Let's get going. Hello, everyone. My name's 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.
Yeah, great. Maybe just to kick off, you've described 2026 as kind of a stepping stone year, some important early readouts from six programs in the second half. I guess, how do you sort of prioritize the focus within the company on the earlier stage versus supporting, you know, CASGEVY, and, you know, w-where are you sort of directing investors sort of in the remainder of this year?
Yeah. 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. Upon the completion of that phase, or as we got that to the end of the clinical trials and to commercialization, we started a number of other programs. 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. We have six assets, as you said, that will all have data in the next 12-18 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 one or two, but several autoimmune diseases. We have CTX611, which is a long-acting siRNA that basically is a promise of a blood thinner, an efficacious blood thinner without the risk of bleeds. That's, you know, another powerful concept that could be a $20 billion market. Beyond that, we have this extension of some of these programs like CTX340, which is a program that treats hypertension by targeting angiotensinogen, which is upstream of the ACE/ARB pathway.
That is important target that can actually reduce your systolic blood pressure by over 10 mm of mercury. That's powerful concept. 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. Finally, we have a foray into rare diseases with alpha-1 antitrypsin, and we think we have the best-in-class product for that program. 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, you know, with CASGEVY, over time, we expect the spend on CASGEVY to keep going down. At some point, we'll turn profitable.
Then we have to get to what the phase III are for these assets that we just talked about, and then advancing the preclinical to clinical. You know, it's hard to put exact numbers on this, but, you know, right now it's 40, 20. It probably becomes more, you know, 30, 50, 20 over time. I think we're keeping a careful eye on all this, and we gain 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? Any other comments coming out of the 1Q print that you'd highlight.
Yeah. It's gaining a lot of momentum. It's very different from typical launches. You know, typical launches, you can start tracking new Rx's or total Rx's right away, and your patients are getting treated right away. Here, we're talking about a one-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. The reason for that is you have to collect the cells, manufacture it, get it back. Now, it takes time to build up. Initially, when you build the ATCs up and you know, have this time period between initiation and infusion, you know, the revenues sort of take a while to start ramping up. You're seeing that ramp now.
If you think about the funnel in terms of three different parameters, one is the number of patients initiated, and what that means is a patient has gone through a referral, expressed an interest in getting CASGEVY. Oftentimes, they're already pre-authorized from an insurance standpoint. Those patients then move to the next step of the funnel, which is cell collection, and then finally to infusion. There is a time lag between all of these. If one starts inflecting, if initiation start inflecting, you're gonna see, you know, a quarter, two quarters later, you're gonna see an inflection in collections, and a quarter or two later, you're gonna see inflection in revenues.
What we said in the in this recent 1Q print, as you called it, which is, you know, in the first year of launch, 2024, we initiated about 100 patients. This is our partner, Vertex, leading commercialization. The second year of launch, 2025, it was 300 patients, over 300 patients, so it's a 3x increase. In this 1Q update, we just said that we have over 500 patients initiated. You're seeing, you know, almost exponential progression in terms of patient initiation and that momentum continuing, which should translate to greater revenues. The other thing is, you know, we're establishing this around the world, you know. 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 five and above because you wanna treat kids early before there's any damage to their vascular system, any damage to their organs. That's a tailwind. That's gonna help. The second thing is the reimbursement. You know, we just announced reimbursement agreement in Germany. That of course, was one of the hardest ones where a competitor of ours had tried to go in there and then withdrew their product because they couldn't get reimbursement. With CASGEVY, we have a reimbursement agreement. Those tailwinds will start to add up and continue the momentum well beyond what we're seeing right now.
Great. 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, you know, getting the cells extracted, right, for the manufacturing? How does that acceleration kind of then accelerate the top line growth?
Yeah, I mean, I think that's why I say is, you know, it's probably there's some lag, whether it's two quarters or three quarters from initiations to the revenues. 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. It's just a matter of time, and over time, that timeline won't matter because, you know, you're gonna have a constant shape of the funnel, if you will.
There's a equilibrium around that timeline from initiation to launch or to getting infused and recognition of revenue. Overall, I would say, you know, we have forward visibility. Our partner Vertex was very bullish on the expectation or I guess they didn't guide to exact number, but generally positive guidance around how they expect CASGEVY to do. I think from what I hear from physicians and patients, the words getting out there, you know, this is without sort of a 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.
Yeah. No, that's great. I know you're also developing, I guess, gentler 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?
Yeah, I mean, you know, we haven't guided to when gentler conditioning might come into play, but it would be a major tailwind for the product. The reason for that is it expands the population. You know, you go from just the most sickest of sickle cell patients to saying even the ones with moderate disease should actually get CASGEVY. What you're looking at then is just a potentially a three-day hospitalization. It's why it's called gentler conditioning, and it's very targeted depletion of the cells, of the HSCs to make room in the marrow. We feel very good that that's gonna be the next leg in the life cycle of the product.
That's gonna 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. 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.
I guess as we think about the commercial landscape there are, I guess, alternatives for patients with beta thal and sickle cell disease. I guess in practice, when, you know, physicians are choosing between CASGEVY and say like a lentiviral approach, you know, what are sort of the key decision factors there and, you know, is CRISPR winning those conversations?
I think it right now, ex-U.S., CASGEVY is the only option, right? You don't have any other products available for patients. That conversation is different obviously. It's just, you know, do you wanna 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. You're seeing some share split at the moment. Generally what we're finding is that the physicians, now that they understand that, you know, CASGEVY has a lot of manufacturing support, there's, you know, strong companies behind it with Vertex and us.
It's a reliable sort of partner to deliver the drug product to patients, I suspect that you're gonna see more and more patients shift towards CASGEVY. One simple reason, because, you know, when you have a viral versus a non-viral product, I mean, you're safer picking a non-viral product because you just don't know the unknown unknown of having a, you know, retrovirus-based product. Now not every patient will care about that, nor every physician. I think you're gonna see a share shift towards CASGEVY that'll be palpable.
I guess, you know, circling back on the pediatric review, you've got a commissioner's CNPV, I believe, for that. That could be available soon, right? If they're true to their 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 one-time treatment like this from your experience?
Well, it's just another bolus of patients, right? I hope with the agency we get that approval soon to go into these younger patients. The other thing is, you know, you're gonna get a number of other centers into play in a big way. You know, a lot of children's hospitals are actually very good at doing these types of procedures. They can start bringing their patients into the mix and become some of the higher prescribing centers.
The pediatric expansion definitely will be a tailwind, not just from expanding the number of patients available in the bolus, but from a center activation standpoint as well, or the center velocity of treating patients. 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 1 Q, but is, you know, sort of the way that the street's thinking about the escalation in sales, is that, you know, is that realistic, you think?
Yeah, we don't see any headwinds, you know, at this point. Really, it's our partner Vertex doing a wonderful job executing against the program and a lot of it is operations with supply chain, with all the, you know.
patient handling and everything else. They're doing a great job, and I think I only see positive momentum with the program. It's hard for me to say what the street expectations are. You know, 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 wanna maybe shift gears here and talk about the pipeline, which I'd say is, you know, equally or even more exciting, for sort of the future growth, for the company. Maybe just starting with CTX310. This is your LDL lowering ANGPTL3 asset. I guess, you showed a single dose reduction in LDL triglycerides, safe early profile. You know, what sort of response thresholds in, you know, 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?
Yeah, for those who are not familiar with the program, we showed some landmark data in a late breaker at American Heart Association last year. These data were for 15 patients that received CTX310. The LNP-based delivery was very safe. You know, we barely saw any elevation of liver enzymes, and even if there's some elevation, it self-resolves within, you know, a very quick period of time. It's very safe. You have this prospect of going out there, sitting in a chair for a three-hour infusion, and your liver cells are edited, and you're gonna have 50% lower LDL or triglycerides for the rest of your life.
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. You know, 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. This is where I see a big disconnect. You know, 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 or LDL cholesterol. Physicians are universally excited about what the prospects are here. By the way, this is not gonna be an expensive $1 million therapy.
It's gonna actually save the system money at the end of the day by doing it one and done. I see, you know, something, you know, CTX310 having unlimited, uncapped value, but it may take some time for the value to be recognized. I think a lot of that will be based on going to the FDA or international agencies to say, "What is a path forward for a phase III?
Yeah.
To your question, you know, for HoFH, which is homozygous familial hypercholesterolemia, the bar is very low. All you have to show is that there's further reduction of LDL cholesterol post agents like PCSK9. We've already showed that for two patients in the initial dataset. 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, you know, this type of registrational trial makes sense here or not. I suspect you're gonna see a favorable opinion from the FDA in terms of how big a trial needs to be.
How fast we can go. That, that'll be the unlock on 310. Similarly for 340, is to get regulatory guidance around what a path to registration might be.
That'll come soon enough.
Yeah. I guess on CTX340, different target here, but I guess when this enters the clinic in the first half, you know, what is sort of a 2x yearly, or what does a CRISPR edit offer over like a 2x yearly siRNA in this indication? Is there kind of a minimum efficacy or blood pressure reduction that you'd wanna see?
Well, the benefit of a gene edit for blood pressure is, let's say, you know, people have varying degrees of high blood pressure. You can just basally reduce everyone's blood pressure by 10 mm-15 mm of mercury and still modulate with the different medicine, right? The problem with siRNAs, you know, you have one that's every three months. You may have one that are once every six months or whatever, right? 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, you know, all it takes is one hypertensive event and something fatal could happen or something bad could happen to the patient. What you want is a consistency of the blood pressure so you can manage these patients. That's the promise of CRISPR gene editing.
Even with the best siRNA out there for Lp(a), you saw that after two six-month cycles, only 80% of the patients remained in control for the entire period of time. Towards the end of the dosing periods, you're seeing people, you know, be out of control from what's recommended. I think at some point this question's gonna flip and say, "Why not do gene editing?" 'Cause it's safe. Why would you take If you're high Lp(a), 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 know, you could have compounded toxicity from 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. I do think that this question will flip and primarily led by the physicians 'cause they all see this as a better way to treat patients.
Yeah. That was actually something I was thinking of too, is like which patients actually derive the biggest benefit. These are large, you know, large disease areas. Is, you know, a patient with, you know, 30, 40 years of life ahead of them, is that kind of the ideal patient group versus, say, a 60-year-old with, you know, hypertension or high LDL? Like, is there a way to sort of like break down the market opportunity here? Would you even wanna do that at this point?
Yeah, I think we're doing a lot of work on that. I think one of the axes is gonna be attitudinal as well. Whether it's a 30-year-old, a 50-year-old, or a 70-year-old, there is an element of, you know, a patient saying, "I'll take the risk and do gene editing," right? 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. You know, some people just said, "I'll take a chance because I can't live with my disease anymore." You're gonna see that, I think, over here as well as one of the axes. The other axis is, you know, you're gonna get for genetic conditions like Lp(a), you're gonna know pretty early in your life that you have high Lp(a).
You know, if you have high Lp(a), some people have high Lp(a) levels above 300 mg/dL , you probably wanna take care of it sooner rather than later. You wanna do it as young as possible. With hypertension, you're likely to get it more at later phase of your life, you're gonna be older. Some people have very high blood pressure that's uncontrolled, and they won't have a choice but to do it, right? You have LDL, which is a different ball of wax where you have to segment the population many different ways. You know, do they have high LDL and high triglycerides? Do they only have high LDL? Have they tried PCSK9s? What it's gonna be.
The thing is whichever way you slice and dice, it's a huge market. We're playing in, you know, major markets in a way, in a global scale, where we could, you know, 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?
Yeah, we don't have to. I mean, I think, you know, like if you can do a severe hypertriglyceridemia trial based on pancreatitis events, that is a registrational path that could get us there and get us a label. Beyond that, I think you can, you know, the label and the marketing will all, you know, we can obviously influence it, but I don't think we need to a priori determine exactly what the market's sizes are and the market potential.
Yeah. Makes sense. maybe shifting gears to autoimmune and oncology, I think zugo-cel, great name by the way. That's a new name.
At no coincidence because we're based in Zug, Switzerland, but, you know, it just happened.
Oh, I see the connection. Yep. I guess, you know, are the CR rates in DLBCL sort of tracking with what you would have hoped? You know, 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, you know, 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.
It's autologous-like efficacy, but with the convenience of allogeneic and the cost of goods like allogeneic. In oncology, we showed nearly 70% CR rate with zugo-cel, with at least two of the patients at the time of data cut who were past 12 months. It's durable. Now what we've done also is start dosing patients with a BTK combination, pirtobrutinib. It's seen from some of the investigator-initiated trials that somehow the BTKs actually potentiate the CAR Ts even more. We end up with, you know, in that study it was almost 80% CR rate. We can push that up even more. We could be better than autologous therapies.
I think our strategy in oncology is to, you know, potentially get an approval off a single arm trial in late stage and then pick off patient populations in front line 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, so that's our number one 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 those learnings into how fast we can move in autoimmune indications with zugo-cel. This could be an argenx-like platform.
You know, any disease that's B-cell mediated, you could have a one-time reset that gets rid of a disease. We start with this trial called AID-500, which we were dosing patients with lupus, myositis, and scleroderma. Now we've expanded into two other diseases, ITP and wAIHA, where we're dosing patients. We've just opened an IND for neuroimmune because we've seen with all this hype around, you know, 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.
That has tremendous implications for indications like multiple sclerosis, NMO, et cetera. We've started that trial for neuroimmune indications as well. It's literally all systems go for us on zugo-cel. We announced that we've dosed 14 patients for our 1Q update, and we'll provide further updates as we go along.
That's great. Obviously, you know, autoimmune CAR T space is heating up, and it's quite competitive. Is that kind of a fire lit under you guys to really accelerate things and push forward? You know, how do you sort of maintain your lead given the wealth of development going on?
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.
We've seen that whether it's a big company like Novartis or BMS or a small company like Kyverna or Cabaletta, you know, even though they had a three-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, and you've seen some of that. We don't think it's gonna be a one-time reset in a elegant, beautiful way that we can do with CAR Ts.
We have a competitive edge over TCEs that may require, you know, multiple dosing and, you know, you still come with the risk of CRS, et cetera. Finally, the in vivo space, in vivo CAR Ts, we're working on that as well. We have our own in vivo transient redosable CAR Ts that showed complete B-cell depletion in monkeys with one or two doses. I think it still has, you know, there's more work to do to get that to patients and see what the effects are on patients. At this point, I think we're in pole position, and as long as we execute, we can actually lap everyone else. We'll have to show that over the next months to a year in terms of execution.
Okay. That makes sense. I wanna ask about your siRNA collaboration with Sirius. I know we talked about the benefits of a one-time, you know, gene editing approach over siRNA and like, you know, LDL and those indications. This is a different application. Is this, you know, is this more just a right tool for the job? Or anything to read into sort of your leaning into siRNA through the fraction?
Well, I think the way this came about is we were building a cardiovascular franchise with, you know, ANGPTL3 and Lp(a), we were talking to all our senior company members about what else is exciting in cardiovascular medicine. Factor XI kept coming up. The promise is, you know, you have very effective blood thinners out there in the market. These are Factor Xa based drugs, they come with high bleed risk, right? If you're on these blood thinners, like especially if you're old and, you know, you're taking it for stroke risk or whatever, you have an injury, you could bleed to death. You know, what's the holy grail is to have the same level of blood thinning without the bleed risk.
You don't want that for life, so you don't wanna gene edit your Factor XIa, because that'd be something that's unnecessary. Let's say you're doing this for an acute phase after surgery or something like that. We do believe that all of medicine's moving towards long-acting. I don't think in 10 years you're gonna be taking a pill a day. You're gonna be taking once every six-month injections or once a year or gene editing for life, and that's gonna be the majority of medicines. We are gonna play into that long-acting aspect with this factor of siRNA that right now seems like best in class. It's one, it could be once every six-month dosing. This is with our partner Sirius.
There's so many indications you can go in, whether it's secondary stroke prevention, whether it's AFib patients that are not eligible for DOACs, whether it's patients that have peripheral artery disease, post revascularization. All these are trials we could do. Of course, you know, any attractive space, there's gonna be competition. There are some antibodies from Regeneron or Novartis that are also playing in the same space, and a couple of small molecules. I think an siRNA approach could be the most powerful approach, especially with its dosing convenience.
Okay, great. Well, looks like we're out of time. Plenty going on at CRISPR Therapeutics over the next 12 months, looking forward to seeing the updates. Sam, thanks so much for the conversation.
Thank you very much.
Thank you.