Okay, welcome to the second day of the Bank of America Healthcare Conference. So my name is Geoff Meacham. I'm the Senior Biopharma Analyst. We're thrilled today to have CRISPR Therapeutics. And speaking on behalf of CRISPR is CEO Sam Kulkarni. And so Sam's gonna give a talk, and then we'll do a little bit of Q&A afterwards. Sam?
Thank you, Jeff, for having us here. It's always a pleasure to be at this conference, and great to see a lot of you familiar faces here. We thought with this year, instead of the full fireside chat, we'll do this presentation format and tell you about everything that's going on at CRISPR. It's been an incredibly busy year. We have, by the numbers, if you look at CRISPR, we have CASGEVY, which we're very proud of the approval of CASGEVY late last year, together with our partners, Vertex, and that's off to a great start in terms of commercial launch. But beyond that, you know, if you look at the numbers, we have five programs in the clinic right now across oncology, autoimmune, cardiovascular, rare diseases, and diabetes, and we have 10 preclinical programs.
And we'll talk about a couple of them today that we just announced, targeting AGT and ALAS1, but we continue to expand the platform. And together with our strong balance sheet, our very efficient resource allocation, and, you know, efficient way of running the company, we're able to prosecute that much more. And we feel like we're in a really good position to advance not one or two, but multiple of these candidates that are in the clinic now towards pivotal trials and ultimately towards approval. So, you know, just a historical context, it's our seventh year coming to the Bank of America conference. If you look at the stages of growth of the company, we were in our stage where the first, in stage one, the thing that helped us was relentless focus on the first asset.
You know, that's one of the truisms in biotech. If your first asset fails, you're in a deep hole. It takes a long time to get out of it. But we had this focus on sickle cell and thalassemia, and we were able to advance it pretty rapidly, much faster than everyone else developing these programs. And that allowed us to establish capabilities and expand our portfolio. And now we're in this second stage, which is diversification, and we have all these programs across different therapeutic areas, oncology, autoimmune, cardiovascular, diabetes, etc. And we'll see which of these assets play out.
But once we've established an operating model, and once we see what the parlay is, that leads us to the next stage, which would be a, you know, $20+ billion company, where we're a fully integrated company, and to have an engine that's producing, continuing to produce one or two INDs per year. So over the next five years, we expect that we'll announce at least two programs a year, new programs a year, given the productivity of our scientific engine. CASGEVY, I'm sure you know, it's a very scrutinized launch, and there are a lot of people watching how this goes because it's a bellwether for the industry.
And, you know, the number one question we got when we were at JP Morgan conference this year was, you know, "What makes you think you're going to succeed where ROCTAVIAN completely failed?" And I what I told people is, it's a very different situation. You know, these are indications where there's no other medicine for sickle, people with severe sickle cell and thalassemia. They live a life of pain. They can't even wait two weeks more to get their doses. They wanna get rid of the disease as soon as they can. And what you've seen is tremendous enthusiasm from all the centers, not just the centers that did our clinical trials, but new centers as well, in adopting this therapy. In fact, they all already have plans to sort of market it to their patients and, and bring patients on board.
Vertex is doing an amazing job expanding the number of ATCs, not just in the U.S., but globally. The Middle East can be a big market for this therapy as well, given the incidence and prevalence of sickle cell disease and thalassemia, particularly in countries like Saudi Arabia. I think a lot more to come on CASGEVY. I think, you know, Vertex's last earnings call, they did mention that five patients already had their cells collected and number of centers were activated. What we're doing beyond that also is to say, "What's the life cycle of this drug?" While we have busulfan-based conditioning now, we're developing targeted conditioning. Both Vertex and us have our own assets that we're putting forward into animal studies, and we're gonna pick the best one.
What targeted conditioning will do is expand the market at least threefold, if not more, and increase the penetration in the market. Very good progress so far in targeted conditioning, and we're also doing this collaborative effort with the Gates Foundation on in vivo HSC editing that expands not only the sickle cell and beta thalassemia addressable population, but expands into other diseases as well that you can treat with in vivo bone marrow editing. Beyond CASGEVY, we have three additional franchises. We have the in vivo franchise, which is modular and scalable within its own set of indications and diseases, where we have established an mRNA and LNP platform that we think is safe and effective.
It's different from what some of the other players have disclosed data on recently, and we're very confident that this mRNA- LNP platform provides a good therapeutic window to have very high, efficient editing in the liver. We're doing editing in vivo beyond the liver as well in our research efforts, and we'll talk more about that. And then we have this very strong CAR-T franchise, where arguably, we have the most potent allogeneic CAR-Ts out there among the 15 or so players that are developing allogeneic CAR-Ts. And not only do we have this amazing opportunity in oncology, we now have this opportunity in autoimmune, where we're positioned to be the best in class in indications like SLE, and we've begun clinical trials there.
We also are in solid tumors, you know, with our CTX130 program, which was a precursor to our current CTX131 program. We showed the world's first confirmed complete response in a solid tumor in the renal cell carcinoma setting. And that bodes well for the CTX131 trial, where the cells are that much more potent. And then in diabetes, we have a multipronged approach, but we are steadfast in investing in this vision of creating allogeneic stem cell-derived hypoimmune cells that produce insulin and can eventually make you insulin independent. So the in vivo platform, what we've done is, we showed. This has moved very quickly. You know, I think, to a certain point, we had focused on ex vivo therapies, and our in vivo platform took a little longer to develop, but we've gone pedal to the metal on in vivo platform.
And we showed nearly 70% editing in NHP studies in the liver, which equates to about 100% of hepatocytes. It basically means you're saturated the editing in the liver for hepatocytes. And we quickly translated that into two indications, ANGPTL3 and Lp(a). Now, you have to think about these two indications very differently. ANGPTL3 is more of a rare disease-type development approach, and Lp(a) is a large population with 11 million patients in the U.S. alone. And there are good reasons why we picked these two indications, and I'll talk about that. But we've quickly expanded beyond that. We just announced a program with angiotensin, angiotensinogen, AGT, and then we announced a program with ALAS1, which is a rare disease. So we're going across both common and rare diseases with a modular and scalable platform.
ANGPTL3 is one of the most validated targets in cardiovascular disease. Large studies were done showing that, if you had ANGPTL3 knocked down and there were patients or populations which had a naturally occurring SNP, that it was cardioprotective. And what we showed is by recapitulating that using CRISPR, we can get very high liver editing in monkeys, and we showed the same 70% editing with ANGPTL3 that resulted in a very sustained reduction in triglycerides. Not only do you get triglyceride reduction, you also get LDL reduction with an ANGPTL3 knockout. So we're in the clinic with this program. You know, we're quite excited about, about this, and so are a lot of physicians, KOLs.
You know, there is an approved product called EVKEEZA from Regeneron, which is an antibody against ANGPTL3, which is doing reasonably well in a rare disease population. But a one-and-done editing approach is gonna be transformative for these patients. Some of these patients, you won't believe it, the triglyceride levels are over 1,000. So it's very high triglycerides. There's nothing else they can take to control their triglyceride levels. Then we have CTX320, which is targeted towards Lp(a), or as some people call it, Lp(a). Now, this is an emerging target that I would say at least half the pharma companies in the top 10 are interested in. You know, this, if you look at what is one of the top targets that the pharma is looking at, Lp(a) is up there.
In fact, you know, when we have these BD meetings at these types of conferences or JPMorgan or other conferences, you know, the amount of interest there was in CAR-T, autoimmune, and Lp(a) was significantly higher than all the other programs, and for a reason. Lp(a), there's, you know, there are no small molecules that can easily target Lp(a). It's very hard to develop. There are some siRNA programs, but if you have a sustained one-time intervention that can lead to sustained reduction in Lp(a), I think you're gonna have a dramatic impact on outcomes. Now, outcomes will be demonstrated through the clinical trials that Novartis and Amgen are doing with their siRNA programs or ASO programs, and that will come out in the near future.
But, you know, again, we've shown durable reduction of Lp(a) in the, in the chart here, in NHP studies, that is as high as it can get effectively, and, you won't have the burden of doing it every 1 month or every 3-month injection with an siRNA, or ASO, if you have an editing approach. CTX340 , this is a new program we announced, and we've got a lot of questions since we announced it, but, it's based on some of the data that was seen with, an siRNA from Alnylam, Zilebesiran. And it showed that if you knock down angiotensin, angiotensinogen, which is upstream of angiotensin I and II, you're able to effectively reduce, blood pressure by, you know, 15 mmmHg-20 mmHg . That's a pretty significant reduction.
And again, the first reaction people will have is, "Gosh, you're going after this broad population of hypertension. Who's gonna do gene editing for it?" Again, we're gonna take an approach where we're gonna take this in layers. If you take refractory hypertension, there's about 1 million patients with that. They are on four or five agents, and they just cannot get their blood pressure under control. They take diuretics, they take five different agents, ARBs, ACEs, but they have no control. Then there's treatment-resistant hypertension, which is another population. Again, these patients have, like, three-plus agents that they're taking, and they still have a significant risk. And so what we can do with the CRISPR-based therapy is the one-time intervention, and that'll reduce the blood pressure.
It could reduce it, you know, as we showed in these mouse models, by up to 30 mmHg in a very established model, which is called a spontaneously hypertensive rat model. And these are very exciting data. I mean, we talked to some of the key experts in the field, and they're saying this axis of car- you know, cardiometabolic, the world's gonna change in terms of how we think about paradigm of medicine. You know, on one hand, you have cardiovascular risk reduction, and then you have medicines like these, with AGT, that can really change how you think about the progression of the class of medicines patients may take and how you eventually control them, control their hypertension. And then we have a rare disease targeting ALAS1.
Now, this is acute hepatic porphyria, you know, this indication is getting diagnosed more and more. You know, it used to be a small number of patients in the U.S. per year, but after Alnylam got their drug approved with their ALAS1 targeting siRNA, what you're seeing is greater and greater diagnosis. At the same time, GIVLAARI, which is a drug that Alnylam has approved, doesn't have great uptake, and there's a lot of dropouts because there's some tox associated with that drug, and the safety elements are an overhang on the uptake of the drug and increase in penetration.
So what we have is a one-time edit, again, for these acute hepatic porphyrias targeting ALAS1, which is an enzyme in the heme biosynthesis pathway that effectively reduces these neurotoxic byproducts of heme biosynthesis, PBG and ALA. We've shown again in models where this is an artificial model where you induce the model to produce high levels of PBG and ALA, and if you have the edit, you see that there's no increase in PBG and ALA in this model, which again, is an established model working with the top KOLs in the field. That, you know, is very indicative of how this may work in humans, potentially, as we go into those clinical trials. So then let me move on to allogeneic CAR-T.
What we have is, are probably the most potent allogeneic CAR-Ts out there, and this is because we made these edits, targeting Regnase-1 and TGFβR2. Regnase-1 is not a well-known target in immuno-oncology until recently. We did this massive screen to say, "Let's edit every possible gene and see what makes these CAR-Ts better." What we found is this, this target, Regnase-1. Incidentally, three years later, Carl June, who many call the founder and father of the CAR-T field, did the same empirical screen and came up with Regnase-1 as the edit to make CAR-Ts better. What we've done is paired this with TGFβR2, which is a well-known receptor blocker, where you don't want to have TGFβ-induced suppression of the CAR-Ts.
When you combine the two, these CAR-Ts are 10x better than the first-generation CAR-Ts. We've shown some data here where we show, for instance, the left side, CTX112, compared to our first-generation CTX110 in these mouse models, and you see a dramatic difference. You know, the mice that have CTX112, the tumors are eradicated. With CTX131, which is targeted towards CD70, again, we have these TGF-βR2 and the Regnase-1 edit, combined with the CD70 knockdown. And again, you see a dramatic difference. You know, it's not always obvious unless you play with these mouse models a lot, but you see a big difference between how CTX131 is doing versus CTX130, which again, you know, bodes well for the trials we're doing in humans against tumors, where we already saw responses with the first-gen programs.
And then all of a sudden, we've had this breakthrough in the last six months in autoimmune. I mean, and this is —you know, the world was abuzz when ASH happened last year, and these data were disclosed from, Georg Schett and Fabian Müller's lab in Germany, and they showed durable remissions in patients suffering from, SLE and, some of the lupus nephritis patients, where they were. They had no other treatment available to them, right? And they failed everything else. And it was just remarkable. And that then led to people saying, "Oh, maybe auto CAR-T can have tremendous impact, with these patients." The problem with auto CAR-T is, again, you're gonna have a huge scaling issue. You're not gonna be able to reach all these patients. It's gonna take a long time to do the clinical trials.
But also, you know, what you have is a smaller B-cell burden compared to tumors with SLE or autoimmune diseases. So allogeneic CAR-T should be able to get deep, durable B-cell depletion in these patients. And what we show here on the right side on the chart is the data from our patients that we treated in the oncology trials that had B cells, and you see that the B cells are completely depleted and stay depleted, whereas their NK cells and T cells come back, which shows the mechanism of action of CTX110 in that case. And it shows that with our allo CAR-T, you should be able to get that deep depletion, which should result in durable remissions in autoimmune indications. So that's, you know, we're very encouraged.
Not only that, for various reasons, it puts us in pole position relative to all other modalities in autoimmune therapies. One is, you know, we have site-specific CAR, which when you use lenti, there's always a risk of secondary malignancies. Now, in oncology, people shrug it off, but I don't think you can shrug it off in autoimmune diseases. So any therapy that uses, you know, lentivirus is gonna have that much more scrutiny. You know, the other thing is we are more potent than all the other allogeneic CAR-Ts and NK cells, in our opinion, with these potency edits. We also have commercial-ready manufacturing. We have tons of inventory. We can get these trials going very quickly. And then, you know, there's a lot of buzz lately about T cell engagers in autoimmune diseases.
But there are papers that have come out, and KOs have said this. It's gonna be harder to get durable responses with T cell engagers or antibodies, because they're not going deep into the tissue and getting rid of the tissue-resident B cells. You know, CAR-Ts have an ability to migrate and find their targets unlike T cell engagers or antibodies. And so all these advantages come into play, you know. There is obviously, you know, the question of how much lymphodepletion you need and what's the conditioning you might need for these patients, and you can titrate that down over time. But it puts us in a position where we could be the leading agent in autoimmune diseases, and we're going to go beyond SLE as well in short order. In diabetes, we have three parallel efforts.
We have. You know, we had our first-in-class, edited cells derived from stem cells, CTX211, that went into patients. It was actually a big deal for the field. You know, in the investor circles, you know, probably didn't have the same impact, but if you go to the academic circles, and I was just at a big stem cell institute conference, you know, it's the world's first edited stem cell-derived product going into humans. You know, we're continuing these trials. We had a partnership with Vertex, and we kind of reshaped that partnership where we have two different efforts now. So we provided our licenses to Vertex, so they, as you see in this slide, in number 3, they will advance their programs.
They haven't yet gotten to all the edited programs yet, but they will get there, and then we're going to parallel process our programs going forward, which is namely CTX211 and other programs. We're also doing a lot of innovation on sort of the deviceless approach. Eventually, we want to be able to do these cells naked, that we inject directly into patients, assuming we can get a safety switch in there, because if you ever have a negative event, we want to be able to turn these cells off. So we're going to have that safety switch with our deviceless approach. This is our manufacturing facility in Framingham, Massachusetts. You know, we kept it close to our R&D headquarters so that there's a huge interplay between the process development and research folks with the manufacturing folks.
But this is one of the most state-of-the-art facilities. In fact, we won the FOYA award, Facility of the Year Award, which typically every year it's been big pharma winning it. For the first time, a biotech company won that award, not because we're spending a lot of money, but because it is designed in a way that really allows you to multi-multiplex and process significant number of cells through this facility in a very efficient fashion. And then next-gen editing. You know, a lot of hoopla and noise about all this. You know, ultimately, the notion of CRISPR, you know, is changing, where we had molecular scissors to depict CRISPR, right?
And now it's sort of a Cas9-guided cargo bus that takes you to a particular place on the genome, and then you can make, have any effector protein, make a cut or a nick or a base change or whatever else. And so we, we've redoubled our efforts with next-gen editing. We may in fact. I don't know, it's hard to predict these things, but we have progress with gene writing that may get to the clinic faster than some of the companies dedicated to gene writing. But we'll only announce those once we get much closer. But combined with our LNP efforts, where you do need bespoke LNPs for next-gen editing, because the mRNAs are a lot bigger, you know, the guides are different, so you do need to work, do that work.
So we've established a huge LNP group as well to enable all the next-gen editing, including gene writing, and we'll talk more about that. Some of it's based in Boston, some of it's based in San Francisco, and we're trying to get the best talent in the world to add to these groups. So where does that leave us? It leaves us with a very broad and diversified pipeline across our franchises. We have CASGEVY on the market now, but also have this lifecycle plan for CASGEVY with targeted conditioning and in vivo. That could make it a multibillion-dollar opportunity, even with the first gen, but with targeted conditioning, can be much, much larger. We have our CAR-T efforts across autoimmune oncology with the best CAR-Ts, allogeneic CAR-Ts in the world.
We have our in vivo platform that we continue to scale with more and more indications, and we'll have data in the not-too-distant future. We have our type one diabetes franchise, and then we have a number of licenses which also provide us milestones and economics as we go forward that we've licensed to Vertex. You know, many of you, you know, keep asking us about catalysts, and I always say it's hard to predict exactly when we're going to disclose data. But, you know, we have guided to data with CTX112 in B-cell malignancies this year. We'll see, we'll be accruing data across all these clinical trials, whether it's SLE, solid tumors, heme malignancies with CTX131, CTX310, CTX320, and CTX211.
But we're trying to figure out when we disclose all the data, what's the appropriate conference, what's the appropriate forum for all these, but it's, it's going to be a catalyst-rich 12-18 months for us. And finally, what is the, what is the bigger vision? You know, I think, you know, everybody talks about becoming the next Genentech, but you have to take this in stages. You have to say, how do you become a $5 billion-$10 billion company first? And then you have the right to say you're going to become a $20 billion company, and then the right to say you're going to be a $100 billion company. But if you look at our—
What tailwinds we have, you know, if CASGEVY continues to grow and expand, that by itself can get us in that territory of a mid, you know, reasonably large biotech company. That's an industry leader, not just a sector leader. And then, if any of these click, CAR-Ts in oncology or autoimmune or our in vivo platform, we're easily in that territory where we're, you know, as big or not bigger than some of the siRNA companies that are at the top of the sector right now. And if we can get gene writing working, and open up a whole host of indications there, I think the sky's the limit.
We're feeling this is my ninth year at CRISPR, hard to believe it, and the company is about 10 years old, but I'm feeling as excited as I've ever been at the company in terms of what the prospects are and what we're looking forward to in the next year or so. So we look forward to a lot more updates over the months and but thank you for this opportunity here today to present this for you.
So Sam, we have just a few more minutes. Yeah, do you wanna? We'll do, we'll do some Q&A. I think one of the things that investors are looking for with CASGEVY, the, you had the initial, you know, adoption, which is five patients, is pretty good for, you know, first quarter out of the gates. Give us some metrics, though, about, you know, the timelines for the, the optimized, you know, conditioning regimen, the targeted conditioning. Are there points along the way that you'll say, "Okay, we now have solved for that, and, you know, file for approval?" Or is this sort of a, you know, kind of a one to two-year process where you're optimizing, and then you have a new regimen?
Yeah, I mean, I think we're very pleased with the CASGEVY launch, and it's amazing to see Vertex in action. They're just the best executors you could ever have as a partner in terms of commercializing a rare disease, and globally, not just in the U.S. And you know, a lot of, I would say, in biotech, we're not used to modeling these, but there's this installed base model where you get a double driver acceleration. You know, a lot of the device players do it. You know, if you look at an Illumina in the early days, people were like: "Oh, my God, why are the sales growing so much?" Because they were installing sequencers, and each install, they were using more and more, right? And so it's the same phenomenon here.
You have more ATCs installed, you know, effectively, and each of those centers are doing more and more patients, right? So you get this accelerated growth, and having five patients collected in the first quarter is a really good sign of how that may go up. But you need two to three quarters of data to see what that trajectory is, and then you can probably predict where this may end up. So we're extremely pleased with that. On targeted conditioning, obviously, you know, Vertex and us, we're not gonna talk too much about it because what we don't want to do is, you know, impair our current launch with people warehousing, et cetera. But what I'll say is, you know, the companies in 2019, if people asked, if you asked you, they said, "Oh, yeah, conditioning is gonna be solved.
There are all these companies, Forty Seven, Magenta, et cetera, they're gonna figure it out." The problem is all those companies were developing these assets for oncology, and it's a different PK/PD profile than what you need for a transplant procedure or for sickle cell. And so we're designing it, you know, with a blank slate, and that gives us the ability to develop the right PK/PD profile to have these agents come in, deplete the bone marrow, and then disappear, and not impair your drug product. And so we've picked c-Kit, Vertex have picked other targets, and we're gonna put them all head-to-head and see what's the best. But we're gonna take our time to find the best agent here that we wanna bring into the clinical trials.
Okay, that makes sense. On the cardiometabolic portfolio, you know, you're in the clinic or going to be in the clinic for a number of the indications. And so I, you know, I imagine once you turn that card over, what informs the decision to sort of partner versus, you know, go it alone? Because these could be, you know— I mean, even if they're more refractory populations, they're still meaningfully, you know, large investments—
Yeah.
To make, in a phase II or a phase III.
Yeah, I mean, the beauty of it right now is we have the ability to prosecute these ourselves, right? In the next four, well, four or five months, we're gonna have, be sitting on data. It's gonna be early data, but we'll know internally—
Yeah.
-how these LNPs are working, you know, what's the trend in terms of dose escalation. And then the question is: do we want to retain all the value or do we want to partner? And, you know, for it's much better to think about partnerships beyond that point where we have some data. But there's tremendous interest, especially in AGT and Lp(a) as targets. These are, you know, pharma companies are searching and saying, what's the next big thing that's gonna give them a $5 billion- drug, right? And there's not that many places you can say, oh, you know, in cardiometabolic, we're gonna make a difference, and Lp(a) and AGT are those targets.
So we're gonna see where this is going because, you know, I don't wanna over-partner because that's gonna impair our M&A value, that's gonna impair our own prospects in terms of growth, but we may partner one or the other, depending on what data we see.
Okay. And then last question on the, you know, the CAR-T platform. With the next-gen, you know, assets in hematology, oncology, you know, there is a clear step up in the activity, but you're right, the world has sort of shifted to where, you know, autoimmune is the major focus. How should we think about, you know, your sort of next priorities, right? I mean, is autoimmune, you know, going to emerge in the next couple of years as the, you know, the major focus for CRISPR?
In the next six months. You know, because, you know, one of the things is, in autoimmune, it's actually perfectly set up for allogeneic CAR Ts, because the B-cell burden is lower, so you can get this deep depletion. You do need it off the shelf. You know, an autologous trial. These trials are bigger than oncology, right? You know, so the— think about a 300-patient, 400-patient trial, and for autologous companies to do a 400-patient trial, it's gonna take them forever. So they're not going to be able to enroll quickly. You, a lot of the other emerging—