Thank you for joining Guggenheim during our second SMID Cap conference. I am Debjit, one of the therapeutic analysts here, and joining me from CRISPR Therapeutics is CEO Samarth Kulkarni. Thank you so much, Sam.
Thank you for having us.
Before we get into the Q&A, a very quick overview of where you are and some of the key milestones for 2025.
Yeah, happy to do that. You know, I think we've been around as a company almost 10 years, which many people don't appreciate and know about. But we've, ever since our founding, been focused on developing medicines that can transform the disease for patients with severe disease. And we started with what is now CASGEVY, with sickle cell and thalassemia, and developed a transformative medicine that's on the market now in a commercial setting. But beyond that, I'm also very proud of the pipeline that we've built, and a very diverse pipeline. For those who are new to the company, we have a focus in cardiovascular diseases with in vivo gene editing, where we take the CRISPR-Cas9 components, encapsulate it in an LNP particle, and we inject that into patients. And these LNP particles go to the liver and make an edit, reducing these cardiovascular risk factors.
I'll talk more about that. So that's one pillar that's continuing to expand. We have the best-in-class allogeneic CAR-T. And so with CAR-T, what we mean by that is taking cells, or T cells, from a healthy donor and engineering them and training them to kill a cancer. And we've also made additional edits using the CRISPR system that makes them autologous-like. So you get the efficacy of autologous CAR-T without any of the side effects that autologous CAR-Ts have, like ICANS. And obviously, the convenience of having allogeneic off-the-shelf therapy. And that we're developing both in oncology indications as well as autoimmune indications. And the autoimmune opportunity is significantly larger than oncology. And we're in prime position on both as the best-in-class allogeneic CAR-T for CD19. We have other CAR-Ts as well in that franchise.
And then beyond that, we have regenerative medicine, where we're developing iPS-derived cells for type 1 diabetes that can act as artificial pancreas. Eventually, the vision is to have many different organ replacements off of iPS cells. So those are all things we're doing. In addition, we continue to push forward on the platform with CRISPR-X. And that's to do all sorts of advanced editing that enables us to open up more diseases for patients.
Thanks for that. Maybe we start on CASGEVY first. How much visibility do you have into how the commercial launch is going? And there has always been a little confusion as to what the exact profit share is going to look like, or the flow through to CRISPR from Vertex.
The profit share is very clear. You know, we're a 40/60 relationship. The CASGEVY program started off as a 50/50 partnership with Vertex. At some point, we decided to change that construct to a 60/40, where Vertex owns 60% of the profits and we get 40% of the global profits. So that's very clear. And I think the way it's going to show up for us on our P&L is a single line item at this point, because it's a net cost. And you see this as a collaboration expense. And when the franchise becomes profitable, you'll see that as the net profits attributed to us become net revenues, essentially. So that's how you're going to see it flow through to CRISPR. It'll all become clear as the launch continues to mature.
But overall, I think we're very pleased with how the launch is going with the Vertex partnership and their leadership in commercializing this globally.
Is there a level where the program becomes profitable in terms of number of patients per year?
It's hard to say. You know, we haven't guided to when that is. But I think what you've seen, you know, a few things that people need to understand about these launches that they don't understand when cell therapies. People look at, you know, the cost structure. And there was a note coming out about the cost structure of cell therapy launches broadly. And the numbers are very high. So you have to have relatively high revenues to make it profitable. What people don't understand is that only a part of those expenses are what you need to have a commercial infrastructure and to sell the product. A large part of the investments that we're making right now essentially are to expand manufacturing capacity as well as to continue our trials. You know, we're expanding the label not just across regions, but also in patient populations.
So that's lifecycle management. So when you take all that away, you're still at a relatively attractive gross margin with these types of therapies that are priced at this level for rare diseases. So, you know, our hope is ultimately that, you know, the franchise becomes profitable in the not-too-distant future, and then ultimately that the company has a path to profitability. And again, not to, you know, again, not very long term, but we've said in other places that potentially by 2028, we could be break-even as a company.
Awesome. So you sort of alluded to lifecycle management. Given busulfan is such a hot-button topic, what are you and Vertex thinking about from next steps' perspective trying to move away from toxic conditioning?
Yeah, we're very invested in developing better and better solutions for this patient population. You know, sickle cell and thalassemia have been diseases that we've known about for a very long time that have not had the level of investment in terms of medicines developed from big pharma for a very long time. And so here we have CASGEVY, which is a remarkable medicine for these patients. And we continue to invest in next-generation conditioning, which could be gentler for these patients. And so what that would do is allow more patients to benefit from CASGEVY and expand the addressable market. And ultimately, to get to in vivo gene editing, that would get to, you know, millions of patients around the world potentially as that becomes more scalable. With gentler conditioning, the way it works is, you know, we have our own efforts essentially.
We have an ADC where we acquired the antibody from another company. It's an antibody towards c-Kit or CD117. And then we have our own toxin that we've conjugated to that antibody. And so we're developing that for gentler conditioning. Vertex have said that they have other agents that they're developing, not just one, but multiple agents towards gentler conditioning efforts. And so we're going to put it all together and see what's the best, and ultimately bring that to bear for patients.
Got it. And talked about gene edits. CTX112, you had some interesting data at ASH. It has two sort of unique edits. Could you walk us through that patient population? Why you think this was, you know, an update that the street largely missed, especially from a disease severity perspective and the amount of expansion that you got?
Yeah, I mean, I think, you know, I would say that all the KOLs at ASH were very excited to see the data and reached out to us to say, oh, wow, this is spectacular. You know, this is a target that we found through our large-scale screens. It's called Regnase-1. It's not a well-known edit. OK, so we found this back in 2018 together with the different partnership that we had as well. And it turns out that this edit in T cells is a very interesting edit. It keeps the cells more naive and more central memory phenotype, at the same time have more cytokines and more inflammatory discharge from the cells that improves their cancer-killing capacity, essentially. So that's a very unique combination edit.
And a couple of years beyond that, you know, Carl June, who's sort of the founder of all the CAR-Ts, came up with their own analysis and their own large-scale assessment of what the best edits are for these CAR-Ts and landed upon Regnase-1 as the best edit to make these CAR-Ts more potent. Which is very interesting that, you know, looking at thousands of genes, we all arrive at the same gene. And we have a lot of IP to cover the use of Regnase-1 in CAR-Ts. But essentially, in our December update, while the N was small, it was only 12 patients. And we have subsequent data that we disclose beyond that. But the expansion of the allogeneic CAR-Ts goes up to 50,000 micrograms per copies per microgram, which has never been seen before with an allogeneic construct.
They all are in the 3,000-5,000 range, except for one-off patients that may be immune, that may not have an immune system that's competent. So for the first time, you have something that's showing autologous-like expansion, yet you don't have ICANS like you do with autologous cells or autologous CAR-Ts that are commercially available. And that's a very unique combination to get all the efficacy that you want without having the side effects. And you have the convenience of being able to do those patients right away. And that's going to come in playing out in a big way in autoimmune diseases, for instance. You know, one of the things that investigators tell us right now with autologous therapies in autoimmune diseases is that they have to, these patients are lymphopenic.
You have to take them off of therapy for a couple of months to even get their T cells and collect cells for autologous CAR-Ts. It's just not an easy way to do it. If you had an off-the-shelf solution with allogeneic CAR-T, you can immediately dose those patients with lupus or myositis or scleroderma. It's a remarkable advantage to do it that way, and we now have tremendous data to show that a CAR-T will have better efficacy than a bispecific or TCE. The bispecific or TCEs or naked antibodies are just not penetrating deep enough to have a very durable or full remission of the symptoms for patients suffering from these autoimmune diseases.
So for CTX112, what's the registration pathway going to look like? And have you started having this conversation with the FDA?
Yes. So we're pleased to have received the RMAT designation from the FDA for CTX112 in oncology. And so we're going to have that discussion on what the registration path may look like in oncology, not in the not-too-distant future. So we'll update the, we promised a mid-year update on the program. So we'll guide the market on what that registration path looks like. In autoimmune, we need to collect more data before we have those discussions.
So when do we get to see the autoimmune data? And what specific subtypes are you looking at right off the bat?
In autoimmune, we started a trial for lupus patients. But we've expanded the trial to a basket trial now, which includes scleroderma and myositis. So we want to include as many patients as we can before we do a data update. We've set mid-year for an update on the program. So we'll see where we get to on that.
So during mid-year, you have the regulatory update. You have potentially autoimmune, you know, basket study update. And more likely than not, also cardiovascular programs?
You know, also mentioned oncology. So for 112, we'll have an update on, you know, one of the questions is, yes, you're seeing remarkable data with 112, like autologous therapies. But what's the durability look like? And we want to show durability data as well in oncology in the heme setting, in both indolent and aggressive lymphomas. So that's the other part of that update. And in cardiovascular, for both CTX310 and 320, we said we'd have a first-half update.
Got it. So let's switch to the cardiovascular side. You have two separate programs ongoing right now. What kind of, as your dose escalates, where do you want to be, you know, as you get closer to the data sort of disclosures? How many cohorts? How many patients?
Yeah. I think for those who are not aware of these programs, we have two programs, CTX310 and CTX320. CTX310 targets ANGPTL3, which is an enzyme which breaks down lipoprotein lipase. And essentially, if you inhibit ANGPTL3, you have more lipoprotein lipase to get rid of lipoproteins that are in circulation. So eventually, you have less LDL and triglycerides. So you'll see both triglyceride reduction as well as LDL reduction. The second program, CTX320, targets Lp(a). This is sort of the third silent killer beyond LDL and triglycerides that people don't often talk about. But now there's a lot of awareness of Lp(a) because, you know, it's now, you know, sort of the explanation for why there are people who have very low LDL, you know, reasonable triglycerides or in-control triglycerides, are fit but still have MACE events or heart attacks in their 40s sometimes, early 50s.
And Lp(a) is one of the reasons, which is a pretty atherogenic factor. In fact, it's almost 6x more atherogenic than LDL cholesterol, which you pointed out too, Debjit, in your reports. And you've actually been one of the few that have shone a light on Lp(a) and what an important target it might be in cardiovascular medicine. And so 320 targets Lp(a). And I think what we want to get to in both of these, you know, first order is with our LNP platform, you know, what dose level do we need to go to to get the target reduction in either ANGPTL3 or Lp(a)? And how much room do we have there at the top? And then, of course, what does the safety profile look like for a single administration of an LNP particle?
On the LNP, how much work has gone into? Do you have two unique LNPs for Lp(a) and ANGPTL3?
It's the same LNP platform.
And how much work has gone into that LNP? Because there was obviously a lot of noise around LNPs about a year and a half ago.
Yeah, so we've done a tremendous amount of work on the LNP. You know, people often say, OK, where does the LNP come from? You know, LNP systems are very complex. There's four components, sometimes five components. Some of the components are the common ones between different approaches that companies have taken. And then, you know, the ionizable lipid is one component. But a lot depends on the formulation. You know, you can formulate the same LNP components six different ways, you know, different sizes, different densities, different solvents, et cetera. And that will change your attributes in vivo quite a bit. And you have to think about what fenestration do human cells have versus monkey cells or mouse cells. All those things come into play.
So we have a very proprietary formulation where we did a lot of work, which gives us confidence that we'll have a very good safety profile for these LNPs while achieving the target reduction. But, you know, again, the data will tell.
Is the goal to be in that, let's call it 0.7 mg per kg range where Intellia kind of settled in? Or can you shoot for something lower?
I mean, I think we'll have to see where things land on the right dose level for expansion. Some of these factors depend on the guide potency, the availability for editing for that gene from a chromatin standpoint. So I think, you know, it's hard to say how do you go from monkey dose levels to human and how that may translate to humans. It may not all just be the same. You know, in some indications, it may be lower. In some places, you may need to go higher on the LNP dose.
Let's stay with Lp(a) for a while. The push out for the HORIZON study, does that complicate plans for the team CRISPR when you start thinking about what a registration study could look like? Or do you really need to wait for HORIZON Lp(a) to read out to see the magnitude of benefit, et cetera, et cetera, before thinking about what this could be?
The HORIZON readout is a very important readout to show that, yes, we've seen Mendelian studies. We've seen natural patient studies, epidemiology studies, et cetera, et cetera, showing the effect of Lp(a). Does a pharmaceutical or pharmacological reduction of Lp(a) result in lower risk? That's the big question mark. The HORIZON study will show that, hopefully, and show that it's, you know, across thresholds in that study. It is an important study for us to determine whether we would need an outcome study versus a biomarker-driven study for eventually a registrational trial. I don't think we lose any time right now. I think that this year for us is more about establishing the right dose, expanding that dose level once we establish a dose, getting more sites opened, and getting ready for what could be the pivotal trial.
So you don't think you need an outcome study with Lp(a) or any of the cardiovascular targets, and it could just be sort of commercialized on a biomarker?
You know.
Especially on the reimbursement side, for example?
On Lp(a) right now, we don't know. I mean, I think at this point, it hasn't been established, right? So the presumption is you need an outcome study. But if the HORIZON trial reads out positive and it shows that Lp(a) reduction leads to better outcomes, then I think we could make an argument that you don't need an outcome study. You know, especially because, you know, here is something that we know is 6x more atherogenic than LDL. And then how, as a regulator, would you ask a company or a sponsor to say you put several thousand patients on a placebo when there are available therapies out there? You know, that becomes very challenging. Or you kind of lose clinical equipoise. So if the biomarker is established, and it's not a very complex biomarker, right?
It's Lp(a) itself that is the protagonist in creating these plaques and creating, you know, atherosclerosis. Then it should be a much easier equation to say you don't need an outcome study. But all that, you know, depends on how HORIZON reads out and Amgen's study reads out over the next year, year and a half.
Got it. So just switching back to the allogeneic programs. So now you have three knockouts and one knock-in, right? Is that sort of the upper limit? Or sort of have you settled on the edits you need to do based on the data that you have at hand so far?
Yeah. So the short answer is it's not the upper limit because we now have another very elegant way to do editing ex vivo for CAR-Ts, where we can have a single cassette that we can insert that can express multiple effectively multiple knock-ins and have multiple knockouts with hairpin RNA that are also inserted in. So you don't have any of the risks of translocation. But you can have a single edit that can create a much more sophisticated construct, which may be necessary in the case of some solid tumors. You know, for heme malignancies right now for CD19, I think, you know, we have what's best-in-class allogeneic. So I don't know that we need to do much more in terms of editing at this point.
For solid tumors, I think we continue to create very scalable, easily manufacturable ways of editing that can incorporate even more sophisticated engineering in the cells.
Got it. Within the cardiometabolic franchise, you also have the AGT as a target. How are you thinking about that, especially, you know, given the permanency of the edits and the risk of hypertension?
Yeah. I mean, you know, for those who are not aware, CTX340 targets a factor known as angiotensinogen, which is upstream of ACE, you know, where the ACEs and ARBs work. So you're going, you know, most blood pressure medications work either with ACEs or ARBs. And, you know, what people don't realize is refractory hypertension is a huge burden across the world, but especially in the U.S. You know, there's almost a million patients with refractory hypertension that are on three to five medications per day to manage their blood pressure, which is, you know, oftentimes these patients are thrown off, you know, because they take something else. They have an infection or whatever else. They take some other medication. There's some side effects. And it's actually one of the big causes of hospitalizations and mortality in this population of refractory hypertension.
So what we're aiming to do is bring that baseline blood pressure level down so then you can manage with, you know, one or maybe one other agent. You can titrate and manage it. The second thing is with zilebesiran, you know, with the siRNA approach for AGT, you haven't seen many cases of hypotension, even at the very high knockdown levels. Because I think the body has its own way of regulating the hypotension aspect, not so much the flares above. But I think, you know, first instance, the goal is to bring that blood pressure down to a manageable level. And that, you know, I continue to be amazed by how, you know, using genetic markers, we can control these very fundamental processes in life, which is maintaining blood volume and pressure is like one of the most important things for us to remain alive.
And we can modulate that using angiotensinogen. And the other one that, you know, we showed data on recently in both monkeys and mice was in the eye, you know, maintaining intraocular pressure. We were able to edit a protein called myocilin in the eyes. And we were able to reduce the intraocular pressure by several millimeters of mercury with one single edit in the front of the eye. And it's quite remarkable that we can do that. And similarly, I think with angiotensinogen, which we found KOLs to be extremely excited about as a very important unmet need that we can address.
Got it. So if I understand this program, then you go after treatment-resistant hypertension patients and try to get out, let's say, 10 to 12 millimeter reduction in mercury and kind of get to your goal. You don't really need to push dramatic.
You know, some patients, you know, I think one thing is that we may do that differently for angiotensinogen versus Lp(a) or ANGPTL3, is potentially leverage the fact that we can multi-dose. So we may not want to get every patient to a 90% reduction with one dose on editing. What we've shown, actually, we haven't shown these data. But we've done experiments, studies in monkeys, where we can show that we can do multiple doses. And, you know, two doses doesn't mean 2x the editing. It's like one point something. But you get, you're able to titrate editing up to a certain level. So you may, for these patients, potentially interrogate a two-dose regimen to get the editing exactly where you want it to be. And then, in some cases, you may not need any other agents to manage their blood pressure.
In other cases, you may have one residual agent where you can manage it up and down.
Got it. I wish we had more time to talk about the hypoimmune cells on the diabetes side. But maybe a very quick sound bite on that?
Yeah. I mean, I think, you know, iPS-driven organ replacement is becoming a bigger and bigger deal. I think the data from another competitor, Sana, showed recently that these cells are generally hypoimmune, you know, islet cells, by the time they're differentiated. And one or two edits on top, you can make them very hypoimmune. And now we're like one of the furthest along with iPS-derived gene-edited hypoimmune islet cells. And so we're continuing to push that forward. In addition, we have cells that are embryonic stem cell-derived program, CTX211, in a device, which we've continued to push forward as well.
Awesome. Thank you so much, Sam. Appreciate the time today.
Thank you very much.
Good luck for 2025.