Xa after surgery and then you like hit something in the shower and you have a nose bleed or something like that, and you could literally end up in -- you could die or you end up in the ER because it's uncontrolled bleeding, right?

And these bleeding events happen, and some of these are external bleeding events. Others are internal bleeding events that could cause other complications. And so Factor XI is very interesting. You get APTT levels above 2 on a sustained manner with this siRNA. And we found this siRNA, this is a former Arrowhead CSO who founded this company with sort of the next-generation backbone modifications and siRNA that lead to durable 6-month effect. And a lot of the Arrowhead drugs right now are on a 3-month dosing schedule. I'm sure they're working on longer term, but the siRNAs were moving towards potentially even once a year. It's that durable. It's all the modifications that are being made.

And so if we have a -- and what we have -- we got with this deal from Sirius is a Phase II-ready asset. The Phase Is -- 2 Phase Is have been completed. The Phase II is starting now in a TKA study at total knee arthroscopy, where we're comparing with the low molecular weight heparin to see if you can prevent clotting post surgery with one injection that's done presurgery, and you don't have to worry about it for 6 months. And what are the bleeding rates associated with that, right? And so that's really -- this study is a key sort of leveler. It will tell you where you stand versus milvexian, asundexian or other siRNA or ASOs that are in the space or antibodies, which we have from both Novartis and Regeneron now. All in all, I expect excitement to only keep going up with this target.

Yes. What -- I mean, how do you think about that long half-life because on one hand, it's good from an adherence perspective. But on the other hand, if there is some issue with bleeding, like how do you think about that as the trade-off if you do need to like, for example, like my father is on warfarin, for example, had a surgery, he had to go and he had to come off of the warfarin. So how do you think about that trade-off?

Well, that's the beauty of siRNA. You can just supplement with factor or other ways, too. And that just reverses it, right? With antibodies, it's actually very hard to reverse it, if you have, with the Anthos and the Regeneron antibodies, this once-a-month dosing. But if you have a complication, I don't know what their strategy is going to be, but it's actually hard to reverse it because even if you add factor, it still binds to it. With siRNA, you don't have that complication. So it is actually a beautiful setup, long-acting, but has reversibility. And I think once in 6 months is probably durable enough. I don't think you need to get to once a year in this setting. In fact, you probably don't want to because you want to see your physician every 6 months.

Yes. What -- and then I guess the other question that we get a lot more so for the oral Factor XI is read-through from the various programs to each other. And so as you think about, I think Bayer has guided to seeing some data for their program, asundexian later this year in secondary stroke prevention. Again, similar to the Novartis question I asked you earlier on Lp(a), like what are you looking for in that data set to maybe give you confidence in your program or inform trial design? Because TKR is always, like you said, like kind of proof of concept, very quick readout, easy, but you typically do it versus Lovenox or something. But for these bigger Afib ACS, SSP, I think there's still a question about like what people want to see from these bigger studies. So what are you focused on?

Well, I think 2 factors of asundexian, which is one is there's a lot of controversy about they had their own proprietary assay for asundexian, how much target engagement were they getting, right? And I think when you're going after -- with the small molecules, you're going after the activated Factor XI, so not Factor XI itself. And so there's a notion that by the time the small molecule acts, you already have an activated Factor XI that started to cascade through Factor Xa. And so with the siRNA -- advantage of siRNA is you're actually preventing Factor XI from even being formed, so you don't have Factor XIa.

So you may get a very different target engagement with Factor XI siRNA versus the small molecules. And I think the current thinking in the field is that milvexian may be a stronger binder than asundexian. So milvexian readout is going to be very important. But that said, I think one of the things that these big pharmas were trying to do is directly go up against the Factor Xa inhibitors, which are amazing drugs, right? I mean our goal is not necessarily to beat them and show that Factor XI is better than Factor Xa drugs in all these indications. But there is a significant population of people that are ineligible for DOACs. They just can't take DOACs for various reasons. And in all those patient populations, Factor XI is a beautiful solution. And I think there's different reasons for why they're ineligible, but that's one setting.

The second setting is, I think in cancer-associated VTEs and sort of venous thromboembolism indications, definitely, this is the only solution that actually makes sense versus DOACs. And then there are patients that have multiple complications like warfarin, like you mentioned with your father. There are actually people who are -- who genetically can't take warfarin, for instance. It's a very complicated space. And patient by patient, depending on what other drugs they're on, this could be a very low burden drug they can add on to everything else they're taking.

Great. Maybe just -- I think we've got 1 minute left. So just on any last catalyst you want to highlight quickly of the other programs that we should pay attention to before you end?

Yes. I mean I think CTX112 and allogeneic CAR-T, this is the only allogeneic CAR-T that has shown expansion levels of -- to show up to 50,000 copies per microgram. That's sort of the traditional currency which you measure cell expansion. So autologous CAR-Ts, Yescarta and Breyanzi and others, they get to that 50,000 level copies per microgram and some slightly less, some slightly more. All the other allogeneic cell therapies, whether it's NK cells or T cells have gone to about 5,000 copies per microgram.

And CTX112 with the edits that we've made is the only one that gets to autologous-like expansion without the same side effects of CRS or ICANS. It's -- actually, it's a really great asset. We're developing in autoimmune diseases. And all the data from Georg Schett indicate that you could get 99% ablation of B cells, but it's the last mile that counts. You want the last mile ablation in the germinal centers that are formed by these B cells. And if you don't do that, the disease is going to come back. And I think that we have confidence that our asset could get to that 100% reduction, which will be very powerful in autoimmune disease.

Great. Well, thank you so much, Sam. Really pleasure and best of luck.

All right. Thank you very much.

Hello, everyone. My name is Mitchell Kapoor. I'm a senior biotech analyst at H.C. Wainwright. Today, I have the pleasure of welcoming CRISPR Therapeutics. And from the company, Raj Prasad, CFO, is joining me today. Thank you so much, Raj.

Thanks for having us.

So maybe to set the stage, you can just give us an overview of where we're at with CRISPR today, CRISPR Therapeutics. A lot has transpired over the past -- since the year started. So could you just level set for investors and then we can jump into more specific questions across the pipeline?

Yes, absolutely. Yes, it's been an exciting time at CRISPR. We're going through the launch of CASGEVY with our partner, Vertex, where things are going well on both cell collections and revenue from infusions of patients. And we're hearing the feedback of the patient community as well, which is fantastic. It's great to have a transformative medicine out there and especially the first one using CRISPR/Cas9 technology.

What we've done since then is we've been busy. We've been parlaying the technology into multiple therapeutic areas outside of our hemoglobinopathies franchise. So we have wholly owned internal programs in autoimmune and oncology. We have programs in cardiovascular medicine, rare diseases and type 1 diabetes. And if that wasn't enough, we expanded our technology basket with a deal with Sirius Therapeutics earlier this year to bring in some siRNA technologies with the thought that gene editing might not be the best approach for every indication.

And we think that RNA has certain areas where it can build upon and be synergistic with our platform gene editing technology. So we did that with the lead asset where we're 50-50 on it for Factor XI, which is in the anticoagulation space. And we think it's an extremely valuable asset as well that will be one of the biggest targets going into next year with a competitor trial abelacimab that will read out sometime next year. So tons to talk about. I'm sure you do have some follow-up questions, but we could not be more excited about where CRISPR Therapeutics is sitting at this point in time.

Yes. And so with so much going on, so many different verticals in the pipeline, a key question that we spend time on is capital allocation trade-offs and how big is this business? Where do you spend time? So you have CASGEVY, you have in vivo cardiometabolic, allo-CAR-T, sRNA, diabetes. What, I guess, hurdle rates do you have to keep or partner assets?

Yes. I mean we think about this question like every day. The key point with our next suite of programs is we've invested a lot of time and effort over the last several years in creating next-generation medicines that are actually at a low cost of goods sold or will be at a low cost of goods sold. So with the allogeneic CAR-T program, we've made a significant effort with our manufacturing facility in Framingham, Massachusetts, to produce allogeneic CAR-Ts at a fraction of an autologous CAR-T therapy.

Similarly, the in vivo program, it's a lipid nanoparticle plus mRNA, significantly low cost of goods so that we can be extremely competitive while also offering potentially onetime durable cure to patients. So when we think about the return on invested capital, the margin profile of these next-generation products are going to be extremely high at a reasonable cost at this point. When we think about our portfolio more broadly and where to add the incremental dollar, there's obviously the return on investment, there's the market opportunity.

But then we also need -- we also have the experience of having an extremely successful partnership with Vertex and CASGEVY where we were able to bring this transformational medicine forward and continue to commercialize it successfully. So we are being very thoughtful of that. We do have a good cash balance. We have $1.7 billion on the balance sheet. So we don't want to do a hasty deal, and we don't want to do a deal where we haven't fully fleshed out the target product profile, the competitive landscape and what we can bring to the table versus maybe a strategic partner.

But we are continuing to sort of analyze that as now we are reaching hPOC or human proof of concept across all these programs. I think that's going to be an important question that we hope to answer in the near term.

Okay. Great. Yes. And in the space after the Ver Lilly deal has kind of showed renewed interest in gene editing platforms and the ability to integrate those into like a broader play. How is CRISPR in vivo gene editing engine with ANGPTL3 Lp(a) [ AGT ] position as a platform partner. What's underappreciated about kind of the ability to scale this platform?

Yes. I mean I mentioned the COGS point earlier. I think it was good to see -- the Lilly see the landscape of genetic medicine similar to the way we do, I think, and that it's a continuum. I think that there is a subset of investors that I thought felt that it could be -- it was one or the other between RNA medicines and gene editing. And we don't see it that way. We do see it as a continuum. We obviously did an RNA deal ourselves.

In cardiovascular medicine, in particular, it also -- I'm not surprised that this was the first large-scale investment from a pharma in gene editing or acquisition. We had always felt that cardiovascular medicine was going to be an area that would be transformed by genetic medicines because compliance is the biggest issue that we hear from cardiologists.

Even PCSK9 therapies that are available that have once in 6-month profile, we're seeing 30% -- or we're seeing papers that let's say, 30% of patients aren't compliant with therapy. So if you're a cardiologist from that perspective, you're having issues with patients that are -- in the case of AGT, for example, or hypertension, patients with refractory hypertension are on 5 medications plus a diuretic.

And the ability to take those every day or multiple times a day in some cases gets difficult for patients. And those are things where you want to be in a controlled range. You want to be in a normalized range. So if we have the ability with a one course therapy to get patients into that range potentially for lifetime, I think, that value creation and that transformation to the patient profile is extremely enticing to doctors and cardiovascular specialists.

Great. Okay. And so moving along into that segment of the pipeline with CTX310 showed some interesting data so far. The Phase I includes SHTG, HoFH, HeFH and mixed dyslipidemias. And so with olezarsen's win, we just had Ionis up here a couple of slides ago, with their win in SHTG, is this now a lead registrational path potential still? Or how do you think about this with olezarsen?

Yes. No, I mean, kudos to the CORE, CORE2 trial and Ionis for that result. I think that highlighted to us that significant reductions in triglycerides leads to a significant benefit in acute pancreatitis. And I think from the data we've put out, we're seeing reductions in triglycerides in patients up to 86%. And we think that, again, that SHTG could be a very enticing indication for that.

We're also seeing reductions in LDL. So with one target, we're seeing both. And we're seeing reductions in the LDL patient that we called out, I mean, we're seeing a reduction of up to 82%. And so if we have this dual benefit, then patients that have severe hypertriglyceridemia and an increased LDL maybe not to that level might see a benefit we're getting -- to get within the normal range for both.

We think that, that actually might be a differentiating factor. And obviously, the durability of effect and no need for multiple doses is obviously a huge benefit to our therapy. So yes, that trial was groundbreaking, and we look forward to sharing more data with our patients in SHTG in the second half of this year as well as later to come.

Okay. Great. Yes. And you mentioned a key facet there, durability. I'm wondering if that ends up being like the defining feature of what could be incremental versus what is in the space. So if you have something that's similar, but a more durable response, is that something that a patient would be more apt to go on? Is that how you're thinking?

Yes. I mean we think so in the high-risk populations, I think, again, doctors are going to be likely to put patients on it. I think you also think about patients that are in that maybe the younger age range where they're staring down 40 years of therapy does a one course therapy just transform themselves. I mean we have patients that we've treated with sickle cell that are [indiscernible] Mounjaro now, right? If you gave them the option of having a lifetime treatment regimen or CASGEVY, I think you have a strong percentage of that population is going to choose CASGEVY.

So yes, we think the same thing for severe hypertriglyceridemias. Again, with those patients, when you pull the -- if you pull their blood, there's a thick, milky white layer on there. And so you're seeing that annually. And you know we all know now that increased triglycerides does -- is associated with acute pancreatitis. So there's going to be a meaningful patient population in our opinion that will opt for one course therapy.

Okay. And then as investors are thinking about modeling that type of a commercial adoption for a therapy like this, in SHTG or mixed dyslipidemia, how do you model uptake for like a onetime therapy versus like a chronic siRNA? And how do you think about like the payer economics, the adherence, pricing, things like that?

Well, there's -- adherence is easy. That's an easy question. The -- again, the COGS of this will give us a lot of latitude. So this isn't going to be something where we're going to price significantly higher. When we get later in development, we'll have more to comment on pricing specifically. But you can imagine that if we have COGS in a very low 5-figure range, to get to 90% margins doesn't need a super high price point.

So we'll have to look at the pharmacoeconomic data that we have, obviously, the durability when we file a BLA or get approved at some point in the future. But we do think that in these larger indications, there's going to be a strong subset of severe patients that will choose this therapy. And I think over time, like any new technology, people will get more and more comfortable with it over time. But we do think that, again, in these high TAM indications where even the high-risk SHTG population is over 1 million patients, there's going to be room for multiple modalities and I think multiple blockbuster products.

Okay. Great. So moving from 310 to 320 [indiscernible]. The readout delay that you all have aligns well with the Novartis HORIZON trial with pelacarsen with Ionis as well. If results are modest at the first initial update, how does CRISPR differentiate? What is the way that this would be positioned versus pelacarsen or others in the Lp(a)?

Yes. Again, I think we attended a conference last year with like FDA and some industry folks where the question came up of you need HORIZON to sort of say, reduction in Lp(a) as a biomarker. And I think the FDA, I mean, they're going to look at both HORIZON and OCEAN. I think that there's not a significant delta between the readout of those two, and we'll have to look at both of those studies, I think, before truly understanding if there is a mixed result in that hypothesis.

But for us, we continue to look at patients with a high baseline. So in the HORIZON study, I think at 80 milligrams per deciliter, there's a high cohort. So we'll be looking at that data in particular in addition to the primary endpoint to see whether patients with a high Lp(a) in that upper quartile do achieve an effect. because that would be the most relevant to us.

But for us, we wanted to make sure that we fully understood the -- what happens when you therapeutically knock down Lp(a). And we also wanted to determine from the KOL community as well, is there going to be a threshold thesis? Is there a normal range you want to see in between? Do you not want to go down close to 0 like you do with LDL? I think these are questions that are still open that we'll get more answers from next year.

Okay. And Editas is now in this race with LDLR. How do you view LDLR as a gene editing target relative to ANGPTL3 or Lp(a)?

Yes. I mean I think we're very happy with the targets we selected. I think again, with ANGPTL3, there are -- it's a loss of function mutation that's out there. There's people that are genetically -- that have genetically knocked out ANGPTL3 that have a reduction in cardiovascular events. And so we felt very comfortable going after that thesis. And again, we've produced good clinical data. So to be determined, I wish Editas the best of luck. And again, cardiovascular medicine, I think, is going to be changed by genetic medicine.

But we really like the target selection strategy that we have. And we'll be taking angiotensin into the clinic in the near term as well. So in the not-too-distant future, we're going to have 3 clinical programs in genetic medicine [indiscernible] cardiovascular medicine.

And so for siRNA briefly touched upon that branching out in terms of modality from gene editing, you also have now RNA. Can you help us understand, is the siRNA play a tactical bolt-on? Or is it the start of a multimodality type of a model for CRISPR?

Yes, it's a good question. I think for us, we wanted to supplement our current pipeline. And when we talk to these CV docs, we were hearing about anticoagulation and Factor XI from a lot of them as being an interesting target as well as being an extreme unmet need, especially in terms of bleeding that happens with the Factor Xs.

So the Factor XI thesis was born out of not saying we need this technology, and we need to bring something on. It was more of this is a very interesting target. It's complementary to some of our efforts. We think that we're still talking about the durability thesis. So the small molecules and antibodies that are out there, we're still looking at potentially a 6-month -- once every 6-month option. So we're still focusing on this durability benefit over other players in the space.

But the market opportunity for anticoagulants, especially patients that are ineligible for Xa because of bleeding risk is significant. And so we looked at this as a deal with a great counterparty partner in Sirius Therapeutics. We think this could be another multibillion-dollar asset for us in the future. And then also we got EMA approval. So Phase II trial will be initiated in the short term or it has been initiated. And these trials don't take very long to read out either for the Phase IIs. Historically, the abelacimab trial took about a year from start to finish. So we'll be moving forward potentially in the near term as well.

Okay. Great. And so you're starting in surgical VTE. How do you think about sequencing into broader chronic cardiovascular indications because that could certainly be interesting.

Yes. So we have -- I mean, the benefit here is that we will see the abelacimab trials readout and the milvexian trials read out prior to making that decision, but we'll have the Phase II TKR data in hand. So we'll sit at a good strategic point sometime in the back half of next year, where we'll see all these competitor trials develop and then we can sequence our Phase III development based on that.

But again, we thought that this was a very interesting asset with clear differentiation in a multibillion-dollar market. It sort of hit all of our metrics. And then you don't want to knock out Factor XI for life. So we also thought that, that was a good target to go after with this technology synergism.

Great. Okay. And finally, in 3 years, which franchise, cardiovascular or autoimmune or diabetes would investors view as CRISPR anchor in your thoughts? And what milestones by the end of next year would make that vision credible?

Yes. I mean I think right now, it's too early to call what the lead candidate is going to be moving forward. I think we're seeing interesting data across all verticals at CRISPR right now, and that's a good problem to have. Again, we can -- in the next, say, 12 to 18 months, I think we can determine at our -- based on our balance sheet and our cash burn, we don't have any funding concerns in the near-term future.

We can determine, based on our fundamentals, what do we need a strategic partner for, what would be a 1 plus 1 equals 3 type of equation where a partner would bring something that we don't have or we don't think we can develop to a certain of these verticals. And we can't do everything. I think that's sort of your resource allocation question. We know we can't do everything even with $1.7 billion.

But I think the most important thing to do in biotech is you don't want to do a deal too early where you leave value on the table. And we have put ourselves in a position where we're one of the few that can actually do that. And so again, over the next, I would say, 12 to 18 months, we'll see more data. We'll see durability of data. And I think you'll see us make strategic decisions both on partnership as well as resource allocation in certain indications where we're maximizing ROIC. And we're really trying to aim to be that next $25 billion company in the space.

Makes a lot of sense. Raj, thank you so much. Really appreciate your time today. And thank you to all the investors in the room for joining.