Good. You all set? Okay. Hi, everyone. My name is Maury Raycroft. I am one of the biotech analysts at Jefferies. I'd like to welcome Sam Kulkarni, the CEO of CRISPR Therapeutics. Sam, thanks so much for joining us today.
Thank you for having me.
We're going to do fireside chat format. For maybe those who are new to the story, if you want to give a one-minute intro to CRISPR.
Yeah, happy to do that. And thanks for having us. We're now in the 10th year of CRISPR as a company, and it's been a remarkable journey. We were originally founded based on the Nobel Prize-winning discovery and elucidation of CRISPR-Cas9 as a tool to edit genome. And we've applied that tool, a powerful tool, to develop transformative medicines, the first of which was directed towards beta thalassemia and sickle cell disease. And we now have an approved drug called CASGEVY that's being launched by our partner, Vertex, around the world. And I'll talk more about that. But beyond that, really, we've taken the platform and parlayed that into a number of other areas, both rare diseases and common diseases. So we have a platform with CAR T- cells that are best in class for oncology, as well as autoimmune diseases.
We have in vivo gene editing now, where we're in the clinic with programs directed towards cardiovascular risk factors like Lp(a) and ANGPTL3 validated risk factors. And beyond that, we have our platform in diabetes. We're going after solid tumors. We've now shown preclinical data for glaucoma in the eye. So I think it's a pretty broad expansion of the pipeline. And at the same time, we continue to innovate on the technology platform and do all forms of editing that allow us to address even more diseases in the coming years.
Got it. Yeah, that's a great intro and sets the stage. I want to ask a couple of questions about CASGEVY, and then we'll jump into some of the other platforms and programs. Maybe just starting off with the CASGEVY launch, it's been a little bit slower than expected with one patient treated out of the 40 who had their cells collected. Tell us about what have been some of the biggest barriers, for example, reimbursement, and what is Vertex doing to speed up treating the other patients?
Yeah, we're actually quite pleased with the trajectory of CASGEVY. I think the bit slower is all in the question of how it's been framed. But if you think about the funnel, the demand equation is very strong. We've only disclosed the number of patients who had cells collected. But the number of people interested in the drug is very high across the world. Second, the payer support and the system support for it is equally strong, not just in the U.S., but now we've seen support in the Middle East, Europe with early access. And that was sort of a big boost to enabling this to become a multi-billion-dollar drug. And now it's a question of mechanics. I think as we activate centers, this is like molecular surgery. If any of you are familiar with surgical procedures, know that you have to schedule a time.
Over time when you do an elective procedure, whether it's a hip surgery or a mitral valve replacement, and eventually, you get momentum, and there's a lot more patients that do it, so we're actually pretty pleased with how the funnel is shaping up right now, the number of ATCs that have been qualified around the world, and if you just do the simple math of saying, here are the 75 ATCs that are targeted, and each of these ATCs, even if they do a minimum of 10 a year, you're looking at a pretty big number in terms of revenues, so I think everything's on track. We're actually generally feeling very good about CASGEVY, in fact, so much so that with certain developments around the competitive landscape, Vertex and us are saying we're going to invest even more to make this available globally from a capacity standpoint.
Got it. And yeah, you've definitely talked about the funnel before. And so it's good to hear that that is kind of playing out commercially. And just how have the market launch efforts so far shaped your views on what type of patients could be the early adopters to translate to more patients being treated?
Yeah, I think interestingly, this is not a typical launch where people say, here's the total top-down number. Here are the patients with X, Y, or Z comorbidity or condition, and they're the ones coming forward. A lot of what we see here is attitudinal as well, and there are patients who just can't live with their pain, who say they don't want to go through another pain crisis. They don't want to have this specter hanging on their head of early death, and some of that's just who's going to raise their hands early and say, I want to get this therapy.
So, nothing to report in terms of what kind of patients are coming in, which basically is a good thing, because I think all 25,000 of those severe patients in the U.S., I think eventually, as you see more success and more data, might raise their hands. Globally, we now think that there's 30,000-odd severe patients in the Middle East, both sickle cell and thalassemia. We're even finding out that there are a lot more sickle cell patients, for instance, in the U.K. and France than we originally imagined. I think all in all, I think this is shaping up really nicely.
Got it. And you mentioned you could potentially have 10 patients per site going forward. Is that the plan for?
No, that was an illustrative comment. That's not a goal or anything like that. I'm just saying it was taken from comments from the early days of Yescarta launch, for instance. One of the comments they had made was, well, why don't we just get these centers to do 10 per year? And now centers are doing 10 per month, right? So with autologous therapies, it's a little bit of mechanics. But I think the centers figure it out. Once they figure it out, they can keep doing more as they see benefit, as they see that the whole system becomes familiar to them, whether it's scheduling or receiving the cells, et cetera.
Got it and now that you have some visibility with being on the market for almost a year, how are you and Vertex thinking about the 2025 commercial setup?
Yeah, I think 2025, I think we're obviously going to get more data in terms of number of patient cells, number of patients who have cells collected. We're going to see what the uptick might be on revenues and how fast it's growing. From a commercial setup standpoint, the actual commercial infrastructure to commercialize CASGEVY is relatively lean. The two parts of the cost that we're still investing in is global label expansion, whether it's expanding to new geographies or to patient populations like pediatric patient population, and the other part of the expenses that are on capacity expansion, and we want to do this anticipating demand and the fact that we're encouraged by what we're seeing on the demand funnel, so that's what's leading us to continue investing in it, so from a commercial setup standpoint, Vertex will make more comments and provide that color.
But generally, everything's at scale.
Got it. OK. And I don't know if you can comment on just the competitive landscape for sickle cell disease. Beam had an update recently where there's been chatter around the efficacy data that they showed. What are your thoughts on that, and how do you view some of the other competitors in the space?
Yeah, I mean, I think it's good for patients to have more options and for more companies to develop therapies in an indication where there haven't been many options for patients for 70-plus years. So that said, I think a couple of competitors of ours are facing headwinds or are slowing down their programs or slowing down the rollout because it takes a different kind of balance sheet and commercial model to really grow a therapy like this. It's more akin to medical devices and those launches versus a traditional pharma launch. And I think those are all tailwinds for us as competitors see headwinds. And I think we'll see what other data people present. But in general, it just solidifies the hypothesis around HbF induction as a way to alleviate the symptoms and comorbidities of the disease.
Right. Yeah. And I think that's an interesting point where it does require a lot of investment for these competitors, which could be a challenge for them. How do you think about just expenses as it relates to the collaboration with Vertex? For your share, I think it's trending toward about $200 million for this year, given that you're responsible for about 40% of the cost. Is there more perspective you can provide about how this could look going forward into 2025 and potentially a few years out as well?
Yeah, I mean, I think it's hard to put specific targets on it. But I think 2025, we may continue investing in the franchise. But at some point, I think our hope is by 2028, as a company, we're profitable. At the very least, we're break-even as a company in the 2028 time frame. So we feel very bullish about the franchise. I think there are other puts and takes in terms of our own clinical trials that we're doing outside of CASGEVY and the expenses associated with it and what that might look like. But generally, I think one thing our CFO, Raju, is always saying is we have about $2 billion in the bank. And we see a path to profitability with almost half of that as a buffer in terms of our run rate.
Got it. OK. Well, let's shift gears to the in vivo programs. You've got two wholly owned programs, CTX310 for ANGPTL3 and then CTX320 for Lp(a). Maybe talk about the ongoing studies. How many patients have you dosed so far in each study? And what could we expect to see in an interim data update?
Yeah, both those studies are going forward nicely, and we're in dose escalation across both. One thing, I saw Jefferies' note on Lp(a) yesterday or a couple of days ago. This target is one of the highest interest targets for all of pharma, top five across the board. And it's because there's a significant proportion of people that have high Lp(a), and it's been ignored as a risk factor compared to LDL or other measures. And a lot of people I talk to have had relatives or friends or know of someone who are young, 40, 45-year-olds, very fit, but all of a sudden have a heart attack. Why does that happen? Because they have high Lp(a). And it's very interesting, the notion of Lp(a). A lot of it you see because of sort of the colder climates. And then we see a lot of incidents in Africa.
I think it's related to sort of it's almost like linked to the starvation genes and everything else, right? I think it conserves energy. In today's world, where there's a lot of food, it actually is a bad thing. There are different modalities at play here, small molecules, siRNA, gene editing. There'll be some mix of it going forward that people will use. I think more and more people will prefer a one-time therapy. In the gene editing front, we're well ahead of others. As we will have data next year as well, that'll help us solidify our position with Lp(a). ANGPTL3, I think, has been very validated with the antibody from Regeneron and Evkisa. That has tremendous potential as well as we move that forward and may not require an outcomes trial.
Got it. Yeah, I definitely agree. Definitely a lot of validation and a lot of interest in Lp(a) too with the outcomes study readout from Novartis expected next year. Maybe let's talk about that and what your expectations are for that and how that could inform your strategy.
Yeah, I think the HORIZON readout from Novartis and the readout from Amgen on Lp(a) will be a pivotal moment in, I think, cardiovascular medicine, where we know whether pharmacologic reduction of Lp(a) will lead to better outcomes or not. And we're particularly also interested in the subset analysis as you go higher and higher in Lp(a). The subset above 125 nanogram per milliliter is of great interest to us because with gene editing, we're going to start targeting the very severe or very high Lp(a) level patients. Small molecules, while there's encouraging data, it's not very easy to target Lp(a) because you're basically targeting the interface of apolipoprotein(a) and ApoB. And it's not clear that, yes, you may eliminate some of the Lp(a) particles, but there's still free-floating apolipoprotein A out there. And then siRNA, I think there's data emerging.
But gene editing for a younger population that may have to take a drug for the next 40, 45 years of their life is a very powerful tool. So we're very excited for what data we're going to see next year from the outcome studies and then also from our own data as to how that positions us.
Got it. And what more can you say about what you're going to show from your data next year and maybe set the stage for expectations?
I always ask this question. I always get the same answer, which is we typically don't comment on what kind of data we're going to have. But if you project, if you look at other people's data, you want to get through dose escalation all the way. I don't think we want to report data too early, whether it's wildly positive or not. And we want to look at a certain duration of time before we draw any conclusions from it. So I think we'll have a robust data set for both CTX310 and CTX320 next year.
Got it. And for the Novartis data, for the other outcome study, for the subsets of patients in there, would you potentially the next study that you run? Would you focus on a particular subset? I guess it depends on what they show.
We're starting with the higher threshold in terms of Lp(a) levels than some of the siRNA studies because I think that's an appropriate population for gene editing at this stage. So I think whether we broaden from that, we'll see.
OK. Anything else you can say about the types of patients that you're enrolling into the studies?
No. I mean, again, these are patients that this is secondary prevention, right? It's not primary prevention. So they have high Lp(a). They've had an event or two sometimes. And often, all of them are surprised by why they have a cardiac event. Many of them have that risk, and they know that there's no other agents available to them to reduce their Lp(a). So other than that, I think there's differences in these patients, of course, in terms of age, et cetera. But you'll see more when we disclose our data.
Got it. And you mentioned the silencer approach. And in the ATTR space, with the silencers, it can get to a certain degree of knockdown. And that continues to improve. But with editing, you could potentially get to deeper knockdown. And that could potentially lead to greater outcomes, greater benefit for patients. Do you look at it the same way with Lp(a) and ANGPTL3? If you can use editing to get to deeper knockdown, could that translate to greater benefit?
Yeah. I mean, I think our Chief Medical Officer, Naimish, was speaking with Steve Nissen at a conference recently, and one of the effects that you see with siRNA is a sawtooth effect. Towards the end of the dosing period, you see pharmacodynamics around the biomarkers or what you're trying to suppress, and by the way, if people miss their dose and take an extra month to go back to the infusion center to get their dose or whatever, you don't know what the effects are, but what's better is a single decrease in the risk factor that remains low for life, and there's not a lot of pharmacodynamics, and I think these top KOLs are saying that gene editing can definitely be superior. It may take a little while for that to show in outcomes trials.
But eventually, I think that's a better way of treating these patients or people. They're not even patients yet, right?
Right. Right. OK. Let's shift gears and talk about your CAR-T platform and programs. And so for your next gen CD19 program, CTX112, you're going to have some interim data at ASH coming up in December. How will the Regnase-1 and the TGF-Beta knockouts impact the efficacy signal with respect to responses? And talk about six-month CR rate and safety as well versus your prior 110 program.
Yeah. I am convinced that we have the best allogeneic CAR-Ts out there between all the companies that are developing it. And that's primarily because of this edit called Regnase-1, which we discovered out of a large screen. And in fact, now you have a TILs company that's doing the same edit. And Carl June, who looked at a large 1,000-edit screen and came up with the same edit is the best for CAR-Ts. And these CAR-Ts are like energizer bunnies. They remain in a central memory phenotype and naive state for longer. At the same time, they are more cytotoxic in the tumor microenvironment. And that's a very interesting edit combined with TGFBR2 that prevents tumor mediated suppression of the CAR-T efficacy in the tumor microenvironment. And so those edits are making these CAR-Ts very robust.
While it's a small data set, we'll present data at ASH in oncology. Of particular interest and relevance would be the pharmacokinetic data for CTX112 versus our first generation. Recall, with our first generation CAR-T, we actually got durable responses in non-Hodgkin's lymphoma. One in five patients have been in durable CR for very, very long, some patients now going on three to four years. Can that number become one in three and be the same as autologous CAR-T in relapse refractory setting? That's the question. I think we'll probably get, at the end of the day, pretty close to autologous with all the benefits of allogeneic. The other question everyone's looking at is, how do these pharmacokinetic data read through to autoimmune where the B- cell burden is lower?
If it works in oncology, it definitely will work in autoimmune and could be in pole position to be best in class in autoimmune.
Got it. And yeah, for autoimmune, I want to ask a couple of questions there too. For oncology, after the ASH update, what's going to be the next step there? And could you potentially move this into a registrational study at some point?
Absolutely. I think oncology, we have a number of discussions teed up with regulators, both in the U.S. and ex-U.S., to determine what the path would be for registration. On the autoimmune side, I think we have to just generate data that will determine what the path forward is, but in any case, in autoimmune, we're starting to expand beyond lupus into other autoimmune indications like myositis and scleroderma, which all lend themselves to this allogeneic CAR-T approach, particularly with some of the case studies emerging out of China and other companies in the U.S. as well.
Got it. Yeah. And for autoimmune, how do you see CRISPR differentiating versus some of the other competitors out there? There's definitely been a lot of progress in this space. I think still a long ways to go in some respects. But how are you guys differentiating?
I think we're in a sweet spot because if you look at autologous and bispecifics, what's emerging now is that autologous is very good data, but it's been slow to enroll, and it's going to take a long time and just not be practical in the autoimmune setting. Plus, there's risk of ICANS. There's a risk of taking people off of their therapy while they harvest their T- cells. These are things that may not make it a scalable product. Bispecifics, while the data are encouraging, are not durable. They're not getting to all the deep tissues where these diseases manifest, especially under skin or nerve endings, et cetera, and they're not durable, so allogeneic CAR-T is right in the sweet spot. Within the allogeneic space, I recognize there's other players in there, but we have, I think, one of the best allogeneic CAR-Ts.
So I think that puts us in pole position together with our very advanced manufacturing facility that allows us to manufacture very low COGS at a commercial scale with all the features built in for commercial manufacturing already. So I think that's going to give us a big leg up as we run this race, especially in the third and fourth legs of this race.
Got it. Makes sense. And what do you think about the target? So there's debate around CD19, CD20, BCMA. What are your thoughts there and the right target?
I think CD19 is a great target because I think you're getting all the early progenitor cells that express CD19. I think there's a lot of talk about a BCMA and a CD19-BCMA combo, but there's risk of losing all your vaccinations with BCMA. It's not clear to me that BCMA alone gets to all the earlier stages of B- cells where the disease is manifesting. You may get rid of some of the symptoms, but it's not going to be durable, so I think CD19 is actually the appropriate target for these autoimmune indications.
Got it. And I know conditioning regimen is something that you guys think a lot about. For Lupus, it would require some conditioning, potentially at lower doses. How are you exploring or zeroing in on the optimal conditioning regimen for autoimmune?
Yeah. It's a huge focus for us. We're starting with the standard Flu/Cy conditioning, and recall, our data on allogeneic CAR-Ts in oncology, we didn't do any enhanced conditioning. We just did the standard conditioning. That's what tells you that our CAR-Ts are the ones killing the cancers, and we're seeing a beautiful dose response with CTX110, and CTX112 hopefully has the same. With conditioning, we're starting with Flu/Cy, but eventually, we'll see if we can do it without fludarabine and only Cytoxan or eventually even do maintenance doses without any conditioning, so we don't want to start that way. We want to start with standard, demonstrate the efficacy, and then move beyond that to get to our lower intensity conditioning, but to be honest, I think what we're hearing from a lot of the docs is it's all an efficacy question.
If it works and it's going to be durable, they're totally used to Cytoxan, and they'll get used to fludarabine. You'd never know if some of the effects, such as getting rid of the T helper cells with fludarabine, may be important in having this immune reset, so there are unknowns here. We'll learn from the clinical trials, so we don't want to rush anything. We want to do a systematic development given our advantage in this space.
When's the next update for autoimmune disease? When could you potentially have an update there?
I mean, we'll be accruing data. I mean, the question is, hopefully, at some point next year. But I don't know what point. We haven't committed to that data yet.
Got it. OK. And for your RegenMed platform, haven't spent a lot of time on that. But it's kind of another whole part of CRISPR. Maybe talk about that and just provide a status update there.
Yeah. Increasingly, we're seeing more and more evidence of iPSC cell-based organ development that is seeing successes in various case studies around the world. In fact, there was one in China recently, which was around an autologous iPSC-derived islet cell transplant that rendered the patient insulin-free for a year. I think there are two things that are happening. So you're seeing more evidence. Second is, I think the regulators are being more open to trials. You saw Vertex just say that they're going to do a phase one, two, three for type 1 diabetes, and those systemic effects are going to help us advance much quicker, both with the device and without a device with our type 1 diabetes programs.
Got it. OK. I think we're out of time. Maybe to close out the discussion, if you want to highlight key events or catalysts ahead for CRISPR that investors should focus on.
Absolutely. I mean, I think CASGEVY will be a continuing unfolding. But our in vivo data with Lp(a) and ANGPTL3, our oncology data, and then our autoimmune data are the key things to watch out for in the next nine to 12 months.
Got it. Thanks so much for joining us, Sam.
Thank you, Maury.