Good morning, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference. For our next session, it's a privilege to have a fireside chat with CRISPR, and it's my pleasure to introduce Samarth Kulkarni, the Chairman and CEO of CRISPR Therapeutics. Sam, privilege to have you here. Thank you very much for joining me.
Thank you for having us.
Sam, 2025 felt like a defining year for CRISPR in terms of establishing the pipeline beyond Casgevy. I've heard you say that you are thinking about transitioning from a technology-backed company to a disease-backed company. I was hoping you could expand on that and highlight what you see as CRISPR's different business segments before we dive into the specific programs.
Happy to. 2025 was quite the pivotal year for us as we switched away and went to the next phase of the company to go beyond Casgevy. Different lenses to look at our business today. One lens is from a value perspective, you know, about a third of our value is Casgevy, a third of our value is probably the phase 1 assets that have shown promising data. These are namely CTX310, CTX320, which we'll talk about, and CTX611, which is our siRNA foray with Factor XI. Then there's a very rich pipeline beyond that. You know, in fact, by mid 2027, we'll have data for six programs beyond Casgevy across more than six indications. That platform and pipeline is quite productive.
The other lens which we talked about is this question that you asked about technology, forward versus disease backed. I think from a disease area perspective, the two areas that we're quite committed to and we're building quite a bit of capabilities, one is cardiovascular, because we have CTX310, we have CTX611, we have LPA, we have a new entrant that's gonna go into the clinic soon, which is for refractory hypertension in CTX340. This is targeting angiotensinogen. We have a number of programs there, and we're building quite a bit in cardiovascular. The other area we're quite excited about is autoimmune. We have CTX320, which are cell therapy that could be a, you know, FcRn-like platform and apply across a number of indications.
We're quite committed to autoimmune, and we actually, will announce another target, with our siRNA platform that also is, you know, in the autoimmune space. That's the second franchise that we're quite committed to. Obviously, we're working other areas. We have Type One diabetes, we have oncology, these two areas we're gonna build quite a bit of capabilities that will keep driving the engine forward.
That's great. We'll start with a couple questions on Casgevy and the Vertex partnership. Casgevy finished 2025 with some building momentum, well over $100 million of full year sales. Can you talk about expectations for 2026 Casgevy sales and what you think will continue to drive momentum in the launch?
Yeah. You know, our partner, Vertex, and us were both quite excited about 2026. We both said that 2025 was a foundational year for Casgevy, both 2024 and 2025. If you look at the top of the funnel, which is patient initiations, it went from 100 patients or so initiated in 2024 to 300+ in 2025, and we expect that number to be quite much larger in 2026. You know, the demand is quite strong from a patient perspective. Now, the second part of the funnel is the cell collections, or patients with first cell collections, and that's also starting to inflect. It's just a matter of time before the revenue inflects in a big way. I mean, you already saw a big jump in revenues in the Q4 of last year.
I think as we see more patients initiated and we get more sites becoming fully productive, you're gonna get this geometric growth, and similar to what we've seen with some, you know, med device type launches in the past. We feel quite good about where Casgevy is and the leadership in the segment going forward.
Can you remind us how long it takes from referral to cell collection to treatment to reimbursement?
Yeah. We haven't put exact numbers out there so far, but from our experience right now, you know, with thalassemia patients, it can be quite fast. It could be six months, potentially. For sickle cell patients, it could be as long as a year. The number is somewhere in between. You know, over time, it matters less and less because I think this is an elective procedure, and as we get the funnel moving, these patients are all gonna get dosed. The important factor in all this, the dropout rate's very low. As long as the patient's initiated, and their cells are collected, they're gonna get treated at some point. The revenue's coming, you know, it's just a question of when that's gonna be.
Okay. Can you talk about, just in general, profitability and cost as part of the partnership, when you expect it might start impacting, your P&L, at least from a profit standpoint?
Yeah. We did say last year from a CRISPR standpoint that we expect 2025 to be the peak year of spend for the franchise. You know, we have our own models, obviously, but we can't say right now when the franchise is gonna reach profitability. That's for Vertex to guide at some point, but it's gonna get there, I think. The part that I also wanna highlight is we're making quite a bit of investment in both gentler conditioning agent and in vivo HSC delivery. On gentler conditioning, again, Vertex will guide to when that might enter the clinic and when it may actually impact in the commercial setting. That's gonna dramatically increase the addressable market and the launch curve.
You know, the expenditures around gene editing, for instance, are included, you know, and the in vivo HSC are all bundled together in our P&L, if you will, or collaboration expense, so it's hard to disaggregate. What you're gonna see is from a pure franchise perspective, we are gonna drive towards profitability. In vivo HSC, we showed some data at JP Morgan, which showed durable editing of HSCs and NHPs, and we're quite excited about that. Still more work to do there. All in all, I think these forces, together with other ways we're expanding the market, which is the pediatric expansion, I think, can, you know, really put a lot of wind behind the sails for Casgevy.
That's great. Since you mentioned in vivo, we will continue on the theme to CTX310 for ANGPTL3. Furthest along in development, you guys have shown very encouraging early data. Can you talk about enrollment of the phase 1b expansion study and what we should expect from the data update later in the year in the second half?
Yeah, absolutely. We had, you know, our presentation at American Heart Association for CTX310 was quite the event, you know, coming out party for our in vivo platform. We had a smallish booth compared to all the big pharma companies, there were people all flooding in to say they wanna be part of our trials, whether it's physicians or patients. The data we presented, for those who are new to it, you know, the program, it's targeting ANGPTL3, we showed that at the highest dose levels, we completely saturate editing of the liver cells or hepatocytes for ANGPTL3. We get about 80% reduction of ANGPTL3. Some ANGPTL3 is produced outside of the liver, which is not impacted by 310.
With that 80% reduction, what you see is nearly 50% reduction of LDL and nearly 60% reduction of triglycerides in patients. It's sort of a built-in bispecific from a target standpoint. You're getting both LDL and triglyceride reduction. What do we do with, you know, these amazing and remarkable data? You know, we're trying to now define, you know, look at each of the different subpopulations. There's patients with severe hypertriglyceridemia, and we wanna establish for those patients, especially ones with, you know, triglyceride levels over 800, for instance. You know, what is the reduction we're seeing? There's a population of mixed dyslipidemia that have both high LDL and high triglycerides, so what level of reduction we're seeing for those patients. Obviously, there's the familial hypercholesterolemia.
You know, almost 90% of patients with homozygous FH are refractory to PCSK9 therapies. They really don't have many options. There's an antibody called Leqvio that's on the market, but really not many options for the patients. Can we get a fast path to a label in that indication, for instance? All that's in play right now with CTX310. We'll provide further updates. The key de-risking obviously is the meeting with regulators to say, what's the path forward for registrational trials? I think that'll give us a clear, you know, sort of, both a de-risking event, but ungate all our spend in terms of larger trials.
Got it. You mentioned 80%, but what do you think is the minimum required kinda LDL reduction that you'd like to see in these populations to get confidence to move forward? Could you move forward into a pivotal trial in all three populations, or how are you thinking about ultimately developing this program to approval?
Absolutely. I think we could. There's a lot of potential in all these subpopulations. You know, what's amazing about this target is, you know, we had two patients that were on PCSK9 therapies, and they had, you know, 50%-60% LDL reduction on top of the PCSK9 therapies. And it makes sense because ANGPTL3 works in a very different way than PCSK9. PCSK9 is regulating surface expression of LDL receptor and uptake, right? What ANGPTL3 is doing is working on the you know, lipases downstream, and so you will get a synergistic effect on LDL reduction. I think, you know, I think the, you know, the...
Hard to say what the bar is for LDL reduction, but we expect that you're gonna see you know, high LDL reduction for all the patients that have high LDL, even if they're on PCSK9 therapies. I think we're quite encouraged by that. We could move forward across all these indications. There is big pharma interest in the program, you know, at this point, we wanna move it forward ourselves until we get this regulatory clarity because that'll obviously increase the value of the program quite a bit. I think we're looking at pedal to the metal on this program.
Great. Trying to be efficient with all your programs here, so we'll move to CTX320, CTX321 Lp(a). You know, there's some clinical data for CTX320 and then preclinical data for CTX321. Can you talk about how you're thinking about both these programs and potential prioritization and development between them two and, you know, if there's any external data that you're paying attention to make that decision?
Yeah. The entire category for Lp reduction, you know, hinges on the HORIZON data. It doesn't completely hinge on HORIZON, but it's a big indicator, right? Because, you know, it could also have a situation where HORIZON shows benefit, but the next trial from Amgen could be, and Eralt could show tremendous benefit, you know, because it's a we think it could be a more potent drug than the siRNA. But, you know, I think the HORIZON data from Novartis for the ASO program is a very important readout. We did the dose escalation with 320. We said that we saw about a 73%, you know, at peak, 73% reduction of Lp levels.
you know, we're not gonna click go on a large Phase II before we see HORIZON data. We had this sort of dead pocket of time. We had a second, you know, originally was a backup, but now, you know, is a potentially equal on equal footing with CTX320, which is CTX321, and it showed almost 2x greater editing in animal models. I think it behooves us to sort of move that forward and after HORIZON, we can make a decision on how we wanna move it forward between the two assets. All else equal, you obviously want a more potent guide, but there's a slight time differential between the two. Based on HORIZON data, we'll see what level of Lp(a) reduction is required.
you know, I was talking to, yes, I don't know who did this, but someone did a poll of a lot of the big you know, pharma companies and said, "What are some of the biggest readouts that you're looking forward to over the next couple of years, or 2-3 years in cardiovascular medicine?" Lp(a) was right up there, number one. I mean, this is one of the biggest readouts for the industry, and I think the we'll talk about hypertension, but the Zilebesiran readout for... Well, that's a few years away, but that also will be an important one for the industry and, you know, people look to IL-6, et cetera. I think Lp(a) is one of the biggest ones, and that's gonna have a huge impact on our program.
You know, we're at the forefront of gene editing for Lp(a). You know, we did a physician survey that for Lp(a) where we said, "If there's an siRNA versus gene editing, what would you pick?" The reality of Lp(a) is you're born with high Lp(a) if you have high Lp(a), and you actually wanna intervene as soon as possible, you know, potentially in your 20s or even earlier. Gene editing is the most optimal solution for these patients because you don't wanna keep taking siRNA drugs for the rest of your life. We're quite excited about it, pending obviously HORIZON data.
Yeah. Just in general, before we move to the next in vivo program, on the safety side, what you've seen so far in people, obviously, early on, I think there were some concerns around like liver tox and stuff like that. What have you seen on the safety side that gives you confidence to move forward with these multiple programs?
Yeah. You know, I think given some of the other dynamics in the space with other competitors, and obviously Intellia came off hold today, which should be a good positive boost for gene editing overall. I do think the regulators are very, very supportive of gene editing. By the way, I think they see gene editing as the future to bring cures versus other modalities like the traditional gene therapies, it's just accelerating, you know, their moves are accelerating the move towards gene editing. Given all those, we were pretty open about our data with CTX310, for instance. We kinda put the LFT data out there for each patient, you saw that the platform is very safe. The LNP platform is very safe.
Even if there's a, you know, minor increase in LFTs for a patient, it's, you know, self-resolves. Compared to taking years of siRNA, where you don't know what the compound toxicities might be over time, I think gene editing is gonna be a much safer solution for patients.
Great. You mentioned hypertension, we'll move to CTX340 AGT program. Just can you talk about when we might get initial dose escalation data there, and what level of blood pressure reduction you'd like to see to move into later stage development?
For those who are not familiar with CTX340, this targets angiotensinogen. We built this program off of the back of very exciting data from Alnylam with the same target with an siRNA. They did multiple trials called KARDIA-1, KARDIA-2, and KARDIA-3, where they saw, you know, nearly 90% reduction of angiotensinogen with an siRNA directed towards the liver, and that resulted in double-digit reduction of systolic blood pressure. That's quite exciting. You know, what you have is a, you know, very safe drug, no hyperkalemia, no other side effects, essentially very low level of side effects, and potentially once every three months or once every 6 months, sustained reduction of blood pressure and no risk of hypotension either, which was one of the risks with the target.
You know, if you're looking at that KARDIA data, for us, one thing I'll point out is in the same mouse models, which are the spontaneously hypertensive rats, we had nearly 50% reduction in blood pressure, right? Which was almost 2x the effect of what you saw with siRNA in the same models. I'm pretty excited about this program. We're gonna enter the clinic soon here. We haven't committed to when we'll have the data from the dose escalation. You know, there's possibility that you see double-digit reduction of systolic blood pressure. You know, obviously, it's very different based on whether patients are on ACEs ARBs or whether they're on, you know, diuretics, et cetera.
You know, for those that were on diuretics, for instance, there was a much greater reduction of blood pressure from the KARDIA 2 trial. I think we're gonna look at KARDIA 2 and their data to guide us with this target. We'll have data in the not-too-distant future for a very exciting target.
Great. Maybe to round out the in vivo discussion, the SyNTase technology was unveiled not too long ago. Can you just discuss maybe briefly why you're excited about that technology, why you chose A1AT as the first indication, and how you feel you guys could be differentiated there given all the competitors?
Yeah, I think the SyNTase technology that we developed, this is a technology that allows for very precise editing at very high efficiencies. I think we've shown near saturating edit in hepatocytes in animal models with 0.1 mg per kg dose, which is about 6x better than our CTX310 program, for instance, from potency standpoint. There are many reasons why that happens, but it's very potent, very precise. A1AT made the most sense to start off with because what you're seeing is, we'll see all the data that come out from existing clinical programs, but, you know, there's some saturation of how much A1AT elevation you can get. That's predictable, by the way, from mouse or rat models.
You know, there is a specific PIZ rat model where you can look at background rates of the faulty Z allele, and then you look at the normal allele, and you see how much fold increase you can get. You know, the base editor that's in the clinic has shown about a 2.2x improvement over background. If you then look at patients, you know, they have about five to six micromolar of AAT production at baseline. You're looking at, you know, somewhere in 2 and 2.5x improvement of that baseline level of AAT. The same experiment, the same model, again, it's done in different hands, so I can't say that it's 100% exactly the same, but in very similar models, we had a 5x elevation of AAT.
If you look at the baseline levels of 5 micromolar, it's plausible that we get up to 20 micromolar or more. I think there's a lot of room here. you know, AAT is an indication where gene editing, I think, is gonna be the superior solution regardless of RNA editing and other modalities that are also trying to play in the space because, you know, it's a terrible disease and you're unlucky to be born with these mutations, but you wanna address them as soon as possible. I do think we're a little bit behind, but we're in pole position in terms of becoming the best in class in that indication.
We'll be in the clinic this year, we said mid this year, so we're not that far from where others are in the space.
Wonderful. Let's move to, I guess, in vivo gene editing's technology cousin with siRNA, right? A kind of natural partner, as you kind of alluded to already. We've met with Sirius, impressive team. The technology's very impressive, so I encourage the audience to take a closer look at their technology if you haven't. Just maybe, again, why you decided to do this partnership, expand into this technology and go into Factor XI and why you're so excited about that program, and when we could get data.
Yeah, you know, I couldn't say enough about our partner, Sirius, from a technology standpoint. You know, one of the questions people ask, including, you know, our board, was, you know, "How do you know you're gonna be good at siRNA? There's so many companies. There's this, you know, there's a $60 billion company out there that's been doing siRNA for so long." The reality is, if you look at the best siRNAs coming out right now, there is a set of four or five modifications you can make on every base, and there are certain other modifications that you do structurally around hinges, et cetera.
If you put the best of what happened at Arrowhead, the best of what happened at Dicerna, and the best of what happened at Alnylam, and you put it all together, you can actually create a much better vehicle, something that could be, you know, very potent, yet durable for 6 to 12 months even. That's what Sirius has done. You know, they've learned from other people's mistakes and come up with a proprietary new platform that is yielding best in class siRNAs. Our deal with them gave us 50% of a Factor XI siRNA that already had Phase I data, and we have two other assets, siRNAs, that we're gonna reveal the targets on this year that are also moving forward to the clinic very rapidly. For Factor XI, you know, it makes sense.
I don't think you wanna do gene editing for Factor XI. That's not a permanent change to your clotting cascade that you wanna do for hemostasis. You know, having a once every 6 month type approach for Factor XI makes a lot of sense, especially, you know, in indications where, you know, for instance, you're doing secondary stroke prevention. Asundexian, which is, you know, in our minds not the most potent molecule acting on Factor XI, showed tremendous success in 11,000 or 12,000 patient trial, the OCEANIC trial, where they showed a significant reduction in stroke, secondary stroke prevention. Okay. That's a big, big market. Now there's so many other settings where you wanna have reduction in thrombosis without increasing your bleed rate.
You know, a lot of people go through surgeries, they go through procedures, and, you know, they're taking DOACs and other powerful anticoagulants, and then they have a, you know, they fall or hit their nose somewhere, you know, get a nosebleed, and next thing you know, they're in the ER. I think this is sort of the, you know, beautiful combination where you're going against the Factor XI, you know, the one of the pathways, the intrinsic pathway versus the extrinsic pathway, or the tissue factor pathway, and you're shutting down that one pathway that matters that prevents thrombosis. So we're quite excited about both the mechanism of the action, but also the possibility of being best in class within this category, I think, which is gonna explode within the pharma industry soon.
What do you wanna see from the data that we're gonna get in the second half of the Phase II proof of concept? I guess there's so many different indications to go after. Is there an indication that is more exciting to you than the others?
Absolutely. I mean, I think, you know, the TK study for us, you know, it's become sort of a rite of passage in this, in this sort of, target realm, which kind of tells you where you stand versus something like heparin, but also where you might be. Are you in the ballpark as some of the other Factor XI inhibitors, right? You know, people are trying to tease out what does Regeneron's data mean that's 98% at peak versus what is Abelacimab's data versus what you may see with some of the small molecules, both Asundexian and Milvexian, and where do we stand in that schema. I think we're gonna get a good sense of that from the TK study that would inform our future development.
I think obviously we also need data from a multiple ascending dose cohort that we're in parallel moving forward. When we have those two pieces, which shows us what kind of reduction we see in the TK study, along with how the dosing paradigm might develop, we can pick which indications we wanna go after. Now, obviously, secondary stroke prevention is right there in front of us, but there are other smaller niche markets as well, like cancer-associated VTEs, et cetera, or stent procedures and subsequent VTEs. Both venous and arterial indication, we're gonna take a hard look at it, but I think we may have a very exciting program here that we're co-developing with Sirius.
The next two siRNA programs, when will we learn of those targets again?
This year at some point. I think, you know, we're just waiting for NHP data to make sure you know, it's a clear path forward to get to the final candidate. You know, I think those are going pretty well.
All right. Running out of time here. With one minute or so left, there's so much to discuss. With cell therapy, zugo-cel that you mentioned, could you talk about the follow-up in lymphoma in the second half of the year, expectations for that, as well as, autoimmune and plans there?
Yeah. In the one minute that we have, I think zugo-cel is probably the most underappreciated asset in our entire portfolio. I think it was two years ago at this conference or one of the Cowen conference, there was a little poll done to say which one is the best allogeneic CAR T out there, and at that point, CTX112 had been the one that won, but it wasn't clear how much better. It is a lot better than all the other classes of CD19 allogeneic CAR Ts or CAR NK out there. We've done that experiment in animal models, and I think we're getting a lot of momentum in terms of number of patients now in, you know, especially in autoimmune across different indications, and we'll have updates on autoimmune.
I think in autoimmune, we're positioned, I think, to win the autoimmune race with zugo-cel . Oncology, you know, what we're trying to do there in oncology is, you know, we have spectacular CR rates. The development paradigm is a little more expensive and longer, but I think we have this very unique combination with pembrolizumab as well that could allow us to actually get to autologous levels or better in oncology. More to come on zugo-cel , but I personally I'm very excited about zugo-cel and what we're seeing both in oncology and autoimmune.
How focused are you on in vivo CAR T, and when might we get the next update from those efforts?
Yeah. I think we showed a little snippet. you know, you've seen three transactions in the space for an in vivo CAR T that hasn't... You know, it's not editing, by the way, it's just mRNA engineering. We're the only ones. We've shown that our mRNA engineering allows to have persistent CAR Ts out to day 14. Most of the other ones that you've seen that transacted, you know, have a peak at about day four, and they're gone by day seven, you know, if you look at like models. I think this is gonna be pretty exciting. I won't talk about all the things we've done with the mRNA that makes it so durable and persistent, but there's quite a bit of engineering we've done.
I think what we're gonna you know, we'll have NHP B-cell depletion data in the not-too-distant future. I have to say, I am surprised by how many inbounds we're getting from pharma on this. People seem to wanna own in vivo CAR T platform. We'll have to see what we do with the platform. You know, I think we may have a chance to be best in class, even if it doesn't have anything to do with editing with the in vivo transient CAR Ts. We have the in vivo permanent CARs that do utilize editing, and we're already seeing exciting data there in mouse models, not yet in NHPs.
All right. With that, we better wrap. We covered a lot. It's impressive, how many programs you're able to follow yourself. Sam, thank you very much for your time.
Thank you.